FDA Strengthens Process of Initiating Voluntary Recalls

Voluntary recalls are a vital means to protect public health and typically are the quickest way to remove defective or potentially harmful food, medical, and consumer products from the market. FDA’s new Draft Guidance includes steps companies may take to plan, prepare and initiate a voluntary recall in the event of a problem. The Guidance includes information on employee training, record keeping and written procedures for executing a recall. Companies in need of assistance in developing these tools or who feel a voluntary recall is warranted may contact EAS for assistance. 

Final Guidance for Food Contact Notifications – Infant Formula and / or Human Milk

FDA’s Final Guidance for preparation of Food Contact Notifications for substances that come into contact with infant formula and human milk is intended to help industry understand FDA’s process for evaluating the safety of food contact substances. It incorporates the latest scientific thinking about the effects chemical substances may have on infant health. If you missed the recent EAS webinar on infant formula submissions, you may find it On-Demand. If you have specific questions about this Guidance, development of infant formula products, including GRAS submissions, or submission of a Food Contact Notification contact EAS.

Final Guidance for Abbreviated Drug Application Submissions

FDA has issued Final Guidance related to drug marketing application submissions for human drugs and recommendations for considerations of whether to submit a 501(b)(2) New Drug Application, commonly referred to as an NDA, or a 505(j) Abbreviated New Drug Application, commonly referred to as an ANDA. These are two of the four available pathways for drug submissions for FDA approval, with ANDA known as an abbreviated pathway.

While an NDA is required for all new drug products, administration routes, etc, an ANDA may be an appropriate submission for products which duplicate a previously reference listed drug (RLD) that FDA has already determined is safe and effective. In such cases where the active ingredient(s), dosage form, route of administration, strength, previously approved conditions of use, and labeling (with certain exceptions) mimic that of a RLD, an ANDA may be appropriate. ANDAs must still include full investigative reports of safety and effectiveness, and may also rely on FDA’s previous finding of such to the extent that the proposed drug shares the same characteristics as the RLD.

It is important to note that in cases where an ANDA is the appropriate submission choice, FDA will reject a 501(b)(2) application as a duplicate of an RLD. Therefore, a thorough consideration of the drug under submission compared to RLDs already approved by FDA is warranted. Firms wishing to outsource this review and seek recommendations on the appropriate FDA filing are invited to contact Bryan Coleman, Senior Director of Drugs and Medical Devices.

June 2019 Ask the Expert

By Robert Fish

Each month EAS independent consultants answer one question sent in by readers of EASeNews. This month’s question on adverse events reporting for both OTCs and dietary supplements is answered by Independent Advisor for Quality and Compliance, Robert Fish. Mr. Fish spent 33 years with FDA, including time as the Director, Division of Field Investigations where was responsible for general policy and guidance for the Agency’s domestic and international investigation activities. He has expertise in compliance matters and cGMPs as they relate to pharmaceutical, device, and biologics manufacture. Further, Mr. Fish is ISO 9000 Lead Assessor Trained and is an AFDO Certified HACCP Instructor. He is a sought-after expert, speaking at international events on FDA inspections and GMPs.

Question: What are the steps to reporting an Adverse Event to FDA? 

Fish: In December 2007 the Dietary Supplement and Non-prescription Drug Consumer Protection Act (The Act) became effective. That law required that all over the counter drug and dietary supplement manufacturers and distributors investigate and report to FDA any serious adverse event reports concerning any of their marketed products.

The Act defines an adverse event as any undesirable experience associated with the use of a medical product in a patient. The event is considered serious when the patent outcome is:

  • Death
  • Life-threatening
  • Hospitalization (initial or prolonged)
  • Disability or Permanent Damage
  • Congenital anomaly/birth defect

Other serious (example-required medical or surgical intervention, allergic bronchospasm)

The Act requires that reports of serious adverse events be reported to FDA within 15 business days of receiving the information. The reports are required to submitted using Med Watch Form 3500A.

FDA issued Guidance for Industry concerning this adverse event reporting as well as guidance for completion of the Med Watch 3500A form.

Companiesmust have procedures in place to screen all complaints for any possible indications of adverse events with the marketed products. Those that meet the definition of serious must be investigated and reported on the Med Watch Form 3500A within 15 business days. Screening of the complaints may require the assistance of medically trained staff.

Once a 3500A has been submitted, update reports can and should be submitted as more information becomes available. 

EAS offers assistance with the completion of 3500A reports as well as assessments of consumer comments and complaints for applicability to this regulation. Contact EAS for more information.

EAS offers Pre-Clinical Safety/Tox Study Services for GRAS and NDI Submissions.

EAS offers holistic and cohesive services for clients looking to submit GRAS and NDI submissions to FDA. From the assessments to design of early feasibility studies, ongoing study oversight with the Contract Research Organization, strategy meetings with FDA and the preparation and dossier submissions, EAS’ expert toxicologists, microbiologists and chemists work closely to ensure prioritization of you study needs and execution. 

