Category Archives: Issue of the Month

Big Data, Real World Evidence and The Digital Revolution – Hang On!

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Executives from AbbVie, AstraZeneca, Bristol-Myers Squibb, Merck and Co., Johnson and Johnson, Pfizer and Sanofi were grilled on Capital Hill in February on topics ranging from drug pricing, reimbursement, rebates and patent extensions to executive compensation. Senators called for new actions to address the high cost of prescription drugs in America.

Costs to the consumer and healthcare systems are immense. The US spent 345 billion USD on prescription drugs in 2018 and growth estimates could reach 500 billion by 2025. Although not discussed at the hearing, a significant portion (15% to 20%) of the pharma revenue stream is used for pharmaceutical R and D. This investment is the lifeblood of the global pharmaceutical industry. However, discovery, development and commercialization of a NCE or biologic could cost as much as 2.0 billion USD when failures and opportunity costs are taken into consideration. Adding to the cost and risk is the complexity of modern drug development. Establishing drug safety, determining efficacy and ensuring product quality are expensive tasks that must be monitored by sponsors and regulatory agencies. Then, there is the issue of reimbursement: market access, value proposition and pricing are the domain of the commercial payers, the new stakeholder with requirements that must be addressed in all development and commercialization scenarios.

Designing and aligning the appropriate regulatory strategy for each development asset is a critical component of program success. Here are a few of the emerging topics in drug development that should be contemplated when constructing the regulatory pathway for a NCE or biologic.

“Big Data” is a term used to describe large complex historical data sets that can be extracted and analyzed using methods that are different from traditional data management procedures. One application of “big data” gaining some traction in clinical trial design is the use of historical information to create a “synthetic” control arm instead of a traditional placebo treatment. The use of synthetic controls will never replace the randomized controlled study design but the new analysis tools for complex “big data” sets could cut control groups in half or replace them altogether, especially when traditional designs become prohibitive or historical data is complete and well-characterized.

Real World Evidence (RWE) and Patient Centricity. RWE is information collected outside of a formal clinical trial. It includes electronic medical records, claims and billing data, patient and disease registries and data gathered through wearable digital devices. In a recent address to the National Academy of Sciences and in a subsequent publication, CDER’s Janet Woodcock advocated for the use of RWE as a way of collecting and using patient data in clinical trials. Woodcock noted there has been little use of RWE in drug regulatory decisions regarding drug effectiveness. A draft guidance on RWE and a framework for its use is in the works at FDA and scheduled for release in 2020. Further, regulatory agencies have been asking for information on how clinical trials can be “fit for purpose” “with the patient population. Sponsors are now checking protocol design and interventions with patients, not just investigators, KOLs and internal experts. Patient centricity will be very relevant in future regulatory dossier reviews and approvals.

The Digital Health Revolution. Ten years ago it was hard to envision that connectable biosensors, wearables, implantables, smartphone applications, artificial intelligence, remote patient monitoring and machine learning would impact data collection and enable the emergence of personalized medicine. Now, many study protocols use digital and mobile technology as an integral part of study execution.

Value Proposition and Reimbursement. The “fee for care” model used in healthcare is shifting to value-based reimbursement. While regulatory approval requires demonstration of patient safety and efficacy, payer access requires a clear demonstration of a value proposition to qualify for reimbursement. Pipeline commercial development centered on pricing, market access and payer acceptance are now built into development programs long before final investment decisions are made at the governance level. Elements of the value proposition could include differentiation over standard-of-care, price, ease of use and innovative packaging.

These are just a few of the issues that impact strategic regulatory drug development right now. There are others: biosimilars, regulatory guidance for cell and gene therapy and precision medicine applications to minimize patient variability and improve response rate. On top of all this, regulators and sponsors will have to guide new product promotion to be consistent with product labeling as drug development and regulatory approval become more complex.

EAS offers a wealth of knowledge, enabling the development of regulatory strategies that best position your products in today’s environment. For more information or to discuss your product’s challenges contact Bryan J. Coleman, Senior Director for Pharmaceuticals and Medical Devices at bcoleman@easconsultinggroup.com. We also invite you to view our industry services sheet or the pharmaceutical tab on the EAS website.

Preparing For a FDA Preventive Controls Inspection

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The new rule on Preventative Controls for Human Food is mandated by the 2011 FDA Food Safety Modernization Act. Preventive Controls (PC) are steps that a food facility must take to reduce or eliminate food safety hazards. The rule also includes updates to the Current Good Manufacturing Practice (CGMP) requirements such as mandatory training and procedures to control allergen cross-contact. In general, the new rule applies to you if you are required to register with FDA and if you manufacture, process, pack or hold foods. By now, all firms meeting the activities in the prior sentence have to be in compliance with the PC rule unless they are exempt or subject to modified requirements. 

Firms covered by the new rule must have and implement a written food safety plan (FSP) and are further required to conduct a hazard analysis in order to identify food safety hazards requiring controls including preventive controls. The new rule requires an appropriate control be developed and implemented that could include process, allergen, sanitation or other controls. When preventive controls are required, the FSP must also include written procedures for monitoring, corrective actions, verification (including validation as deemed necessary) and supporting records, as well as a written recall plan and a supply chain program. The FSP must be prepared or its preparation overseen by a preventive controls qualified individual (PCQI).           

If your company is using an existing HACCP program, changes are required in developing a FSP because control need not always be at a CCP (critical control point), but can be handled by a prerequisite program or a preventative control program. For example, allergen cross-contact can be controlled by a written sanitation preventative control program that requires proper cleaning methods be implemented rather than establishing critical limits at a CCP.

The preparation of a proper FSP is crucial, since this is one of the first documents FDA will likely request to see during a PC inspection. There is no standardized or required format for the FSP, but all of the elements as required in 21 CFR 117.126(b) must be in the written document. FDA has published guidance regarding the preparation of a FSP and hazard analysis. See https://www.fda.gov/downloads/Food/GuidanceRegulation/FSMA/UC517391.pdf.

You can expect FDA to arrive unannounced to conduct a PC inspection unless you are located outside of the US, in which case FDA will provide written notice prior to arriving. During the inspection you can expect FDA to carefully review your company’s written food safety programs and to review all required records, such as monitoring and verification records. If deemed necessary, FDA may collect extensive environmental monitoring microbiological samples throughout your facility to determine if pathogens are in the plant environment. If there are positive sample results for pathogens, FDA can require products to be recalled. FDA can also compare the DNA fingerprints of any pathogens found to isolates in the CDC’s database and then require recalls if any matches are identified. If FDA deems your facility as not being compliant, you can expect the agency to take regulatory actions against your firm if voluntary compliance is not taken

You can properly prepare for an FDA PC inspection by considering the following:

Have a written plan covering how your company will handle an FDA inspection that includes a working area for the FDA and that assigns responsibilities for your employees who will be involved in the inspection. You need to have a policy on how to handle any objectionable conditions FDA may bring to your attention and make an attempt to correct any of these conditions while FDA is on-site.

Be sure your FSP is in final form and is signed by your firm’s owner, operator or agent in charge and be sure there is at least one person who is familiar with the overall food safety program who can explain it to the FDA.

Have training records readily available including PCQI training / qualifications, employee sanitation training and records documenting the qualifications all employees including supervisors.

Be sure record keeping is in order and is easily accessible including monitoring and verification records. 

If operational or FSP deviations have occurred, be sure appropriate corrective actions have been taken supported by records that must be made available for FDA review.

Be sure your allergen control procedures are in order. All ingredient labels should be reviewed to assure they are accurate and contain all required allergen labeling. Be sure all cGMPs are being followed to prevent unintentional allergen cross-contact issues during ingredient receipt, storage, process, packaging and labeling operations.

Conduct your own environmental monitoring. FDA will likely swab for microbes if you are producing ready-to-eat (RTE) foods that are exposed to the environment prior to packaging. You need to be sure you are conducting an appropriate monitoring program before FDA arrives. If problem areas are identified, corrective actions need to be implemented.

If product testing is used to verify a control, be sure the test is scientifically valid and have corrective action procedures in the event of positive results.

You must conduct reanalysis of the FSP at least once every three years or whenever there is a significant change that effects food safety.

Be sure you have information and records regarding where raw materials are sourced and documentation that the materials are being purchased from approved vendors. It is no longer an option to purchase raw materials from just any source. The new rule requires there must be a supply chain program which includes documentation demonstrating that either suppliers provide safe raw materials, or that another party will apply controls for the hazard.

For food with a hazard requiring a PC, there is now a requirement to have a written recall procedure that includes descriptions of the steps to be taken as well as assigning responsibility for taking those steps.

Conduct or hire an experienced consultant to perform a mock FDA inspection that includes a thorough sanitation audit and review of your programs and records. Conducting a gap analysis audit of your operation will assist in identifying areas that require improvement before FDA finds them.

Be sure all labels being used have been reviewed and approved by a food label expert. In summary, FDA is in full enforcement mode related to the FSMA Preventive Controls regulation. The food manufacturing industry needs to have its food safety program updated to incorporate the Preventive Control provisions. Your PCQI and entire QA staff as well as plant supervisors should be prepared to answer FDA’s questions and demonstrate that you conduct your business in a preventive mode of operation. With proper planning you can have a positive experience from an FDA PC-based inspection and continue to provide consumers with safe foods.

Will FDA Suspend Your Food Facility Registration Based on Environmental Results?

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In October 2018 FDA suspended the registration of Working Cow Homemade, Inc., of Florida. Working Cow is an ice cream manufacturer, ceased operations, and has cooperated with FDA. As part of its decision to suspend their registration FDA determined: 

  • Insanitary conditions were observed during inspections in both 2017 and 2018.
  • Following a 2017 inspection, an environmental sample tested positive for Listeria monocytogenes. Per FDA protocol, the whole genome sequencing data for the pathogen was uploaded to the Genome Trakr database.
  • In 2017, Working Cow conducted a recall. According to FDA, Working Cow did not implement corrective actions after the 2017 findings and recall.
  • In September 2018, the CDC informed the Florida Department of Health of a genetic match between the 2017 environmental Listeriaand a 2018 patient plus two patients in 2013.
  • Working Cow has a Florida customer base that includes potentially immunocompromised adult consumers at nursing homes and assisted living facilities.
  • A 2018 Listeria monocytogenes environmental isolate matched the 2017 environmental isolate, making the pathogen a potential resident strain.

The pathogen was not isolated from the finished product.

If Listeria monocytogenes is found in the environment from an area after a kill step and before the packaging is sealed, there is the potential for the pathogen to be transferred from the environmental site to a food contact surface and then to the product. This concept is recognized in the scientific community and is the justification for environmental monitoring programs which verify the effectiveness of equipment and facility sanitation programs, employee hygiene, and employee training programs. A pathogen in zone 4 can go to zone 3, in zone 3 can go to zone 2, and in zone 2 can go to zone 1. While every facility is different and there is no single citation of what constitutes each zone, here is one description:

  • Zone 1 – Direct product contact & indirect product contact (surfaces from which contaminants can drip, drain or be drawn onto product contact surfaces), includes pressurized air
  • Zone 2 – Equipment non-product contact areas immediately adjacent to processing equipment
  • Zone 3 – Facility non-product contact areas within processing, packaging & ingredient/finished product cooler areas, i.e. floors; walls; ceilings; overhead piping, conduit & structural supports; drains; forklifts & pallet jacks that enter processing & packaging areas
  • Zone 4 – Facility and equipment non-product contact areas located outside of the processing, packaging & ingredient/finished product cooler areas, i.e. warehouses, dock areas, break rooms, hallways

I understand the thinking that the pathogen from the environment could get into the ice cream and as a consultant I have seen the certainty of a problem break down when the details and specifics are thoroughly evaluated. Questions to ask as sites evaluate their pathogen control programs are: What is the proximity of the finding to the finished product? Is there a history of environmental sample results related to detection of pathogens? What is the laboratory’s positive control culture to ensure the reported results are correct?

PulseNet was formed in 1996 enabling laboratories to use the genetic matching method of pulsed-field gel electrophoresis (PFGE). FDA started to transition from PFGE to whole genome sequencing (WGS) after investigating a 2012 Salmonella outbreak. Isolates have been added to the Genome Trakr database at an exponential rate, and laboratories have converted or are in the process of converting from PFGE to WGS.

WGS use and values are evolving in risk assessment and investigations. There are several different WGS equipment manufacturers. The laboratory method for WGS at FDA is not the same method used by CDC. One uses SNPs, and the other uses alleles. A “match” is not always a perfect match, and there is debate among FDA, CDC, academic, and commercial laboratories as to how close the specific genetic data must be for a “match.”

The analogy I use is calling twin babies “identical” where there may still be a few physical differences; identical twins are genetically identical and a “match.” Fraternal twins are not genetically identical and clearly not a match. When WGS is conducted on an environmental isolate and a patient isolate of a pathogen to see if they match, the data may show genetic differences. The scientific community has not agreed on how much of a difference can be measured and the isolates be labeled as genetically identical.

WGS data lives forever in Genome Trakr, so it is conceivable and perhaps likely that environmental samples taken in your facility this week could be matched to a pathogen from six years ago, but without an isolate from your finished product! Even though the concept is mind-boggling, this is where enforcement currently lies in and CDC today.

So to answer my question, Will FDA Suspend Your Food Facility Registration Based on Environmental Results?, based on recent history with FDA using the tool of WGS as the “Holy Grail” for proving microbiological contamination, the answer could be is “Yes.” When there is a match between an environmental pathogen with a finished product isolate or a patient isolate, FDA will be on your doorstep. Your work is to train employees, re-emphasize and enhance current Good Manufacturing Practices, build a strong and positive food safety culture, re-evaluate your current FDA-compliant food safety plan to ensure effectiveness, and keep records that prove your food safety and corrective action efforts are occurring daily.

In conclusion, the food manufacturing and retail food industry need to prepare themselves for the increased use of all types of genetic screening of environmental and finished product isolates by not only FDA or CDC, but by state food safety regulators, third-party auditors and their customers. One way to prepare is to learn as much as possible about whole genome sequencing (WGS), identify private laboratories that conduct WGS and learn about their methodology and equipment. This will allow you to get out ahead of this new regulatory tool that has the potential of improving the safety of the US food supply but with potential damaging consequences in cases where matches are found.

Qualified Individual and Preventive Controls Qualified Individual – What’s the Difference?

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The Food Safety Modernization Act (FSMA) Preventive Control for Human Foods (PCHF) regulation (21 CFR 117) signed into law in 2011 offers a wealth of opportunity (and a requirement) for companies to improve their food safety procedures and protocols through the implementation of a preventive strategy against foodborne risks. As part of this regulation, food manufacturers must require that employees are qualified to perform their assigned tasks in a manner that protects food safety and prevents against adulteration. In addition, each company must have at least one employee, preferably located at the food manufacturing facility, who functions as a Preventive Controls Qualified Individual (PCQI). The PCQI functions as the responsible party overseeing the development and execution of all food safety programs and must have the knowledge, skills and abilities to perform these tasks based on their education, on the job experience or a combination.

Also, as part of FSMA, the Foreign Supplier Verification Program (FSVP) Final Rule for importers of human and animal food requires in Part 1 Subpart L that food manufacturers enlist a “Qualified Individual” who has responsibility for ensuring that all foreign suppliers of foods or food ingredients imported for consumption or further manufacturing in the U.S. produce their products in a manner consistent with FSMA requirements. This FSVP Qualified Individual (QI) must also have the knowledge, skills and abilities (KSAs) appropriate to evaluate foreign supplier compliance through their education OTJ experience or a combination of both. 

The FSMA PCHF regulation calls for a PCQI while the FSVP regulation calls for a QI. Though the terms are nearly the same and the regulations are related, they have different meanings. What exactly is the difference, in FDA’s view, of a PCQI and a QI, and how can companies determine that they are meeting FDA’s intent?

PCHF’s PCQI

PCHF’s big focus is on preventive controls for all food manufacturing facilities producing foods or food ingredients that will be consumed in the US. FDA requires that risk be assessed and mitigated so the risk no longer has public health significance, and that specific controls or mitigations steps be evaluated for effectiveness by a PCQI. A new term in the PCHF Final Rule, the requirement for a PCQI applies to covered domestic and foreign facilities producing human and animal food, generally those that need to register under section 415 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), (though there are, as expected, some exemptions). Though one PCQI can develop food safety plans for multiple facilities, it is important to note that each plan must be specific to the facility and address the unique processes and hazards within.

As a PCQI, considerations for biological, chemical and physical hazards must be thoroughly understood and assessed. Biological hazards include parasites and disease-causing bacteria; chemical hazards include radiological exposure, pesticides, drug residues, natural toxins, food decomposition, unapproved additives and food allergens; and physical hazards include items such as glass, rocks, metal parts or other foreign objects. FSMA requires that a food safety plan that specifically controls each of them must be developed by the PCQI. 

FDA accepts that either training or education (or a combination thereof) can provide the knowledge and skills required to perform PCQI duties as long as they equal a standardized curriculum recognized as adequate by FDA, such as that designed by the Food Safety and Preventive Controls Alliance (FSPCA) and instructed by FSPCA “Lead Instructors”. EAS offers the FDA-recognized FSPCA PCQI training curriculum, taught by Lead Instructors, as part of our comprehensive suite of in-house seminars and workshops.

Many who have already received training in HACCP, SQF, , BRC, IFS or FSSC22000 may still need additional training due to additional requirements for Good Manufacturing Practices requirements and Preventive Controls specified under PCHF in Part 117. FDA does not require, but it does recognize a formal FSPCA certificate verifying competency in Preventive Controls, for participants who successfully complete FSPCA PCQI workshop. 

FSVP’s QI

Companies importing finished food and food ingredients for further processing into the U.S. must have an FSVP QI to develop their FSVP food safety assessment program. An FSVP QI may be employed by the FSVP “Importer” or the Importer can contract with a private individual or consulting company like EAS Consulting Group to perform the FSVP QI responsibilities. A FSVP QI must evaluate the overall food safety risk of a food or food ingredient provided by a foreign supplier utilizing various documents originating from the foreign supplier and determine whether the foods or food ingredients meet FDA’s strict food safety requirements found in the PCHF and FSVP regulations. Much like PCHF’s PCQI, the FSVP QI will use the foreign supplier’s documents and the nature of the imported food or food ingredient to assess whether adequate controls are in place for potential biological, chemical and physical hazards. In addition, the FSVP QI will assess food safety risk by looking at whether their foreign supplier has been the subject of an FDA warning letter or import alert, their food safety performance history, results from testing, private or government audit results, and the supplier’s record of correcting problems. 

Once the QI has determined that a foreign supplier’s risks have appropriate controls, they will continue to monitor their performance by conducting appropriate supplier verification activities including some combination of onsite audits, reviewing supplier relevant food safety activities and sampling and testing of a food.  By regulation, these evaluation activities must be performed no less than every three years, or sooner if the FSVP importer becomes aware of new information concerning food safety or the foreign supplier’s performance.  It is our recommendation that these evaluation activities be updated annually as the food manufacturing environment is constantly changing and performing food safety risk assessments of a foreign manufacturer once every three (3) years may result in a significant food safety issue being allowed to continue for too long.

In addition to a QI’s assessment duties for a food importer, the FSVP Importer must also make sure their US Customs Broker identifies them for each incoming food or food ingredient shipment on the US Customs and Border Protection “ACE” electronic database as the FSVP Importer. The information must include the FSVP importer’s name, mailing address, and a unique facility identifier (UFI) recognized as acceptable to FDA. At present, FDA recognizes only DUNS numbers as an acceptable UFI.

Everyone with a role in importing foreign sourced foods should be familiar with applicable FSVP requirements including US Customs Brokers,foreign exporters, foreign food manufacturers, and US importers. This comprehensive approach is required under FSMA’s PCHF and FSVP regulations, intended to improve the nation’s level of protect food safety protection. FSPCA has developed an FDA-recognized FSVP training curriculum and EAS offers this in a workshop format in addition that of FSPCA’s Preventive Controls training curriculum. 

The microscope under which food safety assessments are evaluated has never been as detailed and is being scrutinized by FDA as now. With the possibility for potentially damaging regulatory enforcement consequences, many firms need to review, upgrade and have an outside, objective assessment of their food safety plans, whether they are domestic food manufacturers that have to comply with FSMA’s PCHF regulation or foreign food manufacturers that have to comply with both FSMA’s PCHF and FSVP regulations. An objective outside compliance assessment of a food manufacturer’s food safety plan needs to evaluate both the written plan and the effectiveness of its implementation. Third parties, such as EAS, can perform this objective outside assessment using a team approach to bring the correct level of expertise for development of an in-depth understanding of food manufacturer’s existing food safety system. The use of outside objective and qualified third-party private organizations such as EAS to evaluate and test the food manufacturer’s food safety program is part of any food manufacturer’s due diligence effort and can also offer a greater peace of mind to senior management of the facility and company owning the food manufacturing facility. Murphy’s Law says that if something can go wrong, it will. With a detailed food safety strategy in place, those risks can be identified and minimized before they become a problem.

More Like This?

EAS offers a wealth of additional learning opportunities on FSMA and FSVP. Check out the On-Demand Webinars page under Resources of our website for more topics like this including:

  • FSVP – What Does it Mean for your Business? – Presented by Charles Breen and Susan Moyers, Ph.D.
  • FSVP – What Does it Mean for your Business? – Presented in Spanish, Gustavo Gonzales, Ph.D.

Also, look for EAS in the News for articles such as:

FDLI Update: “FSMA After One Year: Advancing and Building Food Safety Systems for the 21st Century”, Steve Armstrong, EAS Independent Advisor, Food Law and Regulation


Dietary Supplement Specifications Development – Still Challenging the Industry Ten Years Later

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Specifications Development, as defined in FDA’s Good Manufacturing Practices for dietary supplements (21 CFR §111) have posed one of the biggest challenges to industry since the inception of the requirements in June 2007. Specifically, 21 CFR §111.70 requires manufacturers to develop specifications for each component used in the manufacturing process and the finish product, including raw material components, in-process controls, packaging/labeling materials, and finished products. To be compliant with 21 CFR §111, each specification must ensure the quality of the material or product by addressing its identity, purity, strength or concentration, physical composition and lack of potential contaminants or ensuring that potential contaminants are present at acceptably safe levels. However, manufacturers continue to struggle with understanding specifications development and compliance. This is evidenced by the many Warning Letters and Form 483s issued by the FDA in the past ten years.

Certainly, the intent of specification requirements is well understood, at least conceptually by industry. The main purpose for requiring adequate specifications is to prevent product(s) adulteration and ensure that the finish product meets at least 100% of all nutrient claims declared on the Supplement Fact Panel (SFP) throughout its best by date or expiration date per 21 CFR §101.9 under the Nutritional Labeling and Education Act (NLEA). Once a specification is set, the specification must be verified using scientifically sound and justified testing analysis and/or visual examination analysis such as organoleptic, macroscopic, microscopic, chemical, or microbial. Recognized test methods can be obtained from compendial sources like USP monographs, AOAC, FCC, or NF and used a starting point in determining an appropriate method. Multiple tests and examinations are usually deployed to ensure specifications are met per 21 CFR §111.75 and 21 CFR §111.320. All of this ensures consistent reproducibility and reliability of a finished product that is either being manufactured or packaged.

A look at recent warning letters illustrates this lack of understanding with findings such as: 

  • A lack of or incomplete identity component specifications (e.g. dietary ingredients, excipients or process aids, coating materials etc.) for each component per 21 CFR §111.70(b)(1) and 21 CFR §111.70(b)(2).
  • Lack of or incomplete specification(s) for in-process controls in manufacturing process per 21 CFR §111.70(a).
  • Lack of or incomplete product specifications for finish products per 21 CFR §111.70(e) to include package/labeled products (e.g. 21 CFR §111.70 (d) & (f) & (g)).

Briefly, specifications are a set of defined parameters benchmarked against associated acceptance criteria providing characteristics and quality of a finish dietary supplement. The expectation is that when specifications are established, they will be written, managed in a controlled system with revision histories that are tracked, monitored, reviewed and approved by the Quality Department. This means materials and products being used from other sources will be unequivocally identified, the microbiological purity and other purity requirements will be assessed to determine strength and concentration of a dietary ingredient. The physical composition will be evaluated, and any potential contaminants will be identified.

When developing specifications, it is a good idea to begin as early as possible by identifying critical quality attributes of finish product(s) and the manufacturing process as a whole. These quality attributes are to be identified with acceptable ranges determined in order to assess the attribute. Scientifically sound/valid test methods and examinations are tools used to conduct the assessment. Each specification developed should address sections of identity, purity, strength, composition, and contaminants to meet regulatory requirements outlined in 21 CFR §111.

Dietary supplement manufacturers must consider component specifications, including dietary ingredients, as defined in 201(ff) of the FD&C Act and label claimed on SFP, and non-dietary ingredients such as excipients, capsules, and coating materials.

In addition, in-process specifications must be established for any point, step, or stage of manufacturing and packaging processes. Simply put, these specifications focus on verifying material composition thorough a series of physical tests and examinations such as in-process checks and metal detection. These specification requirements can be met by developing a comprehensive Master Manufacturing Record (MMR) as required in 21 CFR 111.210.

Packaging and labeling specifications for components including container closure systems and materials that may come in contact with finish product including desiccants, cotton, pouches, lids, outer cartons, labels, and inserts should include approved/qualified supplier information, name and description of item, and physical attributes such as material type, size, dimensions, and color. Physical attributes and item descriptions can be obtained from a reliable C of A. Keep in mind that packing specifications must be developed for every packing configuration used for finish products. Set process and control specifications within the MMR and set a requirement that visual examination for each batch will be performed.

Finally, finished product specifications (FP) establish the identity, purity, strength, composition, and limits of contaminates for each finished batch of dietary supplement. In short, the finish product specification details testing requirements for a finished batch. All dietary ingredients listed on the SFP must be identified on the FP specification and additional requirements of minimum and maximum acceptance criteria.

It is expected that the claimed SFP ingredients meet at least 100 percent of the label claim in order to meet the requirements NLEA detailed in 21 CFR 101.9. Release specifications may be set at a higher percentage to account for any needed overage amounts formulated into the product to ensure the 100-percent requirement is met throughout the product expiration date or best buy date.

In closing, specifications development can be established based upon acceptable ranges and values set forth by industry, academia, and scientific data/results from published journals, and/or product history in manufacturing. Refer to NLEA mandatory and voluntary labeling disclosure set forth by FDA 21 CFR 109 (j). Accredited laboratories and American Herbal Product Association can provide guidance for building the appropriate specification to include test method. Reference any sources used to determine appropriate specification. If further assistance is needed, manufacturers can also work closely with the qualified supplier(s), an accredited 3rd party laboratory, and/or qualified consultants to help with specification development.

EAS’s 2018 Year in Review and Expectations for 2019 – Evolving FSMA, Anticipation for TPMPs

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As we reflect on 2018, we are again honored that so many look to EAS as their regulatory solution to a complicated world of FDA requirements. FDA’s continued focus on safety as well as the industry’s embrace of regulations that often challenge their old methods of doing business can only mean continued improvements and communications in the name of public health. In 2018, the Food Safety Modernization Act (FSMA) again dominated the news as numerous compliance dates arrived. We received questions from all over the world, particularly on issues pertaining to the Foreign Supplier Verification Program (FSVP). As of June 1, 2018, FDA had completed 256 inspections of foreign firms resulting in the issuance of 483s. Based on that, one of the primary concerns our callers have is understanding what constitutes an FSVP in FDA’s eyes and whether their documentation or documentation they were in the process of preparing, would qualify as compliant. Questions on what is a Qualified Individual and how EAS can assist in that regard with foreign suppliers are also a concern.

Our Independent Advisor for FSMA, Charles Breen, stayed busy preparing updates on FSMA compliance as part of our EAS-e-News monthly column “FSMA Perspective” and he, as well as all of our consultants who work in Foods, collaborated on numerous webinars and articles helping the industry to gain a greater understanding of FDA expectations. We even conducted our first webinar in Spanish presented by Gustavo Gonzalez, Ph.D., “FSVP – What Does it Mean for Your Business?” which is available on-demand free of charge on the EAS website. More recently, Charles presented a webinar on FSVP for the National Customs Brokers and Forwarders Association of America.

It wasn’t just FSMA that got industry’s attention. New labeling regulations for food and dietary supplements have kept food and supplement manufacturers busy. From sugars to fibers to new requirements of what and how to include nutritional information, our Food Labeling and Dietary Supplement Labeling seminars have been very well attended. (Our spring series is scheduled for Philadelphia and hyperlinks here point to registration information should you be interested in joining us). In addition, EAS published articles on the subject and is pleased to be in the final preparation stages for a webinar on December 6th where James Hoadley, Ph.D. one of our expert labeling consultants and trainers will discuss the new dietary fiber regulations with two members of FDA’s CFSAN for the Institute for Food Technologists. These labeling issues are requiring firms to rethink how products are not only labeled but marketed and our Product Development and Labeling team is enjoying the challenge of helping firms navigate new requirements as they find solutions that meet both business and FDA expectations.

The dietary supplement industry continues to be challenged by GMPs dictated in 21 CFR 111 as evidenced by 2018 statistics indicating the top observations issued are still Specifications and Testing, Master Manufacturing Records and Batch Production Records, Quality Unit Responsibilities, and Complaints; the same as they have been since 2010 when the 21 CFR 111 regulations applied to all sizes of dietary supplement firms. Following is a graph prepared by the Senior Director for Dietary Supplement and Tobacco Services, Tara Lin Couch, Ph.D., which summarizes the posted FDA statistics through 2017 and clearly illustrates this never-ending trend. If there is one bright spot, it is that the percentage of firms getting an Official Action Indicated (OAI) or Voluntary Action Indicated (VAI) is down to 54%. It has been significantly higher in previous years.

TOP FDA Observations: 2010 - 2017

RankCitationDescriptionNumber of Times Cited
201020112012201320142015201620172010-2017
121 CFR 111.75Testing541112262871881441952161421
221 CFR 111.70Specifications321041762342041542142511369
321 CFR 111.205MMRs28539411782678794622
421 CFR 111.255BPRs1852749371717287538
521 CFR 111.103QU Operations1843476647455576397
621 CFR 111.553Product Complaints1534427036283163319
721 CFR 111.453Holding & Distribrution618294732273046235
Total Observations631132819642211154912941625184212444

In medical devices, FDA’s decision to expand the use of the De Novo submission pathway was welcomed by industry. De Novo applications are appropriate in cases where it appears that the device meets the statutory standards for classification into Class I or Class II under section 513(a)(1) of the FD&C Act, and when the sponsor has determined that the device does not fall within any existing classification regulation. EAS authored an article for MedTech Intelligence on the subject.

EAS expanded its services into the area of cannabis GMPs in 2018. This newly evolving industry, regulated by some states as a food, others a dietary supplement and in some cases as a pharmaceutical, is challenged in many regards with how to set up, validate and verify a quality system. Quality is one of EAS’ many strong capabilities and our team of consultants is rising to the challenge of assisting this newer industry. Tara Couch presented a webinar “Quality Systems for the Cannabis Industry” and for the first time, we incorporated cannabis applicability into our two-day dietary supplement GMP seminar for a special presentation. We were also frequent contributors to the Cannabis Industry Journal including Gabe Miller who authored an article on Food Safety in the cannabis industry and Celia Schebella who discussed designing cannabis edibles in the state of California.

As we look ahead to 2019 there are a few notable things on the horizon that EAS consultants are watching for:

On the Tobacco front, the Center for Tobacco Products’ director Mitch Zeller, announced at the annual Tobacco Merchants Association (TMA) meeting that the agency is actively working on developing its own set of GMP protocols for the tobacco industry, called Tobacco Product Manufacturing Practices (TPMPs). In an effort to help tobacco firms begin forward thinking in these terms, EAS Senior Director for Dietary Supplement and Tobacco Services, Tara Lin Couch, Ph.D. and President and COO, Dean Cirotta presented a webinar in partnership with TMA (now available on-demand) on how to prepare for these TPMPs based on the long-standing GMPs for the dietary supplement industry.

In addition, OTC Monograph reforms have been underway for some time and it is anticipated that 2019 will bring these new requirements to light. Independent Consultant Norma Skolnik prepared an article for EAS-e-News on expectations earlier in the year and EAS Independent Advisor for OTC Drugs and Labeling, Susan Crane, will present a five-part webinar series on the subject starting January 16. She’ll discuss why these reforms are necessary, are being undertaken now, and how OTC drug companies can expect those changes to impact their labels.

In the Dairy world, FDA has fast-tracked a review of how the words “milk” and “cheese” are used in dairy substitutes. The Dairy industry is also anticipating enforcement of the new Appendix T of the PMO which will implement FSMA-like requirements aimed at preventive measures to improve safety. More information on both of these as they unfold.

On the home office front, the EAS staff was very pleased when the extensive expansion and renovation of our office space was complete, and we think it looks great! This new area enables EAS training hosted in the DC area to move in-house and offers enhanced meeting capabilities, both in-person and remote. If you are in the D.C. area, we invite you to come by! In addition, we completed a major redesign of our website, found at easconsultinggroup.com. We hope you’ll agree that this new digital space is not only improved in appearance but provides easier access to not only information about EAS services and seminars, but also regulatory information prepared by our independent consultants and distributed through a variety of professional trade journals and organizations.

