FDA Responds to Comments in FSVP Final Rule

FDA released three significant FSMA final rules last month, on foreign supplier verificationproduce and accreditation of third-party auditors – all formally published in the Federal Register on November 27.

Each of these three significant rules deserve separate commentary, so I will first consider the FSVP rule in this article and comment separately on the accreditation and produce rules in upcoming issues.

The agency plans to issue two more final rules, on sanitary transportation and on intentional adulteration, by May 31, 2016. These two rules, along with the final rules on preventive controls for human and animal foods published on September 17, will complete what the agency calls the “seven foundational final rules” implementing the Food Safety Modernization act (FSMA).

As is required in final rules, in each of the new rules FDA responds to the numerous public comments and explains why it did or did not make requested changes in the final versions. The 128-page FSVP rule, for example, includes 334 specific responses to comments.

FDA says the FSVP requirements are intended to be “sufficiently general and flexible to apply to a variety of circumstances without being unduly burdensome or restrictive of trade.” For example, the final FSVP rule adds flexibility by not requiring an importer to conduct supplier verification when the hazard will be controlled by a subsequent entity in the distribution chain in the United States.

Responding to comments, the agency declined to extend the effective date of the rule beyond the customary 60 days after publication of the final rule in the Federal Register. So the FSVP rule will be effective from January 26, 2016. But it did agree to revise the 18-month compliance dates for some circumstances.

Some comments had asked the agency to set uniform compliance dates for all the FSMA rules, to help businesses plan for the extensive changes. The agency was receptive to this request and says it wants to align the FSVP compliance dates with the compliance dates of the supply-chain program provisions in the preventive controls regulations “to the extent feasible.” In the FSVP final rule, the date that importers must comply with the regulation is the latest of the following dates:

  • 18 months after the publication of the 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.

The agency also revised other elements of the proposed FSVP rule in response to comments. For example, because the requirement to perform supplier verification on an establishment that manufactures/processes, raises, or grows an imported food could impose a greater burden on importers when the foreign supplier is not the immediate source of the imported food – such as for consolidated raw agricultural commodities (RACs) – the agency revised the rule to allow an importer of a food to obtain information needed to meet certain FSVP requirements from other entities, such as a distributor or consolidator of the food.

The final rule also excludes from most FSVP requirements certain types of food from a foreign supplier in a country whose food safety system FDA has recognized as comparable or equivalent to that of the United States if:

  • The food is within the scope of the relevant official recognition or equivalency determination;
  • The importer determines that the foreign supplier of the food is in good compliance standing with the relevant food safety authority; and
  • The food is not intended for further processing in the United States, e.g., packaged food products and raw agricultural commodities (RACs) that will not be processed further before consumption.

The final rule also establishes modified FSVP requirements for very small importers and importers of food from certain small foreign suppliers. The agency has aligned the definition of “very small importer” with the definitions of “very small business” in the final rules on preventive controls for human food and animal food.

Depending on the circumstances, supplier verification activities could include audits, records review, sampling and testing, some combination of those, or other activities, FDA says. Importers have the flexibility to use a different approach if they can establish that it will provide adequate assurance that the foreign supplier is significantly minimizing or preventing the hazard.

Importer facilities in compliance with the supply-chain program requirements under the preventive controls rules would be deemed in compliance with nearly all of the FSVP requirements, the agency says. The “importer” is the United States owner or consignee of a food offered for import into the United States, or – if there is no United States owner or consignee at the time of U.S. entry – the importer is the U.S. agent or representative of a foreign owner or consignee of the food offered for import at the time of entry, as confirmed in a signed statement of consent.

There may be many circumstances in which an importer evaluates the hazards in a food and determines that there are no hazards requiring control. In these cases, FDA says, the importer would not be required to conduct a supplier evaluation. Examples of foods for which there might not be hazards requiring controls include salt, many kinds of crackers, many cookies and many types of candy, bread, dried pasta, honey, molasses, sugar, syrup, soft drinks and certain jams, jellies and preserves, the agency says.

FDA has prepared a one-page decision-tree, titled Am I Subject to FSVP?, which may be a good place to start if you are uncertain whether your activities are covered by this rule.