Choose EAS for:

  • Determination of required performance outcomes and appropriate studies 
  • Development of study design and protocols
  • Identification of an appropriate Contract Research Organization (CRO)
  • Coordination of the study initiation and management oversight with the CRO
  • On-going monitoring of study protocols and outcomes
  • Input of appropriate data for inclusion in study reports
  • Support the writing of the dossier for FDA submission

Meet New Consultants for June 2019

Tom Jonaitis

Tom Jonaitis

Canadian-based Tom Jonaitis works with clients in the food, dietary supplement, consumer product and related industries, providing comprehensive toxicology and regulatory consulting guidance and support. He is an expert in regulatory evaluations including scientific literature hazard reviews and summaries, as well as creating pre-market quality and safety dossiers for novel food and dietary supplement ingredients applications to government agencies – FDA, Health Canada and Australia’s TGA, FSANZ. Tom reviews and evaluates the results of in vitro and in vivo toxicological studies and has additional expertise in pesticide/agricultural chemical regulations, workplace hazard classifications, and spray foam human health risk assessments.

Veronica Ortiz de Montellano

Veronica Montellano

Veronica Ortiz de Montellano is based in Mexico and offers assistance in foods, packaging and preservation. She is an expert in food design and process developments including structure, formulation and additives including Thermal Process controls and records for Aseptic Processing and Packaging Systems including microbiological testing for Aseptic Production and CIP programs for Aseptic Systems. In addition, she conducts analyses of packaging materials and utensils to analyze stability, migration, contamination, flavor degradation and more.

Meet June 2019 Issue of the Month Author Miguel Montalvo

EAS Consulting Group independent consultant, Miguel Montalvo, is an expert in GMP and GAP assessments for pharmaceuticals, including injectables, solid dosage, OTC topicals and biologics, as well as medical devices and dietary supplements. He has developed, implemented, reviewed, managed and audited quality and GMP compliance functional procedures including those related with laboratory operations, Quality Systems, CAPA, Non-Conformance documentation, Change Control management, calibrations, procedural and documentation controls and internal auditprograms. Prior to consulting Miguel worked in industry holding positions at Baxter Healthcare and Bristol Myers Squibb.

Challenges with Implementing Cleaning Validation

By Miguel Montalvo

Though published well over 25 years ago, FDA’s guidance surrounding cleaning validation continues to cause industry confusion. While everyone agrees that cleaning validation is critical, the application of incorrect or ineffective approaches whether by misunderstanding the purpose of validating cleaning procedures or taking an extremely conservative approach create impractical demands on resources.

Planning is the root of all successful and compliant cleaning validation programs to ensure the assessment will accurately test the desired points. These plans will include a process flow to determine the activities to be conducted starting with the development of matrices for equipment/cleaning procedure combinations for all manufactured products. The next step is to select a worst-case product for each equipment/cleaning procedure combination. It is acceptable to use product family grouping if applicable. Once the worst-case product(s) is(are) chosen, analytical methods that quantify residue levels of target components of these product must be established, including acceptable limits for the residues (also called Maximum Carryover or MACO). The CV protocol can also be prepared at this point. Also, as part of the planning stage, a review of all training programs and process for the cleaning procedures will help to ensure adequate levels of challenges and qualifications are incorporated.

Prerequisites within each protocol execution must be established before initiating cleaning validations. This includes equipment design, analytical methods, adequate cleaning procedures, employee training and calibration of equipment. Cleaning procedures appropriate to each piece of equipment must be documented in appropriate detail. It is not always necessary for the analytical methods to be specific to the chemical entity under examination. If a non-specific method that appropriately measures and quantifies residues of interest under the sampling conditions applied, it’s use may be appropriate. Non-specific analytical methods save time by a considerable factor.

It should be noted that cleaning and sanitizing are often incorrectly combined into one step. The reason these should not be combined is the differences in the purposes. Cleaning is concerned with removing the residues from the previous product (and the cleaning agent if applicable) using a worst-case dirty hold time. Sanitization is concerned with the condition of the equipment before it is used next, particularly from a microbial consideration. As a good option, many companies are establishing a sanitization process/step before using the equipment again and this step is validated separately from the cleaning validation. Or, separately they may test for the microbial bioburden in the equipment surface after the worst-case clean hold time has elapsed to see whether a sanitization step is necessary. If the test fails, the option will be to apply a sanitization step which could be as simple as a high purity water rinse or other more sophisticated processes such as a hydrogen peroxide rinse/application. Of course, these considerations will be affected by the type of product/process being manufactured – from a topical drug, oral solid dosage to the more critical sterile products, specifically those aseptically filled.

There are many considerations when designing and implementing a cleaning validation approach. Ensuring due diligence is paid to assessing and determining which factors best suit each situation will pay dividends in the long run with a thorough and well documented program.

For more information on cleaning validation, including critical missteps, you may wish to view Miguel’s full length article recently published by the International Society of Pharmaceutical Engineers blog (ISPE iSpeak). EAS offers assessment and development of cleaning validation protocols. Contact us to learn more.