We also welcomed 24 new consultants, re-welcomed three consultants who returned to EAS after a stint in the industry and brought on a new office manager, Jodi Burns. EAS is only as strong as our professional network of skilled and knowledgeable consultants, directors and support staff. We feel we have some of the best in the business!

If it seems like EAS consultants have a wide-reach of educational support, you are right. All told EAS presented 13 two-day public seminars, will have conducted 19 webinars by the end of 2018; published 40 articles, and spoke or moderated at 25 industry events such as IFT, Food Safety Consortium, Supplyside West and a variety of FDLI-hosted events. We also exhibited at important trade shows such as IFT, Supplyside West, Food Defense Conference, IAFP and others.

One trade show event, nearest and dearest to our hearts was the 2018 AdvaMed MedTech Intelligence conference in Philadelphia where Ryan Steele, granddaughter of Chairman and CEO of Ed Steele, and daughter of CFO Brett Steele, was an invited speaker on the main stage sharing her story as just one many who has been positively impacted by the innovation of science and technology, in Ryan’s case with the implantation of a vertical expandable prosthetic titanium rib, which is the only FDA approved device to treat thoracic insufficiency syndrome.

It is stories such as hers that brings home why we all do what we do, designing products that fill a need and a niche and do so safely and effectively. While FDA regulations may feel cumbersome at times, it is those instances, where important decisions with critical outcomes are in front of us, that we can all appreciate FDA’s diligent focus on ensuring only compliant products are available to the US consumer. Here at EAS, we support firms working in all FDA regulated commodities to do just that and we take great pride in our ability to meet their needs.

Thank you for journeying with us in 2018 and we look forward to a peaceful and prosperous 2019. Have a very happy holiday and New Year!

Four Common Mistakes When Selecting a Rapid Method for Environmental Testing

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We are now firmly in the era of the Food Safety Modernization Act. It’s no longer theoretical, it’s real world, and FDA is auditing and asking questions about what they are seeing.

I think we can all agree on one thing. The way we looked at environmental pathogen testing in the past is out the window. Gone are the days of testing the same 10 sites every few months for generic Listeria and calling it good. Sometimes, you would get a hit and do an investigation, but that was the extent of the excitement.

You now need a robust program that looks at multiple pathogens and takes them all the way out to speciation. Some companies are even going further and developing a “microbiological map” of their processing areas. The technology is overwhelming, but one factor is still critical, and that’s time.

No one has the time to put all their product on hold while waiting for five days to a week for results. Of course, that assumes that nothing comes back as a presumptive positive. If it does, you can wait a few days longer while logistics breathes down your neck, and customers have empty shelves. What to do?

You need a new program to test for your environmental pathogens. But, how do you choose? Instead of evaluating the ever-changing landscape of tests available, it might be more useful to list four rules you need to follow for your decision-making process. This is an expensive decision, so make the right one as you are going to be living with it for a long time.

You need a fast turnaround, and in most cases, that means you are now considering something that wasn’t even possible in the past -testing samples and releasing in-house. The first step is to get out there and see the amazing new micro testing world that is at your fingertips.

  1. Don’t get sold by a fancy presentationYou begin your journey by attending a trade show and marveling at the technology available. You strike up a conversation with a salesperson and after ten minutes, you are convinced that this new whiz-bang machine is the wave of the future. If you place your order today, you can get a huge discount and get one of the few machines that are even available. You can also add in a low monthly payment program. It does everything you want, and more in an hour and costs pennies to operate. It’s amazing, and you are in love.Not so fast, partner. It’s just like when you buy a car. The salesman at the dealership does everything to move you toward a purchase. How? By using your emotions. People buy on emotion and use logic to rationalize their decision after the fact.The thing the salesman wants you to forget is that this is a commodity and another similar model is available just down the street. Remember, any attempt to pressure you into a purchase should be met with a knowing smile. The deal they quote is not a once in a lifetime opportunity, and it will be there once you have time to make a decision in the calm light of rational thought. Be cool, try to find a technical representative of the company to talk with in addition to the sales or marketing staff. Remember it’s a piece of equipment, and one that is equally as good or even better is just around the corner. Add this piece of equipment to your list of possible testing methods and move on down the trade show to the next one.
  2. Not using a validated methodologyThis goes with the first point. You need a method and technology that are approved for your application. It needs to be benchmarked back to reference methodologies. Has it been used on your product matrix? Peanut butter will likely react very differently to the test than yogurt. Everything on your list needs to clear these hurdles before you even consider it. Don’t accept “the approval will happen in two weeks” line or something similar. You are in control of the validation and benchmarking process and must have a test and equipment that hold up to regulatory scrutiny.Ask the following questions as you look at the candidates:
    1. Has it been validated for my product matrix by one of the following?
      • A recognized independent organization such as AOAC, AFNOR, MicroVal or
      • A US regulatory body (FSIS MLG, FDA BAM or an ISO Method?
    2. Is the method?
      • Fit for the purpose and application
      • Performed under validated conditions by a lab that assures the quality of analytical results

    These questions come from the USDA Food Safety Inspection Service. They have compiled a list of validated methods that you can use as a starting point. It’s forty-six pages long! Cross off any candidates that didn’t make your list, realizing that FDA utilizes the BAM as their reference for acceptable analytical methods.

  3. Not testing in-house before you buyNever, ever buy a new testing method without trying it out first – for a long period of time. Any reputable company will have a loaner machine you can use. If they balk, cross them off the list and move on.Decide if you can test as a group or one at a time. This is a question of resources and how many people can do what. Don’t use the results for actual product release. Keep that the same as you are doing now.Another good idea is to test at the point of use in the plants. Don’t test at the corporate lab. You lose too many variables that need to be accounted for at the plant.Test it with every permutation you can think of. Analyze enough samples so you can make sure the results are repeatable. Find out the limits of detection for your product. What are the false positive and false negative rates? What is the turnaround time for results? See if your technicians can screw up the test. Make your test as foolproof as you can.Also ask yourself: Can you get test supplies in a reasonable period of time? What is the minimum order quantity? What is the breakpoint for discounts? Are your supplies expiring before you can use them? Are there other uses for this equipment?This list is not inclusive by any stretch; its a starting point. Create the list and stick to it. Don’t change it as you go along as it will bias the results toward the newest test. Be consistent.Remember, you may need to defend the test results in court one day. This is the litmus test for acceptance that you must always keep in mind in the age of FSMA. Send back any that don’t make the cut and cross them off the list.
  4. Not researching the companyGreat! Your list is down to the top two testing methods. They are both reliable and repeatable, have fast turnaround time, dependability and a decent cost per test. How do you decide now?The test is only as good as the company supporting it. If they are new to the scene, will they be here in five years? Will they come up with a new test and abandon the old one, leaving you with an expensive paperweight? Do they have references you can talk to? Can you talk to references who have had challenges with the test?Are they willing to work with you on price? Can you get other perks such as free service calls? How will they support you and the warranty? Just like the test, you need a huge list of questions to hit them with.

Final Thoughts

Congratulations! This was a big decision, but you made the right one for you. The method and the test you selected are the cornerstones of your new environmental testing program. You are finding out where pathogens hide in your plant and eradicating them. You have a clear record of identification and correction that any auditor will be happy to review. You sleep easy at night knowing that you made the right decision, and you have the ability to defend it if you need to.

Be proud of your work and welcome to the new age of FSMA!

Reference: FSIS List of Foodborne Pathogen Test Kits Validated by independent Organizations

Legislation to Reform the OTC Drug Monograph System: The OTC Drug Safety, Innovation, and Reform Act

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With the aim of overhauling the regulation of over-the-counter (OTC) monograph drugs, U.S. Senators Johnny Isakson and Bob Casey recently sponsored bipartisan legislation, the Over-the-Counter Drug Safety, Innovation, and Reform Act of 2018, S.2315. The bill, which has already passed in the House of Representatives, was approved by the Senate Health, Education, Labor, and Pensions committee on April 24, 2018, and was received by the Senate at large on July 17, 2018. A previous bill, the Over-the-Counter Monograph Safety, Innovation, and Reform Act of 2017, authored by Representative Bob Latta (R-OR) and others, was introduced over a year ago.

As most people know, the current monograph system, which was implemented in 1972, has received much criticism and there have been several prior efforts to revise what’s been called an outdated “broken system”. The current monograph system’s drawbacks include the slow rulemaking process (many OTC drugs are marketed under incomplete monographs), the inability to swiftly and promptly address safety issues, and barriers to innovation (eligibility is largely limited to active ingredients that were marketed before 1972). In addition, FDA has acknowledged that it currently lacks the resources to effectively regulate all OTC monograph products.

The proposed bill is intended to speed up the current slow and time-consuming regulatory procedures by introducing the administrative order process to replace the current rulemaking procedures. It provides options for manufacturers to request administrative orders and for FDA to initiate administrative orders on its own initiative as well as in response to a citizens’ petition.

The S2315 bill would also establish a process for the introduction of new OTC products that are marketed without an approved New Drug Application. This legislation would authorize the agency to grant 2 years of product differentiation and exclusive market protection for certain qualifying OTC drugs, thus delaying the entry of other versions of the same qualifying OTC product.

The bill also includes provisions that would provide FDA with the authority to take rapid action in the event of safety issues with OTC drugs and requires that FDA re-evaluate the OTC cold and cough monograph with respect to children under the age of six and report annually to Congress on the progress of this evaluation. This was prompted by a 2007 internal review that linked the deaths of 54 children younger than 6 years to the use of OTC decongestants and cough medications.

Additionally, the new legislation will help manufacturers who wish to develop innovative products, for example, by adding new ingredients or creating new dosage forms of existing OTC drugs. It should provide a more streamlined regulatory pathway for review of innovations within the OTC Monograph system, accommodating marketplace innovations, such as new uses for ingredients, dosage forms, and other advancements. It should also provide a mechanism to encourage investment in data needed for significant innovations.

Reforming the OTC monograph system should benefit consumers and give FDA the resources that it needs to provide effective oversight of these widely used drug products.

The proposed legislation updates the monograph process by specifically adding a new section to the Federal Food, Drug, and Cosmetic Act (FFD & C) to implement the following:

  • Move away from the cumbersome current monograph finalization process to an “administrative order” procedure. The system for future changes to Monographs would be through the administrative order procedure with an opportunity for development meetings or other consultations, comment on proposed orders, and dispute resolution protections
  • Include by reference existing OTC Review Final Monographs and deem final all existing Tentative Final Monographs by statute
  • Create new pathways to innovation for monograph products, where none currently exits
  • Ensure that the new drug approval pathway and other nonprescription drugs otherwise lawfully marketed are not affected
  • Create a mechanism for faster OTC drug safety label changes;

Importantly, the bill provides FDA with the authority to collect user fees to help cover much of the costs of updating the regulatory system and provide the necessary resources to evaluate and monitor the OTC drug market. It’s hoped that the user fees will provide FDA with the funding and staff required to better oversee OTC drug compliance and build a critical IT/electronic infrastructure. This bill differs from previous versions because of its’ exclusivity provision.

The OTC Drug Safety, Innovation, and Reform Act is now awaiting Senate action. There is a great deal of bipartisan support for this bill, including from the American Academy of Allergy, Asthma & Immunology, the American Dental Association, and the American Academy of Pediatrics, who have urged passage because of the need to overhaul and modify pediatric dosing for OTC drugs, particularly OTC cough and cold drugs. It’s also been supported by the Consumer Healthcare Products Association (CHPA), the leading U.S. trade association representing OTC drug manufacturers and marketers. However, although it has widespread support and appears likely to pass, this is not a “must pass” bill like other existing user fee legislation. When it does pass, this legislation will have an enormous impact on the OTC drug industry in this country.

FDA Mutual Recognition Agreements

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FDA has been implementing the Safety and Innovation Act since it was passed by Congress in 2012. The Act requires FDA to establish Mutual Recognition Agreements (MRAs) which are agreements between two or more countries to recognize a specific process or procedure of the other country. The FDA’s MRA was preceded by the 1998 signing of the U.S. and the EU Agreement on Mutual Recognition which included a Pharmaceutical Annex providing for recognition of each other’s GMP inspections. Unfortunately, this Annex was never fully implemented.

Effective in 2017, the amended Sectoral Annex to the 1998 U.S.-EU MRA allowed for inspection reports and other related information obtained during drug manufacturing facility inspections, conducted by either an EU inspectorate or by FDA, to help determine whether a facility is manufacturing high-quality drugs. If more information is necessary beyond this assessment, FDA or the EU can then require additional inspections or take other action in the interest of protecting the public.

The 2017 Annex provides for greater efficiency in the drug inspection process, eliminating the redundancies of duplicate facility inspections, particularly those with a strong record of compliance. By utilizing each other’s inspection reports and related information, the FDA and EU are able to reallocate resources towards inspection of drug manufacturing facilities with potentially higher public health risks across the globe, benefiting patients and reducing adverse public health outcomes.

FDA’s determination as to whether an MRA is appropriate is made first via an assessment of internal audits in a particular EU country to ensure that their inspectorate is functioning properly and not deviating in any significant way from EU law and guidance.

These audits include observations of drug manufacturing facility inspections conducted by the audited inspectorates and utilize the 78 indicators based on the Pharmaceutical Inspection Co-operation Scheme (PIC/S) compliance assessment program with an EU addendum. PIC/S is an internationally recognized cooperative arrangement between 49 regulatory authorities, including the FDA. The goal of PIC/S is to harmonize inspection procedures worldwide and develop common standards in the field of good manufacturing practices.

In addition, FDA considers any conflict-of-interest policies, specific legislation related to good manufacturing practices, samples of inspection reports, inspector training records, inventory of drug manufacturing facilities, surveillance program, and numerous standard operating procedures to evaluate a pharmaceutical inspectors’ credentials as part of the capability assessment of each EU country. In this way, FDA can ascertain whether the inspection authorities are trained and qualified and have the skills and knowledge to identify manufacturing practices that may lead to patient harm. Maintenance provisions are also included in the Annex to ensure that each capable country continues to meet FDA requirements.

Thanks to this MRA, there is a greater ability of the Agency to appropriately allocate its resources to focus on those facilities where initial audits raise red flags that warrant further inspection, either by continual deficiencies in inspection findings by a country’s own internal audit system or by adverse events reports or other means. One of those means is the “Drug Quality Sampling and Testing (DQST)- Human Drugs Compliance Program 7356.008”, which is a surveillance program that samples and tests pharmaceutical products manufactured both in the U.S. and foreign countries. Surveillance under the DQST is prompted in part by recommendations from CDER and ORA headquarters and FDA district offices based on their intelligence and reported consumer complaints.

The goal of the DQST compliance program is to protect the public health by minimizing exposure to non-compliant and/or poor-quality drugs. Testing is undertaken on finished dosage forms, APIs, and excipients and the samples chosen are based on risk-based selection criteria and a risk-based model. Due to the globalization of pharmaceutical products increasing consumer risk, the surveilled domestic and international products have expanded under this program to include prescription and OTCs, compounded drugs, drug products with approved an NDA or ANDA as well as unapproved drug products and others. This program, in combination with other quality assurance compliance programs, is an integral part of the Agency’s overall post-marketing surveillance strategy. Fortunately, the majority of drugs FDA independently tests meet their specifications. From 2003 to 2013, FDA tested nearly 4,000 of drug samples. During that decade, FDA laboratories found that 1.1% of the drug products analyzed deviated from acceptable standards.

FDA takes its oversight of the domestic and foreign pharmaceutical program very seriously as any safety deviations in these products could have a significant impact on public health. Companies may wish to proactively perform quality assessments and gain an understanding of their current compliance status through independent third-parties such as qualified consulting firms who offer expertise in pharmaceuticals conducted by persons with a strong background in Agency regulations and safety standards. Once a needs assessment has been conducted, a proactive remediation plan of deficiencies can begin.

More information on FDA’s pharmaceutical surveillance programs can be found on the Agency’s website and we invite you to view EAS-produced on-demand webinars focusing on a variety of GMP tools on the EAS website. Should EAS be of service to your firm either in an assessment of compliance status or to assist with an FDA announced facility inspection, please contact Bryan J. Coleman, Senior Director of Pharmaceuticals and Medical Devices.

Getting Your Medical Device Into the U.S. Market

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If you are a manufacturer whose medical device is either a Class I, or a 510(k) exempt device Class II device, consider yourself and your company lucky that you do not have to try to “thread the needle” of the litigious and arduous process known as 510(k) clearance. Getting a device ready for 510(k) submission is usually time-consuming, costly, and full of challenges.

All 510(k)’s are based on the concept of substantial equivalence (SE) to a legally marketed (predicate) device. If you are the maker of a Class II medical device or an IVD and want to launch it in the U.S. market, you must submit a 510(k) to the FDA. For Class III devices, a premarket approval (PMA) submission is needed.

510(k)’s have unique content and format requirements – they are not identical to a European Technical File – and the FDA’s recent changes to 510(k) requirements make the submission process more rigid than ever.

Class II devices are designed to perform as indicated without harming patients or users, but they require a greater level of safety and effectiveness assurance than do Class I devices. Examples include powered wheelchairs, infusion pumps, surgical drapes, surgical needles, suture material, and acupuncture needles.

Class III medical devices do not have enough information to ensure safety and effectiveness through the general or special controls used for Class I or Class II devices. These higher-risk devices need premarket approval (PMA), which includes a scientific review, to ensure their safety and effectiveness. Examples include replacement heart valves, silicone gel-filled breast implants, and implanted cerebral stimulators.

Here are some practical tips for a 510(k) filing:

  • Establish a “Regulatory plan” as early in the process as possible. The regulatory plan should include a list of all the deliverables required. The plan needs to be owned by all the applicable team members not just the person issuing the plan.
  • Don’t be surprised or disheartened that questions will arise despite your best efforts. The FDA is swamped with 510(k) reviews and any deficiency that they can find in your submission allows them to go to the next submission to keep the commitment that the FDA will review all submissions in a timely manner. “Put yourself in the FDA examiner’s shoes”.
  • Don’t try to blind the FDA examiner with excessive or extraneous information in the hope that they will bypass the information for the sake of time. In my experience, the FDA examiners read every document and every page!

The FDA sends back most 510(k)’s during the first review cycle to request more information – in recent years this has applied to more than 70% of 510(k) submissions!

Also, many medical device companies are compiling and submitting 510(k)’s to the FDA for review without establishing a Quality Management System and without documenting Design Controls and without documenting Risk Management which can bode trouble for the submission as well as FDA inspection time.

You might want to consider using a competent consultant or at least asking an objective party to review the submission for completeness before sending it to the FDA. This will minimize the risk of delay and rejections.

FDA 483 Responses – Missing the Mark?

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In recent months, it appears more companies are having difficulties meeting the requirements of FDA Form 483, List of Observations, response. The inspection situation is very stressful and if it ends with the dreaded “483”, it can be positively overwhelming. However, when the initial reaction is over, it’s time to rally the staff and prepare the corrective and preventative action strategy that will be presented in the response within the allotted time frame. It is also critical to understand what is expected of the response letter.

The 483 is a list of inspectional observations that is the result of what the inspectors viewed while in your facility. It is a legal document from federal agents performing a law enforcement function where the evidence is the collection of documents and data that the agents evaluated at the company. All of the observations should first be reviewed for accuracy. Hopefully, any discrepancies or misunderstandings were discussed during the closing meeting and resolved, but if they were not found until after the inspectors left the facility, they will need to be addressed in the response. The 483 response is also a legal document so the tenor and exact wording used are critical. It must demonstrate that the company understands the issues, has made the necessary corrective and preventative actions, and that there is documented evidence to verify the latter.

Each observation requires a response and that response must describe the associated corrective and preventative actions are taken. It should be thorough and detailed and written to present steps in the order taken. Procedures and related documents prepared and implemented during these actions must also be included. It is not enough to only describe actions, there must be documented evidence of the correction such as photographs, procedures, training records, specific forms, and other types of documentation. Many Warning Letters are issued by the FDA because a company’s response letter did not include evidence of the corrective and preventative actions taken for the FDA to evaluate to determine if the situation was appropriately addressed.

Consider three potential categories of actions to be taken for each observation; immediate, short-term and long-term. Think of this from a medical emergency perspective where initial triage occurs to keep the patient’s condition from getting worse, additional short-term actions are needed to stabilize the patient, and then long-term actions may be needed to deal with any underlying problems. A systematic issue will have to be addressed with preventative measures. It is also important to review the observations collectively, in addition to individual, to determine if other underlying systemic issues exist. These too will have to be addressed with corrective and preventative actions.

Please note that, unlike an FDA Warning Letter, a response to a 483 is not legally required. However, it is strongly recommended that a 483 response be provided to the FDA within 15 business days. Some observations can be appropriately addressed and the actions concluded within this time frame, but others, particularly systematic issues, may require more time. When that is the case, all of the planned corrective and preventative actions should be described in the initial response, immediate and short-term actions should be taken, and completion dates for long-term items provided. It is important that these proposed dates be aggressive, yet reasonable and obtainable. Monthly updates to the FDA stating the progress made on these long-term items, with supportive documented evidence included, should then follow. This strategy may prevent the FDA from escalating enforcement actions and issue a Warning Letter.

Confirmation that the FDA is satisfied with the 483 response will be provided by the issuance of an Establishment Inspection Report (EIR) which states that all of the corrective and preventative actions will be evaluated upon “the next inspection.” The EIR is also a more detailed summary of the inspectional findings and it is wise to use this as an opportunity to further review operations, controlled processes, and the overall quality system. Look at these findings from a systems approach; facilities and equipment, materials, production, packaging and labeling, laboratory controls and, of course, the most important and critical one – the quality incident system. The entirety of the inspection and the inspectional review should also be another piece to the internal audit program, make the experience work to improve compliance and not just an exercise in writing letters to the FDA.

For assistance in understanding FDA 483 findings as well as developing an appropriate response and corrective actions contact EAS.

FDA Food Code 12th Edition – What’s New?

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The FDA Food Code is used as the basis for food safety regulation of more than a million restaurants, retail food stores, institutional and other food operations in the US and around the world. It is updated every two years through a collaborative process with the Conference for Food Protection where all stakeholders have a voice in what is included in the next edition published by FDA. Allen Sayler, Senior Director for Food Consulting Services, in his March column in the EAS-e-News announced the release of the 2017 edition on February 12, 2018.

This article will focus on the 10 major changes in this 12th edition since the first modern risk- and the science-based code was issued by FDA in 1993. Twelve earlier editions had been published by FDA and the U.S. Public Health Service since 1934 that were more retail segment-specific guidance, i.e. food service, food store or food vending.

FDA Food Code only becomes a regulation when its requirements are adopted by local, state, and federal food programs for their segment of this vast industry. The new provisions also become the de facto standard of prudence for many companies, even before their operations are required by the local regulatory authorities to comply with it.

A summary of the 10 major updates in the 2017 edition of the FDA Food Code is provided below. This release also had many less significant changes and numerous editorial and clarification amendments.

Chapter 2 Management and Personnel
2-102

 

 Certified Food Protection Manager

Required, for the first time, that the Person in Charge of the food establishment be a Certified Food Protection Manager. The program that awards this recognition must be accredited, meaning that it has been evaluated and listed by an accrediting agency, as conforming to national standards for organizations that certify individuals.
2-103 Monitoring of Food Temperatures

Added a new duty for the Person in Charge, ensuring employees are routinely monitoring food temperatures in hot and cold holding.
2-201 Salmonella Typhi and nontyphoidal Salmonella distinctions

Expanded on the changes begun in the 2013 Food Code in emphasizing the importance of nontyphoidal Salmonella (NTS), such as S. enterica serotypes, that cause more than one million domestically acquired foodborne illnesses in the United States each year.
2-401 Bandages, Finger Cots or Finger Stalls

Required the use of a single-use glove to cover a bandage, finger cot or finger stall used on the wrist, hand or finger.
2-501 Written Vomit and Diarrhea Clean-Up Procedures

Required that a written plan be provided for cleanup of these bodily fluid discharges by employees or customers. A very good detailed explanation for the plan elements is provided in Food Code’s Public Health Reasons Annex.
Chapter 3 Food
3-401 Changed Cooking Times

Raised the cooking temperature dwell time for foods like comminuted meats requiring a cooking temperature of 68°C (155°F) from 15 seconds to 17 seconds. Lowered the cooking temperature dwell time for foods like poultry requiring a cooking temperature of 74°C (165°F) or above to < 1 second (instantaneous).
3-502 ROP Frozen Fish Labelling

Added criteria for fish that is reduced oxygen packaged at retail to bear a label indicating that it is to be kept frozen until time of use.
Chapter 8 Compliance and Enforcement
8-201 HACCP Plan

When a Hazard Analysis and Critical Control Points plan is required by a jurisdiction for variances including those for specialized processing at retail, more detailed information is required to be submitted for the jurisdictions review and approval.
8-402 Regulatory Training

Added requirement for the Regulatory Authority to ensure that authorized representatives, who inspect food establishments or conduct plan reviews for compliance with Food Code, have access to training and continuing education, as needed, to properly identify violations and apply the Food Code. You will see in this month’s FSMA Perspective that employee training is also a requirement of FSMA and documentation of that training should be kept and provided to FDA upon request during an inspection.
8-404 Utility Interruption Contingency Plan

Allowed the regulatory authority to agree to continue operations during an extended water or electrical outage, if written operational plans have been approved by the regulatory authority.

 

As mentioned with the changes outlined in Section 2-501, the Public Health Reasons in Annex 3 provide excellent plain English descriptions of the science and other details behind the requirements of the changed, as well as the older sections of FDA Food Code. Additional information can be provided by the adopting regulatory authority or by the FDA National Retail Food Team. Questions of FDA on the Food Code may be directed to RetailFoodProtectionTeam@fda.hhs.govor should you have questions which you would like to direct to EAS, contact Allen Sayler at ASayler@easconsultinggroup.com

Medical Device Innovations and the Regulatory Landscape

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I’m amazed as I watch a Health Care System and then a Spectrum commercial to what our future holds with the sophisticated, interactive medical device and technology innovations and how they will enhance the capabilities of diagnosis and treatment. My regulatory mind then kicks in and wonders how these amazing innovations will pose operational and data reliability challenges for both industry and regulators in areas ranging from clinical trials to device design and development, and ultimately to the commercially approved and marketed devices.

For Federal Agencies and other institutions involved in the evaluation, funding, manufacturing, distribution, and clinical use of medical devices, it is clear that the landscape of these activities will be changing in considerable ways. The increase in minimally invasive methods and devices to reduce lengthy recoveries, developments in decentralized care, tissue engineered devices, advances in diagnostic and “smart” products, to the growing sophistication of electronic medical information systems hold for substantially better-informed diagnoses and treatments. Yet, these same developments will generate increased pressure for more effective data capturing systems and methods to handle the data, coupled with concerns related to device accountability, source, supply/availability, and quality.

Regulatory health authorities around the globe are taking steps to be prepared. Are you ready and will you be in compliance when new and upcoming regulations take effect…

Data Acceptance

The FDA issued a final rule, effective Feb. 21, 2019.

Under the new rule, FDA is requiring sponsors and applicants to affirm that clinical investigations outside the United States were conducted in accordance with Good Clinical Practices (GCPs) when the data are submitted for medical device applications.[1] The final rule also amends criteria for investigations conducted within the United States to require applicants and sponsors to state that the investigation complies with FDA regulations for human subject protection, institutional review boards, and investigational device exemptions (IDEs).[2] If an investigation is not conducted in accordance with those regulations, a brief statement of the reason for the noncompliance is required.[3,4]

The US FDA’s new requirements will affect device development strategies, including where to conduct such trials. The necessary patient population in the disease prevalent area of the clinical trial may not have the economic means for network availabilities to fully comply with the use of the sophisticated investigational device product. Education of ex-US trial sites will need to be enhanced, and cost of ensuring trial sites have adequate systems and equipment to effectively run and capture trial data will need to be considered as part of the strategic site selection process without creating bias.

European Union’s (EU) Medical Device Regulation (MDR)

The EU MDR is expected to come into effect in late 2019 or early 2020. This will give national regulators more control and oversight of the medical devices industry. The aim of the new regulation is to ensure that products are effective and safe as well as can be freely and fairly traded throughout the EU. The impact of this regulation can alter the operations of medical device manufacturers most notably on the supply chain and quality management systems of the organizations. It is critical that industry takes steps now to prepare their organizations and start implementing changes.

Data Integrity

Data integrity continues to be a priority and a hot topic. Regulators are focused to detect data integrity, data manipulation, and fraud. They must be able to rely upon the accuracy and completeness of the data and information generated, providing assurances to the products’ safety, identity, strength, purity, and quality which are all dependent on the validity of the data and information obtained.

Conclusion

Regulators are gaining more control and oversight of the medical devices industry. They are taking steps to prepare for the new innovations and enhanced capabilities of diagnosis and treatment with medical devices. It is important for medical device companies to proactively prepare for these changes as their impact could be significant. These include impacts on the cost of implementing changes to organizational prioritization and to internal processes around device accountability/supply, source, availability, and quality. If industry and regulators continue to maintain their role of ensuring compliance, new innovative devices can be made available, safely and effectively for patients, providing for better healthcare outcomes.

[1] US Food & Drug Admin., Human Subject Protection; Acceptance of Data from Clinical Investigations for Medical Devices, 83 Fed. Reg. 7366(Feb. 21, 2018) (hereinafter Medical Device Rule).

[2] See 21 C.F.R. §§ 50, 56, 812.

[3] 21 C.F.R. § 812.27(b)(4)(ii).

[4] Medical Device Rule at 7370.

Clean Label, the Challenges

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So, you decided to have clean labels for your products, now what do you do? You are not alone in your pursuits of this endeavor. A couple of years ago, I was approached by a marketing department when they wanted to make certain claims in their product lines and one of the phrases they used was “we want to say that our labels are clean because our clients want this”, so I asked them, ‘What do you mean by clean?” And of course, having several people in that meeting, I got several different answers! Answers like “no GMO’s”, “Natural”, “Gluten-free”, “No antibiotics”, “No pesticides”, “No Artificial ingredients”, etc. So, the first task at hand was to clarify what the term “clean label” means. At that time, we did not find a definition either from USDA-FSIS or FDA for the term “clean label”, what we found was that the term was probably developed by consumers as an “understandable” claim or answer to ingredients in their food. The Clean Label trend has taken center stage and found its way into many respected scientific meetings. The 2015 Institute of Food Technologist Annual Meeting and Food Expo is just one example of many where the topic of Clean Labels and what that means, was discussed.

When the US-based food retailer, Whole Foods Market, published a list called “Unacceptable Ingredients for Food1” around 2014, they began working with their suppliers on creating products only with natural ingredients as part of their Food Ingredient Quality Standards. Around the same time, Panera Bread published their “No No List2” of ingredients, such as preservatives, sweeteners, flavors, and colors, all from artificial sources, that were no longer allowed in their products. The trend was not just U.S.-focused as many International companies were also working on making their labels more transparent to help consumers make better decisions.

So, what does “clean label” mean? Many definitions exist, and all include the fact that terms such as “no artificial ingredients” and/or “natural” are included on labels as consumers expect transparency by using ingredient names that people can recognize. One of my favorite definitions of a “clean label” came from my wife (not biased!) who said that a clean label is one where she understands ingredients in her food without having to ask me and that the ingredients do not come from artificial sources.

This transparency is a great and noble cause to pursue but what are the challenges? In my opinion, the first challenge facing the technical and scientific community is that functionality in many cases drives the choice of almost all ingredients: things like water retention (phosphates), color additives (FD&C Red No. 3 and 40), color development/enhancement (sodium nitrate in processed meats) and flavor enhancement agents (MSG or Monosodium Glutamate not naturally occurring). Some ingredients already have a natural alternative, like the use of celery powder and sea salt as a source of naturally occurring nitrate-nitrite but we are still working on alternatives for others, creating challenges to R&D scientists and chefs all over the country.

This R&D also creates the second challenge in my opinion: cost. Many of these “clean” ingredients are expensive either because of the amount of these “clean” ingredients required or the increase in demand just in the last couple of years. Before a company decides to reformulate, understand your audience and your clients to ascertain whether they are demanding this change or not. I was surprised when the company asked their marketing group to investigate whether the demand for clean ingredients was universal, that only a small percentage of clients were demanding a change to clean labels. Based on that research they decided to invest time in creating a brand-new line of products to fulfill this need instead of reformulating all products.

In my opinion, some of the questions you need to ask before you start changing formulas are:

  • Are all my clients and/or target markets demanding a clean label?
  • Are they willing to pay for this change?
  • Can I afford the change?
  • Do we change our formula or do we create a new line of products?

Depending on your answers, you will be able to make an informed decision for the future of your company.

Note: This article presents the point of view of the author and does not represent any legal advice.

References

  1. Whole Foods “Unacceptable Ingredients for Food”
  2. Panera Bread “No No List”

Homeopathy – What Does the Future Hold?

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It’s been clear for several years that the FDA, as well as the Federal Trade Commission (FTC), are turning up the heat on homeopathic drug products. It culminated in December 2017 when the FDA published a draft guidance document for both FDA staff and industry regarding their new approach to regulating “Drug Products Labeled as Homeopathic”. This followed on the heels of FTC’s “Enforcement Policy Statement Regarding Marketing Claims for Over-the-Counter Homeopathic Drugs” published in 2016.

