FDA’s Transition from CFR 820 to the ISO 13485:2016 – Instituting a New Quality Management System (QMS)

Presented by George Yanulis, D.Eng., EAS Independent Consultant

FDA’s shift to a Quality System Regulation structure of ISO 13485:2016 is an effort to harmonize medical device regulations as well as reduce compliance and record keeping burdens faced by current medical device manufacturers. But will those operating under 21 CFR 820 Quality Management Systems make the voluntary switch?

While ISO 13485 is an international standard, its focus on design and development planning and controls, based on risks and outputs differs in many respects to the GMPs under which medical device firms selling products in the U.S. have been operating. Making the shift to ISO standards requires a shift in thinking, planning and execution of manufacturing policies and working procedures.

Learn more about the ISO standards and how they might benefit your business. Join George Yanulis, D.Eng., and ensure your medical device manufacturing is as efficient, safe and compliant as it can be.

About the Presenter

George Yanulis, Ph.D.

Dr. George Yanulis has consulted in Medical Device Product Development and Research for 20 years and has a Doctorate and Master’s Degree in Biomedical Engineering. He has conducted cardiovascular device research at the Cleveland Clinic Foundation on cardiac pacing paradigms used in heart failure patients. In addition, Dr. Yanulis has been involved in the R&D Medical Device Consulting & Litigation Support as an Expert Witness for over 10 years and has been involved in numerous medical device liability and patent infringement cases. He provides expertise to attorneys, medical device companies, health care systems and insurance carriers related to FDA medical device controls, PMAs, post-market surveillance issues, medical device/product failures, and IP medical device issues. In addition, he has reviewed MDR(s) and other adverse events related to implant device failure. Dr. Yanulis is highly motivated in maintaining and providing the highest level of quality in the design, development and safe and effective use of all types of cardiac device implants.

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Food Defense – Untangling the Challenges and Strengthening Opportunities

Presented by Charles Breen and Kathy Knutson, Ph.D.

EAS Independent Advisor for FSMA, Charles Breen and Consultant Kathy Knutson, Ph.D. co-present a webinar on Food Defense. Food Defense is increasingly a worry for firms as our global business climate opens opportunities for intentional harm both domestically and overseas. The ability of food manufacturers to identify and mitigate the impact of intentional attacks that compromise food safety is not only required as part of the Food Safety Modernization Act (FSMA) it makes good business sense to protect consumer health and brand reputation.

About the Presenters

Charles Breen

Mr. Breen became available to EAS Consulting Group after a distinguished career at the FDA working in areas such as HACCP and LACF and BSE prohibited materials in the dairy. Mr. Breen has worked with the industry on compliance issues related to the Bioterrorism Act of 2003 and led the field and HQ professionals in developing and implementing surveillance and compliance programs, and initial FSMA training implementation. His attention to detail has garnered him an FDA Award of Merit, Outstanding Achievement and five Commissioner Special Citations.

Kathy Knutson, Ph.D.

Kathy Knutson, Ph.D. is a microbiologist and certified lead instructor for Preventive Controls for Qualified Individuals through the Food Safety Preventive Controls Alliance. She consults with companies in meeting FSMA requirements, including manufacturers in the cannabis industry as she educates on issues surrounding cannabis infused food products for sale in states with medical and recreational use legislation. Kathy has a Ph.D. in Food Science from the University of Minnesota and prior to consulting worked as a Food Safety Educator and Proficiency Program Coordinator with the Northland Laboratories.

Register for Upcoming EAS Webinars on Food Defense, Effective Expert Witness Techniques and QMS

Register now for the EAS complimentary webinar Food Defense – Untangling Challenges and Strengthening Opportunities, presented by Independent Advisor for FSMA, Charles Breen and Independent Consultant, Kathy Knutson, Ph.D. which will be held September 12, 2019, at 1 pm eastern. Food Defense is increasingly a worry for firms as our global business climate opens opportunities for intentional harm both domestically and overseas. Charles and Kathy will help food manufacturers understand how to identify and mitigate the impact of intentional attacks that compromise food safety.

On September 25 George Yanulis D.Eng. will present a webinar focusing on the medical device Quality Management System transition from CFR 820 to the ISO 13485:2016. Dr. Yanulis will discuss reasons behind the change as well as some of the more technically challenging areas of ISO compliance. Join George by registering here.

