Drug and Device Corner 2018 July

EAS would like to bring to your attention the Draft Guidance released by the FDA for ANDA Submissions – Amendments to Abbreviated New Drug Applications Under GDUFA. This guidance describes the significant difference between GDUFA I and GDUFA II Amendments and the timelines associated with their review. The FDA considers all submissions to an ANDA to be an amendment, they will be classified based on the content and issued a goal date consistent with that classification. Please review the guidance for further details.

In the FDA’s ongoing effort to make generic affordable drugs available to the public, they have published product-specific guidances describing the Agency’s current thinking and expectations on how to develop generic drug products therapeutically equivalent to specific reference listed drugs. These guidances are hoped to assist the generic pharmaceutical industry with identifying the most appropriate methodology for developing drugs and generating the evidence needed to support ANDA approval. Please see the FDA’s Product-Specific Guidances for Generic Drug Development webpage for more details.

The FDA issued a press release regarding its recent actions on bulk drug substances used for compounding. Their Bulk Drug Substances Nominated for Use in Compounding lists for 503A Category drugs and 503B Category drugs have been updated as of 23 July 2018. Included in the update are the changes to the lists and when the changes became effective. Please see the press release for full details. 

The Food and Drug Administration (FDA) announced a public hearing to solicit input from the public on how to facilitate greater availability of biosimilar and interchangeable products while retaining the balance between competition and innovation. The hearing will be held on Tuesday 4 September 2018, from 9 a.m. to 5 p.m. at the Food and Drug Administration’s White Oak Conference Center. If you would like to participate and weigh in on this hearing, more information on how to register for the meeting or the live webcast can be found in the Federal Register Notice.

Guidance Document updates on the FDA website

All centers

Use of Electronic Health Record Data in Clinical Investigations

CDER

Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations

Smallpox (Variola Virus) Infection: Developing Drugs for Treatment or Prevention

Q3D(R1) Elemental Impurities

Hypertension: Conducting Studies of Drugs to Treat Patients on a Background of Multiple Antihypertensive Drugs

Innovative Approaches for Nonprescription Drug Products

Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products – Quality Considerations

Use of Liquids and / or Soft Foods as Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods for Product Quality Assessments

Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products – Quality Considerations

CDER & CBER

Assessing User Fees Under the Biosimilar User Fee Amendments of 2017

Indications and Usage Section of Labeling for Human Prescription Drug and Biological Products – Content and Format

E17 General Principles for Planning and Design of Multiregional Clinical Trials

Field Alert Report Submission Q & A

Labeling for Biosimilar Products

Inborn Errors of Metabolism That use Dietary Management: Considerations for Optimizing and Standardizing Diet in Clinical Trials for Drug Product Development

Slowly Progressive, Low-Prevalence Rare Diseases with Substrate Deposition That Results from Single Enzyme Defects: Providing Evidence of Effectiveness for Replacement or Corrective Therapies

E17 General Principles for Planning and Design of Multiregional Clinical Trials

CDRH

Metal Expandable Biliary Stents – Premarket Notification (510(k)) Submissions

CBER

Human Gene Therapy for Retinal Disorders

Long-Term Follow-Up After Administration of Human Gene Therapy Products

Human Gene Therapy for Rare Diseases

Chemistry, Manufacturing and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

Human Gene Therapy for Hemophilia

Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

CVM

Antimicrobial Animal Drug Sales and Distribution Reporting

#257 Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Species: Marker Residue Depletion Studies to Establish Product Withdrawal Periods in Aquatic Species

