Steps to Develop Compliant SOPs Discussed in AHPA Report

The December American Herbal Products Association (AHPA) Report (subscription required) included an EAS authored article on steps to develop fully compliant Standard Operating Procedures. Though the development and detail of each SOP is at the discretion of individual companies, they should provide a thorough manual that enables each employee to understand their roles and responsibilities and how to perform and document them with regard to the cGMPs. As current practices evolve, so too should SOPs as they are designed to be living documents, representing best practices and required procedures.

FDA Encourages Innovation and Safety as Part of Medical Device Regulatory Overhaul

EAS authored an article in MedTech Intelligence on FDA’s efforts at encouraging innovation while keeping a close eye on safety as part of a medical device regulatory overhaul. FDA is working to retire outdated predicates for 510(k) submissions as well as improve their post-market surveillance system through a multi-collaborative effort called National Evaluation System for Health Technology (NEST).

Couch Shares Thoughts on Contract Laboratory Best Practices as Part of Insider Q&A

Senior Director for Dietary Supplement and Tobacco Services, Tara Lin Couch, Ph.D. participated in a discussion with other industry leaders on best practices for contract laboratories in a recent Natural Products Insider. Contract labs are often enlisted to certify that products are fully and validly tested, and the relationship with these labs can sometimes be complicated by a lack of provided material and product matrix information to ensure that appropriate, scientifically valid test methodologies are used. Couch and her industry colleagues share thoughts on how to convey expectations and develop agreements.

Join EAS for Complimentary Webinar Series on OTC Monograph Reforms

Join EAS Independent Advisor for OTC Drugs and Labeling, Susan Crane, as she explores the history of OTC Monographs and how OTC drug companies can expect updates to the Monograph system to impact their labels in a webinar series starting January 16, 2019. Part one will discuss the history of OTC monographs and why reforms are necessary. Part two is February 27, 2019 and will discuss understanding the FDA and FTC Labeling and Claim Requirements for Cosmetic and Homeopathic products in the OTC market. The final sessions, with dates to be announced will discuss what makes a drug an OTC and the Monographs Compliance System; and GMP obligations – understanding how the GMPs are Applied and how to prepare for FDA Inspection. Reserve your seat today!

Drug and Device January 2019

Guidance Document updates on the FDA website

All centers:

Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group or Class of Oncology Therapeutic Products

CDER:

Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis:  Developing Drugs for Treatment

Post-Complete Response Letter Meetings Between FDA and ANDA Applicants

Current Good Manufacturing Practice—Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act

CDER & CBER:

New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2)

Questions and Answers on Biosimilar Development and the BPCI Act

The “Deemed to be a License” Provision of the BPCI Act Questions and Answers Guidance for Industry

Interpretation of the “Deemed to be a License” Provision of the Biologics Price Competition and Innovation Act of 2009

Biomarker Qualification: Evidentiary Framework

Data Integrity and Compliance With Drug CGMP Questions and Answers

Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

Developing and Submitting Proposed Draft Guidance Relating to Patient Experience Data

CDRH & CBER:

User Fees and Refunds for Premarket Approval Applications and Device Biologics License Applications

CDRH:

Recommendations for Dual 510(k) and CLIA Waiver by Application Studies

Select Updates for Recommendations Select Updates for Recommendations Amendments of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices

Self-Monitoring Blood Glucose Test Systems for Over-the-Counter Use

Blood Glucose Monitoring Test Systems for Prescription Point-of-Care Use

Clarification of Radiation Control Regulations For Manufacturers of Diagnostic X-Ray Equipment

Breakthrough Devices Program

CBER:

Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion

Labeling of Red Blood Cell Units with Historical Antigen Typing Results

CVM:

Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Species: Study Design Recommendations for Residue Studies in Honey for Establishing MRLs and Withdrawal Periods

FDA De-Listing of Synthetic Flavors

Steve Armstrong

Q: FDA’s recent announcement delisting seven synthetic flavors caused a flurry of conversation and some confusion within the flavor and extract world. Would you clarify?

Armstrong: Thank you for the question and the opportunity to clear up confusion on FDA’s October 8, 2018 Constituent Update on the removal or delisting of seven synthetic flavors from the list of approved food additives. FDA was clearly reluctant to take this action, but it did so because several activist groups had petitioned for the delisting and then went to court to force FDA to take the action.