Ronald Levine, EAS Independent Consultant and General Counsel with Herrick Feinstein LLP will present a webinar on considerations for becoming an expert witness on November 6, 2019, at 1 pm​. Ron’s has decades of experience preparing expert witnesses in a variety of legal cases focusing on compliance with FDA regulations. Ron’s complimentary webinar will help those interested in exploring a career as an expert witness understand expectations and those already acting in an expert witness capacity to strengthen their skills. Register here.

GRAS Determination: Lessons and Pitfalls

By Tom Jonaitis

Over the 14 years of working as a scientific and regulatory consultant in the food industry, I have had the opportunity to work with many companies that were bringing a wide range of exciting and innovative food ingredients to the marketplace in the United States and abroad.

Beyond the extensive resources put into the R&D phase to identify and produce the right ingredient and ensure it does what it needs to, companies also need to address the regulatory requirements for these ingredients. Whether in the US (through the GRAS process[1]) or elsewhere, the ingredients must have substantial and robust evidence of safety under intended conditions of use. I will focus on the food additive regulations here and put aside the multitude of other regulations companies need to address.

The safety of food additives is supported by 2 main areas of data: a) chemistry and manufacturing and b) toxicology data that corroborates the safety of the estimated intake of the ingredient. Companies familiar with the GRAS process will plan for the requirements of the regulatory stretch of the journey (or get the help they will need) well in advance of being “market ready”. This ensures that any data gaps or hiccups are dealt with quickly and efficiently to avoid costly delays. There’s nothing worse than needing your ingredient approved to meet customer demands, to find out more data is required, which means more time and resources.

Many times, I’ve worked with companies that may have had a great product yet were unclear of the depth of data required to satisfy the regulatory requirements. Fortunately, in most cases, I was able to work with them to help them obtain the necessary data and compile a robust dossier.

Looking back at the obstacles some companies faced, as well as reviewing the publicly available outcomes of FDA’s review of GRAS notifications (both successful and unsuccessful submissions), I will highlight just a few of the key areas that have cause some issues:

  1. Identification/Characterization:

    • The ingredient should be characterized both qualitatively and quantitatively and defined to 100% purity with validated methods. This is easier to do with a single ingredient compared to more complex ones, i.e., certain botanical extracts, waxes, starches. A company must know exactly what is in their ingredient so as to show that the ingredient, and any impurities, are safe.

  2. Processing Aids used in manufacturing:

    • In the US, anything used in the manufacturing of a food ingredient is technically considered a “food additive” – so every substance used must be permitted for use in food production. It will need to be either a permitted food additive (and permitted for your particular application, as described in the CFR) or a GRAS substance. Otherwise, the safety of the processing aid will need to be assessed and supported either in a separate GRAS determination or within the existing determination. Generally, the best course of action is to ensure only permitted substances are used to avoid the need for additional safety assessments.

  3. Toxicology/Safety Studies:

    The GRAS status of an ingredient can be based either on scientific procedures (safety studies and expert consensus) or a history of use in food prior to 1958. Essentially all new ingredients (>95%) will fall into the former category due to the particular requirements needed to meet the history of use in foods definition.

    • Generally, a 90-day rodent toxicity study, in conjunction with a battery of genotoxicity tests (all conducted to GLP/OECD requirements), on the specific ingredient, will be the minimum testing requirements to support the safety of a novel food ingredient.

    • Many times, companies have identified a plethora of published studies and consider that the safety of their ingredient is supported by existing data. In most cases the data will not meet the minimum safety requirements, due to quality of the safety studies and comparability to actual ingredient and intended uses (i.e., duration of study too short, dose too low compared to intended food uses, issues with study populations used, or purity profile of test article is too different from the novel ingredient).

Obtaining GRAS status for an ingredient is no small feat and preparing for it in advance will create ample opportunity to get all your ducks in a row for a smooth and predictable path to market. If your company has not gone through the process a few times, it could be invaluable to discuss your strategy and data requirements with an experienced food regulatory consulting firm to ensure there are no critical gaps that could cause unnecessary delays and wasted resources.

EAS Consulting Group offers world-class food regulatory consulting services with an extensive team of experts, including ex-US FDA agency officials, board-certified toxicologists, and other regulatory professionals. It has an excellent record of successfully helping companies obtain GRAS status for its ingredients, with and without FDA notification.


