On September 11, the U.S. Food and Drug Administration (FDA) issued a temporary guidance, “Resuming Normal Drug and Biologics Manufacturing Operations During the COVID-19 Public Health Emergency,” urging drug manufacturers to assess the impact of current Good Manufacturing Practice (cGMP) deviations that occurred as a result of the COVID-19 pandemic. The temporary guidance offers key considerations for manufacturers as they transition back to normal operations and will remain in effect “only for the duration of the public health emergency related to COVID-19.” Notably, the temporary guidance discusses: addressing deviations from established cGMP activities; developing a “resumption plan”; and prioritizing activities to resume manufacturing.

As we previously discussed here, FDA issued guidance in August 2020 providing insight into how the agency will determine what drug and biologic inspections may take place during the COVID-19 pandemic because they are viewed as “mission critical.” In that guidance, FDA recognized that, during the COVID-19 PHE, manufacturers may have faced – and continue to face – unusual challenges, such as employee illness and absenteeism, travel restrictions, site closures, and supply chain disruptions. These challenges may impact normal manufacturing operations, and cGMP activities may have been delayed, reduced, or otherwise modified, as described in the 2011 guidance entitled, “Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products.” While that guidance describes high-level considerations for resuming normal operations, the new temporary guidance provides more detailed considerations, and is specific to the COVID-19 public health emergency (PHE).

How to address deviations from cGMP activities

If a manufacturer departed from established cGMP activities during the COVID-19 Public Health Emergency (PHE), the manufacturer should first identify these deviations, as well as any necessary remediation actions. The temporary guidance emphasizes that, where critical cGMP activities – such as critical quality attribute testing – were delayed, interrupted, or reduced in frequency during the PHE, the batch should be quarantined, and the decision to approve the batch should be delayed until remediation activities are completed to ensure drug quality.

FDA specifies that remediation may be needed in the following areas:

• For unresolved investigations into non-critical product or process discrepancies and deviations that occurred before or during the COVID-19 PHE, drug manufacturers should assess whether:

  • the scope of the investigation should be expanded to supplement information;

  • short-term changes to normal operations may have increased the risk to product quality; and

  • procedures that govern investigations covering discrepancies, deviations, and non-conformances need to be updated in light of those procedures’ effectiveness during the PHE.

• If, during the COVID-19 PHE, testing was incomplete or was accomplished under conditions that may have compromised the accuracy of the test results, drug manufacturers should assess:

  • for delayed or reduced testing that indirectly measures a batch operation, the impact on drug quality;

  • for delayed or reduced testing not associated with a batch, whether additional testing should be performed to ensure that the facility is appropriate to manufacture quality drugs; and

  • whether operations or materials used in the production of drugs changed in any way that could impact the quality or availability of the finished drug product.

The guidance notes FDA’s expectation that drug manufacturers should proactively seek out and obtain information about changes to services or materials that occurred outside of their control. If there are changes to, or difficulties in obtaining, materials used in drug manufacturing, FDA advises that manufacturers should assess whether:

• any changes to the operations or materials could impact the quality of the finished product;

• higher demand for certain materials led to doubts about the quality or authenticity of those materials;

• observable differences about a material’s shipment give reason to question the integrity or source;

• measures can be taken to ensure the quality of the materials where an on-site audit of a supplier is not possible due to PHE-related travel restrictions; and whether

• any changes from established logistics or transportation systems could have affected the quality of materials or drugs shipped.

In addition, the temporary guidance advises manufacturers to assess whether any facilities and equipment have been changed or have not been maintained on schedule due to the COVID-19 PHE.

Creation of a “resumption plan”

After a drug manufacturer has identified departures from established cGMP activities that occurred during the COVID-19 PHE, and taken the necessary remediation actions, drug manufacturers should develop a “resumption plan,” to be used in conjunction with an emergency plan, due to the possibility of additional waves of COVID-19. FDA writes, “Drug manufacturers should develop a comprehensive resumption plan that is specific to their operations and organizational needs.” Specifically, the guidance says the plan should:

• include using a risk management approach that identifies, evaluates, and mitigates factors that may impact product quality;

• include a timeline for implementing priorities;

• specify that all changes be reviewed and approved by the drug manufacturer’s quality unit, which must document cGMP activities and include a justification when a drug manufacturer deviates from established procedures;

• specify that drug manufacturers submit the required Field Alert Reports (FARs), Biological Product Deviation Reports (BPDRs), and animal drug product/manufacturing defect and adverse drug experience reports;

• specify that if a drug manufacturer decides that a recall is needed, they should notify FDA;

• specify that applicants and drug manufacturers must notify FDA of a permanent discontinuance in the manufacture of certain products, or of an interruption in the manufacture of certain products that is likely to lead to a meaningful disruption in supply of that product in the U.S.; and

• be updated based on new information, as appropriate.

Prioritizing activities to resume manufacturing

Once a drug manufacturer has a resumption place in place, they should use the findings and conclusions drawn from the risk management approach to plan and prioritize resumption activities. FDA emphasizes, “[h]igh priority should be given to drugs that are in shortage or at risk of shortage.” FDA notes that while some activities must be conducted prior to the restart of a production line, and should therefore be prioritized ahead of normal batch production, other activities may be accomplished in tandem with batch production. When production priorities change, or new information impacting priorities is obtained, FDA says “the drug manufacturer should update the resumption plan and reprioritize activities, as appropriate.”

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