Getting to Grips with the electronic Common Technical Document (eCTD) Process

Completing a successful electronic Common Technical Document (eCTD) submission can be daunting, even with the help of guidance documents from the International Conference on Harmonization (ICH) – which developed the eCTD – or from the Food and Drug Administration.

The success or failure of an eCTD submission depends greatly on processes put in place prior to beginning the process. First, it is necessary to ensure that the company has what’s needed to assemble an eCTD. If the manpower, knowledge, experience and hardware/software are not in place, failure is almost a certainty. These should be sourced from outside if necessary.

Once these are in place, it is imperative to set a timeline. The timeline is constructed by picking a realistic filing date and working backwards to see what needs to get accomplished to meet that deadline. The timeline will be part of a Global Development Plan that will change and be revised but will remain your “road map” for several years.

The eCTD is made up of five modules:

  • Module 1 provides for administration information and is country specific. For example, submissions in the United States require a Form FDA 356h with specific information. Other required forms include Field Copy Certification, Patent Certifications, Financial Disclosures, and Environmental Assessment, to name a few. In the EU, different information is required, such as Consultation with Patient Groups, Pharmacovigilance, Risk Management, and other information associated with the EU Region. Canada also has its own specific requirements.
  • Module 2 provides for quality, non-clinical and clinical summaries.
  • Module 3 provides for CMC information on the drug substance and drug product.
  • Module 4 provides for non-clinical data and reports.
  • Module 5 provides for clinical data and reports (including the ISE and ISS).

In beginning to populate Module 3 and subsequently Module 2, some of the challenges that you will be faced with will include the following:

  1. Key API characteristics.
  2. Pre-formulation and formulation development programs.
  3. Ensuring that your specifications and analytical assays are well developed.
  4. Ensuring that your early and later batches of clinical trial material and commercial material are produced pursuant to Good Manufacturing Practices.
  5. Having a good stability program in place with established stability protocols.

For your non-clinical program you will need to ensure that all the appropriate animal studies have been completed pursuant to good clinical practices and each non-clinical document signed off. Once Module 4 has been populated, you will need to provide a summary of your non-clinical data in Module 2.

For your clinical program, you will need to ensure that all the requisite trials are completed on time, Clinical Study Reports (CSRs) are written and signed off and that you begin the process of writing the Integrated Summary of Effectiveness (ISS) and the Integrated Summary of Safety (ISE). Gathering all the adverse events that transpired through your program is essential. When Module 5 is completed, you will need to provide a summary of the clinical information in Module 2.

As you begin to accumulate information, data reports, you will need to identify, in synch with your development plan, potential issues that could put your program at risk. When these risks have been identified and prioritized, you will need to find ways to mitigate the risks in order to meet your timeline.

It is advisable to form an eCTD Dossier Team early on in the process and assign responsibilities to each member with deliverable dates. For example, who will be responsible for writing the various Drug Substance and Drug Product templates in Module 3? Will the same person be writing the overall summary in Module 2? Will this be an individual or a team effort? Who will write the overall nonclinical and clinical summaries once all the data and reports are in? The same applies for the ISE and ISS which are among the final documents in the process.

Careful coordination is needed to ensure on-time delivery of all the moving parts within the eCTD. It is important to keep the following documents in mind:

  1. A time line chart that needs to be reviewed and possibly modified often.
  2. A Development Plan.
  3. A list of risks and mitigation strategies
  4. A Gap Analysis
    1. Identifying documents, information and data missing in each module
    2. Prioritizing and establishing a timeline for how the missing information will be obtained and when the information will be available
    3. Identifying key issues that could derail your submission and resolving these issues quickly
  5. A tracking chart of the status of all components of the eCTD. This can include a detailed eCTD Table of Contents as well as separate tables of contents for each of the modules.

As you move forward with the eCTD process, be sure to communicate often with the FDA or Boards of Health in discussions that help address any issues that arise. Don’t leave these interactions for the end, because this will just guarantee setbacks.

As a final tip, make sure to version all your documents. There will be hundreds of them. This is a great tracking tool and will have big pay offs.