On FDA’s Latest FSMA Guidance

The Food and Drug Administration recently issued three new guidance documents to help simplify compliance with Food Safety Modernization Act (FSMA) regulations and programs.

On November 7, the agency released new draft guidance on registration of food facilities. The expanded registration introduced by FSMA is a key change that underpins all other FSMA requirements and I would encourage you to read the new draft as it includes substantive information in a useful question-and-answer format, including details on the timing of the biennial registration renewals and other new information. For example, it is not necessary to wait until after October 1 to renew registration.

On November 10, FDA released final guidance on compliance with the Voluntary Qualified Importer Program (VQIP). The eligibility criteria for taking part in this voluntary, fee-based program include compliance with the Foreign Supplier Verification Program (FSVP). But the VQIP importer may be located either inside or outside the U.S., whereas the designated importer under the FSVP must be U.S.-based, the agency says.

In addition, the VQIP importer may be, but need not be, the importer of record listed with U.S. Customs and Border Protection (CBP). CBP defines the importer of record for a food as the person or firm responsible for making entry and payment of import duties, fees, and taxes for the food. So there is some potential for confusion of the various roles. Willingness to participate in the VQIP program may depend on such practical issues of eligibility and compliance, as well as on the bottom line analysis of the program’s costs and benefits.

On October 31, the agency released final guidance for small entities on compliance with the Preventive Controls for Human Foods (PCHF) rule. Because the guidance is designed for companies that may not have in-house expertise in the fundamentals of hazard analysis and current good manufacturing practices (cGMPs) it takes nothing for granted and is a useful introduction to the rule’s requirements, whether or not a company is a “small entity.”

One PCHF requirement that is likely to be a challenge for all sizes of companies is the required risk-based supply chain program for raw materials and other ingredients for which a hazard has been controlled before receipt.

If a registered facility identifies a hazard that requires a control and that control is applied in the supply chain before receipt, the facility must have a supply-chain program, FDA explains. Food facilities covered by the regulation must ensure raw materials and other ingredients for their products are received “only from approved suppliers, or — if received on a temporary basis from unapproved suppliers — ensuring those materials are subject to verification activities before being accepted for use,” the agency says.

If an applied control is applied by an entity other than the receiving facility’s supplier, the receiving facility must either verify the applied control or obtain verification documentation from another entity, the agency explains. Supplier verification activities can include onsite audits, testing of raw materials and other ingredients, review of the supplier’s food safety records, as well as other appropriate supplier verification activities. What’s appropriate will depend on the risk associated with the raw material or ingredient and on the supplier’s performance, the agency says.

The compliance dates for the supply chain program will depend on the size of the receiving facility and the status of the supplier. For example, if a facility is not a small or very small business and its supplier will not be subject to the human preventive controls rule or the FSMA produce safety rule, the compliance date is March 17, 2017. If the receiving facility is a small business and its supplier will not be subject to the human preventive controls rule or the produce safety rule, compliance is required by September 18, 2017.

If the supplier will be subject to the human preventive controls rule or the produce safety rule, the compliance date will be six months after the supplier is required to comply with the applicable rule.

So many registered facilities covered by the PCHF and produce rules have another round of compliance deadlines to look forward to in 2017.

Drug Master File Submissions – An Overview

By Naitry Shah, EAS Intern

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

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

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

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

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

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

FDA Updates Regulations for Establishment Registration and Drug Listing

By Susan Crane, Independent Advisor for OTC Drugs and Labeling, and David Clark, Independent Consultant

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

Here are some of the key changes and clarifications:


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

Establishment Registration

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

Drug Listing

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


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

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

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

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

FDA Invites Comment on Two Draft CGMP Guidances

FDA is inviting public comments by November 23 on two draft guidances — on current good manufacturing practices (CGMP) requirements for food for animals and on CGMPs for human food by-products for use as animal food.

The two guidances are essential reading if your company is required to implement CGMPs for animal foods, especially as FDA is allowing flexibility in compliance depending on the nature of the products and the facilities.

As with all FDA draft guidances, the contents are non-binding and some elements in the final versions may be amended based on stakeholder comments. Nonetheless, the drafts provide useful examples and offer insights into the agency’s latest thinking.

Human food by-products used for animal food must be generally recognized as safe (GRAS) or approved as a food additive. But a substance that is considered GRAS or approved as a food additive for human use “may not always be suitable for use in animal food,” the agency says. Propylene glycol, for example, is considered GRAS as an anti-caking agent for human food but is prohibited in or on cat food.

