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:
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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:
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the scope of the investigation should be expanded to supplement information;
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short-term changes to normal operations may have increased the risk to product quality; and
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procedures that govern investigations covering discrepancies, deviations, and non-conformances need to be updated in light of those procedures’ effectiveness during the PHE.
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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:
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for delayed or reduced testing that indirectly measures a batch operation, the impact on drug quality;
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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
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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:
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any changes to the operations or materials could impact the quality of the finished product;
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higher demand for certain materials led to doubts about the quality or authenticity of those materials;
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observable differences about a material’s shipment give reason to question the integrity or source;
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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
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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:
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.”
If you have any questions on how to address cGMP deviations that have occurred during the public health emergency, or on creation of a resumption plan, please contact your Hogan Lovells attorney or any of the authors of this alert.
Authored by Jim Johnson, Scott Kaplan, and Christopher Fanelli