FDA made clear in its announcement in the Federal Register that it was only de-listing the synthetic form of these substances, which are labeled as “artificial flavors.” This means that a flavor manufacturer need only remove these synthetic substances from its flavor portfolio. These include synthetically-derived benzophenone, ethyl acrylate, eugenyl methyl ether (methyl eugenol), myrcene, pulegone, and pyridine. In addition, the FDA also is amending the food additive regulations to no longer provide for benzophenone’s use as a plasticizer in rubber articles intended for repeated use in contact with food.

In the Federal Register notice published on October 9, 2018 the agency said its revocation of the approvals “does not affect the legal status of foods containing natural counterparts or non-synthetic flavoring substances extracted from food.” FDA noted that each of the seven synthetic substances has a natural counterpart in food or in natural substances used to flavor foods. For example, they say, “benzophenone is present in grapes, ethyl acrylate is present in pineapple, eugenyl methyl ether (methyl eugenol) is present in basil, myrcene is present in citrus fruit, pulegone is present in peppermint, and pyridine is present in coffee.”

According to the Federal Register notice and the communication on FDA’s website, companies may continue to use the seven flavors provided they are only made from the natural extracts and are labeled as “natural flavors.” Companies using these synthetic flavors have 24 months from the publication of the rule in the Federal Register to identify suitable replacement ingredients and reformulate their food products.

This is an unusual situation and one precipitated by the Delaney Clause, an antiquated section of the Food, Drug, and Cosmetic Act. That section of the law prohibits FDA from approving a food additive if, after appropriate testing, it is found that the additive induces cancer in humans or animals. The clause is absolute. It does not provide FDA any leeway for applying a scientific risk assessment, even in situations where, as in the present case, the usage levels of an additive are low and inherently self-limiting, meaning exposures well below any area where they could possibly present any cancer risk. However, the petitioners had submitted data showing high levels of these synthetic substances did induce cancer in lab animals.

So, even though FDA had no concerns about either the synthetic or natural versions of these seven flavors, which had been used for decades, with no concerns about their safety as presently used in foods, the Delaney Clause required that the agency, as a legal matter, take the action requested by the petitioners. Six of the seven were delisted in response to these citizen petitions; the seventh (Styrene) was delisted because it is no longer in use. The agency clearly did not like having to take his step, but the Delaney Clause gave it no choice. The decision to de-list, it said, was required as a legal matter, not a scientific one. It’s possible that this action may signal an effort by the flavor and extract industry to modify the Delaney Clause.

2019 Produce Compliance Dates for FSMA

January 28, 2019, marks the compliance date for four categories of produce growers:

  • Sprouts from Very Small Farms (with certain exemptions), 
  • Sprouts from Very Small Farms eligible for a qualified exemption to comply with other requirements in 112.6 and 112.7, 
  • Other small farms, (except those with certain water requirements), and 
  • Small Farms eligible for a qualified exemption to comply with other requirements in 112.6 and 112.7

must come into compliance.

FSMA’s Final Rule on Produce Safety, Standards for the Growing, Harvesting, Packing, and Holding of Produce for Human Consumption, and FDA’s helpful Small Entity Compliance Guide concerning determination of business size (based on annual monetary value of the food farms sell directly to qualified end users) are two important resources for farms growing and harvesting produce for consumption without further processing.

Recent foodborne illness outbreaks from romaine lettuce illustrate why it is prudent to take a fresh look at some specific areas where the introduction and harboring of pathogens can wreak havoc and cause devastating public health and economic consequences.

FDA’s recently announced that the list of possible growing areas identified as the source of the E. coli outbreak in romaine lettuce has been narrowed to three California counties, and one farm in particular. However, FDA concedes that this does not explain all of the illnesses. As of December 13, 2018, traceback information from five restaurants in four states have identified 11 different distributors, nine different growers, and eight different farms as potential sources of the contaminated lettuce, so it is likely that the outbreak cannot be explained by a single farm, grower, harvester, or distributor. FDA continues to investigate.

It’s also not only E. coli causing produce industry woes. Listeria monocytogenes prompted recent recalls of pre-packaged salad products and asparagus, as did a summer outbreak of Cyclospora in melons and lettuce. 