[1] https://www.fda.gov/food/food-ingredients-packaging/generally-recognized-safe-gras

August 2019 Drug and Device Corner

The FDA has announced FY2020 User fees, please scroll down for further information.

EAS recently sent an email update regarding FDA’s intention to begin inactivating drug listing records, effective 13 Sept 2019. The FDA has found that tens of thousands of drug listing records contain errors. The agency announced their intentions in the Federal Register on 14 August 2019. The main concern with these non-compliant listings is their lack of certification as being active and up-to-date, or the listings are associated with a drug establishment no longer duly registered with the FDA. The notification also points out that some companies have simply opted to not renew registrations / certify listings and have considered this sufficient notification to the FDA. However, this practice is not compliant with the regulations. To appropriately close files, a de-registration SPL file must be submitted to the FDA for an establishment registration and a ‘Marketing Complete’ file (which includes the expiration date of the last batch of product introduced into U.S. commerce) must be submitted for a drug listing.

If the FDA does inactivate a listing, the listing record will note this and it will be removed from all public drug listing databases maintained by FDA. This includes the NDC Directory and the NDC SPL Data Elements (NSDE) file. Any such drug that is still marketed will be deemed misbranded and the company involved will be subject to FDA enforcement action. This would be particularly problematic for foreign companies when importing products into the U.S.

The agency also notes in their announcement that manufacturers and repackagers of products subject to the new product identification requirement, must submit the updated labeling to their product listings. This update will satisfy the annual certification requirement and therefore such products will not need the “blanket no changes” submission to maintain the listings’ active status.

While on the topic, labeler codes should also be current and reflect accurate contact information for the labeler. If you have any questions or concerns regarding your company’s status, EAS is here to assist.

A message was communicated recently from the FDA re approved (A)NADA labeling. By 30 September 2023 the following statements (as applicable) must be included on approved (A)NADA labeling: Approved by FDA under NADA# xxx-xxx OR Approved by FDA under ANADA# xxx-xxx. This requirement applies to all approved animal drugs currently on the market. If you need further information on this topic, please contact EAS.

The FDA, in their ongoing effort to update the IID Database, has announced their most recent changes. Information about FDA’s plans for upcoming changes to the IID can be found on the IID web page. The web page will be continually updated as FDA makes changes to the IID over the coming year.

The FDA has published the following user fee rates for their FY2020, which runs from 1 Oct 2019 – 30 Sept 2020:

Annual Establishment facility fee rates effective 1 October 2019 are as follows:

  • Medical Device: $5,236

GDUFA

  • Domestic API facility: $44,400
  • Foreign API facility: $59,400
  • Domestic FDF facility: $195,662
  • Foreign FDF facility: $210,662
  • Domestic CMO facility: $65,221
  • Foreign CMO facility: $80,221

Guidance Document updates on the FDA website:

ALL DIVISIONS

CDER

CDER & CBER

  • Male Breast Cancer: Developing Drugs for Treatment This guidance provides recommendations to sponsors regarding the development and labeling of cancer drugs, including biological products, regulated by the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) for the treatment of male patients with breast cancer.
  • Child-Resistant Packaging Statements in Drug Product Labeling The guidance discusses what information should be included to support CRP statements in labeling for new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and supplements to these applications.
  • Fabry Disease: Developing Drugs for Treatment The purpose of this guidance is to provide recommendations to sponsors regarding clinical trial design features that can support approval of drugs and biological products intended for the treatment of Fabry disease (FD).
  • Bacterial Vaginosis: Developing Drugs for Treatment The purpose of this guidance is to assist sponsors in the overall development program and clinical trial designs to support development of topical and systemic drugs and biological products for the treatment of bacterial vaginosis (BV).
  • General Clinical Pharmacology Considerations for Neonatal Studies for Drugs and Biological Products This draft guidance is intended to assist sponsors of new drug applications (NDAs), biologics license applications (BLAs), and supplements who are planning to conduct clinical studies in neonatal populations.
  • Rare Pediatric Disease Priority Review Vouchers This guidance provides information on the implementation of section 908 of the Food and Drug Administration Safety and Innovation Act (FDASIA), which added section 529 to the Federal Food, Drug, and Cosmetic Act (the FD&C Act). Under section 529, FDA will award priority review vouchers to sponsors of certain rare pediatric disease product applications that meet the criteria specified in that section.
  • Delayed Graft Function in Kidney Transplantation: Developing Drugs for Prevention This guidance addresses the FDA’s current thinking regarding the overall development program and clinical trial designs for systemic drugs administered to the kidney transplant recipient to support an indication of prevention of DGF.