The agency says it will be reviewing the list of animal food ingredient definitions in the Official Publication of the Association of American Feed Control Officials (AAFCO). Until that review is completed, FDA will accept ingredients in the AAFCO list “provided there are no food safety concerns about the use or composition of the ingredient that would render the food adulterated.”

In guidance on the use of shipping containers and bulk vehicles, the agency says it would expect a facility to know the previous use of a shipping container and whether it needed to be cleaned prior to containing a human food by-product for use as animal food. However, “this does not mean that the shipping container must be cleaned prior to each use in all situations,” the agency adds. But it would be “good practice for the facility to examine the customer’s shipping container or bulk vehicle to confirm that the shipping container or bulk vehicle will not lead to contamination of the human food by-products for use as animal food,” the agency says.

The two guidance documents list exemptions from the CGMP requirements. Generally, if a facility is not required to register with FDA under the Food, Drug and Cosmetic Act (FDCA), it does not have to comply with the CGMP requirements. This includes: farms; facilities regulated exclusively by the U.S. Department of Agriculture (under the Federal Meat Inspection Act, the Poultry Products Inspection Act, or the Egg Products Inspection Act); retail food establishments; restaurants (including pet shelters, kennels and veterinary facilities that provide food to animals are considered restaurants); and foreign facilities – if the food undergoes further processing by another facility outside the United States.

In situations where a facility is required to follow both the human food CGMPs and the animal food CGMPs, FDA will allow them to choose either compliance with the CGMPs in CFR part 117 for its human and animal food or following the CGMPs in part 117 for the human food and the CGMPs in 21 CFR part 507 for the animal food.

Some facilities manufacture, process, pack, or hold food for both humans and animals, FDA notes. For example, a facility that manufactures salt may process some salt meeting certain specifications for human use and other salt meeting certain specifications for animal use.

To decide which CGMPs to follow, the agency suggests that facilities consider how they are manufacturing, processing, packing, or holding the human and animal food. For example, if they have separate employees, production lines, and holding areas for human food and animal food, they might follow 21 CFR part 117 for the human food and 21 CFR part 507 for the animal food. If not, they it might prefer to follow 21 CFR part 117 for both the human and animal food, the agency says.

“We recognize that in many instances animal food facilities will be using the same building, grounds, employees, supervisors, management, equipment, and utensils to perform operations under 21 CFR part 507, subpart B, and part 225. In instances where the facility is subject to both 21 CFR parts 225 and 507 and the CGMPs overlap, the facility must follow the more specific requirements found in 21 CFR part 507, the agency says.

The CGMPs in 21 CFR part 507 are “umbrella” CGMPs that apply broadly to animal foods, but some animal foods, such as low acid canned food and medicated feed, also require specialized CGMPs, FDA explains.

September 19, 2016 was the compliance deadline for larger animal food facilities to comply with new CGMP requirements under FSMA. Small businesses have until September 18, 2017 and very small businesses have an extra year to comply.

As FDA begins to implement the new FSMA rules, the agency is committed to outreach and education rather than enforcement. So I think it would be entirely appropriate to consult with your local FDA district office if you are not clear about anything in the guidance.

What Now for FSMA Compliance?

The sky did not fall on September 19, 2016, the compliance date for larger human food facilities to meet FSMA preventive controls and Current Good Manufacturing Practice (CGMP) requirements, and for larger animal food facilities to comply with CGMPs.

In a September 19 poston the agency’s website, Joann Givens, co-chair of the FSMA Operations Team Steering Committee and director of FDA’s Food and Feed Program in the Office of Regulatory Affairs, gave some good insights about what agency oversight of compliance might look like in the next few months for human food facilities required to comply with the CGMP and preventive controls requirements and animal food facilities required to comply with the CGMP requirements.

“We know that this is new territory for food companies; it’s new territory for us too,” she said. But the agency’s primary focus will continue to be on education, training and technical assistance to help companies comply with the new requirements.

She cited the agency’s recently issued draft guidanceon implementation of preventive controls and CGMP requirements and promised there are more guidances to come, “about two dozen planned over the next few years.”

She advised that the best thing companies can do at this time is to “take the measures required by the new rules – not just the letter of the law but what it represents in terms of transforming the food safety system.” This should include promptly responding to problems, “even if they aren’t yet violations,” to prevent them becoming food safety issues.

She also emphasized the need for “a thorough system” for companies to document what they do. “If there is a problem, state or federal investigators will ask questions like: When problems came to your attention, what did you do? Were you proactive in looking for the problems in the first place? If you could not find a solution, did you get the right expertise? Did you educate your employees?”

It is up to the management of a company to make sure everyone in the production chain understands what is expected and has the training and education they need to get the job done, she said.