Why are these events continuing to happen? FSMA’s many requirements were designed to prevent just such occurrences. Are growers not complying with the regulations because they are too difficult to understand, or too difficult to follow? Or are these outbreaks examples of Murphy’s law, that no matter the risk mitigation strategy, if something can go wrong, it will?

The answer, in my view, is yes to all three – and I’ll add that sometimes downstream consequences are not fully understood until it is too late. 

Take for instance, this past summer’s E. coli outbreak in romaine lettuce. The fact that after so many months FDA still cannot pinpoint the exact source of the outbreak suggests these companies and areas under investigation appear (at least on the surface) to be largely in compliance. As of this writing, Whole Genome Sequencing testing has identified only one result where an agricultural water reservoir sediment contains the same E. coli O157:H7 strand implicated in the outbreak. However, the agency says it isn’t clear how the water became contaminated and that additional illnesses demonstrate that this reservoir cannot be the only cause of such a widespread outbreak. 

As compliance dates for various sized produce and sprout farms arrive, FDA will continue to transition from an educational to a regulatory approach for FSMA and supplier enforcement. Prudent companies will take a step back and review their supplier, manufacturing, agricultural and transportation protocols to ensure that all conceivable entry points for microbiological, chemical and physical hazards are controlled, and, when problems do occur, quickly testing entry points to identify and reduce impacts.

Just because something hasn’t yet happened at your facility doesn’t mean it won’t, and don’t assume that just because something happens at one of your suppliers or distributors, that your company won’t see negative repercussions. Food safety is everyone’s business.

EAS stands ready to help you with all aspects of FSMA compliance. Contact us or more information end-users and we invite you to view our many industry information sheets to learn more about our services with regards to foods, FSMA and other FDA requirements for all product areas.

Meet New Consultants

Timothy Morck, Ph.D.

Timothy Morck provides expertise in nutrition-related research, product development, regulatory and public policy and global scientific affairs. Dr. Morck’s career includes clinical nutrition practice, research, and medical school faculty appointments, scientific association management, entrepreneurial personalized nutrition start-ups, and executive and senior management positions at several global food, nutrition and pharmaceutical companies including The Dannon Company, Mead Johnson Nutritionals, Abbott Nutrition, Nestle Health Science and Nestle Corporate Affairs. The interplay between the legal, scientific, and regulatory framework surrounding medical foods has been a particularly sharp focus for him. He received a B.S. in animal science from Penn State University, followed by MS and Ph.D. degrees in nutrition (biochemistry & physiology minors) from Cornell University.

Paula Trumbo, Ph.D.

Paula Trumbo works with clients on food and dietary supplement labeling, claims, and other nutrition related issues for compliance with FDA regulations. Prior to consulting, she led FDA’s Nutrition Science Review Team responsible for the pre-market review of the scientific evidence for food labeling, including health claims, meeting the definition of dietary fiber, and amendments to the Nutrition and Supplement Fact label. She was the US delegate to the Codex Committee on Nutrition and Foods for Special Dietary Uses. Prior to joining the FDA, Dr. Trumbo served as Study Director for a number of study panels at the Institute of Medicine’s Food and Nutrition Board and was Associate Professor of nutrition at Purdue University. Dr. Trumbo has a PhD in biochemistry with minor in nutrition.

Farm Bill Solves “Added Sugar” Problem for Single Ingredient Products

The recently signed Farm Bill answers a number of questions, particularly for those manufacturers of single ingredient foods, jars of honey and maple syrup specifically, who objected to the requirement in FDA’s 2016 Final Rule of adding a declaration of daily value (DV) for added sugars as misleading.  Single ingredient products no longer require an added sugar declaration on the label.

FDA Technical Amendments for Nutrition and Supplement Facts Panels Released

FDA released a technical amendment correcting or further explaining minor errors and omissions in the May 27, 2016, Final Rules for Food Labeling: Revisions of the Nutrition and Supplement Facts Labels and Food Labeling: Serving Sizes of Foods that Can Reasonably be Consumed at One-Eating Occasion. These latest technical corrections are considered administerial in nature. Should you have any questions on these or other labeling issues please contact us for assistance.

