Guidance Inartfully Mixes New and Old Expectations –
Creates Confusion for Drug and Biologics Manufacturers
As the COVID-19 pandemic continues, FDA continues its efforts to steward public health decision-making in an increasingly challenging regulatory climate. FDA’s most recent guidance for drug and biologics manufacturers, released late last week  reflects a Flying Wallenda-like balancing act between an assertion of legal obligation to comply with drug GMPs  and a pragmatic understanding of challenges manufacturers have traditionally faced with cGMP compliance, now exacerbated by COVID.
Unfortunately, though, FDA’s guidance confuses as much as guides, as it recognizes and references both legal obligations and challenges of this problem but provides little actionable support for internal decision making other than “use risk management principles.”
Exploring the substantive statements in the guidance, we find language that makes it difficult for manufacturers to clearly discern a safe path forward based on the plain language of the guidance.
After describing the need for companies to have a “plan” to return to normal, FDA states:
Although examples of delayed, reduced, or otherwise modified CGMP activities are described in this guidance, CGMP requirements remain in effect during the COVID-19 public health emergency and this guidance is not intended to describe FDA’s enforcement priorities.
So, what does this statement mean? It effectively says, 1) we know that some companies have delayed, reduced, or otherwise modified CGMP activities during this crisis; 2) remember, though, CGMP requirements remain in full effect during this crisis, and 3) despite the issuance of this guidance, once we get back to inspecting companies, we can enforce the law any way we think is situationally appropriate.
Further on the guidance states:
Where critical CGMP activities were delayed, interrupted, or reduced in frequency, the batch should be quarantined and the decision to approve the batch delayed until remediation activities ensuring drug quality are completed.
* * *
Drugs not manufactured in a manner that ensures their quality must not be distributed.[citing FDCA 501(a)(2)]
Again, this language speaks to both strict requirements and acknowledgement of challenges faced by manufacturers during COVID. In essence, FDA is saying that if you have manufactured product during the crisis and CGMP activities were delayed, interrupted, or reduced in frequency, your product is adulterated under FDCA 501(a)(2) and must not be distributed until “remediation” has been undertaken. However, it is not clear whether “remediation” under this guidance “cures” the deficiency, or whether FDA will decide situationally during an inspection that the remediation was inadequate.
What is disconcerting is that if FDA is trying to say that it knows CGMPs were not strictly followed during this crisis period, and is tacitly acknowledging that fact (and that it’s understandable) why then does it assert GMP requirements references [FDCA 501(a)(2)] at all? If FDA is trying to make a statement here, this lack of clarity of meaning does not help. What would be helpful is clarity, clear enforcement guidance, and clear expectations for manufacturers to follow.
FDA next states:
As part of the effort to identify areas in need of remediation, drug manufacturers should proactively seek out and obtain information about changes (e.g., to services or materials) that occurred outside of their control.
The list below includes examples of areas where remediation may be needed. The questions below are intended to help drug manufacturers identify the need for, and type of, remediation for their specific operations. [Emphasis added.]
Danger Will Robinson! Be careful here – FDA then lists four areas as examples of areas where remediation may be needed:
- non-critical product or process discrepancies and deviations;
- testing that was incomplete or was accomplished under conditions that may have compromised the accuracy of the test results;
- changes to, or difficulties in obtaining, materials used in drug manufacturing; and
- where facilities and equipment may have been changed or may have not been maintained on schedule, or if operations were interrupted.
By using the terms “examples” and “may” FDA is not saying that these are the only areas where remediation is necessary. In fact, at best, the examples are illustrative only. Like most obligations under CGMPs, FDA expects the company to self-assess areas of need for control to be compliant. Here, FDA is saying “these are important areas that we can see would be problematic, but if there was anything outside of CGMPs, you need to identify and risk prioritize these areas relative to product quality.”
As before, FDA – in trying to help industry understand there is a need for action relative to products manufactured under the COVID cloud – creates an opportunity for confusion relative to what they will expect. And what you as a manufacturer might expect on your first post-COVID inspection.