Speaking of guidance, I suggest you mark your calendar to attend FDA’s October 14, 2016webinarin which agency staff will discuss the draft guidances for current good manufacturing practices requirements for food for animalsand the human food by-products for use as animal food. The webinar will offer an overview of the two draft guidances and will also include a question and answer session. These Q&A sessions often provide key insights into the agency’s thinking on specific issues, so I encourage you to listen in.

EAS Reaches Ten Year Milestone

By EAS Chairman Ed Steele

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

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

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

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

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

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

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

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

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

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

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

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

FDA Issues Draft Guidance on FSMA Rules, Extends Compliance Dates

As the September 19 deadline approaches for compliance by large food facilities with new preventive controls and Current Good Manufacturing Practice (CGMP) requirements under the Food Safety Modernization Act (FSMA), FDA released five chapters of a 14-chapter draft guidance to assist in compliance.

The non-binding draft document is now open for stakeholder comment and the agency promises to consider those in the final guidance and says it will release all 14 draft chapters by early 2018.

The first chapter deals with food safety plans and how a facility will control hazards. Other chapters discuss how to conduct a hazard analysis, common biological, chemical and physical hazards, implementing preventive controls, and monitoring, corrective actions and verification activities.

The agency also released two draft guidances dealing with preventive controls for animal food. One explores ways to comply with the rule’s CGMP requirements for animal food facilities and discusses the training of personnel, among other topics. The other document considers by-products of human food production used as animal food, including grain products and vegetable pulp. These also include foods such as potato chips, baked goods and pasta that are safe but considered the wrong size, shape, color or texture, explained Susan Mayne, director of FDA’s Center for Food Safety and Applied Nutrition, and Tracey Forfa, acting director of FDA’s Center for Veterinary Medicine, in an August 24 FDA Voice blog.

Producers of human food had been concerned that they would have to meet a whole new set of requirements for such by-products sent for use in animal foods. But by-products will only be subject to limited CGMPs to protect against contamination during holding and distribution, provided the human food facility complies with human food safety requirements and is not further processing the by-products for use as animal food, the draft guidance explains.

If the human food facility is further processing the by-products, it may comply with the requirements of either the human or animal food rule, as long as the food safety plan addresses how the facility will prevent or significantly minimize the hazards for the animal food that require a preventive control, the agency says.

“These draft guidances, and the others that we’re working on for the FSMA rules, will be further refined based on input we receive from the public … [W]e want to be sure that we’re all on the same page and these draft guidances will help get us there,” Mayne and Forfa noted.

The agency also issued a separate draft guidance to help businesses to determine whether their activities are covered by the definition of a “farm.”

FDA also released a final rule extending and aligning the compliance dates for certain provisions in four of the seven “foundational” FSMA rules — the CGMP and preventive controls rules for human and animal food, the Foreign Supplier Verification Programs (FSVP) rule, and the produce rule.

Human food companies other than small and very small businesses must be in compliance with the preventive controls and CGMP rule by September 19, 2016. Animal food companies other than small and very small businesses must be in compliance with the CGMP requirements under the animal foods rule by September 19, but they have an extra year to comply with the preventive controls requirements in the animal food rule.

The agency is allowing an extra two years for manufacturers to meet requirements for assurances by their customers who perform some needed food safety step.

The produce safety rule also clarifies the timeframe for agricultural water testing and offers considerable flexibility. Farms covered by the rule have two to four years to fulfill the testing requirement. For example, a farm that is not small or very small must begin sampling and testing untreated surface water no later than January 26, 2018. The relevant compliance date for the related microbial quality criteria is January 27, 2020. But the farm has discretion as to the number of samples included in an initial survey provided that the total is 20 or more samples. The samples must be taken over a period of at least two years and no more than four years, the agency says.

In other produce news, FDA is hiring 40 new consumer safety officers to help implement the FSMA produce safety rule. The safety officers will be working both in the United States and internationally, conducting inspections, investigations and providing technical assistance, the agency says.

New NDI Guidance – Still a Work in Progress

By Robert Martin, Ph.D., EAS Senior Advisor for Food & Color Additive Safety

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

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

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

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

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

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

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

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

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

By Robert Martin, Ph.D., EAS Senior Advisor for Food & Color Additive Safety

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

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

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

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

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

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

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

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

Why FDA Views Registration as a FSMA Priority

The Food Safety Modernization Act’s provisions on food facility registration are especially significant from FDA’s perspective because they will enable the agency to know much more about the businesses whose products are covered by the landmark law.