Challenges with Implementing Pharma Cleaning Validation

Dear Reader,

Welcome to the June 2019 issue of EASeNews, the free newsletter for FDA regulated industries. FDA has been busy with initiatives this month. As you’ll see in our What’s New at FDA section, two of these include FDA has finalized Guidance for abbreviated drug submissions as well as food contact notifications products that come into contact with infant formula and human milk. In addition, FDA announced the decision to extend the registration period for the Voluntary Qualified Importer Program (VQIP) for fiscal year 2020 until July 31, 2019. Annual benefits will then take effect beginning October 1. VQIP is a voluntary fee-based program established by the FDA FSMA that provides for expedited review and importation of human and animal foods into the US for approved applicants who achieve and maintain a high level of control over the safety and security of their supply chains. If you feel your company qualifies for VQIP or would like an assessment or assistance completing the application process, please feel free to contact me.

I am happy to say EAS has announced our fall line-up of compliance seminars taking place in Irvine, CA. We are offering Dietary Supplement Labeling November 12-13, 2019 Food Labeling November 14-15 and Dietary Supplement GMPs November 14-15. We invite you to register now for early-bird pricing.

We welcome two new consultants this month, Tom Jonaitis and Veronica Ortiz de Montellano, both of whom will be of invaluable assistance particularly to clients working with both USFDA and Health Canada as well as firms operating in Mexico who export products to the US.

Our issue of the month is written by Miguel Montalvo and discusses some of the many challenges with pharmaceutical Cleaning Validation. This article is a condensed version of a full-length feature published by the International Society of Pharmaceutical Engineering’s website, ISPE iSpeak. EAS consultants are pleased to provide monthly articles for ISPE iSpeak readers on a variety of topics pertaining to the pharmaceutical and OTC-drug industry. Our Ask the Expert is written by Robert Fish, Independent Advisor for Quality and Compliance and discusses Adverse Events Reporting requirements; and our Did you Know covers EAS capabilities with Contract Research Organizations (CROs) which are heavily utilized and a lifeblood for companies conducting safety studies in the preparation of food additive submissions.

We have two complimentary webinars coming up in June – on June 18 independent consultant Mehrdad Tajkarimi, PH.D. and Leann Chuboff of SQFI will discuss the food fraud puzzle. This webinar is co-sponsored by Food Safety News magazine. On June 20 Bryan J. Coleman, Senior Director for Drugs and Devices will present onGMPs for OTCs and how to improve compliance. We hope that you join us for these and watch any of our previous webinars available on-demand on the EAS website, including May’s webinars on cosmetics claims and how FDA views certain terms when considering whether a product to be a cosmetic or unapproved new drug; and compliance with 21 CFR Part 11.

Thank you as always for your interest in EAS and please feel free to share this newsletter with your colleagues.

FDA 21 CFR-Part 11 Compliance Audit

Presented by Independent Consultant Jeffrey Roberts

Regardless of the type of industry, if you are regulated by the FDA you are bound by the rules around electronic data integrity. Whether preparing to release a finished batch of material, making decisions on data and information that was created and generated electronically or preparing to file a technical dossier with the FDA; your electronic recordkeeping and other electronic data forms require more than just being available for review and inspection. The FDA requires these sources of evidence to be generated, processed and maintained in a manner that provides complete traceability, prevents unauthorized alteration and requires a verified electronic signature that ensures identity and authenticity. 

Learn the specifics of Part 11 requirements for electronic signatures with Jeffrey Roberts. This complimentary webinar will discuss how record keeping is inclusive of a larger focus on GMPs for electronic records that are created, modified, maintained, archived, retrieved, or transmitted as well the specifics of content that must be included in these records for verification and validation.

About the Presenter

Jeffrey Roberts

EAS Independent Consultant, Jeffrey Roberts, is an expert in software and systems auditing/validation including compliance with 21 CFR Part 11, 21 CFR Part 820 and ISO-13485. He writes Software Development Life Cycle (SDLC) documents including Validation Compliance Plan (VCP), Functional Requirements Specification (FRS), System Design Specification (SDS), Installation Qualification (IQ), Operational Qualification (OQ), Performance Qualification (PQ), Requirements Traceability Matrix (RTM) and Validation Summary Report (VSR).

Cosmetics Claims – Words Do Matter

Presented by Independent Consultant Norma Skolnik

In the competitive cosmetics world, discerning consumers are carefully considering product purchases to determine which offer the results they are hoping to achieve. In response, the pressure on marketing and labeling teams may entice to push the envelope with regards to product claims. However, words do matter, particularly in the eyes of FDA.

The manner in which labels are worded and claims are made can make all the difference in a cosmetic product inadvertently being marketed as an unapproved drug. Once a company has crossed that line, FDA takes notes and immediate changes to the marketing strategy to correct the errors or the product will be forcefully pulled from the market with potential liability risks for the company and product owners.