The practice of homeopathy has been around for more than 200 years and has its share of both critics and adherents. Homeopathy is a form of alternative medicine based on the concept that a disease can be treated with minute quantities of natural substances that would, if given in larger amounts to a healthy person, produce symptoms of the same disease.

Prior to this most recent regulatory action, the FDA regulated homeopathic medicines as drugs under the Federal Food Drug and Cosmetic Act but did not otherwise evaluate their safety and efficacy as long as they were marketed for self-limiting conditions and contained active ingredients listed in the Homeopathic Pharmacopeia of the United States. The enforcement policy was described in a Compliance Policy Guide (“Conditions Under Which Homeopathic Drugs May be Marketed”) that was issued in 1988.

As the homeopathic industry grew, the Agency re-evaluated its position and announced in 2015 that it was going to evaluate the regulatory structure for these products. It hosted a public meeting that spring during which interested parties (manufacturers, health care professionals, industry associations, etc.) could provide input and make suggestions as to whether the current framework was appropriate for ensuring the safe use of these products. As a result of the meeting and FDA’s own evaluation, it determined that a new guidance document, applying a “risk-based” approach to enforcement, would better serve public health and be consistent with the Agency’s general approach to products marketed without FDA approval.

Because there are currently no homeopathic products approved by the FDA, the guidance document, when finalized, would serve notice that any product labeled as homeopathic could potentially be subject to enforcement action. However, the FDA recognizes that some categories of products pose a greater risk to public health and so provided a list that would receive prioritized enforcement. These include:

  • Products with reported safety concerns
  • Products that contain or purport to contain ingredients associated with potentially significant safety concerns
  • Products for routes of administration other than oral or topical
  • Products intended to be used for the treatment of serious and/or life-threatening diseases and conditions
  • Products for vulnerable populations
  • Products deemed to be adulterated under the Food, Drug and Cosmetic Act

As noted earlier, in addition to this increased FDA oversight, the FTC (which monitors marketing and promotional claims) is taking a more proactive approach to homeopathic drugs. In the aforementioned policy statement, it indicated that OTC homeopathic drugs would be held to the same standard as other products with regard to claims. In other words, companies either needed to have competent and reliable scientific evidence to back up the claims OR, alternatively, they could revise their labeling to include disclaimers communicating that “there is no scientific evidence that this product works and that its uses are based on theories of homeopathy from the 1700s that are not accepted by most modern medical experts.” No longer would it be acceptable to rely on statements that the “FDA has not evaluated the product” or that the treatment relied on “homeopathic principles”.

These actions by the FDA and FTC are not encouraging to the homeopathic industry. How strictly this new approach will be enforced is unknown, especially in the current political climate of decreased regulation. However, it’s a safe assumption that any homeopathic product that presents a safety risk or makes egregiously deceptive claims, will likely come under scrutiny and could land the offending company in proverbial “hot water.”

Have a Cup of Coffee and Pray – It’s the 20th Anniversary of the Seafood HACCP Rule

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HACCP, of course, stands for Hazard Analysis Critical Control Point, is a highly effective preventive control system for foods and other commodities. “Have a cup of coffee and pray” was how one skeptical USDA union official described HACCP implementation in meat and poultry processing plants when it was implemented in the early 2000’s. It is an example of some of the reservations public health officials had as early as 1980. FDA implemented this systematic control system in seafood effective December 1997. Although controversial its implementation proved to be a tremendous success for the agency and public health in general.

First, let me provide a little history. In the early 1980’s there was a developing trend towards exercise and healthy eating. A nutritionist named Anne Fletcher published a highly popular book about the nutritional benefits from eating seafood entitled Eat Fish, Live Better. This book received a tremendous amount of attention in the media that spurred the consumption of seafood as part of a healthy lifestyle. However, the seafood industry at the time had some systemic quality control problems that allowed significant amounts of low-quality seafood on the market. Most of these quality problems were hygienic in nature and did not pose a food safety problem. However, it did cause concern in the media about seafood safety and the public began to believe that seafood was good nutritionally but not always safe.

Congress at the time also became concerned about seafood safety and offered various legislative bills for so-called mandatory inspection of seafood. Congress also provided money for a Model Seafood Surveillance Project whose mission was to determine what governmental regulations were needed to address these issues. NOAA Fisheries conducted the project and dozens of workshops with industry to garner feedback about what would address the issue of safety and would work best for them. The conclusion of that report was that the implementation of mandatory HACCP was the best way forward. Circa 1990 President H.W. Bush ordered FDA and NOAA Fisheries’ Seafood Inspection Program to work together on a voluntary joint program to implement HACCP principles into the seafood industry and under President Bill Clinton, then FDA Commissioner Kessler decided that FDA would develop its own mandatory program for Seafood HACCP.

The resulting Seafood HACCP rule can be best understood and implemented by referencing the FDA drafted complex guidance document called the Fish and Fishery Products Hazard Guide (FFPHG). It is used worldwide as the, most authoritative, comprehensive guide to the science behind HACCP and FDA policies related to seafood.

While seafood HACCP regulations have been in place for 20 years, there is always work to do and vigilance to keep with regards to the safety of our food sources as the volume of seafood imported to the United States continues to increase. In 2009, 80 percent of the seafood in the U.S. food supply was imported, and by 2015, more than 90 percent was imported. A quick review of FDA warning letters at any point in time demonstrates this challenge, with as of this writing, six out of ten of the most recent FDA warning letters pertaining to seafood HACCP. Challenges such as implementing and verifying that seafood is processed, held and transported insanitary conditions; that regular inspection records verify their safe handling, both before they reach US shores and when they are a domestically distributed are areas where FDA inspectors are working diligently.

Over the years the guidance and FDA policy thinking was refined and the regulation became a tremendous success. Seafood safety and quality improved, scientific thinking was imbued into the seafood industry through the FFPHG which promoted the health of consumers, consumers were less worried about safety issues and seafood HACCP became a template for the Food Safety Modernization Act of 2010 that would apply preventive control principles to the manufacturing of all food commodities. That’s quite an accomplishment. So let’s have a cup of coffee and praise the FDA for their fine work in improving food safety standards for seafood.

FDA’S Policy on Medical Foods

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“Medical food” is a commonly misunderstood term as it is used on FDA regulated products. Many manufacturers want to market their products as medical foods because medical foods are exempt from the disease statement limitations for health and structure/function claims and are allowed to name the diseased population for whom they are designed. The following paragraphs provide details on FDA’s approach to medical foods, but the policy can be summarized as: a medical food is intended for people who have a disease or condition that results in a distinctive nutritional need which cannot be met by a diet of regular food but is met by the medical food. The disease or condition must be identified, the distinctive nutritional need must be substantiated by data, and it must be demonstrated that the product would meet the identified nutritional need.

Prior to 1972, medical foods were primarily formulas for managing patients with inherited metabolic diseases. They were mainly orphan products for limited populations. They were considered drugs to ensure their use under medical supervision. However, in 1972 the FDA reclassified these products from drugs to foods for special dietary use to enhance their development and availability. In the intervening years, a wide variety of products categorized as medical foods have been developed. Currently, marketed medical foods with a wide variety of claims are used extensively as a life support modality in the management of the critically ill and elderly. They are required to conform only to those regulations dealing with general food safety and labeling to be distributed in the United States.

The 1988 Orphan Drug Act (21 U.S.C. 360ee(b)(3)) provides financial incentives (such as drug application fee exemptions, and market exclusivity) to promote the development of “orphan drugs” for treating rare diseases and conditions. Medical foods were included in the Orphan Drug Act to include dietary therapies, along with pharmaceuticals, as eligible for financial incentives for developing orphan drugs. Medical food was defined within the context of new drug development, not for regulating the use of such products. The Orphan Drug Act did not amend the FD&C Act to add medical foods as a regulatory category.

The Orphan Drug Act definition of medical food is:

A food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.

There are presently no FDA regulations specific to medical foods other than the exemption provisions in the nutrition labeling regulation. The following criteria that clarify the statutory definition of a medical food can be found in FDA’s regulations at 21 CFR 101.9(j)(8). A medical food is exempt from the nutrition labeling requirements of 21 CFR 101.9 only if:

  1. It is a specially formulated and processed product (as opposed to a naturally occurring foodstuff used in its natural state) for the partial or exclusive feeding of a patient by means of oral intake or enteral feeding by tube, meaning a tube or catheter that delivers nutrients beyond the oral cavity directly into the stomach or small intestine;
  2. It is intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone;
  3. It provides nutritional support specifically modified for the management of the unique nutrient needs that result from the specific disease or condition, as determined by medical evaluation;
  4. It is intended to be used under medical supervision; and
  5. It is intended only for a patient receiving active and ongoing medical supervision wherein the patient requires medical care on a recurring basis for, among other things, instructions on the use of the medical food.

FDA published in 1996 an Advanced Notice of Proposed Rulemaking (ANPR) in which the agency discussed its interpretation of the Orphan Drug Act definition of medical food. (https://www.gpo.gov/fdsys/pkg/FR-1996-11-29/pdf/96-30441.pdf) While FDA later withdrew this ANPR due to lack of resources to devote to the subject of medical foods, the agency stated that it still retained the positions described in the document. A subsequent guidance document on medical foods provided advice consistent with positions in the ANPR. (http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm054048.htm)

FDA considers the statutory definition of medical foods to narrowly constrain the types of products that fit within the category. Outside of medical foods that have been developed for dietary management of rare diseases, FDA has considered most products marketed as medical foods, not to meet the definition of a medical food. The types of products that have been the target of FDA medical food Warning Letters include products intended for the dietary management of allergies and asthma, lactose intolerance, psoriasis, constipation, Irritable Bowel Syndrome, Crohn’s disease, colitis, arthritis, failure-to-thrive, injury/trauma, pre/post surgery, and prenatal vitamins. The FDA guidance document specifically states that pregnancy and diabetes are not diseases or conditions for which there is a distinctive nutritional need that could only be met by a medical food.

Pharma’s Problems with Data Integrity

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Data Integrity needs to be taken seriously in the pharmaceutical industry today and always! The FDA has issued many Warning Letters and Import Alerts to dosage form and Active Pharmaceutical Ingredient (API) manufacturers in the past several years. Manufacturers need to understand that once FDA finds some of your data to be unreliable, then they consider all your data unreliable. Many companies continue to use paper records [21 CFR Part 11 does not require you to use electronic records] and this is acceptable.

Problems have been found recently with the lack of compliance with chromatographic data acquisition systems used in quality control laboratories to test the potency of drugs and API. These data systems such as LIMS and Empower must be validated to comply with the regulations in 21 CFR Part 11. Electronic audit trails include those that track creation, modification, or deletion of data (such as processing parameters and results), those that track actions at the record or system level, such as attempts to access the system or rename or delete a file.

The Data Integrity regulations have been official since 1997. These new regulations have enabled a new industry to sprout, 21 CFR Part 11 compliant hardware and software. In addition to the hardware and software companies, consulting companies specifically focused on Data Integrity Compliance have also arisen. Please use caution as these electronic data systems must be validated at your site, using your systems, to truly claim that these systems are validated. Do not just take the vendor’s word for it that their data systems are compliant with this new regulation.

FDA expects that data to be reliable and accurate. CGMP regulations and guidance allow for flexible and risk-based strategies to prevent and detect data integrity issues. Firms should implement meaningful and effective strategies to manage their data integrity risks. This should be based upon their process understanding and knowledge management of technologies and business models. In recent years, FDA has increasingly observed CGMP violations involving data integrity during CGMP inspections. This is troubling because ensuring data integrity is an important component of Industry’s responsibility to ensure the safety, efficacy, and quality of drugs, and of FDA’s ability to protect the public health. Not to mention compliance with FDA regulations is the most sound business model for success.

The following statement is taken from a Warning Letter issued to a foreign manufacturer in 2016:

Our inspection revealed that your firm selectively omitted CGMP records directly related to the testing and manufacturing of your products. You are responsible for the accuracy and integrity of the data generated by your firm. A firm must maintain all raw data generated during each testing and manufacturing operation, including graphs, charts, and spectra from laboratory instrumentation. You must properly identify these records to demonstrate that each released batch was manufactured in accordance with validated parameters, was tested appropriately, and met release specifications. Your firm’s executive management is responsible for ensuring the quality and safety of your products. Implementing adequate controls and systems to prevent omission and manipulation of laboratory data is at the foundation of fulfilling this critical responsibility.

FDA’s Guidance for Industry on Data Integrity and Compliance With CGMP is available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ guidances/ucm495891.pdf

This guidance contains a wealth of information, which will help companies understand the definitions and requirements regarding data integrity. FDA’s Introduction to this guidance is included as follows: The purpose of this guidance is to clarify the role of data integrity in current good manufacturing practice (CGMP) for drugs, as required in 21 CFR parts 210, 211. This guidance provides the Agency’s current thinking on the creation and handling of data in accordance with CGMP requirements. These data integrity regulations are included in 21 CFR Part: 11 Electronic Records; Electronic Signatures. This URL includes the 21 CFR Part 11 regulations: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11

As always, consultants with expertise in data integrity, such as EAS Consulting Group, can provide the independent third-party validation that your company needs to ensure processes and procedures are accurately testing the data in question and that data is yielding meaningful results needed to verify integrity and validation. As mentioned, once FDA finds some data to be unreliable it considers all data to be unreliable. Full compliance with 21 CFR 11 will enable FDA to have trust that your data results and ultimately products are safe to market in the US, saving time and money.

Our Year in Review

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As 2017 draws to a close, it is appropriate to reflect on a year full of change, important milestones and growth not only at FDA but also here at EAS Consulting Group. Both organizations saw new staffing and new initiatives. With the inauguration of President Trump, FDA saw a changing political dynamic with new enforcement policies, and guidance documents; and on the EAS front, new staffing, partnerships and initiatives were aimed at helping the industry conduct efficient, safe and compliant business in order to meet FDA requirements.

Here are some highlights from 2017 which we think best demonstrate the commitment of both FDA and EAS to better the greater good.

On the FDA front:

Most significantly for FDA, Scott Gottlieb was confirmed as the new Commissioner. Under his guidance a number of initiatives are underway in all regulated industries, with some specific highlights in pharma, medical device and food mentioned here.

In the area of pharmaceuticals, the compliance date for Drug Master File electronic submissions was extended until May 5, 2018, giving a bit more time for the industry to get a handle on this complicated process. EAS, which has long assisted pharma manufacturers in technical review of stability data and assembling applications and reports added the additional service of electronic filing preparation and submission over two years ago in anticipation of FDA’s move to this requirement. Those firms who have not already updated their processes to e-CTDs, as they are commonly called, should be fully engaged in doing so now.

The Class II Medical Device industry had a reprieve in July when FDA published a sizable list of class II medical device products that no longer require premarket notification under section 510(k) of the FD&C Act (21 U.S.C. 360(k)), to provide reasonable assurance of safety and effectiveness, subject to certain limitations. Medical device 510(k) filings are a laborious process with many confusing elements. Readers may wish to refer to our August 2017 EAS-e-News issue of the month article, where Independent Consultant Joe Ouellette, discussed some ways to simplify the process. If your company requires 510(k) filling assistance, EAS has many medical device experts who can help with these requirements.

The U.S. Agent verification for medical device facilities process saw a change in October whereby U.S. Agents must now confirm with FDA their consent to act in that role. EAS provides U.S. agent services to countless foreign clients. This is not only an FDA requirement, EAS prides itself on providing comprehensive services in this area with open and free flowing communication between the client and FDA as well as answering questions on various FDA matters which can be confusing. In EAS, foreign firms have a dedicated liaison with the agency.

On the Food Safety Modernization Act front, new enforcement requirement deadlines continued to move forward. May 30 was the deadline for food importers to notify FDA whether their products are subject to FSVP regulations. Our Independent Advisor for FSMA, Charles Breen, writes a monthly column on the latest requirements for EAS-e-News, called FSMA Perspective and we have offered numerous webinars on the various requirements, free replaysof which can be found on our website. You may also be interested in our handy digital FSMA Pocket Guide, downloadable and searchable for easy reference on the go.

A significant change for food manufacturers was a 1.5-year extension of compliance dates for new requirements for updated nutrition information on food labels, including dietary supplements. Public comments were requested through November 1, 2017 on various considerations such as the definition of a single-serving container; a dual-column labeling for certain containers; reference amounts customarily consumed (RACCs); and amending the label serving size for breath mints. Even with this extension, EAS saw record numbers at our recently held Food Labeling Compliance Seminar and continues to provide in-house trainings on the subject as well – an indication that the industry at-large is preparing for compliance in advance of FDA’s deadlines.

On the EAS front:

EAS has seen fantastic growth in the past year. With new regulations and requirements set forth by the agency, novel technologies and products requiring the design and review of stability studies, toxicology, data review and statistical analysis prior to highly technical application submissions, FDA regulated industries have sought our support in meeting these requirements. Through outsourcing expertise to firms such as ours, companies are able to enhance their technical capabilities in a cost effective manner.

To meet these demands, EAS gained two new director level positions, welcoming Allen Sayler as Senior Director, Food and Cosmetics Consulting Services in January. His addition to EAS senior management greatly increased our competencies into the dairy industries. Tara Lin Couch, Ph.D., became Senior Director Dietary Supplement and Tobacco Services in August. Tara’s expertise in the dietary supplement industry has been well known to our clients since 2012 when she first joined EAS as an Independent Consultant. She was appointed to the position of Independent Advisor for Dietary Supplements in 2015. Timothy Stewart, Ph.D. accepted the role of Independent Advisor for Dietary Supplements in October. EAS also added 33 new Independent Consultants, accomplished experts in their fields who have hit the ground running in support of our clients and training initiatives.

We also expanded our partnerships through a relationship with Almater Food Technologists based in Italy. This unique collaboration will enhance the ability of EAS clients who seek assistance in exporting foods into the EU as well as Almater’s clients who seek additional assistance with FDA compliance.

Our Product Development and Labeling Strategic Services initiative, started in 2016, saw huge growth as companies continue to seek advice on how to position their products and guidance on the proper use of various claims such as “healthy”, “natural” and GMO labeling. The success in this area has led to the creation of additional specialized teams of independent consultants who can address client needs requiring multiple areas of expertise.

EAS greatly increased our training capabilities in 2017. Our Food Labeling Compliance seminar was awarded 16 CEUs by the prestigious Commission on Dietetic Registration, lending further credence to the quality of our long running program, and providing an additional service to those participants who seek continuing education credits. We are proud that a number of our Independent Consultants are Lead Instructors for Preventive Controls for Human Foods (PCHF) under the Illinois Institute of Food Technology’s Food Safety Preventive Controls Alliance, and for the Foreign Supplier Verification Program (FSVP) under the International Food Protection Training Institute. EAS also became a training center for the Safe Quality Foods (SQF) 8.0 and Quality courses under the Safe Quality Foods Institute. Finally, Allen Sayler’s popular Dairy Processing 101 three-day seminar has become a new fixture in the EAS training center.

Finally, EAS was honored to be invited presenters at over 30 trade organization conferences and tradeshows and webinars for outside organizations. From the Institute of Food Technologists (IFT), Food Drug Law Institute (FDLI) Consumer Healthcare Products Association (CHPA), National Customs Brokers and Forwarders Association of American (NCBFAA) and the Safe Quality Foods (SQF) our Independent Consultants and home office staff are well recognized and sought-after experts in their areas.

As we look towards 2018 we are anticipating more movement by FDA in areas such as tobacco as the agency seeks input on its new initiative of pursuing lower nicotine levels in cigarettes to non-addictive levels and create more predictability in tobacco regulation. EAS is one of very few consulting firms to offer comprehensive services to the tobacco industry and we take an active role in the trade organization the Tobacco Manufacturers Association.

As always, EAS stands at the forefront of tracking industry regulations and applying those requirements in a practical and meaningful way for clients. We take great pride in our expertise and ability to provide quality regulatory assistance. We welcome your inquiries as to how EAS may help your business and above all wish you a happy and prosperous 2018.

A Look at the Regulation of OTC Sunscreen Formulations

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The process of developing and testing a sunscreen is not unusually difficult but it does require close attention to the regulations and coordination with the testing laboratory preparing the efficacy data.

Sunscreens may be part of a cosmetic line and those that are intended to provide protection from incidental sun exposure during the normal day’s activities are often called “cosmetic sunscreens”. On the other hand, sunscreens intended to provide protection from prolonged sun exposure activities such as beach, pool, or other activities where sun exposure is high and resistance to water or perspiration is required. These products are often called “active or sport” formulations. The formulation requirements for each class are slightly different but the underlying regulations for the products are the same.

In the United States, sunscreens and several other categories of functional products are regulated under the over-the-counter (OTC) drug regulations of the Food and Drug Administration (21 CFR 352). These regulations define the allowable active ingredients (termed UV filters) and their maximum use concentrations, the performance testing required to establish the efficacy of the product (SPF, Broad Spectrum coverage, and water resistance), and labeling of the product.

An important concept of the OTC program is that the active ingredients used in the formulation will be considered safe provided that the regulations are followed. Therefore, the individual new formulation does not require approval from FDA. The specific OTC drug regulations for sunscreens are unique to the United States, but many of the same principles apply in many markets. In the European Union, sunscreens are regulated as cosmetics (for labeling) but certain restrictions for active ingredients and testing apply.

In all major markets, the active ingredients that can be used as UV filters are prescribed by positive lists (that is, only ingredients on the specific list for that market may be used). The maximum concentration of each active ingredient is also indicated. These lists for both specific ingredients and maximum concentrations are not the same across markets. Thus, a product prepared for one market may well not be acceptable in another. For example, the United States has a shorter list of approved UV filters than does the EU and so many EU products are excluded from the U.S. market.

A functional sunscreen formulation is not simply the sum of its active ingredients. If it were, efficacy testing would be rather easy. The remaining ingredients, termed inactive ingredients under the regulation, are essential not only for the aesthetics of the product but for its efficacy as well. To function effectively, the formulation must hold the UV filters in a film on the surface of the skin. The film holds the UV filters to form a “tortuous path” through which the UV light must pass. The filters scatter and absorb the UV light attenuating exposure to the skin below. Since the surface of the skin is not flat, the formulation must form a film that can cover the skin peaks and valley to block the UV light.

While the formation of a surface film is required for function, it can impact product esthetics. Cosmetic sunscreens, such as facial moisturizers, are intended for incidental UV exposure with limited water or perspiration exposure. These products may be successful with less robust film former. Active or sport formulation require considerable water resistance (once they have dried on the skin) and so need more robust, less water-soluble film formers.

In summary, to ensure regulatory compliance of OTC sunscreen formulations, it’s important to closely follow the regulatory and testing requirements.

U.S. Dairy Industry Challenge – How Many Food Safety Plans Are Enough?

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The U.S. dairy processing industry is facing a significant challenge as it moves toward compliance with the FDA Food Safety Modernization Act (FSMA). This is best captured by a conversation I had with a corporate quality assurance vice president about six months ago. When asked how many written food safety programs each of the dairy plants in his company had, the reply was, “Because of the current regulations, private certification systems, customer expectations and our own corporate food safety requirements, the number ranges between three and five per plant.

I asked how they could manage this number of different food safety programs, which one(s) the plant employees were trained on and how they kept the records required for each written food safety program separated and organized. While he may have had a solution, he did not provide an answer to my question. The challenge is exactly that; with so many demands on dairy plants today to operate in a multi-jurisdictional government world, a multiple customer world and competing, private food safety standards, can one written food safety program meet the requirements for all these different parties?

For many U.S. dairy processing plants, because of industry consolidation, their compliance enforcement deadline for the FSMA “Preventive Controls for Human Foods (PCHF)” regulation was September 2016. The regulation mandates a written food safety program that requires a risk-based hazard analysis incorporating “preventive controls” and development of a supply chain management program. Also, this regulation mandates radiological hazards be considered. The preventive controls program is to be supported by compliance with updated Good Manufacturing Practices (GMPs) found in 21 CFR 117, Subpart B. We will call this “Written Food Safety Plan #1”.

Starting in 2008, many larger dairy companies rebuilt their written food safety programs to comply with the requirements found in one of the Global Food Safety Initiative’s (GFSI’s) recognized third-party food safety certification schemes such as Safe Quality Foods (SQF), the British Retail Consortium (BRC), FSSC 22000 and the International Featured Standard (IFS). While the four GFSI schemes have differences, they all require a written food safety program that utilizes prerequisite programs to support the written HACCP Plan. The hazard analysis part of the HACCP Plan is supposed to incorporate “risk” into the decision-making process but does not require any recognition of potential radiological hazards. The GFSI schemes utilize specific prerequisite programs instead of GMPs to receive their certification. We can designate this as “Written Food Safety Plan #2”.

In May 2017, the U.S.-based National Conference on Interstate Milk Shipments (NCIMS) adopted the most significant changes for Grade “A” dairy plants since the early 1990s. These changes are likely to be accepted by the FDA in October 2017 and enforced in all “Grade A” dairy plants by October 2018. The new requirements will require a FSMA “Preventive Controls-like” written food safety program that will be evaluated by trained FDA Regional Milk Specialists once every three years, in addition to the routine GMP-like state inspections required once every three months. These NCIMS changes are similar, but not the same as required in the FSMA Preventive Controls regulation, with the FDA GMP requirements being somewhat superseded by the NCIMS Pasteurized Milk Ordinance (PMO) dairy plant operational requirements. In addition, the Preventive Control supply chain management requirements were modified to recognize the NCIMS strict requirements for utilizing only raw milk from Grade “A” licensed or permitted dairy farms and dairy ingredients from Grade “A” dairy plants. We recognize this as “Written Food Safety Plan #3”.

Finally, many large dairy companies have mandated policies and procedures on the content and details for a dairy plant’s written food safety plan. These mandated policies and procedures are “enforced” via corporate-based or private auditing companies hired to conduct plant-by-plant assessments. We can call this “Written Food Safety Plan #4”.

The problems related to multiple and possibly competing written food safety programs in dairy plants are significant. First, most dairy plants are challenged, like any food processing plant, with managing one written food safety plan. So how does a plant maintain and implement multiple written food safety programs? Second, how does plant management decide on the instructions and training for the plant staff that are responsible for delivering a safe finished product, based on multiple written food safety plans? Third, most plants are resource-challenged to support one written food safety plan, so where do the resources come from to maintain, implement and train staff on multiple written food safety plans?

A “revolutionary” process is required for a dairy plant with up to four different food safety programs to consolidate into one which contains the key requirements in one written food safety plan. This consolidated plan needs to use hybridization techniques to achieve a “Best in Class” food safety program. Such hybridization in nature many times produces much stronger off-spring with unique and new abilities to meet the challenges of the real world. This is the expectation for the “hybridized”, consolidated written food safety plan that will replace the multiples.

In conclusion, dairy plants need to conduct a hybridization exercise to move toward one “Best in Class” written food safety program that meets or exceeds government, private certification, customer and internal corporate requirements.

With more than 150 independent consultants, EAS has the expertise to assist any dairy plant or company in developing a “Best in Class” hybridized written food safety program. For more information, please contact Allen Sayler, EAS Senior Director of Food and Cosmetic Consulting Services at 571-447-5509 or via email at asayler@easconsultinggroup.com.

Tips for Auditing a Contract Laboratory

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Contract laboratories provide an extremely valuable and necessary service to the dietary supplement industry. The own-label distributor or manufacturer rarely has an in-house laboratory equipped with the appropriate scientific expertise to conduct all the testing required in 21 CFR 111, Current Good Manufacturing Practices (cGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements.However, a contract laboratory must be thoroughly scrutinized by the own-label distributor or manufacturer to ensure the laboratory complies with the applicable subparts of 21 CFR 111.

All personnel must possess the education, training, or experience needed to perform their job function in accordance with 21 CFR 111.12(c). Responsibilities and activities for each job function should be described in a formal job description. A comparison of the job description to on-the-job training provided in a personal training record as well as a resume or biography of several selected individuals should be examined during the audit to verify compliance with the regulatory requirements, but also ensure the laboratory has the scientific expertise to competently perform the desired tests.

The laboratory facility used to perform testing must be adequate per 21 CFR 111.310 and in accordance with 21 CFR 111.27, all equipment must be of appropriate design, construction, and workmanship to enable them to be suitable for their intended use. The latter is generally accomplished using an equipment qualification program. Documentation supporting the qualification of several different types of equipment should be reviewed during the audit. Part of the review must include an assessment of any software or electronic operations being performed by the instrumentation.

All electronic equipment and records must comply with the requirements dictated in 21 CFR 11, Electronic Records, Electronic Signatures. Equipment must then be calibrated and maintained at a frequency dictated by the manufacturer to maintain accuracy and precision and these activities must be documented in equipment log books as governed by 21 CFR 111.35(b)(3).

All laboratory controlled processes, including written procedures for test methods, must be developed and implemented in the laboratory as required by 21 CFR 111.325. There must be evidence that these test methods are being conducted, as written, by laboratory personnel and that this is documented at the time of performance. The documentation must be thorough and detailed and include the performance of each step of the method. Test methods employed must be scientifically valid as required by 21 CFR 111.75(h)(1) and 111.320(b).

The FDA described a scientifically valid test method as one that is accurate, precise, specific for its intended purpose, and consistently does what it is intended to do (rugged). Documentation that a method meets these criteria is accomplished from method validation studies for the sample matrix via experimentation, peer-reviewed literature, or compendial sources. Several examples of such documentation should be reviewed by the auditor.

Other critical laboratory controlled processes to examine during a contract laboratory audit include those for out of specification (OOS) investigations, deviations, and corrective and preventative actions. These situations are inevitable and a strong quality system must be in place for handling them.

There are many important aspects to choosing a contract laboratory, from assessing testing and record-keeping to confirming it is equipped and suitable for its intended use. A pre-audit of a contract laboratory helps to ensure that their procedures match those required by FDA as well as your own internal requirements. This up-front work will go a long way towards finding the right partnership to enable distributors and manufacturers to market safe products.

Changes in What Constitutes ‘Dietary Fiber’ for Nutrition Facts Labeling May be in the Works

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One of the more controversial aspects of the FDA’s final rule on revising the Nutrition Facts Panel (NFP), 81 Fed. Reg. 33742(May 27, 2016), changes the definition of “Dietary Fiber” as it is disclosed on the NFP.

The new rule requires that only certain naturally occurring dietary fibers such as those found in fruits, vegetables and whole grains, and added isolated or synthetic fibers that FDA has determined have a physiological effect that is beneficial to human health, can be declared on the NFP under “Dietary Fiber.” Previously, fibers in foods could be labeled as dietary fiber without necessarily providing evidence of beneficial physiological effects.

Under the final NFP rule, a fiber ingredient that is “intrinsic and intact in plants” automatically meets FDA’s new dietary fiber definition. In addition to fiber that is naturally occurring in foods, the final regulation identifies seven isolated or synthetic non-digestible carbohydrates that, when added to foods, can be declared as “Dietary Fiber.” They are: [beta]-glucan soluble fiber (as described in 21 CFR 101.81(c)(2)(ii)(A)), psyllium husk (as described in 21 CFR 101.81(c)(2)(ii)(A)(6)), cellulose, guar gum, pectin, locust bean gum, and hydroxypropylmethylcellulose.

But other fibers that are “isolated” or “synthetic,” must gain FDA approval and show they have a beneficial physiological effect before they can be counted as “Dietary Fiber” on the NFP. Under the final rule, food manufacturers can submit petitions to FDA for approval of additional sources of “Dietary Fiber” with physiological benefits and many have done so already.

FDA reacted by publishing a request for scientific data, information and comments to help it determine whether certain fibers should be added to the definition of “dietary fiber” published as part of the NFP final rule.

The request for information, along with an accompanying draft guidance, is intended to help industry understand how FDA reviews the scientific evidence to determine whether other fibers beyond the seven identified in the final rule should be added to the regulations. It also provided an opportunity to add to or comment on FDA’s review of the science with respect to whether any of the 26 additional specific types of fiber provide a physiological effect that is beneficial to human health and thus should be included in the fiber definition. The comment period closed on February 13, 2017.

Some segments of the food industry remained unsatisfied. On April 7, 2017, the American Bakers Association (ABA) filed a petition urging the agency to revoke its new definition of “Dietary Fiber” for Nutrition Facts labeling purposes. Whether the ABA’s request will receive serious consideration remains to be seen.

On June 13, 2017, FDA’s Office of Nutrition and Food Labeling announced that it intends to extend the compliance date for the new Nutrition Facts rules. ABA praised the move. But how long the compliance date will be extended and whether FDA also will reconsider certain aspects of the regulation are unknown. FDA Commissioner Scott Gottlieb stated before a Senate Appropriations Sub-Committee hearing on June 20, 2017, “We are not reopening the regulation…We are just using this time to develop additional guidance documents.”

Whether industry dissatisfaction with FDA’s final regulation on the disclosure requirements for “Dietary Fiber” on the Nutrition Facts label will lead to a wholesale change in the agency’s approach, or merely the addition of a few more substances to its list qualifying as having beneficial physiological effects, remains to be seen. But some changes can be expected.

Process Labeling – Pathway to Transparency?

