The FDA Advises on GMP, Manufacturing and COVID-19By
The FDA has issued guidance to advise drug manufacturers how to resume normal manufacturing operations that were impacted by the COVID-19 pandemic, which has caused unusual challenges: employee illness and absenteeism, travel restrictions, site closures, supply-chain disruptions, quarantines, and social distancing. How is the FDA advising pharma companies and CDMOs/CMOs to get back on track?
Prioritizing drugs when resuming manufacturing operations
The guidance, issued earlier this month (September 2020), applies to all drugs, but in issuing the guidance, the US Food and Drug Administration (FDA) says the risk of a shortage of particular categories of drugs is important when determining whether certain manufacturing and quality assurance activities may be reduced in frequency, delayed, or handled differently than prescribed in established procedures. These categories include, for example, drugs that are life-supporting, life-sustaining, intended for use in preventing or treating a debilitating disease or condition, or any drug that is critical during a public health emergency.
The FDA stresses that its current guidance builds on and goes beyond a previous FDA guidance, issued in March 2011, which addressed how to prioritize drugs when dealing with high absenteeism in manufacturing operations. That 2011 guidance advises to use a risk-based approach to determine which products should be prioritized for manufacturing and which cGMP activities could be delayed, reduced, or otherwise modified during an emergency.
The high-absenteeism guidance from 2011 describes high-level considerations for resuming normal operations. The current guidance issued this month (September 2020), however, provides more detailed considerations and is specific to the COVID-19 public health emergency. In the current guidance, the FDA makes recommendations to help drug manufacturers, which have delayed, reduced, or otherwise modified cGMP activities due to the COVID-19 public health emergency, prioritize products and remediation activities when returning to normal operations using a quality risk-management approach. The guidance may also be useful for drug manufacturers that have already resumed normal cGMP operations.
FDA’s recommendations to pharma companies, CDMOs/CMOs and suppliers
The FDA’s current guidance centers on three main areas: (1) addressing deviations from established cGMP activities; (2) risk management and other elements in a plan for resuming normal drug manufacturing; and (3) prioritizing activities to resume normal drug manufacturing.
Overall considerations for a resumption plan and remediation
The FDA guidance specifies that remediation may be necessary for activities impacted by the COVID-19 public health emergency that were delayed, interrupted, or reduced in frequency. Remediation could include a modification to an activity, a new activity, or a more comprehensive program change that mitigates the risk of a drug-quality issue due to the deviation from normal operations. The FDA advises that where critical cGMP activities were delayed, interrupted, or reduced in frequency, a batch should be quarantined, and the decision to approve the batch be delayed until remediation activities ensuring drug quality, such as critical quality attribute testing, investigations of critical deviations, and evaluation of unapproved changes to critical operations, are completed.
As part of the effort to identify areas in need of remediation, the FDA advises that drug manufacturers should proactively seek out and obtain information about changes (e.g., to services or materials) that occurred outside of their control. In the guidance, it provides examples of where remediation may be needed to help drug manufacturers identify the need for, and type of, remediation for their specific operations. These areas, outlined below, include: (1) information from suppliers about changes in their operations due to COVID-19; (2) batch release impacted by COVID-19-related issues; (3) changes in facilities or operations resulting from COVID-19; and (4) non-critical product or process discrepancies and deviations arising from COVID-19-related issues.
Information from suppliers about changes in their operations due to COVID-19
The FDA guidance says that drug manufacturers should proactively obtain information from suppliers about the impact of the COVID-19 public health emergency on their operations. If there are changes to, or difficulties in obtaining, materials used in drug manufacturing, the FDA advises that the following questions may be helpful in assessing whether additional measures are needed.
Changes in operations. Are drug manufacturers aware of any changes to the operations or materials that could impact the quality of the finished product, such as a change in starting materials for an active pharmaceutical ingredient (API) or interruptions in the supplier’s supply chain?
Vulnerabilities to the authenticity of materials. Has the higher demand for certain materials led to doubts about the quality or authenticity of materials through, for example, economically motivated adulteration or the potential for increased impurities?
Changes in shipping of materials. Are there observable differences about a material’s shipment that give reason to question the integrity or source (e.g., broken tamper-evident seals, unexpected changes to packaging or labeling)?
Audits of suppliers. If an on-site audit of a new or existing supplier is not possible due to travel restrictions related to the COVID-19 public health emergency, what measures can be taken to ensure the quality of the materials (e.g., a remote supplier audit, reassessment or revision of a quality agreement, additional testing to verify a certificate of analysis)? Should the supplier-qualification program be updated?
Changes in logistics and shipping conditions. Were there any changes from established logistics or transportation systems (e.g., excursions from temperature or humidity parameters during transport) used for the movement of materials or supplies that could have affected the quality of materials or drugs shipped?
Batch release impacted by COVID-19
The FDA guidance also advises on batch testing and release impacted by COVID-19. If, during the COVID-19 public health emergency, batch testing was incomplete or was accomplished under conditions that may have compromised the accuracy of the test results, the FDA advises that the following questions may be helpful in assessing whether additional measures are needed to determine suitability for batch release.