Learn how the words used on a cosmetic label can alter the intended meaning of a claim and FDA views on them. Ensure your cosmetic products are labeled and marketed in a compliant manner, offering consumers an accurate understanding of what they can expect and protecting your products from FDA concerns. Join Norma Skolnik on May 7, 2019 for a complimentary webinar and ensure your cosmetic product labeling and claims are compliant with FDA regulations.

About the Presenter

Norma Skolnik

Norma Skolnik has over 35 years of regulatory experience working with the pharmaceutical, OTC drug, cosmetic and dietary supplement industries. Prior to consulting, she served as Director of Regulatory Affairs for the Americas for Cadbury Adams until her retirement. She also held the positions of Director of Regulatory Affairs for the Adams Division of Pfizer and Associate Director of Regulatory Affairs for the Warner-Lambert company.

Understanding the Food Fraud Puzzle

EAS, SQFI and Food Safety News Offer a Complimentary Webinar

EAS Consulting Group
SQF Institute
Food Safety News

June 18, 2019 at 1:00 pm eastern

With long supply chains that can stretch around the world, Food Fraud is a hot topic for the food industry, consumers and government regulators. Food fraud’s negative impacts cause financial harm to the food manufacturing industry and public harm while fostering consumer mistrust. Examples of food fraud can be found in many food sectors including spices, seafood, meat and dairy as well as more specific examples such as olive oil, honey, coffee and saffron, just a few.

Substituting cheap ingredients and food additives is called “economic adulteration”, a violation of US federal law. In addition, when dangerous ingredients are used, crossing the line into “intentional adulteration” the crime is a felony, with the potential for jail time.

Learn what tools are available to food manufacturers and government regulators to combat this growing problem. Novel application of next-generation sequencing (NGS) screening and identification of multispecies which aims to improve food authenticity and tackle food fraud will be discussed.

How can you confirm suspicions of food fraud in order to avoid being a victim? What can you do to protect against food fraud and how can you ensure your products have all the safety nets in place to defend against intentional adulteration?

This webinar will provide a background on food fraud and provide an overview of tools available to meet the challenge of economic loss and consumer illness, injury or death caused by those with s nefarious, and potentially deadly, criminal intent.

Join Mehrdad Tajkarimi, Ph.D., EAS Independent Consultant and Leann Chuboff, VP of Technical Affairs at the Safe Quality Foods Institute (SQFI), co-sponsored by Food Safety News, for a webinar covering the many facets of food fraud and food defense and some of the mitigation strategies that must be put in place for prevention. Learn real world perspectives, definitions and solutions on a micro and macro level.

Register today!

About the Presenters

Mehrdad Tajkarimi, Ph.D.

EAS independent consultant, Mehrdad Tajkarimi, is an expert in national and international food safety regulations, warehouse and wholesale manufacturing, dairy, grain, poultry and retail industries, HACCP, food defense, ISO 22000, BRC. He assists clients with organic requirements, Food Safety Modernization Act (FSMA), as well as in natural food preservatives and packaging, foodborne pathogenic and spoilage microorganisms characteristics, SPC and shelf life studies.

Leann Chuboff

LeAnn Chuboff has over 30 years of foodservice experience specializing in supply chain food safety and quality assurance. Currently LeAnn is the Vice President of Technical Affairs for the Safe Quality Food (SQF) Institute responsible for the technical elements of the SQF program including the development, maintenance and technical support of the SQF Code and supporting materials. Prior to working at the SQF Institute, LeAnn worked for the National Restaurant Association Solutions as the Director of Science and Regulatory Relations. In this role, she was responsible for the technical accuracy of the ServSafe food safety program and developed program and services on food safety and food defense to fit with all segments of the restaurant industry. LeAnn has also worked for Long John Silver’s and Boston Market in corporate quality assurance where she developed food safety and vendor approval program. LeAnn graduated from Iowa State University with a B.S. in Food Science and is active with many organizations including GFSI, AFDO and the International Association for Food Protection. She sits on several committees in an effort to enhance policy and develop programs for the industry to help protect public health.

About EAS Consulting Group

EAS Consulting Group continues 55 plus years of leadership in providing regulatory consulting to the industries regulated by FDA and other federal and state agencies. Our network of independent advisors and consultants enables EAS to provide comprehensive consulting, training and auditing services to the dietary supplement, pharmaceutical, food, medical device, tobacco and cosmetic industries. Whether the need is assistance with general FDA or USDA regulatory compliance or more specific needs such as product development, New Dietary Ingredient submissions, FSMA regulation compliance, generic or customized compliance trainings, 483 responses, product market withdrawals or recalls, mock-FDA audits, expert witness services, GRAS & food additive issues, dietary supplement labeling compliance or the development of a detailed import strategy and policy, EAS, with its over 150 consultants, former FDA compliance officials and industry experts, is able to assist. With vast expertise in FDA’s policies and enforcement, EAS is the proven choice for assistance in FDA and other regulatory matters. easconsultinggroup.com