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A thirty-year old federal court opinion that is well known to students of food and drug law holds that in the absence of a detailed, Congressionally mandated definition, courts and regulators should follow the common understanding of “food” as an article that delivers “taste, aroma and nutrition.” In the 21st century, however, food not only nourishes and satisfies, it also frequently makes a statement — about how it was made, where it came from and how the earth and its inhabitants were treated along the way.

Foods with these sorts of claims – called “Process Labeling” — are everywhere. Even on a casual trip to the supermarket, it’s hard to miss the increasing use of labels claiming that a food is “certified organic,” “shade-grown,” “free-range,” or “rain forest certified,” to name but a few. Process labeling is oftentimes also about what was notdone to a food. For example, “Non-GMO” indicates that the food used no ingredients made from genetically modified organisms, or “GMOs,” shorthand for the agricultural bioengineering methods that have helped farmers grow corn, soybeans and other cash crops.

Consumer Appeal

Food marketers today, as one of them recently told me, need to appeal to consumers’ desire to know about the “genealogy” of a food. Of course, this interest is relatively new but growing exponentially and to a very real extent can be attributed to the fact that food in the United States is by and large safe, plentiful and relatively inexpensive. Two authors who have studied communication in modern agriculture explained the phenomenon this way:

As top concerns for consumers are already largely being met, there is a freedom that was not historically available to delve deeper into food issues, to ponder how food was grown and raised and to think about these matters while waiting to check out. Consumers are not wrong for doing this; it is a fundamental right of the consumer to question.

— The Communication Scarcity in Agriculture, J. Eise, W. Hode (New York, N.Y. 2017) at p. 46.

Consumer concerns over the impact of modern food production on health and the environment have helped drive the popularity of Process Labeling. The Council for Agricultural Science and Technology, a nonprofit scientific organization, recently assembled a cross-functional panel of experts to assess the phenomenon and make policy recommendations. The panel concluded:

Under appropriate government oversight, these ‘process labels’ can effectively bridge the information gap between producers and consumers, satisfy consumer demand for broader and more stringent quality assurance and ultimately create value for both producers and consumers.

The mounting popularity of Process Labeling is readily apparent. In the U.S., consumer purchases of organic products have reached record levels, amounting to over $43 billion last year, and up 11% over the previous year. The demand for environmental or “eco” labeling is robust, with more than 460 different labels relating to 25 industry sectors now in use in nearly 200 countries. Food companies are embracing Process Labeling in the name of “transparency,” with many committing to provide more information – via labeling – about how food is produced.

Execution Challenges

While Process Labeling has great appeal and potential utility, execution can be difficult for three reasons.

First, such labels require a “process” clearly defined by a standard fixed either by the government or a well-established, independent agency. The standards for organic farming set by the National Organic Program are the leading example of such a third-party standard.[1] USDA’s systems of grading meat, poultry, butter and eggs, and requiring Country of Origin Labeling (“COOL”) are other examples of clearly defined process standards. Sellers, buyers, trade groups and industry associations have also established quality standards and guidelines against which Process Labeling claims can be assessed.[2] However, it is hard, if not impossible, to find widely accepted, well-established definitions for some of the most popular process claims such as “cage-free,” “grass-fed,” “free range,” “naturally raised,” and many others.

Second, even with a defined standard, substantiating Process Labeling claims can be challenging, especially for large-scale operations with far-flung suppliers. Adequate substantiation requires supply chains operating under strict control, with rigorous oversight and continuous monitoring. The food producer must maintain strong and transparent supplier relationships and check in frequently to assure that the operation is running as agreed and without errors or gaps. Independent verification is helpful, and producers can obtain that kind of help from the USDA’s Agricultural Marketing Service, which provides a wide variety of independent verification services through its Process Verified Program (“PVP”), a voluntary, user-fee-funded program. The PVP uses highly trained auditors to conduct inspections, review processes and documentation and thereby assure that a producer is adhering to the standards supporting the process claim.

Third, Process Labeling can send inferential messages about health or well being that can be highly misleading without prominent disclaimers or other disclosures. The Federal Food, Drug, and Cosmetic Act (“FFDCA”) provides that a food is misbranded if its labeling is “false or misleading in any particular.” The FFDCA has long been interpreted as holding a producer strictly accountable for the claims made in labeling. This includes accountability for omissions, as the FFDCA empowers FDA to find a label misleading if it fails to reveal facts that are “material” in light of the representations that are made for the product.

GMOs are a case in point. A recent consumer survey concluded that an overwhelming majority of consumers worldwide think non-GMO foods are healthier than foods made with GMOs. However, FDA has found no scientific basis to require labeling because GMO foods are safe and not materially different from non-GMO foods. Now consider whether the following claims should appear right alongside each other on a food’s principal display panel:

Healthy / Non-GMO

Is this lawful? Or does the implication that non-GMO foods are healthier violate the FFDCA by failing to disclose the scientific consensus that GMOs are safe and that avoiding them does not brings a health benefit? Information necessary to avoid misleading consumers should be provided at the point where the claim is made. In this case, the label should have noted the FDA’s position on the same panel, or at least on an adjoining one.

Conclusion

Process Labeling can inform consumers about the origins of their food and the methods by which it was produced, and in doing so promote a sense of interconnectedness and a better understanding of agriculture. However, such labeling requires clearly defined standards and significant investments in supply chain oversight and monitoring. Process Labeling claims can mislead consumers about benefits where none exist.

The CAST panel, while seeing the upside of Process Labeling, recommended strict regulation. Labelers should explain the scientific significance of the process (“GMO corn for reduced pesticide use”) and disclose when there is no benefit (“rBST-free / No significance difference has been shown in milk from non-rBST cows”). Such standards of care can certainly help unlock the potential of Process Labeling to educate consumers and help them feel just a bit closer to their world and the ways in which their food is made.

EAS Offers U.S. Agent Services for Foreign Companies

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The FDA’s regulatory requirement for foreign firms to have a U.S. Agent can be confusing, to say the least. There are very specific requirements for foreign firms to have a U.S. Agent, and failure to have a competent and responsive U.S. Agent can cause significant compliance issues, delays in applications and submissions and can even impact the importation of their product into the United States. The information below is provided to offer clarity to these requirements and help firms understand this area of the FDA’s governing requirements.

For FDA purposes (as defined in section 201(e) of the Federal Food, Drug, and Cosmetic Act), a U.S. Agent means a person who is physically residing or maintaining a place of business in the United States. A U.S. agent cannot be in the form of a mailbox, answering machine or service, or another place where an individual acting as the foreign facility’s agent is not physically present. U.S. Agent is not the same as a shipper’s U.S. Agent for CBP (Customs and Border Patrol).

What does a U.S. Agent do? Your appointed U.S. Agent will become your firm’s first point of contact with the FDA. They will facilitate communications between your company and the FDA in the area of applications, site inspections, regulatory notifications and resolution of formal compliance concerns (FDA 483s and Warning Letters).

This is particularly beneficial when time zones put your normal operating hours out of synch with the FDA’s routine working schedule. For all human and animal drug application holders and sponsors (DMF, VMF, NDA, BLA, ANDA and NADA, etc.) the U.S. Agent can work to assist and coordinate the migration to electronic submission filing submitting your Amendments, Supplements, Annual Reports, LoAs, etc. via the FDA ESG system.

The FDA eCTD requirements for submissions to CDER and CBER went into effect May 5, 2017, for NDAs, ANDAs and BLAs and will go into effect May 5, 2018, for DMFs and INDs. Submissions of 10 GB or smaller MUST be sent via the FDA ESG. After these dates, only submissions greater than 10 GB will be accepted via physical electronic media.

Who is required to have a U.S. Agent? All foreign establishments and firms who wish to ship their products into the U.S., firms who have an active regulatory submission or are required to be registered with the FDA are expected to have an appointed U.S. Agent. This includes any drug product applications (INDs, NDA, ANDAs, BLAs, NADAs, DMFs, VMFs, etc.) whether pending or approved, the distribution of drug substances, intermediates and finished dosage forms into the U.S. for either commercial or research and development purposes.

A U.S. Agent must be identified for every single foreign facility registration. This includes food facilities (21 CFR 1.232 (d)) under which dietary supplement facilities fall (21 CFR 1.227), drug establishments (21 CFR 207.40 (c)) and medical device facilities (21 CRF 1.232 (d)). A U.S. Agent appointment is required for all ANDAs (21 CFR 314.95(7)) and NDAs (21 CFR 314.52(7)) as well as foreign color manufacturers (21 CFR 80.21(d)). It is highly recommended, although not necessary, to have a U.S. Agent appointed to your DMFs. While INDs do not require a U.S. Agent, it is certainly beneficial to have one.

When is a U.S. Agent required? The U.S. Agent must be appointed before any registration, application or communications with the FDA can begin. As a foreign firm, at the time of registration and listing, you will be asked to provide the name and contact information for your U.S. Agent. Likewise, at the time of submission of any application to CDER, CBER, CDRH, an appointment letter must accompany each specific submission and be on file with the FDA to facilitate any communications.

EAS Consulting Group offers the full breadth of U.S. Agent services to clients around the globe and we are prepared to assist you with meeting the regulatory requirements in this area. Let us know how we can help you.

The Food Processing Industry’s Newest Challenge: Safe Quality Food’s Edition 8.0

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The Safe Quality Food Institute (SQFI) is coming close to releasing its long-anticipated Edition 8.0. While many things could change during the final review and “sign-off” by the SQFI Technical Advisory Committee and SQFI staff, it is likely that the new SQF Edition 8.0 will have the following formatting and content changes. Some of these changes make the new Edition 8.0 more closely aligned with the FDA’s Preventive Controls for Human Foods (PCHF) regulation.

SQFI has indicated that Edition 8.0 will be enforced by SQF certification bodies six months after the implementation date (expected April 1, 2017). If SQFI meets its final publication schedule, all SQF-certifications after October 1, 2017 will have to have incorporated all Edition 8.0 changes.

Formatting Changes:

  1. Edition 8 has divided the food safety requirements in Edition 8 into specific food sectors as follows:
    • SQF Food Safety Fundamentals (applies to all food processors)
    • SQF Food Safety Code for Primary Production
    • SQF Food Safety Code for Manufacturing
    • SQF Food Safety Code for Storage & Distribution
    • SQF Food Safety Code for Food Packaging
    • The SQF Retail/Wholesale Grocery Code
    • The SQF Quality Code (Formerly Level 3)
  2. All food quality requirements have been incorporated into a separate “SQF Quality Code” and all previous food safety items have been relocated into the specific “SQF Food Safety Codes”.

Specific Operational or Substantive Changes:

  1. Levels #1, #2 and #3 have been eliminated.
  2. A food processor may forgo the unannounced certification audit once during each three (3) year cycle and voluntarily choose to move to annual unannounced recertification audits. Locations with annual unannounced recertification audits shall be recognized on the SQFI Certificate as an “SQFI Select Facility.”
  3. All products produced, stored or processed on site shall be included on the site’s certificate, unless exempted. The site must demonstrate that exemptions that are either site or product specific as part of the scope of certification do not put certificated product at food safety risk.
  4. The requirements for a food processor’s “Environmental Monitoring” have been expanded, similar to the FDA FSMA “Preventive Controls for Human Foods (PCHF)” requirements:
  5. SQFI and the certification body must be notified by the food processor in writing within 24 hours of becoming aware of a food safety problem that requires public notification. SQFI can be notified at foodsafetycrisis@sqfi.com.
  6. The site and the certification body shall agree on the audit scope before the certification audit begins. The agreed upon audit scope cannot be changed once the audit has commenced.
  7. The certification body must advise the supplier (food processor) of the name of the SQF food safety auditor at the time that the SQF audit is scheduled.
  8. In instances where a food processing plant has some operational written procedures or records kept or managed by the corporate office, the SQF audit may need to be conducted at the corporate office location as well as at the food processing plant location.
  9. The definition of “critical nonconformity” has been slightly expanded to include the failure to meet food safety regulations such as state, USDA or FDA regulatory actions.
  10. The section on “Food Defense” is now titled “Food Defense and Food Fraud”.
  11. Significant new requirements on allergen management have been added, consistent with the FDA FSMA “PCHF”.
  12. If a food processor chooses to not implement any Module 11 GMP-like requirements, the reason for not implementing must be submitted in writing to the certification body prior to the audit.
  13. Water requirements have been strengthened. Water stored on-site must be routinely monitored and water used as an ingredient in processing or for equipment cleaning and sanitizing must be treated, with water microbiological samples be taken annually.
  14. Lighting in food processing and handling areas and at inspection stations shall be at an average illuminance of 200 lux, or as required by applicable regulations.
  15. A current list of all chemicals used in the food processing plant is now a requirement.
  16. All ventilation equipment and devices in product storage and handling areas shall be adequately cleaned to prevent unsanitary conditions.
  17. There are significant new written and operational requirements related to maintenance of the processing facility and processing equipment.

For more insight on the new SQFI Edition 8.0, contact Allen Sayler, EAS Senior Director of Food & Cosmetic Consulting Services at 571-48-5509 or asayler@easconsultinggroup.com.

EAS Consulting Group is a licensed SQFI Training Center and has scheduled SQF Edition 8.0 training sessions. EAS can also provide on-site SQF-based assessments by SQF-registered consultants.

Understanding the Drug-Cosmetic Conundrum When Marketing Your Products

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Products marketed as cosmetics can easily find themselves the target of FDA compliance action based on improper claims and statements.

FDA is charged with enforcing the laws and regulations that ensure the safety and labeling of products, including cosmetics, that account for 20 – 25 % of all U.S. consumer spending.

Cosmetics were first regulated under the 1938 Federal Food, Drug and Cosmetic Act (FFDCA). They are defined as “(1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles…”.

By comparison, drugs are defined as articles (1) intended to treat or prevent disease or (2) that affect the structure or function of the body. Cosmetics are products that provide mostly superficial effects that do not include “nutrition” as with foods or that “treat or prevent disease or affect the structure or function of the body” as with drugs. Because of the narrow definition and generally low safety risk for cosmetics, they can be marketed, with the exception of color additives, without pre-approval by FDA.

As with all products regulated by FDA, cosmetics must be safe and properly labeled. A cosmetic is considered unsafe (adulterated) if (among other things) “it bears or contains any poisonous or deleterious substance which may render it injurious to users under the conditions of use prescribed in the labeling thereof, or under such conditions of use as are customary or usual…”. Also, cosmetics must be labeled in accordance with the applicable laws which include the FFDCA and the Fair Packaging and Labeling Act (FPLA).

Under this regulatory framework, a product can be classified as both a drug and a cosmetic. Product classification depends on the intended use which is determined based on claims made for marketing the product and whether or not the statements fit the definition for cosmetics and/or drugs. Because of the difference in the regulatory schemes for cosmetics and drugs, FDA has sought over the years to make sure that a marketed product stays within the established boundaries that apply. For example, a cosmetic may not make claims that the product will treat and prevent a disease or alter the structure or function of the body.

So how does one tell what claims pose a risk that a product will be classified as a drug and subject to FDA compliance action? This is a complicated question and there are no quick, easy answers. Product classification does not necessarily depend on the presence of a single word or phrase and FDA will typically make a determination based on all product statements and representations or “claims” taken together. FDA’s Warning Letters provide the most readily available source of information on claims.

Let’s look at what types of claims are problematic based on recent warning letters. Many problem claims relate to a structure or function of the body (skin) which is appropriate for a drug rather than a cosmetic.

A warning letter dated October 18, 2016, based on an establishment inspection and a website review, noted:

  • The product label said, “It stimulates cell-cell interaction, assists in the formation of collagen, and increases skin elasticity…”
  • The website included the claims “Stimulates cell-cell interactions, and accelerates cell renewal” and “Helps to preserve cellular energy, assists the formulation of collagen and strengthens in structural proteins”
  • The product insert included the claims “[I]nduces signal transduction…reconstructs protein structure…acts as a topical Botox…”, “[S]timulates cell respiration and increases cell turnover.”, “[A] biosafe alternative to Botox, it relaxes muscle contraction…” and “Increase Microcirculation”.

A warning letter dated September 20, 2016, based on a website review, cited the following claims:

  • “Lemon, a powerhouse of vitamin C…with its antibacterial properties, and boosts collagen production…It also lightens age spots…”
  • “By increasing blood flow…”
  • “Organic shea butter is a powerhouse… has natural anti-inflammatory properties that can take the sting out of insect bites.”

A warning letter dated April 14, 2016, based on a website review, noted:

  • The product website included the claim – “Removes Wrinkles Instantly”
  • Product Ingredient Claims – “Tests using a 0.5% concentration of the culture have shown a clear reduction of uneven pigmentation and obvious lightening if the skin.”
  • “A super anti-oxidant …eliminates age spots, contains protection from ultraviolet A and B and boosts collagen synthesis.”

As you can see from these examples, products marketed as cosmetics can attract FDA compliance action based on improper claims and statements. The FDA issued more than 29 warning letters to cosmetic firms in 2016.

EAS labeling experts are available to assist with the regulatory compliance of claims for cosmetic products.

Using Temporary Marketing Permits for Food Products

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FDA food standards of identity are regulations that establish the names and define the basic nature of certain foods. Food standards prescribe, among other things, what ingredients are required or optional and may describe the manufacturing process when that process has a bearing on the identity of the food. If a food is labeled with the name that is included in a food standard of identity, it must comply with that food standard. If it does not meet the standard, it is a non-compliant food product.

So, how can you market foods that have food standards of identity if you want to use a new ingredient or new technology not included in the food standard? You have to either ask FDA to revise the food standard regulation or you must use a different name. However, if you want to use the name specified in the food standard regulation, you can still market a product that deviates from the food standard if you obtain a temporary marketing permit (TMP). A TMP is permission to market a food under a standardized name that deviates from that food standard of identity.

FDA recognized that prior to revising a food standard, market testing is needed to assess the feasibility of making the change and to test for consumer acceptance of the food. Therefore, it established procedures for TMPs that allow manufacturers to market test their products before a standard of identity is revised.

Manufacturers may request a TMP under regulations in 21 CFR 130.17. This regulation requires manufacturers to submit certain information with their application, including information about the applicant, a description of the deviation from the food standard, a statement on how the deviation is advantageous, and proposed labels for the food.

FDA will evaluate the information provided in the TMP application to see if any new ingredient is safe and determine whether the manufacturer has given a rational basis for the deviation from the standard. If FDA grants the TMP, it publishes a notice in the Federal Register granting the TMP for 15 months. The TMP will expire in 15 months from the date the product first enters interstate commerce, but can be extended by application to FDA. When applying for an extended TMP, the applicant must simultaneously submit a petition to revise the food standard regulation. If FDA grants the extension, it publishes a notice in the Federal Register and invites other interested parties to market the product. This extended TMP is in effect until FDA makes a ruling on the petition to amend the food standard.

It is important to note that FDA thoroughly reviews the TMP to determine if there is a rational basis for the deviation and that consumers are not misled by the name or label. FDA also reviews the labels for compliance and needs to accept the labels prior to granting the TMP. Receiving a TMP is an important step in revising food standards to address innovation. EAS consultants are available to assist manufacturers in applying for a TMP.

Recent Developments in EU Food Regulation

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As part of a new series in EAS-E-News on services provided through EAS partnerships, Italy-based food technology and consulting firm Almater shares the following insights on regulatory developments in the EU in the area of foods, including so-called novel foods.

The European Union has significantly revised its legal and regulatory framework for novel foods in recent years, as well as its requirements for labeling, presentation and advertising of food.

The EU updated its 1997 regulation on novel foods with the adoption of a new novel food regulation (No 2283/2015) on November 25, 2015. The regulation, a centralized authorization procedure for novel foods at EU level, offered new provisions on nano-ingredients and on “insect-food,” and a simplified authorization procedure for “traditional products” from third countries. It also clarified requirements for food produced from cloned animals.

Under EU law, a “novel food” means any food that was not used for human consumption to a significant degree within the Union before May 15, 1997. Genetically modified foods fall within a different regulatory framework, as do food additives, enzymes, flavorings and extraction solvents. Some food categories may fall within the scope of the novel food regulation, requiring a prior-authorization to access the EU market. These include: food with a new or intentionally modified molecular structure (for instances a patented synthetic polymer); food from microorganisms, fungi or algae (such as extracts obtained from a mycelium cultivated in a submerged fermentation), food from plants or their parts, or from animals or their parts (for instances lipid extract from a specie of krill), food from cell culture or tissue culture (upcoming cultured meat, for example).

The novel food regulation also includes food consisting of engineered nanomaterials, food consisting of, isolated from or produced from material of mineral origin and food resulting from a new production process.

From January 1, 2018, the EU marketing authorization procedure will be centralized at the European Commission, which will evaluate novel food applications taking into account the European Food Safety Authority’s risk assessment and “other legitimate factors.” The current individual licensing authorizations will be replaced by generic permissions.

The novel food regulation allows applicants protection – for a limited time – for new scientific evidence and proprietary data provided in support of an application for inclusion of a novel food in the EU list. The regulation also includes a simplified authorization procedure for traditional foods from third countries that have historically proved safe for food use.

The novel food regulation includes a better definition and ad hoc provisions on nano-ingredients. As the term “engineered nanomaterials” is currently defined in Regulation (EU) No 1169/2011, nano-ingredients are considered novel foods under EU law. The Commission is called upon to reformulate this definition to reflect scientific and technological change and internationally agreed definitions. EFSA and EU Member State risk assessors are working to enforce scientific and regulatory framework on nanoscience and nanotechnologies in the food and feed chain. The novel foods regulation provides a clear opening for the use of whole insects and their parts in foods, if they pass an EFSA risk assessment.

Regulation (EU) No 2283/2015 entered into effect on January 11, 2016 and will become fully applicable from January 1, 2018, except for certain provisions.

EU regulatory framework on food information

The EU’s regulation on the provision of food information to consumers (No 1169/2011), which went into effect in December 2014, will be fully applicable from December 2016 for nutrition declarations on prepacked food.

A cornerstone of food labeling in the EU market, this regulation requires new mandatory information on allergens and nutrition. In addition, it includes new requirements for specific products such as nano-ingredients, refined oils/fats of vegetable or animal, de-frozen foods or formed fish/meat etc.

The regulation also broadens the role of the European Commission.

Drug Master File Submissions – An Overview

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(This article summarizes a White Paper on DMF submissions prepared by EAS Independent Consultant Albert Yehaskel.)

Drug Master Files (DMFs) are detailed submissions to the Food and Drug Administration (FDA) that may be used to provide confidential details about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. Submitted solely at the discretion of the holder, the information contained in the DMF may be used to support drug applications, supplements to applications, export applications or other DMFs.

Prior to creating and submitting a DMF, FDA requires the drug firm to request a Pre-Assigned Application Number. Once the number is assigned, the DMF may be pDrug Master File Submissions – An Overviewrepared and submitted to FDA. The file must include five core modules providing quality and manufacturing details pertinent to chemistry, manufacturing and controls (CMC) and non-CMC related information (facilities, manufacturing, processing, packaging, and storage requirements) of the drug constituent. Additional items to be included are Letters of Authorization (LOAs) for who may reference the DMF, a user fee form demonstrating proper payments have been made for the submission of the DMF and administrative information, such as contacts within the filing firm and assignment of a U.S. agent. It is important that all required information is accurate and current for the DMF to be active. Also, the holder must provide an annual report on the anniversary date of the original submission to maintain the DMF’s active status. To be accepted for consideration in the New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) in which it is referenced, the DMF must be current at the time of review.

DMFs are neither approved nor disapproved but are reviewed by FDA to determine whether the information contained is adequate to support a particular application which references it. Although the submission of a DMF is voluntary it can be a very important business tool, as it allows FDA to review claims of safety and quality of the constituent without revealing proprietary manufacturing information to another company using that constituent to manufacture a drug product. DMFs also accelerate FDA’s review process for Investigational New Drugs (INDs), NDAs, ANDAs and New Animal Drug Applications (NADAs). For this reason, the DMF must be continuously maintained and current at the time of FDA review and is an essential element in achieving a successful drug application, which can represent a multi-billion dollar profit potential for the drug product applicant.

Manufacturers with a large number of DMFs are often considered to be more reliable in terms of quality, regulatory standards, and capability to meet Current Good Manufacturer Practice (cGMP) requirements.

Effective May 5, 2017, FDA will require all DMFs to be submitted electronically through an Electronic Common Technical Document (eCTD) process submitted through FDA’s Center for Drug Evaluation and Research (CDER) Electronic Submissions Gateway (ESG). More details on the eCTD process can be found in the EAS white paper on DMF submissions as well as a previous EAS-E-News Issue of the Month article and background information on the EAS webpage. Should you or your company have questions on DMF submissions, LOAs or converting documents to the required eCTD process, please contact EAS to discuss your specific regulatory needs.

FDA Updates Regulations for Establishment Registration and Drug Listing

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Ten years after issuing proposed rules to amend and update regulations regarding establishment registration and drug listing, FDA published the final rule on August 31, 2016. The amendments update and clarify existing regulations and implement most of those proposed in 2006, and which were subsequently mandated by legislative changes to the Food, Drug and Cosmetic Act (FD&C Act), particularly those requiring electronic submissions. The effective date for updated regulations is November 29, 2016.

Here are some of the key changes and clarifications:

Definitions

  • Active pharmaceutical ingredient and Bulk drug substance are both included in the regulation to ensure conformity in terminology with the FD&C Act, but they have the same meaning.
  • Establishment registration number and Unique Facility Identifier (UFI) are two different numbers. The former is assigned by the FDA (upon a separate request) after an establishment is registered for the first time and is also referred to as the Facility Establishment Identifier (FEI). The UFI is the DUNS number that is included with the initial registration.
  • Content of labeling was added to describe what information needs to be included in that section of the drug listing submission for prescription, nonprescription, and animal drugs.
  • Private label distribution, Relabeler and Repacker were all added to the definitions as these functions have responsibilities that may have previously been unclear with regard to the registration and listing requirements.
  • Salvage/Salvager were added to the final rule to define activities surrounding segregation of products that may have been subject to adverse storage or handling conditions but for which a firm wishes to return them to the market.

Establishment Registration

  • Establishment registration is required for all foreign and domestic manufacturers, repackers, relabelers and salvagers (unless otherwise exempt as provided for in the regulation).
  • Private label distributors should not register any establishment (unless they also perform one of the functions above or are acting as an authorized agent on behalf of another establishment). They must, however, have their own labeler code.

Drug Listing

  • Registrants are responsible for listing each drug in commercial distribution, including those drug products that are marketed through a private label distributor.
  • While private label distributors are not responsible for listing their products, they may elect to do so if acting as an authorized agent on behalf of a registrant.
  • Drug listings must be submitted no later than three days after the initial registration of the establishment, although the FDA said that this time window relates to drugs for commercial distribution and will allow for situations where products that are held in storage for longer periods prior to launch do not require listing within that time limitation.
  • Registrants must review their drug listing information each June and December and either update it accordingly or certify that no changes have occurred. Registrants are additionally encouraged, but not required, to update drug listing information at the time changes are made, however these updates do not replace the June and December updates nor any “no change” certification.
  • Drug listing submissions must now include a complete listing of inactive ingredients and their corresponding Unique Ingredient Identifier (UNII) – this was previously optional. Registrants will need to ensure that their inactive ingredients are in FDA’s Substance Registration System so that the appropriate UNII can be submitted with the drug listing.

NDCs

  • The regulation allows for FDA to assign 6-digit labeler codes in the future. The product code and package configurations otherwise remain the same.
  • NDC numbers can be reserved as part of a drug application.
  • Changes that trigger a revision to the product code portion (i.e., middle segment) of the NDC were clarified. Although the proposed rule had included a provision such that changes to inactive ingredients would necessitate a new product code, this was not adopted in the final rule.
  • The FDA clarified the restrictions for using NDC numbers on non-drug products (e.g., dietary supplements, medical foods). Such representations render the product misbranded.

There were two major changes proposed in 2006 that were NOT incorporated into the final rule:

  1. FDA did not assume responsibility for the assignment of the complete NDC to a product, but will continue to accept the product and packaging segments of the NDC that are assigned by the manufacturer in the drug listing submission.
  2. Product labeling will generally not be required to declare human readable NDC numbers on drug labels, although FDA will continue to request their inclusion. However, an intervening statutory amendment, the Drug Supply Chain Security Act (DSCSA), does require NDCs to appear as part of the product identifier on certain drug labels.

The information above is not all-inclusive with regard to the establishment registration and drug listing requirements. Companies should review the entire ruling to ensure that their procedures are compliant with FDA’s expectations.

EAS Reaches Ten Year Milestone

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It is with great pride that I share EAS Consulting Group’s celebration of our milestone ten year anniversary!

Never had I imagined when I retired from FDA 22 years ago that I would own and operate one of the nation’s leading consulting firms that specializes in all FDA regulatory matters. I had no clue that when I acquired the food, dietary supplement and cosmetic services from Kendle International in 2006 that EAS would grow to offer regulatory assistance to all areas of FDA oversight, have access to the expertise of over 150 of the industry’s most qualified independent consultants and gain the trust of thousands of clients throughout the world.

I am truly privileged and humbled each day to work with companies large and small, from global leaders in the industry to a small mom-and-pop business just opening its doors. Navigating FDA’s, USDA’s and other federal and state agency’s many rules and regulations can be complex and we thank all our clients for trusting your regulatory assistance needs to EAS. We hope to continue to serve you long into the future.

As many of you know, EAS’s roots actually go back 1960 when Arthur A. Chechhi, a former FDA Associate Commissioner founded Arthur A. Checchi & Associates. After 25 years of service, Mr. Chechhi invited Tony Celeste, then a senior manager at FDA to assume the ownership and management of the company under the name of AAC Consulting Group (Mr. Chechhi’s initials). Tony and I were fellow analytical chemists at FDA’s New York District Office when we started our careers at FDA in the 60’s. When Tony asked me to join AAC in 1994 as a Vice President, after my 30-year career at FDA’s Center for Food Safety and Applied Nutrition, I was only too happy to join him. In 2001 AAC was acquired by Kendle International, one of the world’s largest global clinical research organizations, Tony retired, and I was appointed President of the consulting business. Then in 2006 I had the opportunity to acquire the food, dietary supplement and cosmetic businesses from Kendle, forming EAS Consulting Group, LLC as an independent company on October 1, 2006.

It wasn’t long after forming EAS that we began expanding services to all the FDA regulated areas in order to keep pace with the growing industry needs. As we expanded our services we also grew our network of independent consultants, many of which were former career FDA compliance officials and high level industry executives. I’m also proud to say a significant number of former clients who retired as industry leaders have also elected to join our ranks. Our respected and impressively credentialed consultants are a huge part of why EAS has been so successful. Our mission is to provide quality regulatory advice and service to our clients in an ethical, timely, and cost efficient manner. I am proud to say that everyone standing under the EAS banner embraces this whole-heartedly and always works in the best interest of our clients.

Beginning in 2011 EAS contracted with certain independent consultants with specialized credentials to serve as Senior Advisors (now referred to as Independent Advisors). At the present time our current list of Advisors are:

  • John Bailey, Ph.D., Colors and Cosmetics
  • Charles Breen, FSMA Consulting Services
  • Elizabeth “Betty” Campbell, Labeling and Claims
  • Nancy Chew, New Product Development and Submissions
  • Tara Couch, Ph.D., Dietary Supplements
  • Susan Crane, OTC Drugs and Labeling
  • Robert Fish, Quality and Compliance
  • Robert Martin, Ph.D., Food & Color Additive Safety
  • Jeffrey Springer, FDA Regulatory and Legal Matters
  • Stephen Sundlof, D.V.M, Ph.D., Animal and Human Food Safety
  • Domenic Veneziano, Import Operations

EAS has also established strategic partnerships with companies and independent contractors throughout the world in an effort to extend our services to the global needs of the FDA-regulated firms we support. We now have partners located in Canada, Mexico, Brazil, Chile, Ireland, UK, France, Netherlands, Korea, Japan, Australia, New Zealand and elsewhere.

On the business front, I am pleased to say that Dean Cirotta, President & COO and my son Brett Steele, Chief Financial Officer are now partners in EAS and play a critical role in running today’s business and will play a strategic role in leading us into the future. They, along with Cathryn Sacra, Senior Manager of Client Relations, Bryan Coleman, Senior Director, Pharmaceutical & Device Consulting Services, Victoria Pankovich, Regulatory Specialist, Amy Scanlin, Marketing Coordinator and Jason Steele, Creative Director and webmaster all play a key role in the integration of client services and project management on a daily basis.

EAS is also poised to meet new areas of needs, such as the launch of our most recent strategic consulting services on Product Development and Labeling, that we just announced at IFT 2016 in Chicago. FDA’s new regulatory initiatives are creating new opportunities for EAS to expand its services. For example, FSMA, the new Nutrition Label requirements and increased demand for GRAS determinations in the food area alone have increased opportunities. The new deeming regulations has telegraphed increased oversight for the tobacco industry and Congressional interest in increasing regulations within the cosmetic industry all bode well for increased need for quality consulting assistance. EAS will be taking increased advantage of our tremendous drug and device consulting resources that we have to expand our work in these areas as well.

As we look to the future, EAS is well positioned to build on our success. We thank you for trusting EAS with your ever important regulatory needs and engaging with us. I also want to personally thank all the staff and independent consultants who have contributed to our growth and accomplishments in the past 10 years. I particularly want to acknowledge the role that my friend and former lab colleague, Tony Celeste has played in my career after FDA.