CDRH

CVM

  • CVM GFI #257 (VICH GL57) The objective of this guidance is to provide study design recommendations that will facilitate the universal acceptance of the generated residue depletion data to fulfill the national/regional requirements for drugs intended for using in aquatic food-producing species.

Meet New Consultant Penny Vyskocil

Penny Vyskocil

Penny Vyskocil is a food safety, regulatory, and quality professional with extensive experience in both manufacturing and retail, inclusive of corporate and plant leadership positions. She has a proven track record of strategic planning, organizational effectiveness, staff development and project execution. Her expertise includes cereal, snacks, dry meals, IQF vegetables, Low Acid Canned Foods (LACF) and milling.

Meet September 2019 Issue of the Month Author

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 ingredient 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.

FDA Begins Enforcement of FSVP

Dear Readers,

Edward A. Steele

Welcome to the September 2019 edition of EASeNews, the free news publication dedicated to FDA regulated industries.

FDA issued its first warning letter related to FSVP Final Rule enforcement of FSMA. The industry has long been anticipating FDA’s enforcement vs educational-based approach to FSVP. After two years of working to ensure importers of foreign foods and foreign food ingredients understand their requirements to verify supplier safety policies and track records, the Agency will now begin cracking down on those firms still not in compliance. EAS’ Team FSMA offers comprehensive services in the area of FSMA and FSVP. From desk audits of current policies to mock-FDA inspections of facilities, our experts help you to identify gaps and develop actions plans to mitigate risks. Learn more about our services by viewing our short promotional videos and reviewing our industry services sheets.

Additionally, FDA has indicated that drug firms that do not certify updated information or that no changes have taken place since the last renewal cycle can expect FDA to begin delisting products which can lead to misbranding. FDA has been taking an educational-based​ approach to the enforcement of product and facility renewals, however in a constituent update dated August 13, 2019, the Agency confirmed firms can expect greater hardships for not complying. EAS offers assistance with registrations and listings of both facilities and products as well as proactive annual updates and renewals. We invite you to contact us to learn more about our services and how we may assist you.

I am pleased that EAS has been invited to participate in educational sessions at a number of industry events this month. From FDLI to CHPA to NCBFAA to a keynote speaker at an international dairy event in Turkey, our experts will be traveling the globe in September ensuring FDA compliance is at the top of everyone’s agenda.

Additionally, we are offering a number of complimentary regulatory webinars with topics ranging from Food Defense, (September 12); to Quality Management Systems for medical devices (September 25) and a reintroduction to our expert witness training via webinar on November 6. There is always something new happening at EAS and we look forward to your participation in any of our regulatory events.

Our issue of the month is written by Tom Jonaitis and discusses common pitfalls with GRAS submissions. If you missed our recent webinar on GRAS submissions, presented by Robin Guy and Robert Kapp, you may now view it on demand. EAS has a dedicated team of toxicologists and regulatory scientists who regularly assist EAS clients with both GRAS and independent GRAS submissions.

Finally, we welcome new consultant, Penny Vyskocil, an expert in food safety in a variety of product types, from cereal, snacks, dry meals, IQF vegetables, Low Acid Canned Food (LACF) and milling.

Thank you for your interest in EAS and as always please feel free to contact me if you have any questions or if EAS can be of assistance.

Sincerely,

Edward A. Steele Signature

Ed

EAS Instructs at FDLI Educational Events

EAS Senior Director for Food Consulting Services, Allen Sayler will present a lunch-time seminar for FDLI’s Law Over Lunch program on September 17 at DLA Piper in Washington D.C.. Allen’s topic, Recent FDA and CDC Human Illness Investigations, Recalls & Enforcement Actions – Trends and Lessons Learned is open to FDLI members only.