Issue of the Month – Tamika Cathey

Tamika Cathey consults with an international client base on regulations pertaining to safety and quality of pharmaceuticals and dietary supplements. She evaluates client compliance readiness by conducting audits, risk assessments and mock FDA/GMP investigations and works to design improvement programs based on findings. Tamika has a B.S. in Biology from Greensboro College in North Carolina. Prior to consulting she held positions such as Associate Director, Regulatory Affairs for Charles River Laboratories, and Consumer Safety Officer at FDA’s Atlanta District. She is a certified auditor with the Natural Products Association and holdsFDA Level II certifications for the Clinical Bioresearch Monitoring Auditor and Drug Auditor Program.

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

Tamika Cathey

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.

Government Shut Down Impacts FDA and Industry Operations

Dear Readers,

Edward A. Steele

Welcome to the January 2019 edition of EASeNews! We hope this year, as with each year, brings a renewed commitment to safety and innovation in the advancement of your product lines and business.

As the Government Shut Down continues, FDA recently announced that agency operations will continue to the extent permitted by law, maintaining core functions that address imminent threats to the safety of human life as well as activities funded by carryover user fee funds. FDA will continue to respond to emergencies – such as monitoring for and quickly responding to outbreaks related to foodborne illness and the flu; support high-risk food and medical product recalls when products endanger consumers and patients and pursue civil and criminal investigations as appropriate and continue screening food and medical products that are imported to the U.S.. Mission critical surveillance for significant safety concerns with medical devices and other medical products will also continue.  During this period of lapsed funding, however, FDA does not have legal authority to accept user fees assessed for FY 2019 until an FY 2019 appropriation or Continuing Resolution for the FDA is enacted. This includes regulatory submissions for FY 2019 that require a fee payment and that are submitted during the lapse period.

At EAS we are also committed to ensuring our message of compliance reaches the industry. Most recently, our initiative to create video shorts discussing industry challenges and EAS capabilities is well underway! I am pleased to announce the release of Senior Director of Pharmaceuticals and Medical Devices, Bryan Coleman’s discussion of the importance of good preparation for FDA’s GxP audits as well as our auditing services; and Senior Director of Food Consulting Services, Allen Sayler’s discussion of challenges for the dairy industry, particularly in light of the many oversight organizations, as well as EAS’ dairy capabilities. In December we also released our first Hot Topic Report, a short video with Bryan Coleman discussing CDRH increased numbers of medical device inspections and what that means for the industry. We plan to release new hot topic videos to coincide with important FDA announcements. Watch your inbox for these pertinent updates impacting to your industry.

For those who work in Dietary Supplements I am pleased to announce a new training effort aimed at employees and management who are looking to complete their annual GMP compliance refresher training. EAS will host a series of four one-day GMP Refreshers around the country and we invite you to consider outsourcing your quality department’s training to our experts! Join us at one of our upcoming events taught by our internationally recognized compliance experts and gain a greater understanding of your requirements under FDA’s 21 CFR 111.

For those looking for a deeper dive into GMPs we remind you of our two-day full GMP Compliance seminar, which will take place April 2-3, 2019 in Philadelphia, PA. Earlybird rates will expire on February 2, 2019.

In addition, our Food Labeling and Dietary Supplement Labeling Compliance seminars will also take place in Philadelphia, March 12-13 and March 14-15 respectively. More information is found on our EAS website.

Our Issue of the Month article, written by Independent Consultant Tamika Cathey who works in dietary supplement GMP compliance (and who is our trainer for the August 13 Refresher training in Andover, MA), discusses specifications development – which continues to challenge the manufacturing industry. Our Ask the Expert is written by Steve Armstrong, Independent Advisor for Food Law and Regulation, and discusses FDA’s decision to delist seven synthetic flavors and how that decision impacts those firms still using them. Finally, our FSMA perspective, written by Independent Advisor for FSMA, Charles Breen, reminds all firms, (and specifically those working in produce and sprouts as new compliance dates for these industries arrive at the end of January), that food safety is a diligent and on-going process of review, redevelopment (as needed) and execution of pertinent practices to keep consumers safe.

As always, thank for reading our updates and for your interest in EAS. Feel free to share this newsletter with your colleagues and let me know if you have questions.

Sincerely,

Ed