We appreciate your business and look forward to the next ten years of service.

New NDI Guidance – Still a Work in Progress

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On August 11, 2016, FDA issued an updated revised draft guidance on new dietary ingredients used in dietary supplements which replaces draft guidance the agency issued in 2011. FDA developed the draft guidance to address confusing issues involving new dietary ingredients, synthetic dietary ingredients, botanicals, and requirements for New Dietary Ingredient Notifications.

In FDA’s own words: “The revised draft guidance, when finalized, will help industry in evaluating whether to submit a premarket safety notification for a new dietary ingredient (NDI), or for a dietary supplement containing an NDI, and in preparing such premarket safety notifications (also referred to as NDI notifications).” FDA is inviting comments on this guidance document. In order for the comments to be considered before FDA begins work on the final version of this guidance, the comments should be submitted no later than October 11, 2016. FDA is specifically requesting comments on three issues as discussed in the Federal Register document announcing the availability of the revised draft guidance document.

While the updated draft is an improvement on the earlier draft, it is still a work in progress. What can be interpreted as improvements are FDA’s intention to establish a “grandfathered” list of dietary ingredients and to establish Master Files for new dietary ingredients. However, judging from comments issued by many stakeholders on this revised draft thus far, this updated draft guidance does not completely answer all of the areas of concern and interpretations regarding dietary ingredients. As such, this is an ongoing and unsettled area. In the meantime, FDA is urging adherence to these guidelines as it best reflects their current thinking in this area.

The major sections of the earlier draft guidance that have been revised are: chemical alteration; manufacturing changes that create an NDI; synthetic substances; NDI definition; list of “grandfathered” dietary ingredients; and structuring NDINs efficiently including how much safety information and types of safety information that should be provided. The revised guidance document also uses a question and answer format to address the pertinent issues involving dietary ingredients along with several examples of what is a dietary ingredient, synthetic ingredient, etc.

There is general agreement that the process involving dietary ingredients has not worked as smoothly as expected… roughly 25% of the NDINs submitted to FDA are accepted while 75% have met with some objection(s) for a variety of reasons.

One area of controversy involving dietary ingredients has been how the interpretation of the legal safety standard is applied. Under DSHEA, dietary ingredients marketed in the U.S. after October 15, 1994, must meet the stated NDI safety standard demonstrating that “… a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.” (21 CFR 190.6(a)) By contrast, the safety standard applied to food additives and GRAS substances must demonstrate that the ingredient meets the safety standard of reasonable certainty of no harm under the intended conditions of use. (21 CFR 170.3(i))

While FDA has published standards as to how to determine safety under the reasonable certainty of no harm under the intended conditions of use safety standard, no such published standards or guidance exists for the reasonably expected to be safe standard. In fact, a comparison of the safety requirements listed under section VI of the revised draft guidance document share a remarkable similarity to the safety requirements for food additives and GRAS substances.

EAS is encouraging clients to offer comments on this draft guidance as this guidance when finalized will reflect FDA’s thinking in this area for years to come. EAS can assist you in this regard by working with you in drafting the comments and serving as a conduit for submission of comments to FDA. In the meantime, it is strongly recommended that clients seek a pre-submission meeting with FDA before submitting an NDIN to answer all questions/concerns beforehand.

GRAS Final Rule: May Result in More Rejects and/or Longer FDA Reviews

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On August 17, 2016, FDA published a final rule which formally codifies the requirements for GRAS Notices that originated with the GRAS proposal published in 1997. FDA states that the expressed intent of this final rule is to “… clarify the criteria used to determine whether the use of a substance in human or animal food is generally recognized as safe (GRAS)” and applies to GRAS Notices submitted to the Center for Food Safety and Applied Nutrition (CFSAN) and/or the Center for Veterinary Medicine (CVM). The final rule addresses the scientific evidence that should be used to demonstrate safety, the availability of this data in the public domain, and the criteria for formulating this data into a GRAS Notice that would establish a consensus among experts that the material is safe in food and/or animals for its intended use(s).

Overall, this final rule is welcome. However, based on our reading of this document, there are some areas that will need to be clarified and addressed going forward, in particular, expert panels, conflicts of interest, and independent (self-GRAS) GRAS determinations. This document does not go into much detail regarding independent GRAS determinations as it is made clear that FDA prefers GRAS notices. FDA has indicated that it will issue guidance documents in these areas at a later date. The agency did not provide an option to comment on this final rule aside from requesting comments related to the Paperwork Reduction Act only.

The final rule will also change, and codify, some of the terminology used to describe certain actions. For example, “GRAS determination” in the previous GRAS notices will now refer to “GRAS conclusion” or “conclusion of GRAS status.” The new GRAS notices will refer to “signed statements” as opposed to a “claim” in earlier GRAS notices. FDA has established new sections in 21 CFR 170.203 and 21 CFR 570.203 that list the new definitions and terms to be used in future GRAS notices, for food and animals, respectively.

Notable in this final rule, as compared to the proposed rule, is the use of the word “required” by FDA for the new actions and many of the actions performed in GRAS notices based on the proposed rule and FDA guidance documents (See Table 2 – Summary of the Principal Changes to the Proposed Notification Procedure; 81 FR 54969 – 54970).

The format for future GRAS notices will now be divided into seven parts, all of which must be discussed in the document. FDA describes this format in new sections 21 CFR 170.225 through 170.255 and 21 CFR 570.225 through 570.255, respectively, for human food (CFSAN) and animal food (CVM).

One very troubling aspect of this final rule is that FDA has now expressly given itself the option of extending the targeted 180 day review/completion period for another 90 days “… on an as needed basis.” Most notifiers would prefer a shorter review/completion period rather than a longer one.

One predictable outcome of this final rule is that FDA is likely to receive more GRAS notices to review. As discussed, and implied, in the preamble to the final rule, one way for the agency to keep up with the workload is to refuse to accept submissions during their pre-filing review if, in FDA’s opinion, the document does not meet the requirements for GRAS or conform to the prescribed format. Coupling this with the agency’s ability to extend the review to 9 months could result in longer review times.

The GRAS final rule, which becomes effective on October 17, 2016, will present challenges and difficulties in understanding and making certain that all of the requirements are met. Going forward, EAS stands ready to assist all clients in successfully managing these requirements to secure a successful GRAS notice.

FDA’s Design Control Requirements for Medical Devices

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FDA reviewers and field investigators evaluate design control requirements and processes for medical devices and make recommendations based on whether the manufacturer has the required checks and balances in place.

Design controls are a mechanism for bringing the design of certain class I and all class II and class III investigational devices under the umbrella of the good manufacturing practices (GMPs). In 1996, the GMP requirements were revised to include design control and they have become a part of the Quality System Regulations (QSR). Manufacturers must demonstrate compliance with the QSR and, as of 1996, with design control requirements.

Once the product definition and regulatory strategy have been prepared, medical device developers must work to comply with the design control provisions of the QSR as the device development process moves forward. The QSR is the medical device equivalent of the pharmaceutical current good manufacturing practices (cGMPs). The QSR, unlike cGMPs, also regulates the device development process via its design control provisions (21 CFR 820.30) which describes the device developer’s requirements under the design control provisions of the QSR.

Design controls are an integrated set of management practices (policies, processes, and procedures) which are applied to control design activities while assessing quality and correcting errors through a reiterative device process control. Once management has determined that the device is feasible and the decision has been made to transition from research to clinical applications, the design control process begins. As such, the device application becomes part of corporate quality system.

Here is a summary of key points from the full White Paper on FDA’s Design Control Requirements for Medical Devices posted on the EAS website:

  • Risk and hazard analysis activities are required as part of total product life cycle (TPLC).
  • The standard for the application of risk management (ISO 14971) for medical devices is part of TPLC.
  • The risk management process covers risk analysis, risk evaluation, and risk controls through Corrective and Preventive Action (CAPA) plan and design control requirements.
  • Design control requirements play a key role from device design prototype, manufacturing process controls and the finished device for user needs.
  • The extent of testing and evaluation is proportional to the level of risks associated with the device technology and intended clinical use.
  • FDA reviews the “safety and effectiveness” of the device and it is essential that any risks and hazards are mitigated to “acceptable” levels.

The full White Paper reviews medical device design, medical device quality systems and GMPs. device design control components, and FDA’s Quality System Inspection Technique (QSIT).

Expect More Food Labeling Changes Now FDA has Finalized Its Nutrition Facts Regulations

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FDA issued its final Nutrition Facts and Serving Size regulations last month, which in part were based on the new U.S. Dietary Guidelines for Americans (2015-2020).

However, those actions will not mark the end of new food labeling regulations issued by the agency. The food industry should brace itself for still more regulations that will align FDA’s nutrient content claims and health claims regulations with the new Nutrition Facts label and the new Dietary Guidelines. Some companies are looking forward to such changes to establish a level, competitive playing field while others fear new nutrition and health claim regulations will change the number and type of claims that currently can be made.

This matter was already raised by Dr. Stephen Ostroff, Deputy Commissioner for Foods, at a February 24, 2016, House Appropriations Subcommittee hearing on FDA’s FY ’17 budget. California Representative David Valadao (R) asked whether FDA would be updating the rules for nutrient content claims in light of the new Dietary Guidelines for Americans. The Congressman stated that, for example, some pastries can be labeled “healthy” while salmon, nuts, and avocados cannot.

This is because FDA’s current regulations governing the use of the term “healthy” require foods to be low in saturated and total fat, but do not adequately distinguish between other types of fats found in foods like salmon and nuts which newer evidence finds may be healthful.

Further, FDA’s definition of “healthy” does not take into account either total or added sugars content. That will almost certainly change now that FDA has finalized regulations requiring the disclosure of added sugars labeling on the Nutrition Facts label. In addition, FDA’s new Daily Reference Value (DRV) for added sugars means that the agency may create new nutrient content claims such as “low in added sugars.”

In addition:

  • Expect a new round of proposed regulations amending nutrient content claims such as “Low Fat,” “Low Cholesterol,” and “Lite.” The 2015-2020 Dietary Guidelines raise questions about existing FDA regulations for “low cholesterol” and “low fat” claims. The new Dietary Guidelines deemphasize the role of dietary cholesterol and put into question whether a “low cholesterol” claim would help consumers maintain healthy dietary practices. The new Dietary Guidelines also recognize that not all fats are the same – some can be part of a healthful dietary pattern. Accordingly, FDA may review whether an across the board “low fat” claim is still helpful to consumers and whether a “low cholesterol” claim should be discontinued.
  • FDA criteria for “lite” claims may be affected, as the definition of “lite” is intertwined with the definition of “low fat.”
  • Changes to nutrition claims like “low sodium” will also follow as FDA reduced the current DRV for sodium from 2400 mg to 2300 mg per day (although the agency has previously set special rules for “low sodium” claims given the difficulty food companies face in reducing sodium content).
  • A domino effect of changes in disclosure requirements (like “see back panel for nutrition information about _____”) that at times must accompany nutrition claims such as “High Calcium,” will likely be proposed as serving sizes for foods like ice cream have changed.
  • The new Dietary Guidelines may lead the agency to review its authorized health claim for total fat and cancer.

In short, after finalizing changes for the Nutrition Facts label on the backs of food packages, FDA will turn its attention to the fronts of the food package where the stakes on what the agency decides is permissible will be even higher. It is well accepted that nutrition information on the front of a food package attracts more consumer attention than information on the back. Expect FDA’s treatment of nutrition and health claims to be just as or more controversial as the changes the agency has made to the Nutrition Facts label.

Now is the time to plan ahead. EAS Consulting Group can generate nutrition profiles from databases, review revised labels and provide a customized analysis of how FDA’s new Nutrition Facts regulations may affect your company’s front label claims. Contact Cathryn Sacra at csacra@easconsultinggroup.com or call 571-477-5505 if you would like more information.

FSMA and Dietary Supplements

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FSMA’s preventive controls rule, 21 CFR 117.5(e), exempts finished dietary supplements (DS) from the requirements for preventive controls and a supply-chain program if they are in compliance with 21 CFR 111, and with adverse event reporting. Exemption from these two elements of Part 117 does not mean dietary supplement manufacturers are unaffected by FSMA.

The revised Current Good Manufacturing Practices (CGMPs), largely relocated to Part 117 subpart B, still contain general provisions that apply to DS manufacturers if not otherwise covered by Part 111. For example, if a DS relies on moisture control for product safety, the applicable provision in 110.80 Process Controls is carried over to 117.80.

FSMA directly affects dietary ingredient (DI) manufacturers. Only finished DS products are exempted from subparts C and G or Part 117. Facilities making DI’s must comply with not only the revised CGMPs, but must also implement preventive controls and a supply-chain program. This may assist DS manufacturers to assure that dietary ingredients they buy are really what they receive.

The Foreign Supplier Verification Program (FSVP) places new requirements upon importers of finished DS and DI products. Which requirements apply depend on a number of factors, including whether the import is a finished product or an ingredient/component. Briefly:

  • Importers who establish and verify compliance with specifications for dietary supplement components and packaging, which are required under Part 111 Current Good Manufacturing Practices (CGMP) regulation, do not need to comply with most of the standard FSVP requirements.
  • Likewise, importers whose customer is required to establish such specifications and verify that they are met do not need to comply with most of the standard FSVP requirements. The importer is, however, required to obtain written assurance that its customer is complying with those requirements.
  • Importers of other dietary supplements, including finished products, who do notestablish and verify compliance with specifications, are required to comply with most of the standard FSVP requirements (except for hazard analysis). Their verification activities would focus on compliance with the Part 111 dietary supplement CGMP regulations.

In many respects, the very flexibility of FSVP makes it difficult to understand what FDA wants in a particular situation. FDA knows it has a responsibility to provide guidance well in advance of any enforcement activity.

FSMA also affects DS manufactures in a few other ways. FSMA’s primary goal is preventing food safety problems. An FDA prevention through enforcement mindset appears to extend to DS and DI products, using both FSMA and the tools available under the Dietary Supplement Health Education Act. For example:

  • June 2013. FSMA administrative detention authority was used by FDA to detain approximately $8 million worth at retail of USPlabs’ OxyElite Pro and Jack3d for containing DMAA, an unsafe ingredient. USPlabs voluntarily destroyed the detained products.
  • Nov 2015. USPlabs was indicted by the US Department of Justice on criminal charges related to DS manufacturing.
  • Nov 2015. DoJ announced it, and state authorities, were pursuing over 100 civil and criminal investigations of makers and marketers of DS.

The current DS enforcement push is at least partially due to a long history of continued failures by some DS manufacturers to comply with Part 111 requirements. FDA is not going to rely on FSMA education among DS firms as it is for other food facilities.

Simultaneously, FDA knows of many firms, including DS manufacturers, which do comply with applicable regulations. FDA wants to publicly recognize compliance and offer incentives for doing so. Less frequent and shorter inspections for compliant firms are under consideration.

What Makes a Good Sampling Plan?

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You have a question, so you design a study to explore it. You determine that A is better than B and that the average difference is 3 units. It should be obvious that this is not sufficient information, but why not? After all, it is exactly what you wanted to know.

First of all, is a 3-unit difference a large number or a small one? You would likely know this from your experience as a scientist or engineer. And this is certainly important. But it is also important to know whether the difference is well or poorly known. This is more of a statistical question.

The first issue is the variation encountered in the study. If two of the experimental units in the study on different treatments are just as likely to have an 8-unit difference or even a difference of 2 units in the opposite direction, the 3-unit difference is no longer so impressive. So in designing the study a statistician would want to take enough observations to ensure that with high probability the study would recognize an important difference as an important difference (a statistically significant comparison) but would not declare a small difference to be significant.

The procedure for calculating sample sizes for a simple two-treatment comparison study is well known and widely available on the Internet. Unfortunately, this is not the only issue to consider. Recently the National Institutes of Health and the Food and Drug Administration have become concerned that a large number of preclinical studies are not reproducible (Landis, et al 2012). The stakes are very high. NIH spends about $30 billion per year to support scientific research and it has been estimated that half of these studies cannot be reproduced. Studies and clinical trials that would follow up on the results shown could well be looking in the wrong direction.

The NIH has recently been emphasizing the need for reproducible and repeatable studies. First, some definitions. In this context, a repeatable study is one that an independent scientist/statistician can analyze and get the same answers as the original scientists did. It is a matter of clarity in reporting the (statistical) analysis methods and in having the same data available. A reproducible study is one that independent scientists can begin again from scratch and follow the study description to produce very similar results as described in the original reports.

Repeatability is a rather minimal requirement, but one that is easily failed in a study of any complexity. There will likely be several scientists involved and each will be evaluating the data. Someone may modify the data after someone else has finished their analysis. It will then be impossible to get the same result as the first scientist did. Early in my career with the FDA, I ran into this problem frequently. When we did, we had to stop our review and send the application back to the sponsor. Sponsors soon learned to lock the database before anyone proceeded to an analysis and to be sure that FDA statisticians received only that database.

There is more flexibility in the requirement for reproducibility because variation in the responses of a second study are anticipated. This variation should be largely overcome by the sample size. Difficulties in reproducibility may be subtle and therefore more difficult to correct. Scientists may not even recognize the cause of a problem. For example, it might not even be known that there are important differences in the subspecies of animals used in the study. Or a reagent used in the study might have run out midway and have been replaced by a fresh batch, corresponding to the changeover to laboratory evaluation of animals on Treatment B from that of those on Treatment A.

Scientists may well have a good idea about how the study “should” come out. It would be unreasonable to expect that they run randomly or haphazardly chosen studies. In some cases, animals that did not respond as expected were eliminated from the study and not included in the analysis. There may have been a good reason for this, such as a determination that the animal failed to eat enough to receive a proper dose of its assigned treatment. The problem was that neither this evaluation nor the course of action was preplanned and the evaluation was not conducted for every animal in the study. The resulting bias prevents reproduction of the study.

Neither of the above definitions of repeatable or reproducible insist that the statistical analyses be appropriate for the study. In many cases in the literature, they have not been. It should be taken for granted that the appropriateness of statistical methods is as important as the appropriateness of laboratory methods.

A good sampling plan is one that will reliably produce a repeatable, reproducible study. It should start with a protocol that describes both the laboratory and statistical procedures to be employed. It should cover all anticipated events of the study in detail, and it should make provision for unexpected events.

In this short article I have not covered many of the potential statistical issues that occur in a study. These include interim looks at the data, specification of primary and secondary hypotheses, treatment of missing data, etc., all of which can affect the analytical methods to be used and the interpretation of the results.

The Purpose of a DEA Regulatory Investigation

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Everyone has read recent newspaper and internet stories about the rise in heroin abuse and its relationship with pharmaceutical opiates that were originally prescribed for legitimate medical reasons. Unfortunately, this problem has been around since the Civil War when morphine was given to soldiers for horrific injuries, and the soldiers became dependent on that narcotic. Any controlled substance—narcotics, depressants, or stimulants—has the potential for abuse.

It is the responsibility of the U.S. Food and Drug Administration (FDA) to protect the public health by assuring the safety, efficacy and security of human and veterinary drugs, but the U.S. Drug Enforcement Administration (DEA) is responsible for a subgroup of drugs—controlled substances. A controlled substance differs from a regular prescription drug in that controlled substances have the potential for physiological and/or psychological abuse and have been designated as controlled under U.S. law or international treaty.

The DEA is responsible for preventing the diversion of controlled substances and listed chemicals (used to manufacture illicit drugs) from their legitimate medical use to illicit drug trafficking. To prevent the diversion of legitimate controlled substances and listed chemicals, DEA registers and issues individual registration numbers to all businesses that import, export, manufacture or distribute controlled substances; all medical professionals licensed to dispense, administer or prescribe controlled substances; and all pharmacies authorized to fill prescriptions.

When a business or individual is issued a DEA registration, that business or individual is responsible for keeping all controlled substances under their control from being used for illegal purposes. This is accomplished by requiring each DEA registrant to keep certain records and maintain specific security measures to manage their controlled substances. The records allow the registrant to know the kinds and amounts of controlled substances under their supervision at any time. There are different security requirements for specific controlled substances, depending on their potential for abuse.

When DEA investigators conduct a regulatory investigation of a business establishment, their primary purpose is to assure that no controlled substances are being diverted illegally. The investigations are required under federal law and are usually unannounced. The investigators will take an inventory of controlled substances on hand and review records. The investigators will usually audit individual controlled substances using records and documents provided by the business.

During the DEA regulatory investigation, the DEA investigators will attempt to account for every dosage unit of controlled substance at the location during a three-month to one-year period. The investigators accomplish this by reviewing all controlled substance records including records of receipt, sales or dispensing, destruction, theft or loss, and any other record relating to controlled substances.

The investigation will also include a review and testing of the security measures for all controlled substance storage locations at the business. This includes providing the names and personal information of employees having access to controlled substances. The registrant must check the background of all employees with access to controlled substances to ensure they have not been convicted of a drug related felony or used controlled substances illegally.

Depending on the results of the regulatory investigation, the investigators may use the visit to educate the registrant. If deficiencies are found, DEA may issue a Letter of Admonition requiring a written response describing the actions to correct any deficiencies. If more serious deficiencies are noted, the registrant may be subject to a formal administrative hearing or federal civil or criminal charges.

A regulatory investigation is one of the tools DEA uses to ensure that controlled substances are used for legitimate reasons.

What Are Medical Foods (and What They are Not)

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Prior to 1972 medical foods were regulated as prescription drugs under section 201(g)(1)(B) of the FD&C Act, requiring manufacturers to conduct drug trials and submit Investigational New Drug license applications and New Drug Applications. It was extremely difficult to innovate new dietary products for medical use because of these time-consuming and cost-restrictive measures. In an effort to foster innovation and ensure reasonable cost and availability of such foods to those needing them, Congress passed the Orphan Drug Act, (21 U.S.C. 360ee (b)(3)), and FDA published its implementing regulations and guidances. FDA differentiated medical foods, which were part of the larger categories of special dietary use foods and dietary supplements, from the even larger broad category of general or conventional use foods. Medical foods would not have to undergo premarket review or approval, thus enabling manufacturers to innovate and develop medical foods according to the latest scientific research in a timely and cost-controlled fashion.

A medical food according to the Orphan Drug Act and clarified by regulation can be found in FDA’s regulations at 21 CFR 101.9(j)(8). A food is a medical food only if:

  1. It is a specially formulated and processed product (as opposed to a naturally occurring foodstuff used in its natural state) for the partial or exclusive feeding of a patient by means of oral intake or enteral feeding by tube.
  2. It is intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone;
  3. It provides nutritional support specifically modified for the management of the unique nutrient needs that result from the specific disease or condition, as determined by medical evaluation;
  4. It is intended to be used under medical supervision; and
  5. It is intended only for a patient receiving active and ongoing medical supervision wherein the patient requires medical care on a recurring basis for, among other things, instructions on the use of the medical food.

Medical foods differ from foods for special dietary use and general use foods that can make health claims by the requirement that medical foods are intended to meet distinctive nutritional requirements of a disease or condition, are used under medical supervision, and are intended for the specific dietary management of a disease or condition. Further, FDA in its updated Draft Guidance for industry on medical foods considers the statutory definition of medical foods to narrowly constrain the types of products that fit within this category. The guidance gives as example of medical foods, “inborn errors of metabolism” (IEMs) such as phenylketonuria (PKU). In this example, inherited biochemical disorders in which absence of an enzyme interferes with the metabolism of protein, fats, or carbohydrates would be treatable with medical foods. For these IEMs, a medical food is required in addition to a specific dietary modification (e.g., reduced total protein/phenylalanine for PKU) in order to obtain adequate levels of essential nutrients.

The guidance also excludes from medical foods products dealing with diseases resulting from essential nutrient deficiencies like scurvy and pellagra, and does not consider foods designed for the dietary management of diabetes or pregnancy to be medical foods because 1) diabetes can be managed with modification of the normal diet alone, and 2) pregnancy is not a disease. The FDA might consider, however, a medical food to fit legal criteria if it is to be used with a specific disease or condition associated with pregnancy and for which there are distinctive nutritional requirements that cannot be met by the normal diet alone. Conventional foods that do not ordinarily contain protein or are ordinarily low in protein (such as what might be used in the PKU dietary plan) would also not meet the regulatory criteria for medical foods.

It is important to appreciate that medical foods are not those simply recommended by a physician as part of an overall diet to manage the symptoms or reduce the risk of a disease or condition, and not all foods fed to sick patients are medical foods. Further, FDA does not interpret either the Orphan Drug Act or FDA’s regulations at 21 CFR 101.9(j)(8) to require that medical foods be made available by prescription. Medical foods may not bear on labels the symbol “Rx only,” and are not prohibited from being dispensed without a prescription. Medical food should also not have National Drug Code numbers on labeling.

Medical foods are exempt from the labeling requirements for mandatory nutrition labeling, health claims and nutrient content claims under the Nutrition Labeling and Education Act of 1990 (21 U.S.C. 343(q)(5)(A)(iv)). As foods, however, they must comply with all applicable FDA requirements for foods, including the Current Good Manufacturing Practice regulations (21 CFR part 110), Registration of Food Facilities regulations (21 CFR part 1 Subpart H) and, if applicable, regulations specific to the product formulation and processing, such as the Thermally Processed Low-Acid Foods Packaged in Hermetically Sealed Containers regulations (21 CFR part 113), Acidified Foods regulations (21 CFR part 114) and Emergency Permit Control regulations (21 CFR part 108). FALCPA’s allergen labeling requirements apply to all packaged foods including medical foods. Further, an ingredient that is added to a medical food must be safe and suitable and comply with all applicable provisions of the FD&C Act and FDA’s regulations. Any ingredient added to a medical food should be 1) a food additive used in accordance with FDA’s food additive regulations (see 21 CFR 172); 2) a color additive used in accordance with the color additive regulations (see 21 CFR 73 and 74); 3) a substance that is generally recognized, by qualified experts, to be safe under the conditions of its intended use (Generally Recognized As Safe, GRAS) (see 21 CFR 170.30 and 21 U.S.C. 321(s)); or 4) a substance that is authorized by a prior sanction issued by FDA (see 21 CFR 170.3(l)).

Medical foods for infants that are to be used as a sole source of nutrition are called exempt formulas and are subject to their own requirements.

Because the FDA does not approve medical foods before marketing, the first time a manufacturer may hear from the FDA could be in the form of a warning letter. And because some manufacturers would appear to use loopholes in the medical foods regulation to develop and market products with disease indication claims that would not be allowed if marketed as conventional foods or dietary supplements, FDA has indeed issued such letters, citing, among other issues, that the manufacturer has failed to substantiate the disease and its distinctive dietary or nutritional requirements for which its products are intended [21 CFR 101.9(j)(8)(ii)]. The FDA’s conclusion is that the product is not a medical food but is by default, an unapproved new drug because of its claims and thus is misbranded.

More and more companies appear to be entering the medical foods area, but they are finding, even global companies, that medical food regulations may not be as clear cut and understood as thought or hoped for. It is important to understand the intent of the FDA as well as its regulations – in particular where medical foods differ from other categories of foods, and how medical foods can be marketed and labeled so that they would not be misbranded and require reclassification and relabeling, maybe even penalties and market withdrawals or recalls.

Adverse Event Reporting for OTC Drug Products

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The Food and Drug Administration monitors the safety of drug products marketed in the United and requires the pharmaceutical industry to document and, as applicable, report adverse events experienced by consumers when using their products.
Documenting of adverse events has always been part of the record-keeping requirements of the Good Manufacturing Practices (GMP) regulations related to complaint files. However, until passage of the Dietary Supplement and Nonprescription Drug Consumer Protection Actin 2006, the reporting of such events was not required for OTC drug products (unless marketed under NDA or ANDA applications). The FDA subsequently issued two guidance documents to assist firms in complying with the law, the first dealing with reporting requirements and the second addressing labeling.

The law mandates that manufacturers, packers and distributors submit reports of serious adverse events received on their OTC products to the FDA. Serious adverse events are defined as those that:

  • Result in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect; or
  • Require, based on a reasonable medical judgment, a medical or surgical intervention to prevent an outcome described above.

To facilitate the reporting of these events by consumers, the law requires that OTC drug labeling includes a domestic telephone number or complete domestic address through which a “responsible person” may receive the report. It is essential that this designated person has the necessary training and/or experience. While larger firms often employ health care professionals, this may not be feasible for smaller companies. In these cases, a standardized questionnaire should be developed to ensure that all relevant information is obtained to determine if an event is “serious” and therefore reportable.

In addition, it has become clear through recent FDA warning letters that company and/or product websites are considered an extension of labeling, so firms should monitor posts and comments received through these and other social media platforms. This presents a challenge in that these posts may lack sufficient detail to adequately complete Individual Case Safety Reports (ICSRs) required as part of the submissions – and there may be privacy concerns. However, companies should make good faith efforts to follow-up with the consumer if possible.

As of June 2015, all serious adverse event reports received on OTC drug products must be submitted to the agency through FDA’s Adverse Events Reporting System (FAERS) in electronic format using either a Database to Database Transmission or through the FDA’s Safety Reporting Portal. Additional information is available both on the FAERS website and in a draft guidance document issued in 2014.

When completing the electronic ICSRs, firms should follow good pharmacovigilance practices and include the four basic data elements: information about (1) the patient, (2) the suspected product, (3) the adverse event details and (4) the reporter (if different from patient). The format and content of such reports are completed using the Medical Dictionary for Regulatory Activities (MedDRA), a medical terminology standard developed by the International Council for Harmonization for coding the medical terminology used in the report.

The law requires that serious adverse event reports are submitted to the agency within 15 business days of receipt of the four data elements. The submission should include a copy of the product label, preferably the version associated with the product used by the consumer/patient. In addition, if any new medical information is subsequently received that relates to the initial event, this should also be submitted within 15 days.

With the widespread use of OTC drugs, the reporting of these serious adverse events is a crucial step in monitoring their safety. Manufacturers, packers and distributors should develop procedures and programs to ensure that this regulatory obligation is managed competently and efficiently to assist the FDA in its mission to protect public health.

Getting to Grips with the electronic Common Technical Document (eCTD) Process

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Completing a successful electronic Common Technical Document (eCTD) submission can be daunting, even with the help of guidance documents from the International Conference on Harmonization (ICH) – which developed the eCTD – or from the Food and Drug Administration.

The success or failure of an eCTD submission depends greatly on processes put in place prior to beginning the process. First, it is necessary to ensure that the company has what’s needed to assemble an eCTD. If the manpower, knowledge, experience and hardware/software are not in place, failure is almost a certainty. These should be sourced from outside if necessary.

Once these are in place, it is imperative to set a timeline. The timeline is constructed by picking a realistic filing date and working backwards to see what needs to get accomplished to meet that deadline. The timeline will be part of a Global Development Plan that will change and be revised but will remain your “road map” for several years.

The eCTD is made up of five modules:

  • Module 1 provides for administration information and is country specific. For example, submissions in the United States require a Form FDA 356h with specific information. Other required forms include Field Copy Certification, Patent Certifications, Financial Disclosures, and Environmental Assessment, to name a few. In the EU, different information is required, such as Consultation with Patient Groups, Pharmacovigilance, Risk Management, and other information associated with the EU Region. Canada also has its own specific requirements.
  • Module 2 provides for quality, non-clinical and clinical summaries.
  • Module 3 provides for CMC information on the drug substance and drug product.
  • Module 4 provides for non-clinical data and reports.
  • Module 5 provides for clinical data and reports (including the ISE and ISS).

In beginning to populate Module 3 and subsequently Module 2, some of the challenges that you will be faced with will include the following:

  1. Key API characteristics.
  2. Pre-formulation and formulation development programs.
  3. Ensuring that your specifications and analytical assays are well developed.
  4. Ensuring that your early and later batches of clinical trial material and commercial material are produced pursuant to Good Manufacturing Practices.
  5. Having a good stability program in place with established stability protocols.

For your non-clinical program you will need to ensure that all the appropriate animal studies have been completed pursuant to good clinical practices and each non-clinical document signed off. Once Module 4 has been populated, you will need to provide a summary of your non-clinical data in Module 2.

For your clinical program, you will need to ensure that all the requisite trials are completed on time, Clinical Study Reports (CSRs) are written and signed off and that you begin the process of writing the Integrated Summary of Effectiveness (ISS) and the Integrated Summary of Safety (ISE). Gathering all the adverse events that transpired through your program is essential. When Module 5 is completed, you will need to provide a summary of the clinical information in Module 2.

As you begin to accumulate information, data reports, you will need to identify, in synch with your development plan, potential issues that could put your program at risk. When these risks have been identified and prioritized, you will need to find ways to mitigate the risks in order to meet your timeline.

It is advisable to form an eCTD Dossier Team early on in the process and assign responsibilities to each member with deliverable dates. For example, who will be responsible for writing the various Drug Substance and Drug Product templates in Module 3? Will the same person be writing the overall summary in Module 2? Will this be an individual or a team effort? Who will write the overall nonclinical and clinical summaries once all the data and reports are in? The same applies for the ISE and ISS which are among the final documents in the process.