On July 14, 2016, the agency issued a final rule on Amendments to Registration of Food Facilities. The amendments aim to improve the registration, which was first required in December 12, 2003 as part of FDA’s implementation of the Bioterrorism Act of 2002. The expanded registration under Section 102 of FSMA builds on the requirement in Section 415 of the Food Drug & Cosmetic Act (FDCA), which requires domestic and foreign facilities that manufacture, process, pack, or hold food for human or animal consumption in the U.S. to register with FDA.

Among other changes, the final rule requires an email address for registration. This may seem to be a small change, but a functioning email contact address will greatly enhance FDA’s ability to contact a registered facility or the registered agent. Similarly, the requirement to renew the registration every two years will help ensure that the on-file information remains reasonably up-to-date. In addition, in order to register, facilities will have to assure the agency that FDA will be allowed to inspect the facility.

FDA believes the changes introduced in the new rule will help it to act more quickly in response to food-related emergencies and will help target its inspection resources more efficiently. Effective July 14, 2016, registrations must specify the type of activity conducted at the facility for each food product category. In addition, all registrations must be submitted electronically starting on January 4, 2020.

The final rule includes a provision allowing a registrant to submit a written request for a waiver explaining why it is “not reasonable to submit the registration, registration renewal, update, or cancellation to FDA electronically or to explain why it is not reasonable to provide the email address of the owner, operator, or agent in charge of the facility.”

Definition of retail establishment expanded 

Currently, retail food establishments are not required to register as food facilities. The final rule broadens the definition of a retail establishment, so operations in the newly expanded category will not be required to register.

Section 102(c) of FSMA directs FDA to amend the definition of the term “retail food establishment” to include: the sale of food products or food directly to consumers at a roadside stand or farmers’ market where the stand or market is located other than where the food was manufactured or processed; the sale and distribution of such food through a community supported agriculture program; and the sale and distribution of such food at any other such direct sales platform.

In addition, the agency is requiring additional data elements in food facility registrations, including a unique facility identifier (UFI) and it is planning to verify information submitted in registrations.

At the proposed rule stage, the agency proposed to amend the regulation to shorten the timeframe for submitting updates and cancellations from 60 calendar days to 30 calendar days. However, in response to comments from stakeholders, it has withdrawn that proposal and the final rule requires updates within 60 days of any change.

FDA’s Design Control Requirements for Medical Devices

By Kaiser Aziz, PhD., EAS Senior Consultant

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

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

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

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

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

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

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

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

By Bruce A. Silverglade, EAS Product Development and Labeling Consultant

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

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

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

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

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

In addition:

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

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

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

FDA Unveils FSMA Final Rule on Intentional Adulteration

FDA has now released its seventh FSMA rule – on intentional adulteration. Published May 27 in the Federal Register, the rule requires registered food facilities to develop a written food defense plan to address intentional adulteration.

In an approach similar to developing a hazard analysis and critical control point (HACCP) plan, facilities must establish food defense monitoring procedures and corrective actions, including a verification step, personnel training and the maintenance of records.

FDA explains that the goal of the rule is to prevent wide-scale public health threats, rather than acts by disgruntled employees or economically motivated adulteration – which is addressed separately in the preventive controls rules for human and animal foods.

The agency knows companies will be working to comply with the other FSMA rules, so it has extended the compliance dates for the intentional adulteration rule. A business that is not defined as “small” or “very small” and does not qualify for exemptions will have three years to comply. A small business employing fewer than 500 employees will have four years to comply, and a very small business will have five years. FDA estimates that the rule will cover 3,400 firms that operate 9,800 food facilities.

In most cases, limiting access to the food product is the key element of an effective food defense plan. But there are other important considerations, such as the volume of food involved and how rapidly the food product is distributed and consumed.

The agency plans to issue guidance on conducting a vulnerability assessment, identifying and implementing mitigation strategies, and writing procedures for food defense monitoring, corrective actions and verification. It is also encouraging stakeholders to look at the existing voluntary food defense program tools at fda.gov/fooddefense.

I believe the process of complying with the FSMA preventive controls requirements should set a lot of the groundwork for the subsequent compliance with the intentional adulteration rule. The vulnerability assessment, risk management, verification and record keeping will be familiar steps for the “qualified individual” who has already mastered the FSMA preventive controls requirements. In addition, EAS consultants can assist in compliance with this additional FSMA rule.

FSMA and Dietary Supplements

By Charles Breen, EAS Senior Advisor for FSMA Consulting Services

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

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

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

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

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

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

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

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

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

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

Are You ‘Qualified’ under the Preventative Controls for Human Food Rule?