About Safe Quality Food Institute

The Safe Quality Food (SQF) program is recognized by retailers and foodservice providers around the world as a rigorous, credible food safety management system. It is the only certification system recognized by the Global Food Safety Initiative (GFSI) that offers certificates for primary production, food manufacturing, food packaging, distribution and retail/wholesale grocers. This enables suppliers to assure their customers that food has been produced, processed, prepared and handled according to the highest possible standards, at all levels of the supply chain. Additionally as a division of the Food Marketing Institute (FMI), the SQF program incorporates continual retailer feedback about consumer concerns. This information is passed on to SQF certified suppliers, keeping them a step ahead of their competitors. https://www.sqfi.com/

About Food Safety News

Food Safety News pulls together a team of talented journalists to provide timely reporting on food safety issues. Our original, in-depth reports are published daily, and are complemented by contributed articles and opinion pieces written by food safety leaders from every sector of the industry. Our reporters have been granted access to the White House, the Supreme Court, and multiple Congressional offices alongside the nation’s leading newspapers and media networks and provide outstanding, award-winning coverage of topics ranging from policy and politics to foodborne illness outbreaks to sustainability, science and research.http://www.foodsafetynews.com

Sayler Interviewed for Food Processing Magazine Article on Trump’s Effect on Food Industry

EAS Senior Director for Food Consulting Services, Allen Sayler, was interviewed for an article published in Food Processing Magazine on the regulatory state of the food industry under the Trump administration. Published during Scott Gottlieb’s tenure as FDA commissioner, Sayler discussed how Gottleib appeared to have the full confidence of the Trump administration. EAS continues to monitor Agency updates under the acting commissioner, Norman Sharpless.

Coleman to Present at CHPA Regulatory and Scientific Affairs Committee Meeting

Senior Director for Pharmaceutical and Device Consulting Services, Bryan Coleman, will speak on recent inspection trends for cosmetic to OTC crossover products at the upcoming CHPA Regulatory and Scientific Affairs Committee Meeting on May 20 in Bethesda, MD. In addition, EAS is a proud sponsor of the Regulatory and Scientific Quality conference which takes place May 21-22, also in Bethesda.

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

By: John Brennan

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.

EAS to Sponsor, Exhibit and Participate on Panel at Upcoming FDLI Annual Meeting

EAS is a proud sponsor of the FDLI Annual Conference, taking place in Washington, D.C. May 2-3. In addition, Senior Director Tara Couch will be participating in a breakout session on day one covering a status update on Modified Risk Tobacco Applications. Also in attendance at the conference, Allen Sayler, Senior Director for Food Consulting Services and Cathryn Sacra, Director of Labeling and Cosmetics Cosmetic Consulting Services. Stop by the EAS table to learn more about our services.

Meet May 2019 Issue of the Month Author

John J Brennan Ph.D.

John J. Brennan, Ph.D. is a former Senior Project Leader in Global Pharmaceutical Research and Development at AbbVie in North Chicago, Illinois. At Abbvie he served as the Enterprise Leader for 3 Global Asset Development teams accountable for creating and executing development strategies in several therapeutic disciplines including exocrine pancreatic insufficiency, cystic fibrosis and diabetic nephropathy. His areas of interest include First-in-Man, Proof-of-Concept, Proof-of-Principle, and late-stage registration studies and lifecycle management. Prior to joining AbbVie, he worked at Solvay Pharmaceuticals, Inc. in Global Project Management and as a Therapeutic Area Leader in Women’s Health, Men’s Health and Clinical Pharmacology. Dr. Brennan is a graduate of Temple University and received the Ph.D. degree in Pharmaceutical Sciences from the Philadelphia College of Pharmacy and Science (now University of the Sciences).

Pharma’s Big Data, Real World Evidence and The Digital Revolution

Dear Reader,

Edward A. Steele

Welcome to the May 2019 edition of EAS-e-News, the free newsletter dedicated to FDA regulated industries. It has been a busy month at EAS, with the release of new complimentary On-Demand webinars, announcements of new training seminars, publication of numerous articles on a wide-variety of subjects as well as a fantastic attendance at the EAS booth during the recent Supplyside East. For those of you who had an opportunity to meet with Tara Couch, our senior director for dietary supplements and Heather Fairman, one of our expert independent consultants I am sure you came away with a lot of great information on EAS and how we can begin to assist your company with any number of FDA requirements. For those who were unable to attend, I invite you to take a look at our quick reference information sheets to learn more about EAS. We are always glad to speak with you about your GMP questions or concerns.

If you will be in Geneva for Vitafoods Europe, May 7-9 we invite you to come by the EAS booth, B149, to meet Tara Couch and Charles Breen, our Independent Advisor for FSMA. In addition to exhibiting at Vitafoods, EAS is a proud training partner for the show, offering a one-day comprehensive look at GMPs for the dietary supplement industry. Registration for this seminar, taking place May 6, the day before the official start of Vitafoods, is being handled through Vitafoods directly. In addition, Charles Breen will be speaking as part of the technical sessions on hygienic commitments for food safety.