Careful coordination is needed to ensure on-time delivery of all the moving parts within the eCTD. It is important to keep the following documents in mind:

  1. A time line chart that needs to be reviewed and possibly modified often.
  2. A Development Plan.
  3. A list of risks and mitigation strategies
  4. A Gap Analysis
    1. Identifying documents, information and data missing in each module
    2. Prioritizing and establishing a timeline for how the missing information will be obtained and when the information will be available
    3. Identifying key issues that could derail your submission and resolving these issues quickly
  5. A tracking chart of the status of all components of the eCTD. This can include a detailed eCTD Table of Contents as well as separate tables of contents for each of the modules.

As you move forward with the eCTD process, be sure to communicate often with the FDA or Boards of Health in discussions that help address any issues that arise. Don’t leave these interactions for the end, because this will just guarantee setbacks.

As a final tip, make sure to version all your documents. There will be hundreds of them. This is a great tracking tool and will have big pay offs.

New Drug Development in the 21st Century

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Most people who work in the pharmaceutical industry know that drug development comprises of pharmaceutical development, animal pharmacology and toxicology studies, and clinical research; many also know that there are quality standards applied to manufacturing and controls that become more and more stringent as the development process evolves. Similarly, the quality standards for animal pharmacology, safety pharmacology and toxicology are implemented in a tiered manner. Clinical research, the most time consuming and costly part of the process, is also controlled by quality practices.

Many more drugs fail during development than make it to market. The Pharmaceutical Research and Manufacturers of America estimates that it requires more than 10 years and $2.6 billion dollars for a drug to be approved for marketing. And only 12% of drugs that enter the development process make it to market. The discovery of clinical lead compounds requires many more potential drugs to be discarded prior to IND development.

This means that FDA holds many more pre-IND meetings than end-of phase 2 or pre-NDA meetings.

Many people hold that “regulatory efficiency” is an oxymoron. The only efficient path to market is to do it right in the first place. FDA provides consultation to pharmaceutical manufacturers throughout the development process. Using the opportunities offered by standard development, pre-IND, end of Phase 2, and pre-NDA meetings with the agency gives sponsors access to the wealth of information FDA has gained from review of previous applications as well as up-to-the minute advice on how to comply with current regulations and standards. There are published guidance documents on how to prepare for and hold these meetings; however, often, a sponsor requires the assistance of consultants who are experts in the various aspects of development that pertain directly to their product (e.g. a new nanotech formulation). Most sponsors also benefit from the assistance of regulatory experts for defining the topics and detailed questions to discuss, preparation of documents, regulatory protocol, and the conduct of the meeting itself.

Today, global drug development is coordinated mainly through the International Conference on Harmonization (ICH) process. The beauty of this system is that when a drug is developed according to ICH Guidelines, the research portfolio will be accepted in all the countries that have incorporated those guidelines into their own regulatory system. For example, the group of toxicology studies required before starting clinical studies is agreed and accepted by all the countries that participate in this process. This allows one body of technical information to be accepted by health regulatory authorities in Europe, Japan, Canada and many other countries.

Because the development of a novel compound into a marketable drug is so costly and time consuming, other regulatory routes to market are available. Perhaps the best known is the Abbreviated New Drug Application, a copy of a previously approved drug, which is available after all patents and marketing exclusivity options have expired. Recently, the 505(b)(2) process has become a popular means of short-circuiting part of the drug development process; it relies, as does the ANDA process, on FDA’s previous finding of Safety and Effectiveness for a drug product.

In summary, this brief overview illustrates that there is no simple route when introducing a new drug and there is more than one possible path to success.

Preparing for FDA Foreign Drug Inspection

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An FDA drug inspection can be a very stressful experience. If it is a pre-approval inspection there is a lot at stake concerning the outcome. If the company does not pass, the application (NDA/ANDA) may not be approved or the approval may be significantly delayed. But with proper preparation the stress level can be significantly reduced and the chances of a successful outcome can be greatly increased.

Foreign drug firms have an advantage over domestic U.S. companies in that the foreign firms are given prior notification concerning when the inspection will be done. This is not usually done for domestic U.S. company inspections.

In my last position with FDA as Director of the Division of Field Investigation, I was responsible for the management of the FDA foreign inspections. We found that if we did not give foreign companies prior notice we often arrived and the management staff required to complete the inspection were not present because of vacation or other travel. As a result it has been a longstanding FDA policy that foreign companies will get prior notice of planned inspections.

Foreign drug inspection pre-approval inspections are conducted under compliance program (CP) 7346.832 Pre-Approval Inspections. The three stated program objectives are:

  1. Readiness for Commercial Manufacturing.
  2. Conformance to Application.
  3. Data Integrity Audit.

Compliance Program CP 7356.002, Drug Manufacturing Inspections may be used in conjunction with the pre-approval program. The Drug Manufacturing Inspections program uses a “systems” approach to the inspection where coverage may be given to two or more of the following systems:

  1. Quality System.
  2. Facilities and Equipment System.
  3. Materials System.
  4. Production System.
  5. Packaging and Labeling System.
  6. Laboratory Controls System.

In your preparation for the inspection you should carefully study these compliance programs. They will give you good insights into what to expect. You must also conduct training of all staff that will be involved in the inspection. The compliance programs should be a part of that training and it should cover the “do’s and don’ts” during an inspection. All staff should:

  1. Support preparation efforts.
  2. Insure that work areas are orderly.
  3. Insure that all equipment and instruments are clean and calibrated.
  4. Insure that all logs and records are filled out completely, accurately, and legibly at time of performance.
  5. Answer questions honestly.
  6. Answer questions directly.
  7. “I Don’t Know” is usually acceptable (refer to person with knowledge and responsibility).
  8. Be professional.
  9. Be courteous.
  10. Be cooperative.

Staff should not:

  1. Volunteer information.
  2. Guess.
  3. Provide any misinformation.
  4. Provide any misleading information.
  5. Be confrontational or argumentative.

You should conduct “mock inspections” to help train staff. EAS Consultants often do this for companies and it is a very good exercise for inspection preparation.

You should also have an inspection plan with details concerning how all activities will be handled from the time the investigator arrives until he/she leaves. The plan should include provisions for taking notes during the inspection, maintaining copies of any documents that the investigators takes and duplicate samples if any are taken. As part of the plan, staff should be identified to accompany the investigator at all times.

The plan should also include provisions for a “war room” for use during the inspection. In the war room, staff will make a quick review of all documents provided to the investigators before they are presented. With this review, staff can be prepared to respond to questions if there are deficiencies noted in the documents and should not be surprised by the questions.

If there are deficiencies noted during the inspection the investigator will issue the FDA 483, List of Observations at the conclusion of the inspection. There normally will be daily wrap up discussions concerning the findings for the day. Those discussions can provide an opportunity to begin some corrections before the inspection is completed. The observation may still appear on the FDA 483 at the end of the inspection, but if corrections have been made the investigator will note those in the report.

If you do receive an FDA 483 at the conclusion of the inspection the investigator will have detailed discussion with management concerning the items. The investigator will expect management to say what corrective action will be taken. If possible, commitments for corrective action should be made. But be certain that whatever commitments are made can in fact be accomplished as FDA may return to confirm corrections.

If you do receive an FDA 483, a written response should be provided to FDA as soon as possible, but at least within 14 days. The response should detail all corrective actions that have been made or are planned. If there are a number of corrective actions and their completion will take considerable time, follow up status reports should be provided to FDA.

When investigators complete an inspection they prepare a written report, Establishment Inspection Report (EIR). The EIR details all of the findings of the inspection. The report is reviewed by FDA management and is classified as:

  1. No Action Indicated (NAI).
  2. Voluntary Action Indicated (company corrections should be made, but likely FDA will not take any administrative or regulatory action).
  3. Official Action Indicated. With this classification the drug application could be withheld and/or a Warning Letter may be issued.

In summary, with adequate preparation, the stress level of an FDA inspection can be decreased and the desired outcome can be made more certain. With a good plan and proper staff training you will likely have a successful outcome.

When Should a Drug Compounder Register as an Outsourcing Facility?

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When is it appropriate for a compounding pharmacy to register as an outsourcing facility under 503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act)?

The Drug Quality and Security Act (DQSA), signed into law on November 27, 2013, introduced Section 503B of the FD&C Act, which allows for compounding pharmacies to voluntarily register as an “outsourcing facility.” But registration is not appropriate in all situations. Pharmacies that intend for all of their products to be compounded in accordance with 503B requirements may choose to register. But pharmacies that do not intend to compound all products in accordance with 503B should not register as an outsourcing facility.

In February 2015, FDA released the following five guidance documents relating to human drug compounders:

The five documents indicate the agency’s current thinking on human drug compounding issues. The guidance also reviews additional regulatory requirements for compounders and addresses Good Manufacturing Practices (GMPs) as well as compliance with United States Pharmacopoeia 797 (which provides guidelines, procedures and compliance requirements for compounding sterile preparations).

Drugs compounded in outsourcing facilities are required to adhere to cGMPs. The new law does not provide any relief for compounding pharmacies from a FDA enforcement action concerning compliance for either traditional or outsourcing facilities from an FDA inspection. Traditional Compound Pharmacies are also subject to the FD&C Act, which can be built upon an FDA investigation where the inspection finds the possibility of contamination in which a drug may become adulterated.

An outsourcing facility is able to qualify for exemptions from the FDA approval requirements and the requirement to label products with adequate directions for use, as long as outsourcing facilities meet the following criteria:

  • Must comply with cGMP requirements,
  • Will be inspected by FDA according to a risk-based schedule, and
  • Must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products, they compound.

Beyond the cGMP requirements, outsourcing pharmacies should be aware of FDA’s criteria for identifying a violation as an unapproved drug. The criteria include any change to an FDA approved finished drug product with a different intended use or a change in the indications, dosage, route of administration, dosage form, strength or container-closure system, or misbranding because of inadequate directions for use or extra-label use. For example, an unapproved drug could be a finished approved IV drug and prefilled into a syringe without dilution, with the intent to use the drug other than the approved use. These are violations of the FD&C Act. The FDA/CDER Office of Compliance is responsible for determining whether a violation exists as an unapproved drug.

Drugs allowed to be outsourced will be published and codified by FDA, in addition to the criteria in the above guidance documents FDA has formed advisory panels to nominate a list of bulk drugs that will be permitted to be compounded.

Although there are several thousand unapproved drugs in the U.S marketplace, these drugs are exempted by grandfather statutes, such as those on pre-1938 drugs, OTC drugs, drug shortages, where FDA and States have arranged oversight. If compounded drugs are found in violation as an unapproved drug, FDA may stay silent with regard to enforcing the FD&C Act, because the agency takes a risk-based approach as part its mission to promote health.

If a compounder chooses not to register as an outsourcing facility and qualify for the exemptions under section 503B, the compounder could qualify for the exemptions under section 503A of the FDCA. Otherwise, it would be subject to all of the requirements in the FD&C Act applicable to conventional manufacturers. FDA anticipates that State boards of pharmacy will continue their oversight and regulation of the practice of pharmacy, including traditional pharmacy compounding.

There is also a concern when repackaging a drug or biological product that a change in the product’s characteristics as part of the repackaging could affect the product’s safety and effectiveness, and cause serious adverse events (SAEs). A biological product that is mixed, diluted or repackaged outside the scope of an approved Biologics License Application (BLA) is considered an unlicensed biological product under Section 351 of the Public Health Service Act and may not be legally marketed. FDA addresses the mixing, diluting or repackaging of a licensed biological product, but it does not address a biological product licensed for further manufacturing use, or to be used in a bulk drug substance.

Serious adverse event reports (SAERs) for outsourcing facilities under 503B are required of outsourcing facilities because the term prescription drug products includes any compounded drug product subject to the prescription requirements in 51 section 503(b)(1) of the FD&C Act. The agency’s AER guidance includes details on when and how to submit SAERs. For example, a 15-Day Alert Report should be submitted no later than 15 days after receiving an initial report of an adverse event.

Under the draft Memorandum of Understanding for use in agreements between individual states and FDA on distribution of compounded human drug products interstate, it is the state’s responsibility to investigate claims and report their investigation results back to FDA.

Animal Drug Compounding Guidance

In May 2015, FDA published draft Guidance for Industry #230 – Compounding Animal Drugs from Bulk Drug Substances. Dr. Douglass Oeller, EAS collaborating veterinary drug consultant, explains that the agency’s latest animal drug compounding guidance reiterates FDA’s long-standing position that sections 503A and 503B of the FD&C Act do not provide exemptions for drugs compounded for animal use.

The guidance seeks to rein in illegal compounding that competes with FDA-approved products while still allowing enforcement discretion when veterinarians must use products compounded from bulk drug substance to treat individual patients.

Legal compounding of animal drugs is restricted to re-formulation of FDA-approved human or animal drug products. This type of compounding is allowed in accordance with the regulations set forth in 21 CFR Part 530 for extra label drug use in animals.

However, FDA has always recognized that, if no drug is approved for a specific animal species or no drug is available under the extra label drug use provisions, an animal drug compounded from bulk drug substances may be appropriate. The draft guidance document provides a set of criteria for those situations. It addresses the source of bulk active pharmaceutical ingredients (APIs) and the need for an additional affirmation from the prescribing veterinarian when compounding from a bulk drug substance.

FDA’s New Medical Device Regulations 

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The Food and Drug Administration has recently implemented two new rules that affect all medical device manufacturers, initial distributors and repackager/relabelers.

The first new rule that went into effect on September 24, 2014, but up until now affected fewer than 10 percent of medical device manufactures, initial distributors and repackager/relabelers, is the Unique Device Identification (UDI) System. The agency is phasing in the UDI system over seven years. The new rule, established under 21 CFR Part 830, requires labels and device packages of medical devices distributed in the United States to include a UDI including easily readable plain text and Automatic Identification and Data Capture (AIDC) technology – usually a bar code.

The UDI rule also requires specified product information be submitted to FDA’s Global Unique Device Identification Database (GUDID). Most of the information in GUDID will be made available to the public. According to FDA, when fully implemented, the UDI system will serve several important public health objectives:

  • It will facilitate the healthcare community, industry, and the public’s rapid and accurate identification of a device using the UDI that appears on the device’s label and device package.
  • Medical providers, patients and others will be able to more easily access important information concerning the device, thereby reducing medical errors.
  • It will allow more accurate reporting, reviewing, and analyzing of adverse event reports so that problems can be identified and corrected more quickly.
  • It will provide a standard and clear way to document device use in electronic health records, clinical information systems, claims data sources and registries, leading to a more robust postmarket surveillance system which can be leveraged to support premarket approval or clearance of new devices and new uses of currently marketed devices.
  • It will enable manufacturers, distributors and healthcare facilities to more effectively manage medical device recalls.

FDA has accredited certain Issuing agencies to operate a system for the issuance of unique device identifiers. The information contained in the UDI must also be submitted to FDA using the GUDID. The manufacturer, initial distributor or repackager/relabeler whose name appears on the device label is considered the labeler and is responsible for complying with this new requirement. The labeler must designate an individual as the Regulatory Contact, which may be an employee of the labeler or a consultant. The Regulatory Contact is responsible for making sure that the labeler meets GUDID submission requirements.

EAS Consulting Group can assist your company by playing the role of Regulatory Contact or by acting as your company’s Third Party Submitter to submit your products’ UDIs to the GUDID.

electronic Medical Device Reports (eMDRs)

The second new rule, which goes into effect on August 13, 2015, is related to electronic Medical Device Reports (eMDRs), which is covered under 21 CFR Part 803. According to the FDA “Each year, the FDA receives several hundred thousand medical device reports of suspected device-associated deaths, serious injuries and malfunctions.” The new rule requires that all MDR reports MUST be filed electronically using FDA’s Electronic Submissions Gateway (ESG). In order to submit eMDRs via FDA’s ESG, you must either set up a Web Trader Account or work with a consulting firm that has a Web Trader Account.

EAS can help you set up a Web Trader Account so you can generate and submit eMDRs, or can generate and submit eMDRs for your company using EAS Consulting Group Web Trader Account.

FDA’s New Labeling Requirements for Restaurants and Vending Machines

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For more than 20 years, FDA has required full nutrition information on the labels of packaged foods. Late last year, the agency published two final rules requiring calorie and other nutrition information for foods sold in restaurants and similar retail food establishments – effective December 1, 2015 – and calorie labeling for food sold in vending machines – effective December 1, 2016. The two rules implement provisions of the Affordable Care Act of 2010.

Menu Labeling

The final rule for menu labeling covers restaurants and similar retail establishments with 20 or more locations, doing business under the same name and offering for sale substantially the same menu item. The covered establishments include:

  • Quick service or sit-down restaurants
  • Take-out restaurants
  • Pizza delivery establishments
  • Food establishments in entertainment venues (e.g., movie theaters, bowling alleys)
  • Cafeterias
  • Coffee shops
  • Superstores
  • Grocery and convenience stores

Food covered by the menu labeling requirements is “restaurant-type” food, which is defined as food usually eaten on the premises, while walking away, or soon after arriving at another location and either served in the establishment or processed and prepared primarily in the establishment. Examples of such foods are:

  • Meals in sit-down restaurants
  • Foods purchased at drive-through windows
  • Take-out food
  • Food ordered from a menu or menu board at a grocery store or convenience store
  • Foods you serve yourself from a salad or hot food bar at a restaurant or grocery store
  • A muffin at a bakery or coffee shop
  • Popcorn purchased at a movie theater or amusement park
  • A scoop of ice cream, milk shake or sundae from an ice-cream store

Alcoholic beverages are covered by the new requirements if they are standard menu items on menus or menu boards in covered establishments. Foods not covered are “grocery-type” foods which are eaten over several occasions or stored for later use (e.g., whole cakes, loaves of bread), foods intended for more than one person or requiring additional preparation before eating (e.g., pounds of deli meats and cheeses, large deli salads), and certain foods bought from bulk bin cases in grocery stores (e.g., nuts, dried fruits, olives from bulk bins).

Covered establishments must post calories for their standard menu items on their menus or menu boards and on signs for self-service food and food on display and provide to the consumer additional written nutrition information for these foods upon request. The covered establishments must also post a statement concerning suggested daily caloric intake and a statement about the availability of the additional nutrition information on menus and menu boards and on the signs for self-service food and foods on display.

A covered establishment must have a reasonable basis for the nutrition information it provides and be able to substantiate the nutrient values if requested by FDA. Restaurants and similar retail food establishments must comply with the menu labeling requirements by December 1, 2015.

Vending Machine Labeling

The final rule for vending machine labeling requires calories to be posted for foods sold in vending machines operated by a person who owns or operates 20 or more vending machines. Vending machines covered by the rule include those that sell:

  • Soft drinks and packaged snacks
  • Hot and cold cup beverages
  • Refrigerated prepared foods
  • Bulk candy and nuts

The calories must be placed on a sign near the article of food or selection button or electronically. If the food item placed in the vending machine permits the perspective customer to view the Nutrition Facts or otherwise provides visible nutrition labeling at the point-of purchase (e.g., front of pack labeling), no further calorie posting is required. Manufacturers of packaged food may want to consider providing front-of- pack labeling that includes calorie declarations for their products that will be sold in vending machines so that vending machine operators are not required to provide additional labeling.

Vending machine operators must provide their contact information on the vending machine so that FDA may contact them for enforcement purposes. Vending machine operators must comply with the vending machine labeling requirements by December 1, 2016.

Detailed information on these final rules is available on FDA’s website: http://www.fda.gov/Food/IngredientsPackagingLabeling/LabelingNutrition/ucm217762.htm

EAS consultants can assist you in understanding and complying with these new menu labeling and vending machine requirements.

  • On July 9, 2015 FDA announced an extension of the Menu Labeling Compliance date to December 1, 2016.  Read FDA’s announcement here.

Corporate Culture Meets FSMA Compliance at the Intersection of Food Safety

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When the FDA’s overhaul of food safety, the Food Safety Modernization Act (FSMA), is fully rolled out in 2016 it will be the largest change the U.S. food industry has seen. And yet with all the increased requirements for compliance there is one link that is not addressed and cannot be addressed by FDA, that of an organization’s corporate culture and employee internal commitment to getting it right.

How can the industry help further corporate culture and individuals to understand, care about and comply with their personal roles in food safety? Food safety culture is communicated not only through written protocols but through unwritten commitment to compliance and attention to detail. EAS Senior Consultants Tim Hansen, Joan Rosen and Joseph Famiglietti share their thoughts on how corporate culture affects a firm’s understanding and response to FSMA.

Food Safety Leadership from the Top Down

“There is no question in my mind that food safety leadership starts at the top,” says Tim Hansen. “There are several reasons. First, it is usually a regulatory requirement. Second, food safety concepts are not always simple so management has to implement procedures that protect food safety as the average line worker may not understand the concepts and third, a food safety problem can cause great economic harm to the producer. It is leadership’s duty to ensure that this does not happen.”

“A food company needs to have a continuous program in place to keep their employees involved with food safety,” adds Joe Famiglietti. “A problem that I’ve seen over the years is the highest ranking officer delegates quality control and training functions to certain employees and holds them responsible for ensuring these programs are successful. CEO’s need to get more involved in product safety and demonstrate their involvement to their employees. Employees need to know that food safety is critical to their jobs and that company management is playing an active role in implementing programs to ensure their products do not adversely affect the public.”

The culture of an organization plays a role, Hansen explains. “If all employees feel like they are part of the organization and the firm treats everyone fairly there is a good chance that employees will go the extra mile. Accomplishing food safety goals can be problematic when there isn’t a highly engaged work force.”

“Employees will care more about food safety when management demonstrates leadership by ‘walking the talk,’” says Joan Rosen. “Simple steps can go a long way to build trust and drive food safety commitment.” She also says that consistent communication and actions will help to convey the company’s food safety mission and vision. This can include posting reminders around the facility, or incentives for sharing examples of food safety practices and improvements with peers.

Training and Compliance – Lessons from HACCP

Hansen cites compliance lessons learned by FDA during the implementation of the 1997 Seafood HACCP rule. “Almost all the processors had findings on the FDA 483 form,” he says. Some firms clearly did not do their due diligence in conforming to the new regulations but most of problems were due to the sheer complexity of the new requirements. The processors did not really understand what FDA expected. FDA had a big learning curve in how to communicate these complexities and have largely succeeded.”

FDA is drawing on it’s experience with HACCP as it prepares to roll out new rules under FSMA. But companies will need to understand that simply conducting a hazard analysis and preparing a written HACCP plan may not be enough,” says Famiglietti. “They may need to take a closer look at their raw material suppliers and conduct more product testing and environmental monitoring to assure they are producing a safe product.”

“A lack of training is frequently the cause of errors,” says Rosen. “Training is not just a matter of sitting people down, explaining a set of instructions and then signing a paper saying ‘I attended and have been trained.’ Verifying the effectiveness of training is just as important or perhaps more important than the training itself.”

Getting it Right – Low Acid Canned Foods

Hansen, who was a Director in FDA’s Office of Seafood and the Director Seafood Inspection Program at NOAA Fisheries prior to joining EAS shares one of his many favorite examples of industry getting it right. “In the 1980’s there had been a couple of botulism outbreaks in canned salmon. These events threatened the viability of this product as consumers were justifiably wary.”

With a few notable exceptions, the industry “really rallied around the principles of food safety for Low Acid Canned Foods,” he says. “Everyone from the President of the companies to the workers on the line became very aware of the hazards associated with canning salmon and the possibility of a botulism outbreak and many important steps were taken to ensure food safety… Everyone involved in the salmon canning process understood that they needed to do more, from the line workers to the company management, to the trade association and government regulators. It is a success story for food safety since it is been over 35 years since there has been a food safety outbreak [in that industry].”

Sometimes food safety is as simple as a choice. As FDA and industry work together to further implementation and understanding of FSMA, remember that with buy-in from all levels these guidance documents will move from merely words on paper to a living document. Staying vigilant to the importance of everyone’s role will have a significant impact.

When the FDA Inspector Wants to Take Photographs

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Managing an FDA inspection is in itself a difficult task, but what should you do when an FDA investigator wants to take photographs at your facility? Whether it is pest sightings, equipment issues, or poor employee practices, the investigator has been trained by FDA to document situations such as these with photographs which can be used as evidence in a legal action.

If you do not permit photography, it is FDA policy to list this action in the inspection report as a “Refusal.” A photography refusal may be used against a company in a future legal proceeding to demonstrate a firm’s uncooperative regulatory attitude.

Your company should have written procedures covering the use of cameras in your facility by visitors, including FDA. The FDA believes they have the right to take photographs. Their procedures direct investigators to take inspectional photographs as deemed necessary without asking for permission to do so. Guidance is also provided to inspectors on how to handle photography refusals including obtaining the contact information for the firm’s attorney or other responsible individual so FDA management can discuss the refusal with them. The current FDA procedures regarding use of the camera are discussed in the IOM, Section 5.3.4.1 (http://www.fda.gov/ICECI/Inspections/IOM/default.htm). If refused, FDA may elect to obtain a warrant to take the desired photographs.

Your company may not want to allow FDA to use a camera in your facility for a number of reasons, including protection of trade secrets or concerns that the photographs may not accurately depict the conditions. Refusing to allow FDA to take photographs can cause delays in the completion of the inspection. The agency could consider this as a partial refusal of inspection and it may be viewed as a prohibited act possibly resulting in a regulatory action.

FDA published a guidance document discussing photography refusals at drug establishments as a behavior that could cause limiting of the inspection, which may result in an adulterated drug charge. The document, “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection” can be viewed at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM360484.pdf.

Although FDA has not published similar guidance regarding photography refusals in other FDA inspected facilities such as food firms, the agency would consider a test case to establish a court ruling on this matter.

At the onset of an inspection, the investigator will probably be carrying a camera as part of FDA issued inspectional equipment. If your company is in compliance, it is likely there will be no need for photographs. With concurrence from your legal advisor, perhaps you should consider having a respectful discussion with the investigator prior to the start of the inspection explaining your company policies and concerns. If your primary concern is protection of trade secrets, perhaps the investigator will be sensitive to your needs and exercise discretion when using the camera.

If an FDA inspector does take photographs, you should always take the same pictures for your own records. Rather than outright refusing any regulatory photography at your facility, you might request to take all photographs under FDA supervision with the agency getting all original discs or film. However, investigators prefer to take their own pictures and they would probably have to obtain supervisory permission to use your photographs.

In some instances, FDA might agree to allow industry participation in taking the pictures, if the agency prefers not to obtain a warrant. FDA considers each situation on a case by case basis and you might be surprised as to what you can get by having an open and honest dialog with the agency. Although the legal issues need to be resolved regarding FDA’s authority for camera use, it would be helpful to negotiate with the agency and perhaps reach some middle ground regarding your particular situation.

Welcome to Europe!

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You say color, I say colour. You say “dietary supplement”, we, legally, say “food supplement.” And of course, the French say “complément alimentaire,” the Danish say “Kosttilskud” and the Italians say “Supplemento Alimentare.” With 27 different Member States within Europe, there are many more ways to say “Food Supplement.”

Although the languages may not be harmonized, the good news is that there has been much progress in the past to harmonize controls on supplements in Europe.

The publication of the Food Supplements Directive in 2002 harmonized basic controls between EU Member States, such as definitions, the forms of vitamins and minerals that can be used and warning statements for use on labels. Together with other harmonized regulations, such as those on additives, novel foods, labeling and claims, it forms a good starting point for anyone looking to market food supplements in Europe.

However, Europe is made up of countries with long traditions and strong national identities so reaching agreements on new controls can be a challenge. The Food Supplements Directive made provision to harmonize other issues relevant to dietary supplements, such as maximum and minimum levels of vitamins and minerals permitted in a daily dose and controls on other nutritional substances used in supplements, but progress on these areas has stalled. On maximum levels that has been, in large part, due to a lack of agreement on how these levels should be derived relating back to national attitude towards food supplements. Typically, countries such as the UK, The Netherlands and Sweden have had a relaxed attitude, with no upper limits set other than for a minority of substances for which there is considered to be strong evidence of a risk to health. Other countries have a history of tight limits, such as 100% Recommended Daily Allowance (RDA) per daily dose of a vitamin or mineral supplement. With such diverse starting points, it is no wonder that the debate continues. Companies looking to sell food supplements in Europe therefore need to check the limits set by each Member State in which they wish to sell.

Beyond maximum and minimum levels, some Member States have created new laws to control the use of botanical substances in food supplements, with France the latest to publish new regulations in this area. Again, until such a time that harmonization is reached, companies need to work with a local market expert to ensure the formulation of their product is compliant with the requirements of each target Member State.

When it comes to labeling your dietary supplement, the majority of the requirements are harmonized and set out clearly in both the Food Supplement Directive and the Food Information Regulations. EU Member States may have minor additional requirements which need to be checked and incorporated before notification to the local market authority and commercialisation.

Launching into Europe will take time, patience – and often a little humor to help overcome cultural differences. A complete dossier of formula, detailed raw material specifications and the proposed label declarations will go a long way towards making the process faster and smoother.

Lessons Learned from the Implementation of Seafood HACCP for FSMA

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One of the tenets of FSMA is the requirement for preventive systems (AKA HACCP) for all food groups regulated by FDA. Up to the time of passage of FSMA, FDA wanted preventive systems only for seafood, fruit and vegetable juices and low-acid canned foods. Since the requirement for preventive systems is about to be extended to all foods regulated by FDA it may be instructive for affected food firms to consider some of the common problems experienced by the seafood industry during the implementation of HACCP. This regulation has been highly successful and truly promoted seafood safety and consumer confidence in these products. There are several useful lessons that may make your transition to compliance easier.

  1. Unnecessary CCP’s. Implementation of the Seafood HACCP regulation came with a great deal of uncertainty for the industry.   Their response was to include a hazard as a CCP even when it did not meet the FDA “reasonably likely to occur” standard. This resulted in some cases overly complicated HACCP plans.   Firms can avoid this problem through rigorous hazard analysis and following agency guidance for the commodity being processed.
  1. Mixing sanitation controls with HACCP controls.The Seafood HACCP Regulation requires that certain aspects of sanitation be properly controlled, monitored and documented through records. While it is feasible to include these controls within the HACCP plan it is much simpler keep sanitation controls separate from HACCP controls.   A sanitation SOP is highly recommended that show how sanitation is controlled, monitored and recorded.
  1. Monitoring need to be available in their original form in an organized fashion.Inadequate or poorly organized monitoring records were a big problem. Ideally, records should not be rewritten unless absolutely necessary. Rewritten records are a red flag to FDA investigators.   If records are missing do not falsify information to fill the gaps. This could be the basis for a severe regulatory action. It is much better to perform a verification review and corrective action that is available to the investigator.
  1. If a new product is introduced to your processing operation the HACCP plan should be amended immediately.Do not wait until a convenient time as a regulator could show up at any time. Also, do not assume that the hazard analysis and HACCP plan for a similar product will be the same.   Either can result in a finding of failure to have a HACCP plan. You should start at the beginning with a proper hazard analysis and develop the plan for that product in accordance with the hazards you identify.
  1. Scientific studies used to establish a critical limit for a CCP should be readily available to the investigator.For example, a study to show the necessary heat penetration time-temperature parameters of a cooked product to achieve sufficient bacterial kill or the proper mix of salt, water and exposure time to achieve a proper level of water phase salts in a cold smoked fish products are important information for the investigator to evaluate whether the critical limit of a CCP is adequate to control the hazard.
  1. Generic HACCP plans should not be used.In the past some operations adopted a generic HACCP plan to cover their processing without performing a hazard analysis.   This often resulted in hazards being missed and a faulty plan. FDA expects that each firm will conduct a hazard analysis.   Not doing so could result in a serious charge.

Verifying Label Claims “By Input” Unacceptable

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The FDA regulations dictated in 21 CFR 111, Current Good Manufacturing Practice (cGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, require that each batch of a finished dietary supplement product must meet quality requirements for identity, purity, strength, composition, and limits of potential contaminants.

Criteria used to establish that these requirements are met are supposed to be provided in a Finished Product Specification developed by the dietary supplement company. FDA issued more than 400 Warning Letter citations for inappropriate specifications in 2013 and 2014. Many of these violations were due to a failure to have Finished Product Specifications at all, but recent Warning Letters have also noted that using solely the input of a dietary ingredient for verifying the strength “By Input” is unacceptable.

The input of a dietary supplement alone is not a scientifically valid analytical test method for determining the strength of a dietary ingredient in a finished product. Chemical testing of the ingredient should be accomplished whenever possible. If that is not possible due to the unavailability of a scientifically valid test method, the testing may be exempted provided dietary ingredient raw material testing, in-process testing, other finished product testing, process controls, and additional information can support that the strength of the dietary ingredient can be verified without testing, as allowed in 21 CFR 111.75(d)(1).

The incoming dietary ingredient raw material must be verified to meet quality requirements for identity, purity, strength, and the lack of potential contaminants. Warehouse controls must then ensure that the material is held in a condition in which its quality is not altered. The material must be formulated at an appropriate amount, with sufficient overage, to meet the label claim while taking into account manufacturing variability. This is dictated in an approved Master Manufacturing Record (MMR). Once executed, the Batch Production Record (BPR) must document that the correct amount of the dietary ingredient was actually dispensed into the product during manufacture. Established in-process examinations and tests are then used to verify that the batch is uniformly mixed and meets the unit dosage weight and weight variation requirements. Variations on weight cannot exceed the overage amount to ensure that even the smallest dosage unit still complies with the label. In-process chemical tests can also be employed to verify the amount of a dietary ingredient. This can be particularly beneficial if the reason a dietary ingredient is exempted from testing is because of matrix interferences or instrumental quantitation limits.