Who is “qualified” under FDA’s final rule on preventive controls for human food? Why would someone want to be “qualified?” What is the role of someone who is “qualified?” How much of a role does a “qualified” person play to ensure a safe and wholesome food supply?

The Preventative Controls for Human Foods (PCHS) Rule under the Food Safety Modernization Act has several definitions such as Qualified Auditor, Qualified Individual, and Preventive Controls Qualified Individual. I will discuss the definitions and responsibilities for the Preventive Controls Qualified Individual and the Qualified Individual only. As implementation of the PCHS rule begins for some, these individuals will play a vital role in the safety of our food supply.

The PCHS Rule was adopted on September 15, 2015 and applies to facilities that manufacture, process, pack, or hold human food. In general, facilities required to register with FDA under section 415 of the Food, Drug and Cosmetic Act are regulated. The rule sets standards for most wholesale food establishments and updates Good Manufacturing Practices. Most noteworthy is that it requires a food safety plan that identities known or reasonably foreseeable hazards; initiates, monitors, and verifies preventative controls; takes corrective action when needed; and requires documentation to demonstrate that the plan is working. It excludes farms, retail establishments, and those facilities under juice and seafood HACCP. Several other exemptions and limited exemptions within the Rule exist, but are beyond the discussion of this article.

There is some similarity between the definitions of the Qualified Individual and the Preventive Controls Qualified Individual, and thereby, some confusion. However, very distinct responsibilities and background qualifications separate the roles. The regulatory definitions of these two positions appear in bold type below.

Qualified Individual means a person who has the education, training, or experience (or a combination thereof) necessary to manufacture, process, pack, or hold clean and safe food as appropriate to the individual’s assigned duties. A qualified individual may be, but is not required to be, an employee of the establishment.

This definition casts a broad net that will include many wholesale food facility employees that have at least some food safety responsibilities. The Qualified Individual is expected to be able to demonstrate competence for their assigned job activities as it relates to food safety. Training in the principles of food hygiene and food safety, as appropriate to the food, the facility, and the individual’s assigned duties, must be provided and documented. There are no defined minimum training requirements within the rule for the Qualified Individual.

Preventive Controls Qualified Individual (PCQI) means a qualified individual who has successfully completed training in the development and application of risk-based preventive controls at least equivalent to that received under a standardized curriculum recognized as adequate by FDA or is otherwise qualified through job experience to develop and apply a food safety system.

The “standardized curriculum” is offered through the Food Safety Preventive Controls Alliance (FSPCA). The courses, found on the FSPCA website, are 2.5 days in length. The FSPCA also provides a train-the-trainer course for instructors. Courses are being scheduled throughout the nation by the FSPCA and others including food facilities, academia, consultants, and private food safety trainers. Individuals can also meet the PCQI requirements through job experience in lieu of the training requirement.

The rule is very clear in defining tasks that only a PCQI can do. The responsibilities of a PCQI include preparation of the food safety plan, validation of preventive controls, records review, and reanalysis of the plan. The PCQI may be a facility employee, but they can also use outside assistance in developing the plan and for other tasks that must be performed by the PCQI. In many situations, more than one PCQI may be needed to effectively develop and implement the food safety plan.

The mandates under the PCHF Rule establish set requirements and standards for the two positions that are vital for proper implementation. The rule places great responsibilities on the regulated community, so competent and knowledgeable food safety staff are essential. Food safety continues to become more complex and demanding as new and emerging challenges arise. Competent Qualified Individuals and Preventive Controls Qualified Individuals will go a very long way towards ensuring a safe and wholesome food supply.

FSMA Final Rule on Sanitary Transportation of Food Includes Major Revisions

FDA released the FSMA Final Rule on Sanitary Transportation of Human and Animal Food on April 6, 2016.

The final rule, which is part of the agency’s implementation of the 2005 Sanitary Food Transportation Act, contains some significant revisions of the proposed version, including affirming that the use of current sanitary food sanitation best practices will allow industry to meet the rule’s requirements.

The final rule focuses more narrowly on food safety and not on adulteration as a result of spoilage or quality defects. The agency also simplified the definitions for parties covered by the rule to make them activity based.

The final rule places primary responsibility on the shipper for determinations about appropriate transportation operations – for example, whether food needs temperature control for safety and the relevant operating temperature and mode of temperature monitoring, whether particular cleanout procedures are needed, and whether the previous cargo must be identified.

“We believe the shipper is in the best position of the parties covered by this rule to know the appropriate specifications for transport of its food,” the agency says.

Businesses other than small businesses have one year from the date of publication of the final rule to comply with the rule. Small businesses get two years to comply.