FDA has OMB approval to initiate a short voluntary survey of the cosmetics industry, which will assess a variety of GMP aspects. This survey is important to help FDA gain a better understanding of the current state of industry GMPs, and the results provided to FDA will have no identifying information, nor will responses be used by the agency to initiate enforcement actions. A Federal Register notice regarding the survey can be found here and we encourage cosmetics firms to participate in this effort.

In other FDA news, a new effort to bolster the collaboration between FDA and the Customs and U.S. Border Patrol (CBP) is underway to better protect against illegal and harmful products from gaining entry into the U.S. through the mail system, or other ports of entry. More information on this effort can be found in the What’s New at FDA section of this edition.

As mentioned earlier, we are pleased that numerous compliance seminars are both approaching and new on the horizon. Our next GMP One-day Refresher training will take place in Denton, TX on May 7, and then Andover, MA on August 13, just outside of Boston. This one-day session is designed as an opportunity to outsource your department’s GMP refresher training. At just $300 per registration it is a great and cost-effective opportunity for your entire team to learn from our experts. More information can be found on the EAS website.

Additionally, we have two complimentary webinars coming up in May. On May 7 join Norma Skolnik for a look at how FDA eyes certain cosmetics claims and on May 14 join Jeff Roberts for a look at compliance with 21 CFR Part 11. Also, on June 13 we invite you to join EAS Senior Director for Pharmaceuticals and Devices, Bryan Coleman for a look at GMPs for OTCs.

Our issue of the month is written by John Brennan and looks at pharma big data, real world evidence and the Digital Revolution and our Ask the Expert on FDA’s plans to revamp the 510(k) process is answered by George Yanulis. Finally, I am pleased to welcome a new independent consultant, Dennis Gaalswyck and a new office manager, Kate Gibson. Learn more in our Who’s Who section of this edition.

As always, thank you for your interest in EAS and we invite you to share this newsletter with your colleagues.


Edward A. Steele Signature

Ed Steele
Chairman and CEO

510(k) Guidance and Substantial Equivalence Discussed in MedTech Intelligence

Independent Consultant, Jay Mansour, discussed the movement away from substantial equivalence in favor of performance testing for the 510(k) application process in a recent MedTech Intelligence. “Expanding on the Abbreviated 510(k) Program for demonstrating substantial equivalence for 510(k) premarket submissions, FDA is identifying certain “well understood” medical devices that may be cleared based on performance criteria,” he says.

April 2019 Drug and Device Corner

It has come to EAS’s attention that there is significant confusion regarding the exemption of Class 1 Medical Device products to comply with the 21 CFR 801.20 requirement for the label of a medical device to bear a unique device identifier. Per 21 CFR 801.30 A class I device that FDA has by regulation exempted from the good manufacturing practice requirements found at 21 CFR 801.20 is not required to comply with the UDI label requirement. You can check the FDA’s Medical Device Exemptions 510(k) and GMP Requirements webpage for more specific information to determine if your product is indeed exempt. All other Class I devices will be required to bear the UDI number on the packaging/device beginning no later than September 24, 2020. If you have questions on UDI requirements, please contact EAS.

Guidance Document updates on the FDA website

Immediately in effect Guidance Document

Compliance Policy for Combination Product Postmarketing Safety Reporting: This guidance document is intended to assist Combination Product Applicants who are subject to the Combination Product Postmarketing Safety Reporting Final Rule issued on December 20, 2016, and codified in 21 CFR Part 4, Subpart B. This guidance document discusses FDA’s compliance policy for the rule. The Federal Registernotification can be found at this link.


Bispecific Antibody Development Programs: This guidance provides recommendations to assist industry and other parties involved in the development of bispecific antibodies. This guidance does not discuss development considerations for other multitarget therapies that are combinations of monoclonal antibodies or are antibody cocktails or polyclonal antibodies. Although this guidance is specific to bispecific antibodies, the principles discussed in this guidance may also be applicable to the development of other types of bispecific protein products. 

This guidance focuses on general regulatory and scientific considerations for bispecific antibodies, not on development of a particular bispecific antibody. Industry and other stakeholders are encouraged to engage FDA to discuss their individual bispecific antibody development program.

REMS: FDA’s Application of Statutory Factors in Determining When a REMS Is Necessary: This guidance is intended to clarify how the FDA applies the factors set forth in section 505-1 of the FD&C Act (21 U.S.C. 355-1) in determining whether a risk evaluation and mitigation strategy (REMS) is necessary to ensure that the benefits of a drug outweigh its risks.


Guidance for Industry Pharmacogenomic Data Submissions: This guidance is intended to facilitate scientific progress in the field of pharmacogenomics and to facilitate the use of pharmacogenomic data in drug development.


Technical Considerations for Non-Clinical Assessment of Medical Devices containing Nitinol: The 25 purpose of this draft guidance is to outline technical considerations associated with medical devices that have at least one patient contacting component comprised of nitinol. Due to the unique properties of nitinol, the Agency has developed this draft guidance to provide FDA’s current thinking on technical considerations specific to devices using nitinol. These recommendations are intended to be general and not product-specific and should be evaluated in conjunction with the intended use and technological characteristics of your device and any relevant device-specific guidances.