Other finished product testing can also be used to support that an exempted ingredient is present in the product at the correct, labeled amount. Test results from chemically similar ingredients that are determined to be as expected suggest that the exempted ingredient is also present at expected levels because these ingredients will tend to react the same way during manufacture, especially if both ingredients are introduced and processed in the same step. Results obtained from finished product testing of other ingredients whose concentrations are associated with the exempted ingredient may also support that the exempted ingredient is present as expected.

Finally, the number of other finished product ingredient tests that are performed is important. If all other test results are determined to be within specification, it indicates that the product was manufactured according to the MMR and there is no reason to expect anything different from an exempted dietary ingredient.

Dietary supplement companies that are compliant with all parts of 21 CFR 111 will already be performing these activities. A procedure that summarizes the overall process of verifying the addition of a dietary ingredient can then be created and used as the test method reference on the Finished Product Specification. A separate document that describes the details of test exemptions per product should also be generated. The actual result obtained should be acquired from the completed batch production record.

The “By Input” approach is no longer relevant.

From FDA Ombudsman to EAS Consultant

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Every Center in FDA, except CFSAN, has an Ombudsman; there is also an Ombudsman in the Office of the Commissioner. I am the only person to have served as the Ombudsman in two different Centers: the Center for Tobacco Products (CTP) for three years and the Center for Devices and Radiological Health (CDRH) for ten years, working in the Office of the Center Director in each position.

An FDA Ombudsman investigates external complaints about the agency; negotiates, mediates or otherwise facilitates the resolution of disputes between FDA and regulated companies; and responds to inquiries from stakeholders who have been unable to get answers elsewhere in FDA.

An Ombudsman, accessible to regulated industry, eases their way to being heard; listens to their issues and concerns; informs them of the regulatory process; and strategizes with them on options to challenge or appeal a decision. Often an Ombudsman is the catalyst that results in an equitable solution to a problem.

I think that having been an Ombudsman at FDA is the perfect segue to being a consultant to companies regulated by FDA. Both roles involve advocating for fairness on behalf of industry; fostering meaningful engagement with the agency; and providing information and assistance to companies in resolving specific issues and problems.

Based on my experience as the CTP Ombudsman, I can help EAS tobacco clients navigate their way through a new Center with new procedures and in compliance with a new law. Specific tobacco topics I have been involved in include: substantial equivalence, deeming (e-cigarettes, cigars, hookah), retail inspections and compliance, menthol, export/import, harmful and potentially harmful constituents, labeling, registration, standards, modified risk, adverse events, graphic health warnings, flavor ban, and user fees.

EAS clients can also benefit from my CTP and CDRH experience handling more general issues that are of concern to all industries that are regulated by FDA, not just tobacco and device companies. These included: level playing field, transparency, regulatory compliance, status of premarket and other submissions, miscommunication or lack of communication, meeting requests, difficult or unresponsive FDA employees, and of course dispute resolution. I also attended meetings between companies and FDA to ensure that they were listened to in a forum that was conducive to effective and productive dialogue.

I am available to make presentations at conventions, conferences, workshops, and other industry sponsored meetings on my new role as an EAS Senior Consultant. This is part of my outreach efforts to inform trade and professional associations and their members about what I did as an FDA Ombudsman, how I did it, and how I might now be of assistance to EAS clients and potential clients.

FDA’s Generic Drug User Fee Act (GDUFA) – Drug Master Files (DMFs)

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Two years have passed since passage of the Generic Drug User Fee Act (GDUFA).

GDUFA is a significant law that introduced new requirements for active pharmaceutical ingredient (API) manufacturers, including fees associated with their Type II drug master files (DMFs), as well as for establishment registrations and for conversion of type II DMFs into Electronic Common Technical Document (eCTD) format.

The FDA does not require that a DMF be filed. The information may be submitted directly in a new drug application (NDA) or in an abbreviated new drug application (ANDA). So why submit a DMF? One reason is to maintain confidentiality of the proprietary information of the active pharmaceutical ingredient. Another is that a single DMF may support multiple applications.

Currently, FDA does not require that the DMF be submitted in eCTD format, but the agency has said the electronic format can aid in the review of the application.

Upon receipt of an initial submission, FDA’s DMF staff will check that the file is complete. If the file is found acceptable, the agency will send a letter to the DMF holder (for foreign DMF holders, the U.S. Agent will receive a copy of the letter) acknowledging receipt of the DMF. If the file is found to be incomplete, a letter will be sent detailing the missing information. Once that information has been provided, FDA will issue the acknowledgement letter. DMF holders are obligated to submit all changes as amendments, to notify authorized parties of changes, to properly maintain the DMF (with annual reports), and to issue Letters of Authorization to each customer to the DMF.

Reporting a change to a DMF can be done at any time through the submission of an amendment. But the DMF holder needs to notify customers of any changes.

It is important for DMF holders to remember that DMFs are not approved or disapproved by the agency. A DMF is reviewed to determine whether it is adequate to support a specific application. If the file is acceptable, FDA will consider it available for reference and will issue a letter to the DMF holder indicating that it has “No Further Comments.”

The Drug Master Files require a one-time only fee. If a holder has paid a DMF fee for a Type II active pharmaceutical ingredient, the holder is not required to pay a subsequent drug master file fee when that Type II active pharmaceutical ingredient drug master file is subsequently referenced in drug application submissions. According to the Act, the DMF fee will be due no later than the date on which the first generic drug submission is submitted that references the associated Type II API DMF. FDA is recommending that the DMF fee be paid at least 6 months prior to the submission of an ANDA. This will ensure that the Completeness Assessments can be performed and the DMF will be available to reference. This will require the ANDA applicant and DMF holder to communicate regarding the timing of the submission of the application. FDA has issued a draft “Guidance for Industry: Initial Completeness Assessments for Type II API DMFs Under GDUFA” listing the information the agency will check for in the DMF.

In addition, FDA will be accepting written requests from the DMF holder within 10 working days from the issuance of a deficiency letter to discuss any questions regarding the letter. The holder will need to provide an outline of the questions to be addressed and will be limited to the content of the deficiency letter. FDA will allow for a 30 minute conference call per DMF holder per month.

FDA will be performing risk-adjusted biennial cGMP surveillance inspections of the API and finished dosage form (FDF) manufacturers. The agency will be prioritizing inspections related to ANDAs that are approvable or eligible for tentative approval and establishments that have not previously been inspected. FDA will post the inspection classification results and the date of the last inspection on its website. Also, the agency will be making use of foreign inspection classifications.

In addition to the user fees on the type II DMFs, FDA will impose an annual fee for each facility registration of an API manufacturer. Here is the fee schedule for FY 2015, which began October 1, 2014.

GDUFA FEE SCHEDULE FOR FY 2015

Fee Category Fee rates for FY 2015
Original ANDA $58,730 (per application)
PAS* ANDA $29,370 (per PAS)
DMF $26,720
Domestic Facility FDF $247,717 (per facility)
Foreign Facility FDF $262,717(per facility)
Domestic Facility API $41,926 (per facility)
Foreign Facility API $56,926 (per facility)
  • Prior Approval Supplement

The Importance of Food Recall Readiness

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Product recalls are a fact of life in the food industry. Recalls occurred an average of 12 times per week. Allergens remain the largest cause of recalls, due to mislabeling, cross-contamination or being undeclared. Large recalls of peanut products, eggs, ground beef and cantaloupe in recent years remind us of the potentially devastating impact of food recalls on the food industry. The good news is that there are measures the food industry can implement to significantly reduce or prevent situations which require product recalls. According to Dan Sowards, senior consultant at EAS Consulting Group, due diligence is critical in protecting against recalls.

On the issue of food safety, Willie Bryant, senior EAS consultant, points out that having the authority to order a food recall gives the FDA leverage over firms hesitant to initiate a recall voluntarily. This is a new authority of FSMA that did not exist during Willie’s 33 years of working in recall operations at the FDA.

It is highly unlikely that an FDA-regulated food firm would fail to protect the public, the company and its brand by refusing to take a recall action after receiving notification from FDA that a recall action is necessary. If the firm takes the action based on the notification by FDA and an FDA order to recall is not required, the recall is still considered “voluntary”, as are all other class I, II, or III recalls.

FDA’s enforcement power for FSMA’s provision for a foreign supplier verification program mandates an approved food safety plan, requires extensive documentation, and audits to satisfy the new proactive science-based preventive control measures. These regulatory provisions will have far reaching implications for recall, shipment tracking and traceability requirements for imported food products including private-label foods manufactured outside the United States. Compliance with FSMA requirements will require smart innovations by the food industry to keep costs down.

Effective product tracking and traceability are vital for speedy trace-back or trace-forward to identify affected products and to remove them from suppliers’ warehouses, retailers’ shelves and consumers’ refrigerators and pantries. A centralized, electronic system that can quickly trace UPC/SKU product codes linking all material ingredients, rework, process conditions and the customers is desirable in any traceability system.

Effective product tracing is an important piece of the puzzle during recalls or foodborne illness outbreaks. In addition to helping to quickly remove adulterated products from the food supply, it assists in pinpointing the problem area within the food production system so corrective action can be taken. A traceability system also provides good record keeping compliance for food defense in case of bioterrorism or economic-motivated adulteration. The effectiveness of the system should be validated annually through mock recalls and traceability testing to ascertain the preparedness of the recall protocol and the recall implementation team.

Staff training is critical at every level of the operational process. Companies should invest in a quality program that evaluates and updates its recall implementation capabilities. From there, your organization can plug in the gaps and protect your business against recalls, reduce recall operational costs, and protect your business brand.

It makes a lot of business sense to invest in proper training of staff and preparedness for a multi-disciplinary recall team that is ready to roll at a moment’s notice. To put the cost of recall readiness or the cost of recall reduction strategies in perspective, managers should consider the colossal cost of implementing a recall and the added cost of recovering from such a huge exercise, including brand image laundering to regain the eroded customer confidence.

EAS can provide specialized training that deals with the nuts and bolts of effective recall and traceability system, emphasizing FDA roles and requirements, best practices for trace-back and trace-forward, legal and regulatory challenges, the recall decision making process, risk assessment/testing, and time management before and after recalls. Other training modules include effective risk communication and media management, creation and preparedness of a multi-disciplinary recall team, and recall reduction strategies. The training highlights specific steps that companies can take to avoid situations that may lead to recalls or to minimize the extent of a recall and its impact on the business.

Expediting FDA Approval of Sunscreen Ingredients

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Eight new sunscreen active ingredients have been awaiting approval—or any sort of decision—from the FDA for at least 12 years, with the last over-the-counter sunscreen ingredient approved by the agency in the 1990s. Meanwhile, some of these sunscreen ingredients have been available in Europe, Asia, or Latin America for more than 15 years.

However, the 12-year backlog may soon be ending. On July 28, the House of Representatives passed a bill, HR 4250, known as the Sunscreen Innovation Act, to expedite the FDA’s approval process for sunscreen ingredients. The Sunscreen Innovation Act passed by a voice vote just before Congress left for their August recess. The bill is expected to be taken up by the Senate in the near future.

The legislation aims to improve on FDA’s latest attempt to make new OTC active ingredients more available—a 2002 procedural change from the FDA that the agency hoped would speed up its approval process. In 2002 the agency created a new process, called the Time and Extent Application (TEA), to give an alternate pathway for over the counter drug ingredients to be approved. Since then, eight sunscreen ingredients have been submitted for review under that process; none has yet been approved.

Without a single ingredient being approved since then, Rep. Ed Whitfield (R-KY) and John Dingell (D-MI) introduced HR 4250, the Sunscreen Innovation Act. HR 4250 sets up a system under which sunscreen active ingredients that have been marketed continuously for at least 5 years in another country and that meet certain other conditions, would be eligible for review by an FDA advisory committee. After the advisory committee issues a recommendation, FDA would have 45 days to affirm or deny the recommendation. If FDA didn’t deny an approval recommendation within 45 days, the sunscreen would automatically be approved as generally recognized as safe and effective. The bill also provides an appeals process for situations in which the sponsoring company disagrees with the FDA determination.

The Sunscreen Innovation Act not only would institute a timeline for review, it would no longer require the FDA to issue a regulation every time it wants to approve an active ingredient. The bill requires final decisions on pending applications within 300 days for new requests and a shorter timeframe for requests that were pending before enactment of the law. Under current law, if an ingredient is on the market in another country for five years, it may go through a process to be determined eligible by the FDA. FDA’s advisory committee of experts weighs in on the safety and effectiveness of the product, and the agency then makes the final determination as to whether the ingredient is approved. However, there’s currently no timeline for review or decision making.

The Sunscreen Innovation Act also directs the Comptroller General of the Governmental Accountability Office (GAO) to report on the progress of the Secretary of HHS in establishing this new process and the role of the FDA Commissioner in issuing determinations on pending sunscreen active ingredient requests. It requires the HHS Secretary to report on decisions made about the safety and efficacy of sunscreen active ingredients, the amount of time between submission and decision for each request, the cost of the review process, and recommended improvements to the review process.

Prior to passage of the bill, an FDA spokesperson said that the agency has “prioritized reviewing the safety and effectiveness of additional sunscreen ingredients as quickly as possible given the agency’s resources.”

FDA recently issued feedback letters about two sunscreen ingredients. Both asked for more data to prove the ingredients are generally recognized as safe and effective. Andrea Fischer, a spokeswoman for the FDA, said that “the FDA will issue responses to the safety and efficacy data submitted for each ingredient in the near future. We are committed to completing the TEA process for the sunscreen active ingredients currently under review as quickly as possible, consistent with available agency resources and competing public health priorities.”

It remains to be seen if the Senate will pass this act and if passage of the act could set a precedent for expediting the approval process for other categories of OTC active ingredients.

FDA to Enforce New Infant Formula Rules Immediately

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An estimated one million infants (roughly one-third) in the United States are fed infant formula from birth, and by the time they are three months old, about 2.7 million (roughly two-thirds) rely on formula for at least part of their nutrition. US-produced and packaged infant formula is in high demand internationally because of its excellent safety and nutrition record and because of the concerns raised by the melamine scandal in China and the tainted milk powder incident in New Zealand.

Based on a number of unfinished infant formula regulations and the need to update existing regulations, FDA published an interim final rule on February 10, 2014 and announced on June 9, 2014 that it was finalizing this rule, intended to set standards for the manufacture of infant formula either processed in the US or intended to be marketed in the US. The final rule is similar to the interim rule with a few modifications based on comments received by the agency after the February 2014 publication.

While infant formula processors have been applying many of the newly required Good Manufacturing Practices (GMPs) as part of their own internal product safety and quality programs, these finalized GMPs and other parts of the new rule now become federally enforceable. As a result, the industry requested that FDA delay enforcement to allow the industry to become familiar with and implement these new requirements. FDA rejected industry requests, setting a date of September 8, 2014 for manufacturer compliance. It is hoped that for the rest of 2014, FDA will instruct its field inspection/auditing staff to be reserved in their enforcement to allow the industry time to adapt to the vast new regulation, but there is no certainty of this.

Below is a reference table with links to additional information as well as the complete and final GMPs for infant formula processing.

The final rule applies only to infant formulas intended for use by healthy infants without unusual medical or dietary problems. Under the final rule, some points addressed include:

  • Current good manufacturing practices specifically designed for infant formula, including required testing for the harmful pathogens (disease-causing bacteria) Salmonella and Cronobacter.
  • A requirement that manufacturers demonstrate that the infant formulas they produce support normal physical growth (of infants).
  • A requirement that infant formulas be tested for nutrient content in the final product stage, before entering the market, and at the end of the products’ shelf life.
  • A few other existing requirements:
  • “Use by” date. This is the date after which a package or container of infant formula should not be fed to infants. It indicates that the manufacturer guarantees the nutrient content and the general acceptability of the quality of the formula up to that date. FDA regulations require this date to be specified on each container of infant formula.
  • Storage. Manufacturers must include instructions on infant formula packaging for its handling before and after the container is opened. They must also include information on the storage and disposal of prepared formula.

FDA does not approve infant formulas before they can be marketed. However, all formulas marketed in the United States must meet federal nutrient requirements, which are not changed by the new rule. Infant formula manufacturers are required to register with FDA and provide the agency with a notification prior to marketing a new formula. Proof of compliance with existing and new requirements will be required when FDA investigators conduct their annual inspections/audits of all infant formula processors selling product in the US market. In addition, FDA also collects and analyzes product samples. Based on the inspections/audits and sampling, if FDA believes that an infant formula presents a risk to human health, the manufacturer of the formula must conduct a recall.

Additional references regarding the FDA requirements for processing infant formula for the US market include:

  • 21 CFR 106 Infant Formula Quality Control Procedures
  • 21 CFR 106.100 Records and Reports Regulations
  • 21 CFR 107.3 – 107.30 Infant Formula Labeling Requirements
  • 21 CFR 107.50 Exempt Infant Formulas
  • 21 CFR 107.100 Nutrient Requirements for Infant Formulas
  • 21 CFR 107.200 – 107.280 Infant Formula Recall Requirement

If you have additional questions regarding this new extension of the existing US FDA infant formula regulation or experiences with FDA enforcement of this new rule, please feel free to contact Mr. Sayler at asayler@easconsultinggroup.com.

The Impact of Social Media on FDA-Regulated Products

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Historically, it has been straightforward for the FDA to review and monitor labeling and advertising for products under their jurisdiction, particularly drugs and medical devices. However, the widespread use of the internet and social media has added increasing complexity to the issue for the agency as well as for FDA-regulated industries.

As a result, the FDA issued several guidance documents this year and, while applicable only to prescription human and animal drugs and medical devices, they should be used to gauge the agency’s current thinking with regard to social media and its use for promoting the products they regulate. The first guidance, issued in January, clarified FDA’s position on what constitutes interactive promotional media and how manufacturers, packers, distributors and those entities acting on their behalf can fulfill their regulatory obligations with regard to such communications. In June, the agency issued two further guidances; one detailing how firms should go about correcting misinformation that is disseminated through a third party and another addressing how risk and benefit information should be presented for those social media platforms with character space limitations, e.g., Twitter. It is clear that this subject is being given considerable attention at the FDA.

These guidances stress that firms are responsible for promotional communications and other content on internet-based platforms that they own, control, create, influence, or that are operated by, or on behalf of themselves (or any employee or agent working for them.) For content posted on third party platforms, a firm may also be responsible if it has any control over or influence on that platform. The FDA recommends that firms clearly disclose their involvement with any platform for which they own or influence the content.

However, the internet and associated technologies have made it easier for those not affiliated with these firms to disseminate product information. This user-generated content (UGC) created by third party entities may be incorrect or incomplete, thus potentially endangering public health either by understating safety information or inflating the benefits of a particular product.

The FDA’s position is that firms are “generally not responsible” for third party UGC as long as they are truly independent of its source. However, if a firm voluntarily chooses to correct misinformation of which they become aware, the FDA has set forth specific recommendations as to how this should be accomplished and recommended that records be maintained accordingly.

While these guidance documents are applicable only to prescription drugs and medical devices, it is reasonable to expect that the FDA believes these same principles apply to OTC drugs, dietary supplements, foods and cosmetics. For such products, the FDA regulates the content of the labeling and the Federal Trade Commission is responsible for regulations regarding advertising. However, on social media platforms the information may be presented in such a way that it could be considered both labeling and advertising. For example, a website or Facebook page may include product usage details and claims, as well as a link to purchase the product or “Share” or “Like” it to another site.

Indeed, a recent FDA warning letter issued to Zarbee’s Inc., a dietary supplement company, dealt with just this issue. While other companies have received warning letters for making false or misleading claims on their websites, in this instance the agency also cited Zarbee’s for personal testimonials that had been posted and subsequently “Liked” on their Facebook page. These “Likes” were considered equivalent to an endorsement or promotion of Zarbee’s products that were, as formulated and labeled, considered “new drugs” and hence subject to FDA oversight.

In all cases, firms must ensure that any communication for which they have control or oversight is truthful, not misleading and substantiated. Although they may not be held responsible for content generated by third parties, they should be careful not use such information or endorsements in their own advertising and promotions. In addition, firms should consider correcting any misinformation of which they become aware, particularly if it is a safety issue.

Social media is a powerful tool and fast-evolving information platform. There is no doubt that the FDA, FTC and other regulatory bodies worldwide will further define and clarify their approaches to monitoring and regulating advertising and promotion of products this way. It would therefore be wise for industry to become familiar with current agency expectations and stay abreast of future developments. In addition, companies should have their websites and social media sites reviewed for compliance with FDA regulations to ensure that all of the content is truthful, substantiated, permissible and not misleading.

Follow-Up to the July Issue of the Month

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Our July Issue of the Month article titled “Why Submit a GRAS Notification for a Dietary Ingredient?” drew a lot of attention from readers. In this follow-up note, Jim Hoadley responds to one significant question.

Is an NDI exempt from the NDI notification requirement when the same substance is the subject of a food ingredient GRAS determination, but the ingredient has not been marketed as a conventional food ingredient?

Good question – I’m glad you brought it up because the newsletter article was not as clear as it could have been on this point. The NDI notification requirement exemption is for “ingredients which have been present in the food supply as an article used for food…” Submitting a GRAS notification does not exempt a dietary ingredient from the NDI notification requirement – the GRAS determination is only the first step and it must be followed by actually getting this ingredient into the food supply through marketing it as a food ingredient. Submitting the GRAS notification to FDA is voluntary; however, when your use of a new ingredient as a GRAS food ingredient serves as an alternative to a NDI notification then it is wise to submit the GRAS notification as documentation of your conclusion that the consumption of the ingredient will be safe. In this sense the FDA’s GRAS Notification Program serves as a substitute to an NDI notification. GRAS self-determination as a food ingredient is not a path to be used to avoid submitting a safety notification for your NDI.

When you have submitted a GRAS notification for a food ingredient use; but, have not yet actually marketed the ingredient for the food use then the ingredient is NOT present in the food supply. The exemption from the NDI notification requirement kicks in only when the ingredient is present in the food supply.

When the marketing of a substance as a GRAS food ingredient is being used as a substitute for submitting an NDI Notification there are a couple points to keep in mind. Firstly, ingredients specified in the GRAS Notification and the NDI must be in the same chemical form without alteration. Secondly, the NDI consumption resulting from its dietary supplement use should be the same as, or lower than, the intake level that has been determined to GRAS.

Why Submit GRAS Notification for a Dietary Ingredient?

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A new dietary ingredient (NDI) is a dietary ingredient that was not sold in the United States as a dietary supplement ingredient before October 15, 1994. Manufacturers of NDI-containing dietary supplements must notify FDA of their intent to market a NDI-containing supplement at least 75 days before the supplement is marketed in the U.S. The NDI Notification must thoroughly identify the NDI, how it is used in the NDI-containing supplement, and present the evidence the manufacturer relied upon to determine their use of the NDI in the supplement is reasonably expected to be safe. The NDI Notification requirement applies to every NDI-containing dietary supplement regardless of whether other firms have submitted NDI Notifications on the same substance. There is an exemption to the NDI Notification requirement provided for dietary supplements containing only NDIs that have been used for food in the same chemical form as is being used as a NDI (21 U.S.C. 350b(a)(1)). FDA has codified these requirements at 21 CFR 190.6.

FDA discussed its positions on NDI related issues in a draft guidance. One Q&A in the FDA’s guidance speaks directly to whether a NDI Notification would be required for a NDI that also has a GRAS food ingredient use. FDA noted that a substance legally marketed as a food ingredient in conventional food would be exempt from the NDI notification requirement because it has been present in the food supply as an article used for food in a form in which the food is not chemically altered. Submission of a GRAS Notification will establish a basis for a NDI to be legally marketed as a food ingredient.

The NDI Notification process intended in DSHEA for FDA to have some oversight on dietary supplement manufacturers’ safety assessments of their NDI-containing dietary supplements. However, in some situations it may make more sense to submit a generally recognized as safe (GRAS) Notification for NDIs.

Dietary Ingredients, are defined (21 U.S.C. 321(ff)(1)), include (a) vitamins, (b) minerals, (c) herbs or other botanicals, (d) amino acids, (e) dietary substances for use by man to supplement the diet by increasing the total dietary intake, or (f) concentrates, constituents, extracts, or combinations of the (a) through (e) ingredient categories.

Something such as a new, patented bacteria strain does not qualify as a dietary ingredient because it is not one of the categories named in (a) – (d), nor is it a “dietary substance” (category (e)) because it has never been in the human diet. Thus, FDA is likely to reject a New Dietary Ingredient (NDI) Notification for the new bacteria strain on the basis that the substance is not a dietary ingredient.

Submitting a GRAS Notification for food ingredient applications of the new bacteria strain establishes food ingredient uses for the new bacteria strain. A substance’s GRAS Notification becomes the basis to assert that the substance is a ‘dietary substance for use by man to supplement the diet’ and thus eligible as a dietary ingredient use.

When the substance of interest for dietary ingredient use is NOT clearly in one of the (a) – (e) dietary ingredient categories, then submitting a GRAS Notification will be imperative because there is a great risk that a new dietary ingredient (NDI) Notification would be rejected outright on the basis that the substance does not qualify as a dietary ingredient and thus cannot be a NDI.

Taking the GRAS Notification path allows supplement manufacturers to side-step the need for filing multiple NDI Notifications for each NDI-containing dietary supplement.

Section 413 of the FD&C Act states that a NDI Notification is not required of a dietary supplement containing only dietary ingredients which have been present in the food supply as an article used for food [413(A)(1)].

Submitting a GRAS Notification for food ingredient and dietary ingredient applications of a substance establishes there are recognized uses of the substance “as an article used for food.” Dietary supplements are not subject to the NDI Notification requirement when they contain only dietary ingredients which have been present in the food supply as an article used for food. A substance’s GRAS Notification becomes a basis to assert that the substance is in the food supply as an article used for food and therefore exempt from the NDI Notification requirement.

The NDI Notification requirement applies to each dietary supplement containing a NDI irrespective of how many previous NDI Notifications have been submitted for the same NDI. It would be advantageous for a dietary ingredient supplier to submit a GRAS Notification for a NDI substance (establishing the NDI substance to be in the food supply) and thereby exempting the NDI from the NDI Notification requirement.

Follow up (August 2014)

Proposed Changes in Nutrition Labeling – Time to Make Your Comments

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In March, FDA published proposals for changes to Nutrition Facts and Supplement Facts. The proposed changes include reformatting of all conventional food labels in the servings per container and calorie declarations. The specifics of the new format may change a little based on information in comments, but it is likely that the basic approach of increasing emphasis on calorie consumption will remain in the final requirements. Most dietary supplement labels would not have to make this change. Other major changes include the addition of Vitamin D and potassium as mandatory nutrients instead of vitamins C and E and the requirement for declaration of added sugars. These changes will impact essentially all labels.

Proposed revisions in Daily Values (DV) may not only require revising the label, but some companies would need to consider reformulating some of their products. Changes in Reference Amounts Customarily Consumed (RACC) would result in serving size changes, but just as important, would result in changes in whether some products qualify for claims. The proposed DVs and RACCs are not likely to be different in the final regulation unless new, persuasive data are provided to FDA in comments.

For more information including the proposals and information on submitting comments see: http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ LabelingNutrition/ucm385663.htm. Companies should be diligently studying the proposals to see how the changes will affect them so that they can submit comments to FDA to ask for different provisions. FDA had originally set June 2 as the deadline for comments, but they have now extended the deadline until August 1. Comments must include data and/or other information to justify requests for different requirements.

Once the comment period has closed, FDA will analyze the issues raised in the comments, prepare responses to all the issues and develop a final regulation. This ordinarily would take about two years, but there appears to be a sense of urgency at the agency that could result in a final regulation by the end of 2015. FDA proposed 60 days after publication of the final rule for the effective date of the regulation and there would be two years after that date for changing labels. The agency didn’t specifically say how we should interpret these dates, but I think it means that any label revised after the effective date must comply with the new requirements and all changes must be completed within the two years. Generally, that would mean any product initially shipped in interstate commerce after the final date (60 days + 2 years after publication) must comply with the new requirements.

The sooner that companies begin to absorb the changes, the smoother will be the changeover. Some industry staff can remember the trauma of creating the Nutrition Facts in the early 1990’s when the NLEA became effective. Numbers of companies found themselves in tight straights with late changes and waiting lines at the printers at the last minute. More recently, there was the addition of trans fat to Nutrition Facts in 2006, which required a relatively small adjustment compared to the changes coming now.

Betty Campbell will be speaking more on this subject in a session called “Anticipating FDA Proposed Changes to Nutritional Facts Labels,” Monday, June 23, 2014 from 8:30am-10:00 a.m., at the Institute of Food Technologists Annual Meeting in New Orleans, LA. For more information, click here.

Food Label Compass

EAS has entered into an alliance with FoodMinds Inc., and Nutrition Impact LLC, called Food Label Compass, to offer a suite of labeling services to assist clients in adapting to the new Nutrition Facts requirements.

Food Label Compass combines the expertise of all three partners and will provide nutrition analysis, regulatory consulting and strategic services to food and beverage companies. If you need assistance with serving sizes, Daily Values (DVs) or nutrition claims Food Label Compass can help.

FDA Has Higher Expectations for Generic Drug Applications

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Generic Drug User Fee Amendment (GDUFA) and You

FDA expects industry to begin submitting higher-quality applications to facilitate expedited reviews and approvals of generic drugs, agency officials explained at the Generic Drug User Fee Amendment (GDUFA) and You Conference in Lake Buena Vista, FL, March 27-28.

The goal of the meeting — which was hosted by the Office of Small Business and Industry Assistance (SBIA) in FDA’s Center for Drug Evaluation and Research (CDER) and presented by FDA’s Office of Generic Drugs (OGD) — was to update participants on FDA’s current activities and future plans for generic drug reviews.

The purpose of GDUFA was to increase the access of U.S. consumers to generic drugs, to ensure that the drugs are manufactured in compliance with FDA regulations, and to improve FDA’s communication with manufacturers of generic drugs and active pharmaceutical ingredients. In short, the goals are to improve access, safety, and transparency. To achieve these goals, FDA will be using a fee-based program to supplement appropriated Congressional funding.

At the Lake Buena Vista meeting, agency officials provided a reviewer’s perspective of an Abbreviated New Drug Application (ANDA), Drug Master Files (DMFs) and the completeness assessment for type II DMFs. The second day featured GDUFA implementation and policy updates; regulatory science; user fees, arrears lists, appeals and waivers; post approval inspections programs and a review of efficiency enhancements.

In GDUFA-related achievements, the agency has made significant progress in reducing the ANDA review backlog. FDA has hired 291 employees, exceeding the hiring target in the Fiscal Year 2013 goal. It has published criteria for Type II DMFs completeness assessments and refuse-to-receive (RTR) standards and it has posted a list of Type II DMFs that have passed the completeness assessment. And it is establishing a public docket to invite comment on ways to improve the quality of the ANDAs, amendments and supplements.

Here are some of my take-home notes from the meeting:

  • The agency will refuse to receive an ANDA if the number of easily remedied deficiencies is equal to or more than 10 or if a response to the fewer than 10 deficiencies is not received within 10 U.S. business days.
  • ANDAs submitted as a single, continuous, non-bookmarked PDF file will be refused.
  • If an applicant is requesting an expedited review, the cover letter must indicate in boldface “Expedited Review Requested” or “eligible for Expedited Review, GDUFA Year 1 or 2 Cohort.”
  • Upon issuing final guidance, FDA will contact a sponsor of an ANDA containing less than 10 easily remedied deficiencies. A response must be provided within 5 U.S. business days. Day 1 of the 5 U.S. business days will commence the day after notification is provided to the applicant. An ANDA will be refused if the number of easily remedied deficiencies is equal to or more than 10 or if a response to the fewer than 10 deficiencies is not received within 5 U.S. business days.
  • Any deficiencies revealed in the Active Pharmaceutical Ingredient (API) review will be communicated to the applicant. If a response is not received within 5 U.S. business days the ANDA will be refused for receipt.
  • Starting in Cohort Year 3 (FY 2015), which begins October 2, 2014, DMFs must be “Available for Reference” at the time of ANDA submission or they will be Refused to Receive (RTR).
  • Starting in Cohort year 3 the DMF fee should be paid a minimum of 6 months ahead of ANDA submissions to ensure the Completeness Assessment (CA) is done and the DMF is available for reference.
  • FDA is encouraging DMF holders to use a 30 minute teleconference for the first cycle of deficiency letters.
  • The agency is encouraging Type II DMF holders to submit the DMFs in eCTD format. This will aid in the review of the applications.

OGD is issuing the ANDA Filing Checklist on a quarterly basis (March, June, September and December). ANDA applicants should use the checklist as a tool to ensure that their application contains all of the appropriate components.

The agency offered other reference tools for applicants to use when preparing their applications, including Final Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Applications and Related Submission Using the [electronic Common Technical Document (eCTD)] Specifications; FDA eCTD Table of Contents Headings and Hierarchy; Portable Document Format Specifications: Guidance for Industry M4: The CTD – Quality Questions and Answers/Locations Issues, etc.