Delayed or reduced testing. For delayed or reduced testing that indirectly measures a batch operation (e.g., certain types of in-process tests), what was the impact on drug quality?
Additional testing of facilities. For delayed or reduced testing not associated with a batch (e.g., microbiological testing of environmental monitoring plates from low-criticality clean areas or routine stability testing supporting a marketed drug with a robust history of minimal degradation), should additional testing be performed to ensure that the facility is appropriate to manufacture quality drugs?
Changes in operations or materials. Were 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? If so, was the change evaluated and implemented under the drug manufacturer’s change-management program? Is an investigation necessary to determine if an associated batch is suitable for release? Should the testing program or other monitoring program be modified to evaluate any long-term adverse effects on the quality of the drug product (e.g., additional stability testing)?
Change of facilities or equipment maintenance due to COVID-19
The FDA advises that if facilities and equipment have been changed or have not been maintained on schedule, or if operations were interrupted during the COVID-19 public health emergency, the following questions may be helpful in assessing whether additional measures are needed.
Change in utilities. Did a disruption or change to water, gas, electricity, or sewage removal utilities pose a challenge to operational capabilities (e.g., the water-purification system was not operated according to established procedures, putting it at greater risk of objectionable microbiological contamination)?
Equipment changes. If the use of equipment changed (e.g., if equipment was reconfigured or barriers were added for operator safety) and was not qualified prior to use, should there be a retrospective evaluation of equipment performance and the type of remediation necessary to continue using the equipment?
Cleaning protocol. Was there a change in the frequency of cleaning/disinfection, or to the type of cleaning agent or disinfectant) used that warrants a reassessment of cleaning procedures?
Specialized technical support. If equipment servicing requires a technician with special expertise and that individual is unable to be on-site, are there alternative means to ensure that the equipment is suitable for use (e.g., when service that is normally performed on-site but was conducted with remote assistance)?
Service delays. Did a delay in preventive maintenance or calibration activities for facilities or equipment impact the function (e.g., adequacy for use) of facilities or equipment?
Non-critical product or process discrepancies and deviations
In its guidance, the FDA is advising how to complete investigations into non-critical product or process discrepancies and deviations that occurred before or during the COVID-19 public health emergency. To complete these investigations, the FDA is recommending to drug manufacturers to consider the following questions.
Scope of the investigation. Should the scope of the investigation be expanded to supplement information lost because staff were not present to fully observe or gather information about the incident, or because the extent of the problem increased due to a delay in response?
Product-quality risk. Were short-term changes to normal operations implemented that may have increased the risk to product quality (e.g., change in material flow or personnel flow)?
Adequacy of procedures for investigations during COVID-19. Are the procedures that govern investigations covering discrepancies, deviations, and non-conformances suitable during the COVID-19 public health emergency, or should they be updated?
Risk management in resuming normal manufacturing operations
In its guidance, the FDA is recommending that drug manufacturers develop a plan for resuming operations that were impacted by COVID-19, in conjunction with an emergency plan to account for the possibility of additional waves of COVID-19. The FDA has detailed the elements that a resumption plan should include as outlined below.
Risk-management plan. In its guidance, the FDA is advising that the drug manufacturer’s resumption plan include a risk-management approach that identifies, evaluates, and mitigates factors that may impact product quality. These factors include activities performed, not performed, delayed, interrupted, or performed remotely; changes to procedures, processes, or programs; and associated outcomes. For effective mitigation, it may be sufficient to conduct additional activities (e.g., increased testing for a specific API). However, in some cases, effective mitigation may require more extensive program changes (e.g., a more in-depth supplier-qualification program, enhanced change-management activities) with a strong emphasis on risk reduction.
Management support. The FDA guidance stresses that management leadership is important to successful execution of the resumption plan.
Timelines. The resumption plan should include a timeline for implementing priorities.
Quality unit approval. The resumption plan should specify that all changes be reviewed and approved by the drug manufacturer’s quality unit. The FDA guidance emphasizes that it is the drug manufacturer’s responsibility to document cGMP activities and to include a justification when a drug manufacturer deviates from established procedures.
Adverse reporting. The plan should specify measures for submitting the required field alert reports, biological product deviation reports, and animal drug product/manufacturing defect and adverse drug experience reports.
Product recalls. The plan should specify that if a drug manufacturer decides that a recall is needed, it should notify the FDA as recommended in the FDA’s guidances for product recalls, including removals and corrections.
Discontinuing or interruptions of products. The resumption plan should specify that applicants and drug manufacturers notify the 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 US.
Updates to the plan. The resumption plan should be updated based on new information, as appropriate. An update to a plan may result in a reprioritization of activities.
Prioritizing activities for resuming normal drug manufacturing
The FDA says in its guidance that drug manufacturers should use the findings and conclusions drawn from the risk-management approach to plan and prioritize resumption activities. High priority should be given to drugs that are in shortage or at risk of shortage. It says that some activities must be conducted prior to the restarting of a production line and therefore should be prioritized ahead of normal batch production (e.g., resolution of deviations related to a specific production line, confirmation that the supply of API is reliable). Other activities may be accomplished in tandem with batch production (e.g., restart activities for a different product).