Technical Performance Assessment of Quantitative Imaging in Device Premarket Submissions: This draft guidance document is applicable to all devices that generate quantitative imaging values across the information, a wide range of imaging modalities, intended uses, levels of automation, and complexity of algorithms. This guidance document provides FDA’s recommendations on technical performance assessment, and user information that should be included in a premarket submission for devices that include quantitative imaging functions. 

Class II Special Controls Guideline: In Vitro Diagnostic Devices for Bacillus spp. Detection: Guideline for Industry and FDA staff. This special controls guideline was developed to establish special controls for in vitro diagnostic devices for Bacillus species (spp.) detection. This guideline identifies measures that FDA believes are necessary to mitigate the risks to health associated with devices of this type and provide a reasonable assurance of safety and effectiveness. Following the effective date of the final rule classifying the device,1 manufacturers of in vitro diagnostic devices for Bacillusspp. detection2 will need either to (1) comply with the particular mitigation measures set forth in the special controls guideline or (2) use alternative mitigation measures, which demonstrate to the Agency’s satisfaction that those alternative measures identified by the firm will provide at least an equivalent assurance of safety and effectiveness.

Surgical Staplers and Staples for Internal Use – Labeling Recommendations: The Food and Drug Administration (FDA) is issuing this guidance to provide labeling recommendations for surgical staplers and staples for internal use. These labeling recommendations are being issued because malfunctions and misuse associated with these devices have resulted in serious adverse events, including deaths.


Review and Update of Device Establishment Inspection Processes and Standards: FDA is issuing this draft guidance to comply with section 702(b)(1) of the FDA Reauthorization 77 Act of 2017 (FDARA) (Public Law 115-52), which directs FDA to issue draft guidance that specifies how the Agency will implement uniform processes and standards that are applicable to inspections (other than for-cause) of foreign and domestic medical device establishments. FDA updated processes and standards as needed, to address the new provisions in section 704(h)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) that were added by FDARA section 702(a), and to establish a standard timeframe for inspections. This draft guidance also describes standardized methods of communication during the inspection process, and identifies practices for investigators and device establishments to facilitate the continuity of inspections of such establishments.


#120 Veterinary Feed Directive Regulation Questions and Answers (Revised)

FDA to Begin Inspections for Intentional Adulteration in March 2020

FDA recently announced that verification of compliance with the Intentional Adulteration (IA) rule will begin in March 2020. Addressing hazards that may be intentionally introduced to foods, including by acts of terrorism, with the intent to cause wide-spread harm to public health, the IA rule requires the food industry to implement risk-reducing strategies for processes in food facilities that are significantly vulnerable to intentional adulteration. Those food facilities covered by the rule will be required to develop and implement a food defense plan, (which is part of the Food Safety Modernization Act (FSMA) requirements), identifying vulnerabilities and mitigation strategies for those vulnerabilities. Additionally, facilities will be required to ensure that the mitigation strategies are working. The first compliance date arrives in July 2019. EAS Consulting Group’s FSMA team can help assess current food defense strategies and strengthen those that do not meet FDA’s stringent requirements.

Insider Podcast on 25 Years of DSHEA Features Senior Director, Tara Lin Couch, Ph.D.

Tara Lin Couch was interviewed for a Natural Products Insider podcast on her reflections of 25 years of DSHEA. Recorded at SupplySide East, she discusses how the dietary supplement industry, pre-DSHEA, was the “wild, wild west” and that 21 CFR 111, Current Good Manufacturing Practices, completely changed the way the dietary supplement industry operates, with “current” processes adapting as technology advances.

New EAS Complimentary On-Demand Webinars Available

EAS recently presented three complimentary webinars that are now available for on-demand viewing. The first, on the challenges of preparing infant formula notifications presented by EAS Independent Advisor Robert Martin, Ph.D., Independent Consultants Timothy Morck and Robbie Burns and Senior Director for Food Consulting Services Allen Sayler, covered an overview of filing and safety study requirements. It can now be viewed on-demand on the EAS website.

Next, The FSMA Foreign Supplier Verification Program requires a Qualified Individual, who has the pertinent education and on the job experience enabling him or her to perform their duties, overseeing FSVP. EAS Independent Advisors, Charles Breen and Domenic Veneziano presented an overview of the program as well as addressed common questions asked by the exporters of food products into the U.S. marketplace. Find this on-demand webinar here.

Finally, in late March, Susan Crane, EAS Independent Advisor for OTC Drugs and Labeling discussed cosmetics labeling and claims requirements. Those wishing for a deeper dive into Cosmetics Claims regulations are invited to join Norma Skolnik on May 7 for a look at how words do matter when it comes to marketing a product.

FDA Proposing to Change the 510(k) Submission Process for Medical Devices

By George Yanulis

Each month, EAS selects one question sent in by readers to be answered by one of our experts. This month’s question is answered by George Yanulis D.Eng., an expert in medical device safety and the 510(k) process.

Question: Why is FDA proposing to change the 510(k) submission process for medical devices?