August 2018

  • From the Desk of the Chairman: Dietary Supplement GMP Compliance Includes Application to the Cannabis Industry
  • Issue of the Month: FDA 483 Responses – Missing the Mark?
  • Who’s Who at EAS
    • Meet Issue of the Month Author and New Independent Consultant, Cindy Beehner
    • Meet New EAS Consultants
  • Standards of Identity: Are Plant-Based Proteins Milking Dairy?
  • Drug and Device Corner
    • Recent FDA Drug / Medical Device Activity
  • What’s New on FDA’s Website
  • EAS in Action
    • Dietary Supplement GMP Seminar to Take Place in Dallas, TX
    • EAS Offers Official FSPCA Preventive Controls for Human Foods and FSVP Seminars
    • New Webinar on Environmental Monitoring Added to EAS’ Summer Compliance Line-Up
    • EAS Offers Complimentary Webinars on Cannabis, Foreign FDA Inspections, Temporary Marketing Permits and more
    • Crane Returns as a Presenter at CHPA’s OTC Academy
    • Yablunosky and Knutson to Speak at Upcoming Food Safety Consortium
    • EAS Consultants Invited Speakers at Two FDLI Conferences
    • EAS Co-Authors Article for FDLI Update on the Benefits of Consultants as Part of a Legal Team
  • Useful Publications and Regulatory Tools

EAS Co-Authors Article for FDLI Update on the Benefits of Consultants as Part of a Legal Team

EAS joined forces with Ronald J. Levine, co-chair on Herrick, Feinstein LLP’s Litigation Department to author an article published in the Food Drug Law Institute Update Magazine on how the use of consultants can benefit a legal team. Consultants provide unique insights, given their detailed expertise in a particular subject matter, offering context and in-depth understanding of FDA regulations and intent of guidance documents. Consultants are frequently engaged, particularly during the discovery and trial stages for the planning and execution of a legal strategy. While the benefits they provide cannot be underestimated, the same due diligence for choosing the right consultant for the particular project must also not be taken lightly. Read more here.

EAS Consultants Invited Speakers at Two FDLI Conferences

EAS is pleased to be invited speakers at two upcoming Food Drug Law Institute (FDLI) Events. Andrea Yablunosky will speak at an in-house event held at FDA CFSAN on Food Labeling: Nutrient Content, Health, and Other Claims on August 7th. Bruce Silverglade will speak on the same subject as part of the Intro to Food Law conference which will be held in Washington, D.C. September 24-25, 2018. For more information on the Intro to Food Law event, click here.

Yablunosky and Knutson to Speak at Upcoming Food Safety Consortium

EAS Independent Consultants, Andrea Yablunosky and Kathy Knutson are invited speakers at the upcoming Food Safety Consortium. Yablunosky will speak on food recalls, discussing the USDA/FSIS recall committee, as well as roles district offices play in a recall. She’ll then move on to the steps in a recall and important to-dos such as the drafting of a recall press release. Yablunosky is a former Director of Government Affairs at ConAgra Foods where she advised the company business units on implications of FDA and USDA policy objectives. With a background in food science and nutrition she is well-versed in policy development, product reformulations and promotions, recall preparedness and effective recall management.

Kathy Knutson, Ph.D. will speak on Lessons Learned in Food Safety and Applied to Cannabis-infused Edibles. She will discuss GMPs as the foundation of food safety and how HACCP builds on GMPs. Dr. Knutson 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 and she educates on issues surrounding cannabis-infused food products for sale in states with medical and recreational use legislation.

Food Safety Consortium will take place November 13-15, 2018 in Schaumburg, IL.

Crane Returns as a Presenter at CHPA’s OTC Academy

Susan Crane, Independent Advisor for OTC Drugs and Labeling will be presenting a session at the upcoming Consumer Healthcare Products Association OTC Academy on OTC drug labeling requirements, to include Drug Facts format and content, translating an OTC monograph into a compliant label, as well as covering other regulations that impact OTC drugs, such as child-resistant packaging requirements and Made in USA claims. This year’s OTC Academy will take place in Wilmington, DE October 9-10, 2018.

EAS Offers Complimentary Webinars on Cannabis, Foreign FDA Inspections, Temporary Marketing Permits and More

Quality Systems for the Cannabis Industry – Preparing for State GMPs
August 6, 2018, 1:00pm Eastern

Tara Lin Couch Ph.D., Senior Director for Dietary Supplements and Tobacco Services, will help cannabis firms prepare for cannabis Good Manufacturing Practices (GMPs). While regulations vary from state to state the quality systems under which cannabis products are grown and manufactured have similarities that can begin to pave the way for putting practices and procedures in place to meet compliance expectations, including those of testing and quality control of in-process materials, finished batches and packaged/labeled products. The time is right for the cannabis industry to begin assessing manufacturing processes and implementing sound and effective quality systems in order to begin preparing for GMP regulations. Reserve your seat by clicking here.