FDA hosted an April 25 webinar in which Consumer Safety Officer Mike Kashtock of the Center for Food Safety and Applied Nutrition reviewed the key requirements of the new rule. The agency plans to post the recorded webinar on its FSMA website.

What Makes a Good Sampling Plan?

By EAS Senior Consultant William R. Fairweather, PhD.

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

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

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

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

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

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

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

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

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

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

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

Implementing FSMA for Imports is FDA’s Biggest Challenge

FDA hosted an excellent day-long public meeting on March 21, 2016 to review the import-related elements of the new FSMA regulations. In opening remarks, FDA Deputy Commissioner for Foods and Veterinary Medicine Michael Taylor noted that implementing import provisions is the agency’s biggest FSMA challenge.

In a March 21 FDA Voice blog, Taylor called the Foreign Supplier Verification Program (FSVP) “the ‘regulatory linchpin’ of FSMA’s historic paradigm‎ shift for imported food from reaction at the border to accountability for prevention at the point of production.”

Section 301 of FSMA requires importers to have a foreign supplier verification program and the Importer of Record must verify that suppliers have adequate preventive controls to assure the safety of their products. It is the importer’s responsibility to determine the hazards and the best way to verify that preventive controls are being implemented.

A preventive control may not be required for some low-risk products. But this does not mean that low-risk products such as candies, cookies or crackers are exempt from FSVP, just that a hazard analysis may show no significant hazard so no special controls are required.

The FDA does not plan to create a list of high-risk products, but the agency may require special preventive controls in some circumstances.

Food exempted from FSVP requirements include juices and seafood covered by existing HACCP rules, food used for research and development, food for personal consumption, and alcoholic beverages and ingredients (when the importer uses them to make alcoholic beverages). Also exempt are foods transshipped through the U.S., foods imported for processing and export, foods originating in the U.S. that is returned, and meat, poultry and egg products regulated by the U.S. Department of Agriculture.

To the surprise of some stakeholders at the March 21 public meeting, foods imported for distribution as samples at trade shows are not exempt from FSVP requirements.

In some circumstances importers may comply with FSVP requirements if they can establish that there is a system in place to control a hazard at a subsequent stage in the distribution chain. If a hazard is controlled by an importer’s customer or other entity in the distribution system, the importer must have documentation in the form of a disclosure statement and written assurances.

The FSVP preventive control requirements are aligned with those of the FSMA preventive controls and produce rules. The goal is to produce food using the same level of public health protection and to assure that the products are not adulterated or misbranded, especially with regard to allergen labeling. Although the FSVP is not a border program, it will require identification of the importer at the point of entry.

In addition to requiring importers to implement FSVP requirements, FDA plans to conduct more foreign inspections and to work more closely with foreign governments. The agency may determine that some countries have equivalent food safety systems, which should benefit suppliers in those countries. But this will be lengthy process and will likely take years to accomplish for each country. New Zealand was the first country FDA designated as having an equivalent system. Currently, Australia, Canada — and most recently the European Commission — are being considered for this designation.

The final FSVP rule was published on Nov. 27, 2105. Because the compliance dates are aligned with those of the separate preventive controls and produce rules, importers will need to comply with whichever is the latest of the following dates:

  • 18 months after the publication of the FSVP final rule;
  • For the importation of food from a supplier that is subject to the preventive controls regulations for human food or animal food or the produce safety regulation, 6 months after the foreign supplier of the food is required to comply with the relevant regulations; or
  • For an importer that is also subject to the supply-chain program provisions in the preventive controls regulations for human food or animal food, the date the importer, as a receiving facility, is required to comply with the supply-chain program provisions of the relevant regulation.

FDA is currently developing guidance that will give more clarity to the FSVP compliance requirements in specific circumstances, such as in the case of suppliers in countries or regions deemed to have equivalent controls. But the agency says importers should not delay in assessing their products and their suppliers with a view to achieving compliance.

The Purpose of a DEA Regulatory Investigation

By EAS Senior Consultant Karen Famiglietti

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

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

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

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

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

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

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

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

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

FSMA and Third-Party Auditing

A key piece of the regulatory jigsaw puzzle as FDA moves ahead with implementing the Food Safety Modernization Act (FSMA) is the voluntary, user-fee based program for the accreditation of third-party certification bodies to conduct food safety audits of foreign food facilities and issue food and facility certifications.

When this program is up and running, U.S. importers will be able to use the certifications of foreign entities to secure expedited entry of shipments under the Voluntary Qualified Importer Program (VQIP).