Yanulis: The rapid technological advances in the medical device arena have been dramatic. A 510(k), otherwise known as a Premarket Notification, is the mechanism by which device manufacturers notify FDA of their intent to market a medical device at least 90 days in advance of doing so. By reviewing the data in a 510(k), FDA is able to determine whether the device is equivalent to a device already placed into one of the three classification categories, Class I (General Controls requiring the least amount of regulatory control because they present minimal harm to users), Class II, (General Controls with Special Controls that must comply with specific labeling requirements, mandatory performance standards and postmarket surveillance) or Class III, (those devices requiring a PMA due to insufficient information to assure the safety and effectiveness solely through general or special controls. As a consultant, Class III medical devices have been my primary focus, particularly in the ICD and cardiac pacemaker device areas.

On November 26, 2018, then FDA Commissioner Scott Gottlieb announced changes to the process for approving medical devices for the U.S. market aimed at dramatically revamping the popular 510(k) clearance pathway which enables approvals based on predicates. FDA recognizes its current approach has the potential to limit advancing technological innovation and FDA is now looking to limit the age of predicates to ten years in order to avoid using outdated technologies as older predicates are less relevant to today’s requirements of interconnectivity and complexity.

FDA is proposing an approval outside of the 510(k) process if the comparable device being used is older than a decade, a change that would significantly disrupt the current process through which the vast majority, (80%) of devices are approved. FDA proposes creating a new alternative 510(k) pathway that will focus on objective safety and performance criteria. While devices more than 10 years old are not believed to be unsafe, nor would those devices need to be removed from the market, the change will encourage use of more modern predicates and as such encourage competition to adopt modern technologies and features while improving overall standards and improving outcomes.

As an expert who has collaborated directly with the FDA and particularly with CDRH, I welcome these changes. My expectation is that all devices will continue to be safe and effective, and substantially equivalent as dictated in the 510(k).

You may find some of the below FDA resources to be helpful, and please contact EAS with specific questions regarding your 510(k) filing.



Final Rule on OTC Hand Sanitizers Issued

FDA issued a Final Rule, effective April 13, 2019, which aims to ensure the safety and effectiveness of OTC hand sanitizers, formally known as topical consumer antiseptic rub products. These products are intended for use without water and marketed under the FDA’s OTC Drug Review.

Active ingredients of ethanol, isopropyl alcohol, benzalkonium chloride, which the majority of hand sanitizer rubs on the market contain, have deferred action to allow for the ongoing study and submission of additional safety and effectiveness data to enable FDA’s safety determination for use in OTC consumer antiseptic rub products.  At this time, FDA states that it does not intend to take action to remove hand sanitizers containing these three active ingredients from the market and their status will be addressed either after completion and analysis of the studies or at another time, if these studies are not completed.

However, 28 other active ingredients, identified in the 2016 Consumer Antiseptic Rub proposed rule, including triclosan and benzethonium chloride, are no longer eligible for inclusion in any future OTC monograph.

This long awaited rule finalizes a June 30, 2016 proposed rule on consumer antiseptic rubs, where FDA requested additional scientific data to support the safety and effectiveness of active ingredients used in OTC consumer antiseptic rubs. FDA has determined that less than 3% of the marketplace will be affected by the issuance of this final rule, as most OTC consumer antiseptic rubs use ethyl alcohol as the active ingredient.

Concerned companies may contact EAS to learn more about how this Final Rule impacts product formulations and compliance with the OTC monograph.

Did You Know? EAS Offers Verification and Validation Services of Electronic Signatures Under 21 CFR Part 11

Increasing usage of electronic methods to capture and produce critical data, which are subject to regulatory scrutiny led to the effect of Title 21 CFR Part 11. This part of the Code of Federal Regulations establishes the United States Food and Drug Administration (FDA) regulations on electronic records and electronic signatures.

The aim of this regulation is to define the criteria under which the agency will consider electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper.

The FDA released a guidance document in 2003 to clarify how part 11 should be implemented and enforced. This has been updated many times, partly due to the fast-emerging changes in technology. In June 2017, the FDA also issued a draft guidance on the use of Electronic Records and Electronic Signatures in Clinical Investigations.

The FDA takes accountability of electronic signatures very seriously and upon inspection of these records deficiencies may result in a warning letter.

These constantly evolving rules can be daunting to understand and implement. EAS’ team of experts is available to assist your firm in understanding your requirements under 21 CFR Part 11 as well as assess your compliance.  Areas in need of strengthening will be addressed giving your firm a detailed action plan for maintaining compliance for both signatures and storage of electronic data.

Meet New Office Manager, Kate Gibson

Kate Gibson is a graduate of UNC Chapel Hill with a degree in Psychology and Peace, War and, Defense. While at university, Kate was involved in the Triangle Institute for Security Scholars and UNC Neural Connections and has a passion for inclusive STEM Education. Prior to EAS she held a position at the UNC Gillings School of Global Public Health, specializing in tobacco marketing regulation research. Kate is originally from Denver, North Carolina.