Additionally, two of our experts in food and dietary supplement labeling are speaking at FDLI’s Intro to Food Law and Regulation on September 24-25, 2019 at Crowell Moring in Washington, D.C.. Gisela Leon will present an Introduction to Food Law and Regulation and Andrea Yablunosky will instruct Food Labeling, Nutrient Content and Other Claims.

Finally, James Hoadley, Ph.D., will teach a session on FDA Food Labeling for an FDLI seminar presented at CFSAN, on September 12, 2019. EAS is pleased to be a frequent contributor to numerous FDLI educational programs on a variety of product areas.

What Should We Consider When Exporting Our FDA Regulated Products to the US?

By Victoria Pankovich

Each month EAS experts answer one question sent in by readers of EASeNews. This month’s question, on considerations for a reliable US Agent, is answered by Victoria Pankovich, Regulatory Specialist, who assists EAS clients with US Agent requirements. If you would like to ask a question of our experts contact us here.

Question: As a firm operating outside of the US, what criteria should we consider when choosing a reliable US Agent for exporting our FDA regulated products to the US?

Pankovich: While most foreign companies engaged in exporting products to the United States understand their regulatory obligation to appoint a US Agent to liaise with the US FDA, what many may not understand is the business benefits that can be gained by working with a professional and reliable US Agent. You should look for a US Agent, who is a proactive partner that can provide guidance on FDA regulations, assist in electronic and paper submission actions and who understands the organization, structure and authorities of the US FDA.

US Agents can be single individuals, or they may be named individuals as part of a larger organization such as the case of consulting firms, like EAS, that provide not only a US Agent service but other regulatory support services as well. The latter provides a depth of capability that allows a firm to be prepared for any eventuality when dealing with the FDA.

Simply put, a US Agent acts as a liaison between the FDA and the foreign company for purposes of communication. This is important in many instances, for example, the case of submitting a food ingredient, medical device or pharmaceutical product application. It is critical for the FDA to have a US-based contact to which they can address any questions or requirements needing clarification prior to the product going to market.

In addition to this basic function, it is not only prudent but extremely beneficial to choose a U.S. Agent with regulatory strength that can assist with any importing issues should they arise. FDA inspects products as they arrive at the US border. Products may be detained for any number of reasons – from lack of prior notice, to product labeling that does not meet US specifications, to products shipped from facilities without an active foreign facility registration or low-acid canned food registration. In the case of detained products, expediting the receipt of required information from the Agency and responding with the missing documentation in a timely manner is critical. Keep in mind, the FDA only allows a certain, generally small, window of time within which to respond to their inquiry. Products waiting for US entry cost manufacturers time and money and a proactive US Agent who understands how to navigate the many bureaucratic layers in order to quickly provide answers to the FDA or US Customs Border Patrol is imperative for business flow.

The FDA copies US Agents on notifications of facility and FSVP inspections. US Agents such as EAS, that possess a broad understanding and capability in all areas of FDA regulatory compliance, can often assist with preparing for these inspections by reviewing documentation and / or conducting a mock-inspection so that plant managers and staff will know what to expect when the Agency arrives. In some cases, a firm may wish to have a consultant familiar with the Agency and their inspection process on site during the inspection itself. After the inspection, should the Agency find violations that need to be addressed, a US Agent knowledgeable in FDA regulations should be able to help the firm makethe needed corrections to bring themselves into full compliance with FDA requirements.

When considering a US Agent, ask important questions to help determine the level of service and competence they will be able to provide. You should also consider how comfortable you are with the clarity of their communications and their ability to represent your firm and its objectives to the FDA, they are after all going to be seen as an extension of your organization. Are they able to meet the most basic requirement of having a named US-based point of contact for US FDA communications? Does the US Agent have the technical know-how to assist with gathering important information in the event of a detained product or a question posed by the Agency? Do they have direct experience in helping firms prepare for a US FDA inspection? Should you wish, are they able to be present and provide support during the US FDA inspection? In the event of a detained product, does that US Agent understand how to interpret the Agency’s requests for documentation so that correct responses can be quickly provided?

EAS provides US Agent assistance with our vast network of independent consultants who specialize in various product areas. We invite you to learn more about our US Agent services on our webpage. Regardless of whether you choose EAS to act as your US Agent, we do recommend that you watch our free on-demand video which discusses the roles that US Agents play. If EAS can answer any questions please feel free to contact us. It is an easy matter to officially change your appointed US Agent.