Set Your Organization and FDA Up for Compliance Success in Shifting Times

Set Your Organization and FDA Up for Compliance Success in Shifting Times

BY Phil Crooker, VP – Technical, Regulatory & Access, Parexel - 1.6.21 -

Once the full fury of the pandemic was understood, the Food and Drug Administration turned to a number of tools that already existed to help fill the gap for information that was normally collected and examined and then assessed during manufacturing facility inspections. One of these tools is the now often cited records request in advance of or in-lieu of an inspection.

Some quick background
The FDA authority to request these records under those situations is found in Section 704(a)(4)(A) of the Food, Drug and Cosmetic Act (FDCA). It was added to the FDCA from Section 706 of the Food, Drug and Administration Safety and Innovation Act (FDASIA). That’s why you sometimes hear references to both “704” and “706” record requests. The authority to request records is not FDA program wide – it only covers human drugs and biologics and animal drugs. This was a new authority for the FDA, and it was not envisioned to be rapidly scaled up as a bulwark against a pandemic – it was originally designed to “level the playing field” between foreign and domestic manufacturing sites. Prior to the pandemic FDA had conducted a 6-month pilot program for implementing the new authority and published its results that you can find here - Leveling the playing field across domestic and foreign inspections (

Policy is not yet consistent
Amidst the FDA trying to manage day-to-day operations while developing and implementing new policies using new and existing tools in unanticipated ways, there have been a spate of press reports about manufacturers facing uncertainty about how the records request authorities is being used and will be used for the remaining duration of the pandemic (and perhaps after the public health emergency ends). Some firms report receiving Complete Response letters (see the story here - Alkermes plc > Investor Relations > Alkermes Receives FDA Complete Response Letter Related to ALKS 3831 Manufacturing Records Review). Some firms report that FDA permitted an action date to lapse and took no action on an application because travel restrictions prohibited an on-site inspection (see the story here - Bristol Myers Squibb - Bristol Myers Squibb Provides Regulatory Update on Lisocabtagene Maraleucel (liso-cel) ( And the publicly available reviews of marketing applications that FDA posts on its website indicate that yet other drugs are approved while inspections are waived, postponed or FDA resorts to using a desktop assessment of the manufacturing facilities (for example see page 9 of the product quality review for this recent approval -

Different parts of the FDA have steadfastly maintained that the records request authority is only being used in advance of an inspection to aid in prioritizing on-site inspections and emphatically not in-lieu of an inspection. Given the draconian travel restrictions in place for the foreseeable future as the pandemic escalates, it’s hard to see how on-site inspections will increase in the near future. Various FDA officials and the FDA Commissioner have remarked recently that the agency is close to releasing more guidance on how the FDA will manage inspections during COVID-19, including expanded uses of existing tools such as the records request authority. That guidance and any new policy – such as a less restrictive reading of the statutory authority to request and examine records in lieu of an inspection – will be a subject for another day once we see the new guidance.

Here’s the problem
In the meantime, regulated industry is left grappling with how to respond to these records requests from the FDA. There is a Staff Manual Guide (SMG) published by FDA that outlines the process for how records are requested and their receipt acknowledged – you can find a copy here Staff Manual Guide 9004.1 ( But the SMG does not provide any information to help a firm anticipate the scope of the records request and what criteria will be used to examine and assess the records. Manufacturers have noted that oftentimes the request for records is voluminous, and the FDA counters with a statement that the reason the request looks overwhelming is because the records are being requested at one time rather than over the course of an inspection that could last days. To get a better sense of what to expect in a records request, here is a brief look at the categories of documents that could be included in a request from the FDA – they are generally organized around the CGMP regulations in 21 C.F.R. § 211.

  • General information about the site (this is the section where FDA could ask for a copy of the site master file – which by itself could be large).
  • Production (this is where the FDA could ask for a manufacturing log that goes as far back as two years and sterile process validation documents).
  • Quality systems (could include a request for a catalog of all standard operating procedures).
  • Facilities and equipment (could include a log of all IQ/OQ/PQ activities for all equipment).
  • Laboratories (this is where the FDA could ask for an OOS and investigation log that goes as far back as two years and all data integrity controls).
  • Material systems (could include a table for all material suppliers for all products and all documents related to the design and qualification of the water system).
  • Packaging and labeling.

The FDA also keeps a companion tool for the assessment of the requested records.  However, unlike an on-site inspection the FDA does not issue a Form FDA 482 or Form FDA 483. If the records request is being used to support a decision whether to recommend approval for an application then there may be a record or memorandum of the assessment (or desktop audit) that will be part of the product quality review that is included (but redacted) in the approval package FDA publishes on the “Drugs@FDA “ website. A cop could also be requested through a Freedom of Information Act (FOIA) request, but that can be time consuming and the content will also likely be heavily redacted.

One approach industry can take that helps all parties – including FDA
One approach to consider is borrowing a page from the process for how legal professionals track and organize documents during litigation, including the process of discovery - which can involve sending and receiving large numbers of documents. This could be somewhat analogous to the FDA requests for information and with some modification could be used to present and organize the information both for the benefit of the FDA and for the manufacturer.
Here are some general principles that are used when legal professionals are involved in organizing documents during discovery:

  • Separate documents into specific categories (in the case of an FDA request for records these categories are provided in the sections for each system involved in manufacturing).
  • Place the documents in chronological order.
  • Sub-files and sub-documents (such as attachments) should be organized under the more general headings based on the systems sections.
  • Large files may need an index for materials within the sub-files (an index within an index).

The index of documents exchanged during discovery typically has several categories of information, but not all would be relevant to responding to the FDA request for records. The information that would be important to use includes:

  • Title of the document.
  • Document number or other specific identifying information.
  • Function which created the document.
  • Date the document was created, reviewed and if necessary approved.
  • Document category.
  • Whether the document was reviewed in past FDA inspections or was included as part of a prior or pending regulatory submission.
  • Remarks.

Here’s how the index could look if a simple table is used in Word™ document or Excel™ spreadsheet:

Title Identifier Function Date Category Past Use Remarks


In my opinion, the most important section of the index is the remarks column. It is like including a “reviewer’s guide” in a regulatory application for FDA review. This information is very effective in targeting the information for the FDA’s assessment of the documents. This section can be used for several purposes including:

  • Summarizing the conclusions from the document – not a reiteration of all the information in the document.
  • It can bring issues to the attention of the FDA and show how the firm has taken the necessary steps to resolve them.
  • It can also provide cross-references to other documents where supporting information is provided or show where documents are related.

As a general principle, but particularly when a firm is involved in exchanging large amounts of information with FDA, it is best practice (both ethically and functionally) to assure that all the critical issues are identified and the position that the firm has successfully resolved them is fully articulated and supported with information and data that can readily be identified and accessed. Taking the time to build an index – no matter how simple – and include it as part of the response can be a tool which enables the records request and the assessment by FDA to proceed with less risk and enable timely decision-making.


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