Preparing for Foreign FDA Inspections
August 14, 2018, 1:00pm Eastern

Have you ever wondered why your foreign suppliers: API, intermediates, food ingredients, etc. are suddenly in trouble with regulatory authorities? Did they just go astray or is your auditing program not performing as designed? Actually, there are several things at play. EAS Independent Consultant, Peter Saxon, will shed some light on reasons FDA inspections can “go south” as well as provide insight on how disappointing results can be managed. His insights will provide an opportunity for companies to consider improvements to their internal audit structure to help minimize regulatory risks. Join us for this webinar by clicking here.

Temporary Marketing Permits – Opportunity and Pitfalls of the Specialized FDA Application
August 21, 2018, 1:00pm Eastern

Food Standards are an important component of FDA’s oversight, ensuring honesty and fairness to the consumer through requirements that provide for the basic nature of a standardized food to be uniform in terms of its characteristics as well as the ingredients that it must or may contain. But what happens when a newly developed food or production method warrants consideration of a product category outside of the standard? Petitioning to amend a food standard or to create a new one, is a lengthy and complicated process; however, a temporary solution may be available through a specialized category called a Temporary Marketing Permit (TMP’s). Learn more when EAS Independent Consultant, April Kates, discusses this unique marketing option in a webinar on the opportunities and Pitfalls of Temporary Marketing Permits and learn best practices for a successful TMP application. Reserve your seat by clicking here.

New Webinar on Environmental Monitoring Added to EAS’ Summer Compliance Line-Up

Are Industry-Initiated Environmental Swab-a-Thons a Benefit?
September 17, 2018, 1:00pm Eastern

The emphasis on proactive management of issues that could cause a food safety hazard, per FDA’s Food Safety Modernization Act, requires firms to improve controls for a variety of issues at all levels. One hot-button concern that continues to wreak havoc in the industry is that of pathogen contamination. It is generally understood that contamination in the processing environment will eventually make its way into the product. Even with the best of safety controls, it is imperative that companies have a robust environmental monitoring program that includes vigilant and regular testing. After all, finished product testing gives limited data and is a small snapshot of the entire lot manufactured. FDA can take hundreds of swabs during inspections, does your environmental monitoring meet that level of testing?

EAS Independent Consultant, Kathy Knutson, Ph.D. will host a complimentary webinar on the importance of Environmental Monitoring. Don’t wait for FDA, conduct your own swab-a-thon! Join us September 17, 2018, at 1:00 pm Eastern to learn important ways your company can stay ahead of the curve. Register by clicking here.

EAS Offers Official FSPCA Preventive Controls for Human Foods and FSVP Seminars

EAS Independent Consultant and FSPCA recognized lead instructor, Jenifer Kane, will co-instruct two FSPCA courses with Independent Consultant and trainer Susan Moyers, Ph.D. on the intricacies of Preventive Controls for Human Food as well as the Foreign Supplier Verification Program. Both courses will take place in early October in Alexandria, VA.

The Current Good Manufacturing Practice, Hazard Analysis, and Risk-based Preventive Controls for Human Food regulation (referred to as the Preventive Controls for Human Food Regulation) is intended to ensure safe manufacturing/processing, packing and holding of food products for human consumption in the U.S. and requires that certain activities must be completed by a “preventive controls qualified individual” who has “successfully completed training in the development and application of risk-based preventive controls”. This course meets FDA’s requirement. Join EAS October 1-3, 2018 in Alexandria for this 2.5 intensive training. Earlybird discounts are available through August 14, 2018.

Next, the “Foreign Supplier Verification Program (FSVP)” requires importers to verify that their foreign suppliers of food, food ingredients and food additives imported into the US market are compliant with all parts of the FSMA and its “Preventive Controls for Human Foods (PCHF) and “Preventive Controls for Animal Feeds (PCAF”) regulations. EAS’ two-day intensive FSVP Compliance Seminar will explain in detail FSVP rules, risk exposure by importers as well as US-based food processors using foreign sources of foods, food ingredients and food additives. Join us October 3-4, 2018 for this 1.5-day training. Earlybird rates are in effect through August 14, 2018.