The final rule on Accreditation of Third-Party Certification Bodies to Conduct Food Safety Audits and to Issue Certifications, published in the Federal Register on November 27, 2015, went into effect on January 26, 2016. However, the agency says it will implement the program after it releases separate Model Accreditation Standards guidance and a final user fee rule.

In July 2015, the agency issued Model Accreditation Standards draft guidance containing draft recommendations on the education and experience needed by third-party auditors and their agents. In the same month, the agency issued a separate proposed rule establishing user fees for accreditation bodies and certification bodies.

FDA does not generally plan to directly accredit third-party certification bodies. Instead, it will recognize accreditation bodies to perform that task. An accreditation body could be a foreign government agency or a private third party. The accreditation bodies will have to monitor the performance of the third-party auditors and submit reports to FDA. They must also maintain records and provide FDA access to the records.

Third-party auditors accredited under the program must conduct unannounced facility audits and notify FDA of any serious public health risk and must ensure that their agents are competent and objective.

The voluntary program allows for two kinds of audits – regulatory and consultative. Only a regulatory audit can be used for certification. A consultative audit is for internal use.

For regulatory audits, the auditor must submit an audit report to the FDA within 45 days. No report is required for a consultative audit, but any potential serious risk to public health identified in a consultative audit must be reported to FDA. All reports and notifications required to be submitted to the FDA must be submitted in English, the rule says.

FDA may grant recognition for an accreditation body of up to five years. Four years is the maximum accreditation period for certification bodies.

With many competing demands from other high-profile FSMA regulations and now with the real possibility of reduced funding in fiscal year 2017 and beyond, FDA may find itself in triage mode in terms of the speed of implementation of the various FSMA rules. But this program could play a significant future role in improving the international oversight of food safety.

What Are Medical Foods (and What They are Not)

By Jeanne Hoskin, Ph.D., EAS Senior Consultant

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

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

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

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

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

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

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

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

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

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

Produce Final Rule Goes into Effect

The Food Safety Modernization Act (FSMA) extended FDA’s authority to include produce all the way to the farm level, which put the agency in unfamiliar regulatory territory. To avoid burdening covered facilities with unreasonable compliance demands, the agency proceeded with due caution in developing a final rule on Standards for the Growing, Harvesting, Packing, and Holding of Produce for Human Consumption, published November 27, 2015.

That rule, which went into effect on January 26, 2016, applies to both domestic and imported produce and has phased implementation dates, beginning in as little as one year for certain sprout growers.

With the exception of sprouts, the implementation dates are two years after the effective date for covered businesses, three for small businesses and four for very small businesses. Again with the exception of sprout operations, the final rule allows an additional two years to comply with some water quality standards, and testing and recordkeeping provisions.

The produce rule includes requirements for agricultural water quality and testing, manure and compost, and the exclusion of animals from growing areas, as well as hygiene and training requirements for farm workers. It also includes standards related to equipment, tools and buildings, and special testing and other requirements for sprouts.

As a first step, produce facilities should determine if they are covered by the rule. In essence, the rule applies to raw agricultural commodities (RACs). But there are numerous exemptions and opportunities for seeking a variance from one or more requirements.

The rule exempts fruits and vegetables that will go through a pathogen-reducing process such as a microbial “kill step” – provided it is appropriately documented — and food that is rarely consumed raw. Items on the rarely consumed raw list include: asparagus; black beans, great Northern beans, kidney beans, lima beans, navy beans, and pinto beans; garden beets (roots and tops) and sugar beets; cashews; sour cherries; chickpeas; cocoa beans; coffee beans; collards; sweet corn; cranberries; dates; dill (seeds and weed); eggplants; figs; horseradish; hazelnuts; lentils; okra; peanuts; pecans; peppermint; potatoes; pumpkins; winter squash; sweet potatoes; and water chestnuts.

The new rule does not apply to food grains, including barley, dent-corn or flint-corn (also known as Indian corn), sorghum, oats, rice, rye, wheat, amaranth, quinoa, buckwheat, and oilseeds such as cotton seed, flax seed, rapeseed, soybean, and sunflower seed.

The rule contains modified requirements for certain types of facilities, for example a farm with food sales averaging less than $500,000 per year during the previous 3 years that sell mainly to “qualified end-users.” Qualified end-users can be consumers or restaurants or retail food establishments in the same State.

The agency faced significant challenges in crafting the water quality requirements, which involve two sets of criteria for monitoring microbial water quality, depending on the product involved. The rule prohibits the use of untreated surface water in various situations, including for sprout irrigation, handwashing during and after harvest, washing food-contact surfaces, or for directly contacting produce during or after harvest.

The rule includes a second set of numeric criteria for agricultural water applied directly to growing produce other than sprouts.