FDA’s final substantive section of the guidance establishes an expectation that manufacturers develop a PLAN for routine operations resumption. Unfortunately, FDA mixes fresh expectations, and long-established — pre-existing requirements — making it hard to discern new from existing. The following should help with understanding what’s new, and what’s old, relative to this plan:
- NEW: The risk management approach of the plan should prioritize manufacturing resumption activities for drug products subject to possible shortages.
- NEW: The plan needs to include a risk management approach based on product quality. In the guidance, FDA outlines several additional, specific factors to include.
- NEW: Management responsibility and governance for successful plan execution needs to be specifically delineated.
- NEW: The plan should be timebound and tied to prioritization based on risk management principles.
Unfortunately, the next few expectations that FDA outlines seem redundant to CGMP requirements. They should already exist in any CGMP manufacturer’s quality system, or, are already required by another regulation or guidance:
- OLD: The guidance states that the plan should specify that all changes be reviewed and approved by the Quality unit. This requirement seems redundant to the routine requirement for change control. As a result, the plan should reference the company’s change management program and that it will be followed for all changes contemplated under the plan.
- OLD: The guidance states that the plan should require the manufacturer to submit the required Field Alert Reports (FARs), Biological Product Deviation Reports (BPDRs), and animal drug product/manufacturing defect and adverse drug experience reports. These are already requirements for the specified regulated product classes. Companies should reference their pertinent SOP and quality system requirement.
- OLD: The plan should specify that if a drug manufacturer decides that a recall is needed, they should notify FDA as recommended in the March 2020 guidance for industry entitled Product Recall, Including Removals and Corrections. Again, this is already a regulatory expectation. Companies should reference their pertinent SOP and quality system requirement.
- OLD: The plan should specify that applicants and drug manufacturers notify FDA of a permanent discontinuance in the manufacture of certain products or an interruption in the manufacture of certain products that is likely to lead to a meaningful disruption in supply of that product in the United States. Again, this is already a regulatory expectation. Companies should reference their pertinent SOP and quality system requirement.
- NEW: Arguably new (since this isn’t explicitly defined by regulation or expectation in this case), FDA expects that the plan be updated based on new information, as appropriate. An update to a plan may result in a reprioritization of activities. This FDA expectation should be well understood by manufacturers.
Given the foregoing, what should pharmaceutical and biologics manufacturers do to address this resumption of compliant operations guidance and corresponding FDA expectations? In our view the following presents a much more concise and understandable approach that should meet the jumble of new and old guidance expectations:
- Perform a comprehensive CGMP quality and compliance gap analysis of execution against requirements during the COVID emergency operations period. As part of this gap analysis, identify any batches, lots, raw materials, testing activities, etc. that could have experienced deviations or contributed to possible negative product quality impact. Ensure the gap analysis is documented in rigorous detail.
- Using a risk-based approach, prioritize manufacturing resumption activities for products subject to possible shortages, followed by product quality considerations. Develop an aggressive, time-constrained prioritized remediation plan from the foregoing gap analysis to remediate any gaps or issues that occurred due to COVID-19.
This remediation plan should be aggressively managed and overseen by executive management. All quality decision-making under this plan should be documented using routine quality system procedural directives, and the entire plan and activities conducted under the plan should be documented as a distinct document.
FDA is doing its best to keep up with COVID-19 public health needs in an environment where clear, unambiguous direction from the federal government is often poorly received. Whether or not these considerations resulted in the confusing guidance issued by FDA last week is unclear. Pharmaceutical and biologics manufacturers must take care to ensure they are ready for future FDA inspections that may very well have a different enforcement lens. We could easily see more rigorous retrospective expectations about what should have occurred after this crisis is over.
For further information or assistance with quality planning development and enforcement risk considerations, contact Jack Garvey at email@example.com or at 732-397-3103.
 September 10, 2020, entitled “Resuming Normal Drug and Biologics Manufacturing Operations During the COVID-19 Public Health Emergency,” (https://www.fda.gov/media/142051/download)
 As required by FDCA 501(a)(2)(B).