Dietary Supplement GMP Seminar to Take Place in Dallas, TX

EAS Consulting Group will offer its two-day intensive Dietary Supplement GMP seminar September 26-27, 2018 in Dallas. Instructed by EAS Senior Director for Dietary Supplements and Tobacco Services, Tara Lin Couch, Ph.D., EAS Independent Advisor for Quality and Compliance, Robert Fish and back by popular demand, Marc Ullman, Of Counsel at Rivkin Radler, LLP, this next GMP course will include a new section on how quality and compliance applies to the emerging cannabis industry. Early-bird registration rates are in effect through August 5, 2018. In addition, we are pleased to offer members of the American Herbal Products Association (AHPA) an extended early-bird rate of $1,000.00. For more information or to reserve your seat, click here.

Are Plant-Based Proteins Milking Dairy?

When FDA announced recently that the agency is seeking public comment for standards of identity overhaul that will focus in part on plant-based products that are marketed as “milk” substitutes, manufacturers of those products as well as the consumers who enjoy them were left wondering how this review and any future changes would affect them. Consumers of soy, almond, rice, coconut and other plant-based “milk” enjoy these dairy alternative products for any number of reasons, but in some cases, their consumption decisions are based on incomplete or inaccurate information and may result in a diet deficient in certain nutrients found in dairy milk but not the substitute protein. This issue is of interest to others outside of the US as Canada, the European Union and Codex all have laws, regulations and beverage standards that limit the use of the term “milk” to only beverages where dairy “milk” is the major or characterizing ingredient.

There are nearly 300 standards of identity on the books at FDA, and these plant-based proteins which use qualified terms as part of their “milk”, “yogurt” and “cheese” product names aren’t in-fact “milk” as we have come to know it. Based on this technical violation of the standard of identity for “milk” and a concern regarding consumer misunderstanding of the nutritional value of plant-based beverages, FDA has decided to look at the term milk as part of its overall effort of modernizing standards of identity and improving information provided to consumers and their physicians so that the nutritional composition and benefits of products is clear.

FDA is currently seeking information on how consumers understand the term “milk” and whether the nutritional differences between dairy-based and plant-based “milk” products is understood. FDA is also trying to understand if the use of the term “milk” in non-dairy products is misleading and if that lack of understanding plays a role in less informed dietary choices. Stakeholder feedback is actively recruited by the agency and, based on initial comments gathered, FDA will provide an additional request for information in late summer or fall targeted more directly towards consumer awareness and understanding of the use of milk and other dairy terms on plant-based alternatives, including a focus on nutritional impact. The agency will use this feedback to refine its policy for these standards of identity and will issue new guidance for industry as well as their compliance and enforcement approach (no timeline is currently established). 

In addition to gaining an understanding of milk products, the agency is additionally seeking feedback on how the agency should consider food technology, nutritional science, fortification practices and marketing trends for not only dairy but all foods as part of their standards of identity review to gain an understanding of how each may enhance or stymie innovation or nutritional improvements.

As manufacturers of foods, standards of identity can at times protect the consumer and food industry from misleading or fraudulent foods, food ingredients, and labels, but they can also hinder efforts at product innovation, use of new ingredients and processing technologies and restriction on modification of the standard to improve nutritional content. Understanding food labels, content, nutritional value and product claims are all critical for consumers to make informed choices today. It is equally important for food manufacturers, who are committed to providing cleaner food labels while trying to deliver more nutritionally sound food into the US marketplace.

Regulatory opportunities, headwinds, and challenges will be facing the Agency as it begins to review and potentially revise the current food standards of identity. As the agency seeks comment, now is the time for food firms to provide their input and begin the conversation as to how technology, fortification, and sound science need to be considered in the review and revision process, to the benefit of the consumer, food industry and FDA. As an innovation for a healthier food supply continues to evolve, the ability to clearly communicate an improved and clear message of food content and nutritional value will enhance consumer understanding and allow for more informed choices. Formulating agency feedback can help to effectively lead awareness of those opportunities and challenges. Incorporating sound scientific assessments, food processing technologies and market research on consumer perceptions and trends incorporated into well-written comments can enhance a firm’s position. EAS independent consultants, toxicologists, microbiologists who are experts in dairy, plant-based beverages and FDA food standards of identity and labeling can help you to formulate your position and develop agency comment.