The agency anticipates developing an online tool for use by farms to input their water sampling data and calculate the statistical values.

Because this is a whole new regulatory area for the agency, working through the complex compliance issues – especially for the water quality and testing requirements – will be a significant challenge.

Adverse Event Reporting for OTC Drug Products

By EAS Senior Advisor for OTC Drugs and Labeling Susan Crane

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

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

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

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

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

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

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

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

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

FDA’s FSMA Funding Boost

FDA’s implementation of the Food Safety Modernization Act (FSMA) is off to a strong start in 2016, with an injection of $104.5 million in additional funding from Congress in the omnibus appropriations bill passed December 18. The substantial increase in funding for fiscal year 2016 will increase the agency’s ability to advance plans for training and outreach relating to the five FSMA final rules released to date and the two additional final rules anticipated this year.

FDA plans to “work collaboratively with companies that are making a good faith effort to produce safe products and meet regulatory requirements,” noted Deputy Commissioner for Global Regulatory Operations and Policy, Howard Sklamberg, and Deputy Commissioner for Foods and Veterinary Medicine, Mike Taylor, in a December 21 post on the FDA Voice blog site.

But the agency won’t be giving out free passes to bad actors. It is “strongly committed to working with companies that take their safety responsibilities seriously – and equally committed to dealing strongly with those that don’t,” Sklamberg and Taylor said.

Over the past two years, FDA criminal enforcement has resulted in 407 cases opened, 348 arrests, 305 convictions, and more than $694 million in fines and restitutions, they noted.

An important first question for any company committed to compliance with the new FSMA regulations is whether its products are covered or exempted. FDA is currently working on numerous guidance documents to help companies find answers to these and other key questions. The agency is preparing guidance for small or very small businesses on the human food and animal food rules, as well as hazard analysis and preventive controls, environmental monitoring, allergen controls, and validation of process controls for human food. It is also preparing guidance on current good manufacturing practices (CGMPs), hazard analysis and preventive controls, and on human food by-products for use as animal food.

Agency officials are still working on some of the thornier questions for these guidance documents. The additional FY2016 funding from Congress should help the agency commit the resources needed to complete these important compliance tools.

On FDA’s Environmental Assessment Guidance for INDs, BLAs

By EAS Senior Consultant Charles Eirkson

FDA’s Center for Biologic Evaluation and Research (CBER) released new industry guidance in May 2015 on environmental assessments for investigational new drug applications (INDs), biologics license applications (BLAs) and supplements to BLAs.

The guidance includes recommendations on what to consider in assessing whether to submit an environmental assessment (EA) for gene therapies, vectored vaccines, and recombinant viral or microbial products. It also contains recommendations on what to include in an EA and what to expect once an EA is filed.

The guidance, Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant viral or Microbial products, finalized draft guidance issued in June 2014 and it supplements the agency’s 1998 Guidance for Industry: Environmental Assessment of Human Drug and Biologics Applications.

The National Environmental Policy Act (NEPA) enacted in 1969 requires all Federal agencies to address the environmental impact of their actions. But many classes of actions are excluded and do not require an EA or an environmental impact statement (EIS). The CBER guidance considers how to decide whether an EA is needed for INDs and licensing applications, as well as other circumstances. It also lists the information that should be in the EA, including, for example, the substances subject to the proposed action, the potential environmental effects, mitigation measures, and alternatives to the proposed action.

NEPA requires an EA to support any Finding of No Significant Impact (FONSI). If some environmental impact may be expected from an action, NEPA requires an EIS.

The processes for applying NEPA’s provisions are extensively outlined by the Council on Environmental Quality (CEQ) regulations found in 40 CFR Parts 1500-1508. FDA’s regulations for meeting its NEPA obligations are found in 21 CFR Part 25.

Court challenges on NEPA grounds are common and any deviation from the NEPA procedures can result in agency actions not moving forward — including actions on approvals of regulated products. Because of the possibility of a court challenge, all scientific assessments need to be rigorous and credible.

As with all agency guidance, the document reflects the agency’s latest thinking on the subject and it is not mandatory to follow the recommendations. An alternative approach may satisfy the relevant statutes and regulations, but it is a good practice to contact the agency ahead of time to check that any proposed alternative approach would raise any red flags. Environmental documents are reviewed by a limited staff at FDA and they review a lot of documents. Any alternatives from the expected approach requires extra staff time and effort to review and reach a decision.

Other FDA Centers have released separate environmental impact guidance over the years for food additives, human drugs, veterinary drugs and tobacco products, including:

Animal drugs and veterinary products



Human Drugs and Biologics