FDA will be holding a public meeting on May 16, 2014 to provide an overview of the current status of regulatory science initiatives for generic drugs. The agency wants input from industry, academia, professionals and other interested parties as it develops an annual list of regulatory science initiatives specific to generic drugs. FDA will take the information from the public meeting into account in developing its FY 2015 Regulatory Science Plan. The meeting will be held from 9:00 am to 5:00 pm at FDA’s White Oak Campus. Additional information can be found in the February 26, 2014 Federal Register.

In summary, FDA is working on keeping industry updated on the agency’s activities and trying to provide them with as much information as possible. The agency’s expectation is that industry will begin to submit applications that can be reviewed more efficiently.

EAS has available upon request copies of all the slide presentations for the GDUFA and You 2014 meeting.

The Top Ten Reasons for FDA Warning Letters to Medical Device Firms

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Since December 1978, medical device manufacturers have been subject to FDA regulations and inspections based on the Good Manufacturing Practices (GMP) requirements. On June 1, 1997 FDA amended the 1978 regulations to include quality system regulations (QSR).

An FDA “Warning Letter” is considered by the agency to be the first step in the enforcement process. In the letter, the agency threatens to take regulatory action if a firm does not correct the violative conditions. The agency requests a response, normally within 15 working days. In situations of a danger to health, the agency may request a response in 24 hours.

In fiscal year 2013, FDA’s Center for Devices and Radiological Health (CDRH) issued 217 Warning Letters, seven more than the center issued in FY12. EAS reviewed a total of 105 of the warning letters issued to manufacturers or other establishments that market medical devices in the U.S. The following were the Top 10 observations noted in those letters:

  1. 21 CFR 803.17 – Failure to develop, maintain, and implement written Medical Device Reporting procedures
  2. 21 CFR 820.22 – Failure to establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system
  3. 21 CFR 820.30(i) – Failure to establish and maintain procedures for the identification, documentation, validation or, where appropriate, verification, review, and approval of design changes
  4. 21 CFR 820.50 – Failure to establish and maintain procedures to ensure all purchased or otherwise received product and services conform to specified requirements
  5. 21 CFR 820.75(a) – Failure to ensure that when the results of a process cannot be fully verified by subsequent inspection and testing, the process shall be validated with a high degree of assurance and approved according to established procedure
  6. 21 CFR 820.90(a) – Failure to establish and maintain procedures to control product that does not conform to specified requirements
  7. 21 CFR 820.100(a) – Failure to establish and maintain procedures for implementing corrective and preventive action
  8. 21 CFR 820.181 – Failure to maintain adequate device master records (DMRs)
  9. 21 CFR 820.184 – Failure of the device history record to demonstrate the device was manufactured in accordance with the Quality System Regulations
  10. 21 CFR 820.198(a) – Failure to maintain complaint files and establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit

How to Respond

A firm’s response to a warning letter may be its last chance, prior to a legal or administrative action, to adequately address a situation that FDA has concluded constitutes a violation of the Food, Drug and Cosmetic Act (FD&C Act). Therefore, it is particularly important that the communication be responsive to the issues identified by the agency. Frequently, the letter is the result of an investigator’s inspection and the agency has already received the response to the FDA observations noted on the FDA-483. In some cases, the response may be considered inadequate and FDA will state that and will explain why the response is inadequate. In other cases, FDA may be silent as to their evaluation of the submission addressing the FDA-483 observations. If the initial response has been determined by FDA to be inadequate in whole or in part, FDA has not acknowledged its receipt, or if the firm has not yet responded to FDA’s concerns; this may represent the firm’s last opportunity to prevent a more aggressive action. Immediate affirmative action to correct the objectionable conditions and inform the proper office of the action is necessary to satisfy FDA and to prevent further regulatory action.

FDA may conclude that a firm has already satisfactorily corrected the objectionable conditions, or accept a firm’s response that they have been corrected. However, FDA may still send a warning letter, because they have yet to confirm that the conditions have been corrected and they wish to establish a background of “prior warning” so that if the violations are repeated at some future date, the firm is “on notice” that a more serious regulatory action may result. It therefore, remains important that a firm’s response to a warning letter be adequate to address the issues set forth. It is also important to state what systems and controls have been put into place to prevent these deviations from occurring in the future.

When drafting a response to an FDA warning letter, it is important to remember that the agency has already tentatively concluded that a violation of the law has occurred. The response must contain solid facts to refute the allegations or represent the firm’s action and commitment to afford immediate and permanent correction. If the recipient of the warning letter disagrees with the contentions in the letter, there is an appeal process within FDA. However, our experience indicates that when the situation reaches the point where FDA concludes that the issuance of a warning letter is appropriate, such appeals are futile. The next step would be to have the issues resolved in court.

It is important to meet the FDA timeframe for submitting the response. If you can’t, notify the issuing office and request an extension. The firm should commit to immediate and permanent correction of the violative conditions. They should support their view with facts and expert views. A meeting can be requested with the issuing office to discuss the firm’s views and hear FDA’s position. The firm’s views can be provided in writing as well as verbally in a non-argumentative, straightforward manner. If a specific product(s) are involved, provide the agency with the action the firm intends to take on these products and why. If the firm does not agree with FDA’s conclusion, request a meeting with the issuing office to discuss differing views and hear FDA’s position. The firm should present its arguments in a factual, scientific and if appropriate legal manner.

If the response is satisfactory FDA will, conduct a follow up investigation to assure the corrective action taken is effective. If the response is inadequate or if it has not been accomplished as promised, further regulatory action by FDA is likely.

FDA Proposes Revised Nutrition Labels on Foods (and Some Dietary Supplements)

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FDA announced on February 27, and published in the March 3 Federal Register, proposals to revise the Nutrition Facts label. This is the first time in the 20 years of the Nutrition Facts label that FDA is making major revisions. The proposed revisions incorporate updated information on advice for healthy dietary practices and food consumption patterns as well as technical updates.

FDA has articulated a detailed rationale for each change in two proposals and has posted links to several information pieces on its website.

Major proposed changes include:

  • Require declaration of “added sugars” as a component of total sugars
  • Add vitamin D and potassium to the mandatory nutrients and convert vitamins A and C to voluntary nutrients
  • Update Daily Values (DV) for nutrients like sodium, dietary fiber and Vitamin D. Changes in DVs would affect whether certain foods qualify for nutrient content and health claims.
  • Require that packaged foods, including drinks, that are typically eaten in one sitting (less than 200% RACC) be labeled as a single serving and that calorie and nutrient information be declared for the entire package
  • Require “dual column” labels to indicate both “per serving” and “per package” calories and nutrient information for packages that are 200% – 400% of the RACC. Because of limited space, labels that qualify to use the tabular or linear formats would not have to declare the second column.
  • Update several RACCs and establish new ones to reflect current consumption patterns. As an example, the RACC for carbonated and non-carbonated beverages, water, coffee, tea would be increased from the current 8 fluid ounces (fl oz) to 12 fl oz. Milk, milk substitutes, milk based beverages would retain the 8 fl oz RACC. Changes in RACCs could affect whether certain foods qualify for nutrient content and health claims.
  • Revise the format to make calories and serving sizes more prominent and to shift the % Daily Value to the left of the label

Nutrition Label Changes

While these changes apply to all food labels, not all the changes would affect dietary supplement labels. Dietary supplements that do not contain “food type” dietary ingredients like fat, protein, and carbs would not need to change labels. The added emphasis on calories and added sugars would mean changes for some dietary supplements, particularly flavored liquids. Some of the changes would affect protein supplements, fiber supplements, and supplements containing RDI vitamins and minerals.

FDA has established a 90 day period for interested parties to submit comments on the proposed changes. The agency will take into account information provided in comments when developing the final regulations. We encourage manufacturers to determine how the changes would affect their product labels. You may want to submit information to FDA if proposed changes would have a negative effect for your product. This article cannot include the amount of detail manufacturers need to understand the proposed changes, but EAS can help you to navigate the details to understand your status.

The proposed effective date is 60 days after the final regulation is published and FDA would allow 2 years for labels to be brought into compliance with the final requirements.

EAS has partnered with FoodMinds and Nutrition Impact, LLC to create Food Label Compass, which harnesses the expertise of all three partners to create a suite of nutrition analysis, regulatory consulting and strategic services to guide food and beverage companies in understanding the impact, complying, communicating, and capitalizing on the new FDA guidelines. Food Label Compass will conduct in-depth analyses of the food and nutrient content of clients’ brands relative to the new FDA guidelines. It will identify the potential changes to the serving size rules (Reference Amounts Customarily Consumed (RACCs)), assess the impact of potential changes on Daily Values (DVs) and on nutrition claim criteria.

Food Label Compass will develop regulatory recommendations and guidance to construct labels modified to reflect the new requirements. In addition, it will validate claim opportunities, answer questions on how to comply with the new nutrition information rules and ensure the information is presented in an approved and consumer-friendly manner.

USDA Expands Generic Labeling Regulations

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For years USDA has required labels be submitted for approval in order for product to be shipped out of a plant. In July of 1996 the first set of generic regulations went into effect allowing companies to approved some labels “in house” or generically. This rule included net weight changes, changing the signature line and changing the vignette. The rule also changed how many times the label had to be submitted to USDA for approval and took the inspector in charge out of the equation. Previously, labels were required to receive a sketch approval and a final approval of the actual label. In 1996, the generic regulations did away with final label approvals.

A new generic labeling rule went into effect on January 6, 2014, 18 years after the first set of generic regulations. The new rule states only certain types of labeling – i.e., 1) labels for temporary approval, 2) labels for products produced under religious exemption, 3) labels for products for export with labeling deviations, and 4) labels with claims and special statements — will have to actually be submitted to USDA for evaluation and approval. Some of the labels that will be allowed for generic approvals are labels with allergen statements, defined nutrition claims, and geographic claims. Labels for temporary approval, whole grain statements, nutrition front of package statements, natural claims and animal production claims are some of the types of labels that will still need to be submitted to USDA for approval. The Labeling and Program Delivery Division, which is responsible for all USDA label approvals, will accept labels for review that can be approved generically, but they will be given secondary status. Labels with claims, temporaries, religious exemptions and labels for export that bear labeling deviations will take precedence.

Many see this as another step toward an all-generic labeling system. Establishments will have more responsibility for label approvals. And Inspectors in Charge are expected to know the new rule. Standardized training will be implemented, but there may still be a big difference between how individual inspectors view labels at the plant. Some may still want to see the USDA stamp on the label even though it can be generically approved. That’s where USDA’s Labeling Submission Approval System may prove useful. It includes a section with a series of question to determine if a label can be generically approved. LPDD is hoping this will cut the turnaround time for label approvals. The process can take anywhere from 3-8 weeks.

FDA’s Proposed Rule on Antibacterial Soaps

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In 2010 the Natural Resources Defense Council (NRDC) sued FDA to force the agency to issue a final rule on antibacterial soaps. As part of a settlement signed last month, the agency issued a proposed rule Dec. 16, 2013 and committed to taking final action by 2016. Well before this lawsuit, however, FDA was investigating this area and considering action on this topic.

FDA’s focus centers on triclosan, an antibacterial agent that’s long been under agency scrutiny. More than 30 years ago, FDA reviewed evidence and concluded that triclosan wasn’t proven either safe or effective (category III), although years later toothpaste containing triclosan was approved. Nonetheless, antibacterial products have been widely marketed for years. Widespread use of these products and related public health and environmental concerns provided a backdrop for the NRDC lawsuit that was the ultimate catalyst for FDA’s regulatory action. As Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, stated: “Due to consumers’ extensive exposure to the ingredients in antibacterial soaps, we believe there should be a clearly demonstrated benefit from using antibacterial soap to balance any potential risk.”

FDA Action and Rationale

On Dec. 16, 2013 the FDA released a proposed regulation to ban certain ingredients in anti-bacterial soaps if manufacturers cannot prove that these products are safe to use and more effective than plain soap and water for preventing the spread of infections. Such a move could potentially force makers of antibacterial products to reformulate all bar soaps, liquid soaps, body washes, and dishwashing liquids labeled as “anti-bacterial” and “antimicrobial” to keep them on store shelves.

According to Colleen Rogers, a lead microbiologist at FDA, “there’s currently no evi­dence that OTC antibacterial soap products are more effective at preventing illness than washing with plain soap and water”. Moreover, antibacterial soap prod­ucts contain ingredients, such as triclosan and triclocarban, which according to FDA, may pose risks associated with long-term, daily use that may outweigh the benefits. Active ingredients in these soaps may contribute to bacte­rial resistance to antibiotics, and may also have unanticipated hormonal effects that are an FDA concern based on animal study data.

Because of these concerns, FDA’s proposed rule requires manufac­turers to provide more substantial data to demonstrate the safety and effectiveness of antibacterial soaps. The proposed rule covers only consumer antibacterial soaps and body washes that are used with water. It doesn’t apply to hand sanitizers, hand wipes or antibacterial soaps that are used in health care settings such as hospitals.

Most soaps labeled “antibacterial” or “antimicrobial” contain at least one of the antibacterial ingredients that FDA has targeted in this proposed rule. Certain household cleaning products and some toothpastes may also contain them.

Laboratory tests that have historically been used to evaluate the effectiveness of anti­bacterial soaps don’t directly test the effect of a product on infection rates. That would change with FDA’s cur­rent proposal, which would require studies that directly test the ability of an antibacterial soap to provide a clinical benefit over washing with non-antibacterial soap and water.

Environmental concerns also brought the Environmental Protection Agency (EPA) into the picture and the two agencies have been collaborating on scientific and regulatory issues regarding triclosan. EPA is updating its assessment of triclosan’s use in pesticides and its overall environmental impact, while FDA has focused on the antimicrobial’s widespread use by consumers in soaps and body washes. In sharing information, the two agencies are assessing exposure risks.

Next Steps

FDA’s proposed rule doesn’t require the antibacterial soap products to be removed from the market at this time. When the proposed rule is finalized, either companies will have provided adequate data to support an antibacterial claim, or if not, they must reformulate to remove the active ingredients or relabel to remove the antibacterial claim from the product’s labeling in order to continue marketing these products. The proposed rule is available for public comment for 180 days, with a concurrent one year period for companies to submit new data and information, followed by a 60 day rebuttal comment period.

Manufacturers of antibacterial soap and body wash products and trade associations are sure to respond with comments. Two industry trade groups, the Personal Care Products Council and the American Cleaning Institute, already cited a review of two dozen studies they say showed washing hands with antimicrobial soaps produces “statistically greater reductions in bacteria on the skin” than plain soap.” They may also offer legal arguments about the absence of serious adverse event data resulting from antibacterial soap use as well as study data and scientific literature support. Results of animal studies will likely be submitted as well as clinical studies using standardized microbe doses to try to satisfy the agency’s data requirements. However, it’s not likely that manufacturers would incur the enormous cost of full scale clinical trials to obtain prospective human data.

Industry groups intend to file comments reaffirming that use of antibacterial soap products does not contribute to antibiotic resistance. However, the question is whether they can provide sufficient efficacy and safety data to convince FDA that the benefits outweigh the risks. The assessment of published scientific literature alone won’t persuade FDA, since they’ve already concluded that existing scientific data aren’t adequate to support safe and effective product use.

If FDA determines an antibacterial claim is not supported, companies must reformulate to remove or replace a category III ingredient or relabel their products. How one would relabel such a marketed antibacterial soap product is a big unknown. Would FDA permit a disclaimer stating an ingredient like triclosan lacks evidence of safety and efficacy and allow such products to remain on the market? Would consumers continue to use these products without an antibacterial claim? We suspect it will be a while before these issues are resolved.

Time to Replace PHOs? FDA Proposes to Remove Added Trans Fats from Processed Foods

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Partially hydrogenated oils (PHOs) have been in the news a lot recently. Since the 1990s, a strong association of PHOs (which contain trans fat) with harmful effects on human health, especially on blood cholesterol levels and the risk of cardiovascular disease, has been established. This has caused food manufacturers to take steps to reduce the amounts of PHOs in foods. PHOs are the main source of added trans fat to the diet, which is the focus of all of the safety concerns. Since 2006, FDA has required that added trans fat be listed on the nutrition facts panel. While the amount of added trans fat has been reduced significantly – currently, the consumer consumes approximately 1 – 1.3 grams of added trans fat per day (See bit.ly/1cbakrT) as compared to 4.6 grams per day in 2003 (78 FR 67171; November 8, 2013). Notwithstanding this reduction, FDA believes that given the safety concerns associated with the use of added trans fats, the amounts should be significantly lower. Because of these concerns, in a November 8, 2013 Federal Register notice (78 FR 67169 – 67175), FDA announced that it has tentatively determined that partially hydrogenated oils, the primary dietary source of artificial trans fat, are no longer generally recognized as safe (GRAS) for any use in food and that PHOs are therefore food additives subject to section 409 of the Federal Food, Drug, and Cosmetic Act. If finalized, this finding will mean that food manufacturers could no longer add PHOs, either directly or as ingredients in another food product, without prior FDA approval for use as a food additive. To demonstrate that the use of trans fat under the food additive regulation is safe could prove to be a difficult hurdle.

The agency said it based its new determination on current scientific evidence including the opinions of expert panels and the 2005 recommendation of the Institute of Medicine (IOM) that consumers should limit their trans fat consumption as much as possible while consuming a nutritionally adequate diet. According to the Centers for Disease Control and Prevention, elimination of PHOs from the food supply could prevent 10,000 to 20,000 coronary events and 3,000 to 7,000 coronary deaths annually, if the marginal benefits of continuing to remove trans fats from food items remain constant.

“Given this evidence, we have tentatively determined that there is no longer a consensus among qualified scientific experts that PHOs, the primary dietary source of industrially-produced trans fatty acids, are safe for human consumption, either directly or as ingredients in other food products,” FDA said.

The agency’s latest move takes place in the context of a decline in the use of trans fats. In 2010, FDA prepared an estimate of the intake of industrially-produced trans fat using available food consumption data (2003–2006 National Health and Nutrition Examination Survey (NHANES)), market share information, and trans fat levels based on label declaration data and analytical data for products that were identified as containing PHOs. According to that estimate, the mean dietary intake of industrially-produced trans fat has decreased significantly since the previous estimated a decade ago.

The agency has invited comments on the tentative determination by January 7, 2014.

Many manufacturers have taken steps to reformulate their products to remove and/or eliminate added trans fats, but the process is incomplete. It appears likely that FDA will require labeling of any added trans fat and not the current labeling which requires the amount to be stated only if it exceeds 0.5 grams per serving [21 CFR 101.9(c)(2)(ii)]. It is possible that FDA will set a Daily Reference Value (DRV) for added trans fats.

Among the alternatives that manufacturers may consider would be the use of interesterified oils (where the structure of the oil is enzymatically or chemically modified to make them more solid or stable), or using blends of oils to achieve the desired effects, or using butter (which contains natural trans fat), or developing new products that could achieve the desired oil/fat properties, etc. All of these approaches have their pluses and minuses. For example, new oils may remove the trans fat issues, but could raise formulation, taste and regulatory issues that will need to be resolved.

A large number of products on the market still use PHOs, so reformulating these products will be an ongoing process. The EAS consulting network can provide expertise in nutrition, labeling, regulatory and related areas to help meet the challenges of product reformulation.

A Look at FDA’s Food Contact Notification Program

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A food additive is defined in Section 201(s) of the Food, Drug & Cosmetic Act (FD&C Act) as any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristic of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation intended for any such use); if such substance is not GRAS or sanctioned prior to 1958 or otherwise excluded from the definition of food additives.

For regulatory purposes, FDA divides food additives into two main categories: direct and indirect. Indirect food additives are food additives that come into contact with food as part of packaging, holding, or processing, but are not intended to be added directly to, become a component, or have a technical effect in or on the food. Indirect food additives mentioned in Title 21 of the U.S. Code of Federal Regulations (21 CFR) used in food-contact articles, include adhesives and components of coatings (Part 175), paper and paperboard components (Part 176), polymers (Part 177), and adjuvants and production aids (Part 178). Prior to 1997, all food additives, direct and indirect, were subject to approval via a petition process.

Section 409 of the FD&C Act defines a Food Contact Substance (FCS) as any substance that is intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such use of the substance is not intended to have any technical effect in such food. Examples of food contact substances include polymers (plastic packaging materials), pigments and antioxidants used in polymers, can coatings, adhesives, materials used during the manufacture of paper and paperboard, slimicides and biocides (antimicrobial agents), and sealants for lids and caps.

In 1997, the Food and Drug Administration Modernization Act (FDAMA) amended Section 409 of the FD&C Act establishing a “Food Contact Notification” (FCN) process that allows for alternative review of FCSs. The FCN process, administered by the Center for Food Safety and Nutrition (CFSAN), differs from the older food additive petition process in many ways. Most significant is the new program’s scientific approach to managing risk. With no sacrifice to public visibility or information access, the FDA has established specific process guidelines proactively detailing objective data requirements for manufacturing, chemistry, toxicology, and environmental aspects of the production and use of the proposed FCS that applicants must provide. When the applicant has provided FDA with all of the necessary data (the data requirements are described in guidelines published by FDA and are available on FDA’s website), the agency has a 120-day review period to evaluate the safety of the food contact substance as proposed. If there are no identified concerns, the FCN automatically becomes effective on the 120th day. Unlike approved food additive petitions where a regulation is entered into title 21 CFR, the FCN is then added to an Inventory of Effective Premarket Notifications for Food Contact Substances that is posted on CFSAN’s web page.

It is important to note that a food contact notification (FCN) is only effective for the manufacturer or supplier identified in the notification. Anyone who markets a food contact substance (FCS) based on an effective notification must be able to demonstrate that the notification is effective for their food contact substance. All persons who purchase a food contact substance manufactured or supplied by a manufacturer or supplier identified in an effective notification may rely on that notification to legally market or use the food contact substance for the use that is the subject of the notification, consistent with any limitations in the notification

FDA suggests that an FCN applicant discuss the proposal with agency scientists early in the application process. This allows the applicant and agency scientists to discuss the critical data requirements, test protocols, and validation procedures before either dedicates resources to activities potentially inadequate to support FDA’s assessment of public health risk posed by the FCS. Months of chemical and toxicological testing may well precede the 120 day FDA review.

In more than 14 years of existence, the FCN program has processed and listed almost 1,300 substances. The listing includes the FCS, the supplier’s name, the manufacturer of the FCS, the intended use, the limitations on the conditions of use for the FCS and its specifications, the effective date, and FDAs environmental decision. Successful completion of all the data requirements for complete submission involves a thorough understanding of FDA’s administrative process and the data needs of the agency’s scientific risk assessment.

EAS Consulting Group can assist you in preparing and submitting FCNs to FDA. EAS has a large group of professionals on its staff with years of previous experience working for FDA and other government agencies and industries. Please feel free to contact us to discuss your needs and our services.

Distinguishing Medical Device Recalls

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Do you know when a product enhancement is considered to be a recall in the eyes of the Food and Drug Administration? If not, I draw your attention to the draft guidance from FDA entitled Distinguishing Medical Device Recalls from Product Enhancements and Associated Reporting Requirements. Using plain language and a flow chart, the Guidance offers FDA’s perspective on the differences between the two. It was distributed for comment on February 22, 2013. The comment period ended in May, and FDA is now considering the comments received. I recommend that firms consider this guidance and seek consultation if necessary before making any changes in device design, labeling or manufacturing processes.

I speak with some experience. For twelve years I was a chief of the Ob/Gyn, Gastroenterology and Urology Branch, in the Division of Enforcement, Office of Compliance (OC), Center for Devices and Radiological Health (CDRH). Prior to my retirement in early 2012, certain steps taken by my branch in coordination with others in CDRH were instrumental in the genesis of this document. Let me explain. We became aware that a manufacturer had proposed a design change in a marketed device via the Premarket Approval (PMA) supplement process. Concurrently, we noted that several adverse events involving the same device had been reported through the Medical Device Reporting (MDR) system. Was there a connection?

After in-house (i.e., CDRH and the FDA district office) discussion, we opened dialogue with the manufacturer and shared points of view. The firm acknowledged the original design of the device might have been a contributing factor to the injuries reported via the MDR process, but concluded, nevertheless, that the design change was a product enhancement and a recall was not warranted. We expressed the need for a voluntary recall because of the seriousness of the health hazard, the likelihood of recurrence and other aspects.

This was not a unique situation. Quite often we encountered similar situations requiring meetings with manufacturers to clarify expectations. In this case, as always, we worked closely with the recall coordinator in the FDA district office and engaged the manufacturer only after having an FDA Health Risk Assessment in hand and the support of experts from OC, the Office of Device Evaluation (ODE), the Office of Surveillance and Biometrics (OSB) and others.

In the above situation, the Center’s point of view prevailed, and the manufacturer agreed to conduct a voluntary recall. Once that matter was settled, the firm asked to meet with us to get a better understanding of FDA’s processes to avoid similar problems in the future. We welcomed this discussion and recognized the need for a Guidance document.

The Guidance includes: 1) definitions of terms, 2) identification of what a recall is and isn’t, 3) clarification of violative and non-violative devices, 4) a recall decision making flow chart, 5) recall reporting requirements, and 6) product enhancement reporting requirements. It also discusses associated regulations, including 21 CFR 803 (Medical Device Reporting) and 21 CFR 806 (Reports of Corrections and Removals). A Q&A format is used throughout.

The Guidance is still in draft form and may change somewhat to reflect the comments received. But for now it is of value for helping to understand FDA’s perspective on device recalls versus product enhancements.

 

Regulatory Options for Food Ingredients in the U.S.

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Before releasing any food ingredient into the market, it is incumbent upon the manufacturer/supplier to ensure that the product is safe for its intended use. Oftentimes, deciding how to approach this can be confusing. Under the Federal Food, Drug, and Cosmetic Act, the manufacturer/supplier has primary responsibility for ensuring that a food ingredient is safe, and FDA has the primary legal responsibility for determining that the ingredient is safe under its intended conditions of use. Since 1958, manufacturers have had several options for determining that an ingredient is safe for use in food. These options are listed in the Table below.

Table I: FDA Recognized Approaches to Food Ingredients

Regulatory Option Regulatory Citation Comments
Food Additive Petitions Direct food additive Secondary direct food additive Indirect food additive 21 CFR 171.1 Today used mainly for direct food additives; most indirect food additives use the FCN route if they qualify; some secondary direct additives may also qualify for the FCN route.
Color Additive Petition 21 CFR 71.1 Required for colors
GRAS Petitions 21 CFR 170.35 May be direct or indirect additive; superseded by GRAS Notice program
GRAS Notice See 62 FR 18938ff; April 17, 1997 Voluntary; in practice since 1997; FDA has received more than 400 GRAS Notices since the inception of this program.
Independent GRAS Determination Section 201(s) of the FD&C Act An option; before undertaking, we suggest discussing this option with EAS.
Threshold of Regulation 21 CFR 170.39 Restricted to indirect additives
Food Contact Notification 21 CFR 170.100 This route is now the main route for seeking approval of indirect additives.
New Dietary Ingredient 21 CFR part 190 In effect since 1994; the Dietary Supplement Health and Education Act (DSHEA) amended the FD&C Act to distinguish dietary ingredients as a special case of food ingredients. Prior to 1994, dietary ingredients were treated as other food ingredients.

In effect since 1994; the Dietary Supplement Health and Education Act (DSHEA) amended the FD&C Act to distinguish dietary ingredients as a special case of food ingredients. Prior to 1994, dietary ingredients were treated as other food ingredients.

Food additives can be classified into four main groups: 1) food additives; 2) color additives; 3) ingredients for which either the FDA or the U. S. Department of Agriculture specifically authorized use prior to 1958, the so-called “Prior Sanctioned Substances”; and, 4) GRAS substances, i.e., substances that are agreed upon as safe by the general scientific community on the basis of scientific evidence or history of use prior to 1958. Only food and color additives require premarket approval.

The manufacturer/supplier should first decide which regulatory options meet the intended use. FDA has issued definitions for these food ingredients to assist in this decision. The definitions below are taken from FDA’s Food Ingredients and Packaging Terms.

Direct food additives are those added to a food for a specific purpose in that food.

Color additives may be any dye, pigment or substance which when added or applied to a food, drug, or cosmetic, or to the human body, is capable (alone or through reactions with other substances) of imparting colors.

GRAS (Generally Recognized as Safe) ingredients are those ingredients that are generally recognized by experts to be safe, based on either an extensive history of use in food prior to 1958, or based on published scientific evidence. The determination that a substance is GRAS is not exclusive to FDA. Scientists outside FDA may also make this determination based on the available evidence. However, manufacturers/suppliers may request that FDA review their determination by submitting a GRAS Notification to FDA for review and concurrence. After completion of its review, if FDA concurs, the agency will issue a “No Questions” letter to the submitter indicating that “FDA has no questions at this time …” regarding the GRAS determination.

Any ingredient used in food is expected to be produced and used consistent with Good Manufacturing Practice (GMP) conditions to ensure its safe use. The responsibility for establishing GMP conditions rests primarily with the manufacturer/supplier. Once in use, it is important that the manufacturer/supplier continue to monitor the use of the product to ensure its use continues to be within safe limits.

FDA has also issued several guidance documents to assist manufacturers/suppliers in their effort to seek approval of their food ingredient(s). These guidance documents are posted on the agency’s website.

Should a manufacturer/supplier wish to add an unregulated ingredient to food, we invite them to contact EAS. EAS has a large network of expert scientists with many different areas of expertise and regulatory experience. Among these are food scientists, chemists, toxicologists, and regulatory experts. For specific expertise not available within the EAS network, we also maintain contact with a large number of outside experts to assist on any project.

ISO/IEC 17025:2005 and the Benefits of Accreditation

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There is immense value for medical device manufacturers in having their calibration and testing laboratory suppliers comply with the General Requirements for the Competence of Testing and Calibration Laboratories in ISO/IEC 17025:2005.

From initial design and development to the shipment of medical devices that can be characterized as safe and effective, the accuracy of the testing and inspection results depends on the use of measuring and monitoring equipment that is calibrated. In addition, the materials used in the manufacture of medical devices need to be tested to ensure the materials are appropriate. Design and process validation activities, the assessment of material biocompatibility, packaging studies, sterilization validation and electrical performance testing must be performed to a high-degree of reliability.

The FDA demands that these activities are performed using monitoring and measuring equipment with a high-degree of accuracy. The only way to ensure that the integrity of the testing results is through the use of an accredited ISO/IEC 17025 facility for calibration and testing.

Other Industries

Other regulated industries such as dietary supplements (21 CFR, Part 111), pharmaceuticals (21 CFR, Part 211), Medical Devices (21 CFR 820) and even aerospace (AS9100 – premised on ISO 9001), rely on the integrity of testing and need to employ monitoring and measuring equipment that is accurately calibrated with traceability to a national standard, for example to National Institute of Standards and Technology (NIST) or other recognizable standards. Pharmaceuticals and dietary supplements, similar to medical devices, must be safe and effective in their intended use. These industries also employ extensive verification and validation testing and subsequent inspection to ensure product safety.

Reasons for Compliance

In 2005, Hershal C. Brewer explored the reasons for the use of ISO/IEC 17025-accredited suppliers for calibration and testing. In Quality Digest Magazine, Brewer listed the following reasons:

  • Product testing to verify suitability of product for market introduction;
  • Compliance with regulatory and statutory requirements;
  • Ensure product safety and efficacy;
  • Achieve product certification from organizations such as Intertek or UL; and
  • Regulatory requirement to achieve product listing.

The need for medical device manufacturers to calibrate equipment is a fundamental requirement mandated by 21 CFR Part 111 (Subpart D – Equipment and Utensils § 111.35), 21 CFR 211 (Subpart D – Equipment Section 211.68 and Subpart I – Laboratory Controls Section 211.160), 21 CFR Part 820 (Section 820.72 Inspection, measuring, and test equipment) and enforced by FDA during their inspections of device manufacturers. A similar requirement is mandated by ISO 9001:2008/ISO 13485:2003 and AS9100 Rev. C under Clause 7.6 (Control of measuring and monitoring devices). Considering the regulatory oversight provided by FDA in the United States, and the notified bodies in support of ensuring compliance to 93/42/EEC (the Medical Device Directive); selecting a metrology supplier that is ISO/IEC 17025 accredited is the prudent path to pursue. If the device manufacturer is performing calibration activities in-house, then complying with ISO/IEC 17025 would be considered a best practice.

For the execution of testing activities, selecting qualified testing laboratories is not considered optional by the FDA. Regulatory bodies expect testing to be performed by qualified laboratories. Additionally, a qualified testing laboratory is expected to be ISO/IEC 17025 accredited. For example, if testing is being performed to IEC 60601-1 (Medical electrical equipment – Part 1: General requirements for basic safety and essential performance) the expectation is that testing be performed at an accredited testing facility such as Intertek. Asking FDA to accept test data from an unaccredited testing facility will not draw a favorable response.

In conclusion, the rigorous standards for medical devices require them to be designed, developed, validated, and manufactured to be safe and effective for their intended use. Obtaining testing and inspection results through the use of calibrated equipment is a fundamental requirement enforced by FDA and other regulatory bodies. For accurate results, the prudent path is to select and qualify calibration and testing facilities that are ISO/IEC 17025 accredited. If the calibration and testing is being performed in-house by a manufacturer, compliance with ISO/IEC 17025 would be considered a best practice. But regardless of the approach pursued for testing and calibration, in-house versus supplier, ISO/IEC 17025 must be considered.