Meet New EAS Consultants

Tamika Cathey

Tamika Cathey provides regulatory compliance services pertaining to safety and quality of pharmaceuticals and dietary supplements. She evaluates client compliance readiness, executes mock GMP/FDA audits, performs risk assessments and gap analyses per FDA regulations and creates improvement programs based on findings. Cathey consulted with EAS from 2012-2016 and we are very pleased that she is again able to offer her expertise to our clients.

Beth Ann Crozier-Dodson, Ph.D.

Dr. Dodson is an international consultant for food safety issues and an invited speaker and trainer on the topics of rapid methods for testing and bacterial identification and food safety. She is a member of numerous professional and honor societies and has received a USDA Commendation for Contribution to Public Health. Her areas of specialty include teaching and training in microbiology, laboratory setup, environmental testing, aeromicrobiology, validation testing, consulting, and plant and facility audits.

Meet Issue of the Month Author and New Independent Consultant, Cindy Beehner

Cindy Beehner has worked as a consultant since 1997, specializing in GMP requirements for food, dietary ingredients, dietary supplements and pharmaceuticals. Ms. Beehner performs due diligence assessments as well as procedures and documentation required for certifications for groups such as Therapeutic Goods Administration (TGA), World Health Organization (WHO), United States Pharmacopeia (USP) and National Food Producers Association (NFPA). She has a Bachelor of Science, Chemistry and Clinical Psychology from Moravian College, Bethlehem, PA.

FDA 483 Responses – Missing the Mark?

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

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

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

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

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

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

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

Dietary Supplement GMP Compliance Includes Application to the Cannabis Industry

Dear Readers,

First, for those whom we had a chance to meet at the recent Institute for Food Technologists Annual Meeting held in Chicago, I am sure you will agree with me that this year’s event was one of the best. With so many changes at FDA with the implementation of FSMA, many timely topics on Food Defense and more, I am sure everyone in attendance returned to their firms with good ideas worth implementing. The two sessions that EAS moderated, PCHF – Successes and Challenges for FDA and the Food Industry and Food Importing: Green Light Strategies for Compliance with Game-Changing FSVP Requirements were both well attended with lively discussions. We’d like to thank the panelists who joined us – JoAnn Givens from FDA, Jeff Acker from DFA who participated in the PCHF session, Bob Brackett from IIT and EAS Independent Consultant, Susan Moyers, who participated in both PCHF and FSVP sessions and Erika Daniel from our Italian partner Almater who participated in our FSVP session.

I am pleased that EAS is presenting the next Dietary Supplement Good Manufacturing Practices seminar in cooperation with the American Herbal Products Association (AHPA). It will include an updated content section on how GMPs have application to the cannabis industry. The early bird rate runs through August 5, 2018, and this rate is extended to members of AHPA for the duration of the registration period. We hope you’ll join us in Dallas, TX on September 26-27, 2018 for this informative and updated seminar!

We welcome new consultant Beth Ann Crozier-Dodson, Ph.D., and re-welcome Tamika Cathey and Cindy Beehner, two consultants who have been a part of the EAS family previously and who are increasingly available to EAS clients. Dr. Dodson is an international consultant for food safety issues and an invited speaker and trainer on the topics of rapid methods for testing and bacterial identification and food safety. Tamika Cathey provides regulatory compliance services pertaining to safety and quality of pharmaceuticals and dietary supplements and Cindy Beehner specializes in GMP requirements for food, dietary ingredient, dietary supplements and pharmaceuticals. Cindy is also the author of this month’s issue of the month on how to appropriately respond to FDA 483s.

We hope that you enjoy this edition of EAS-e-News! As always feel free to reach out if you have any questions and thank you for your interest in EAS.

Sincerely,

Ed