By Barbara Unger, Unger Consulting Inc.
To date, the FDA has published more than five dozen guidance documents identifying enforcement flexibility and more broad interpretations of requirements during the COVID-19 pandemic. Most of these guidances are associated with tools to combat the pandemic, such as expectations for in vitro diagnostics, therapeutics to treat the infection, and devices such as ventilators and personnel protective garb. However, two guidances should be read by all drug and biologic manufacturers, regardless of whether they produce or distribute COVID related products. It would be easy to miss these two amidst the larger collection of guidances with “COVID” in the title. However, both require specific actions to be taken by manufacturers.
The first, Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing published on June 19, 2020. The second, Resuming Normal Drug and Biologics Manufacturing Operations During the COVID-19 Public Health Emergency was posted on Sept. 10, 2020.
We start with the June guidance. The guidance focuses on three areas and relies exclusively on existing regulations. It applies to manufacturers of APIs and drug products. The interpretation is made in light of COVID-19 but does not represent a unique approach:
- Manufacturing controls to prevent contamination: This section focuses on existing regulations requiring personnel with an apparent illness that may adversely affect the safety or quality of drug products should be excluded from direct contact with “components, drug product containers, closures, in-process materials, and drug products” until the condition is resolved.
- Manufacturers should vigilantly monitor employees in the manufacturing areas who have been exposed to others with confirmed or suspected COVID-19. Those who test positive for COVID-19 must be excluded from manufacturing areas and should not return to work until CDC’s criteria to cease home isolation are met. Remember that staff in office or non-manufacturing areas may pose risks if they are co-located in any way with manufacturing staff. (Author’s comment: It may be reasonable to consider taking staff temperatures each morning upon entering the building, along with a short health questionnaire.)
- Risk assessment(s) as it relates to drug safety and product quality: Firms should assess their CGMP controls to determine whether they are adequate to “protect materials, components, drug container closures, in-process materials, and/or drug from sick employees in the context of this new coronavirus.” It would be prudent to review the contamination control strategy to determine its adequacy in considering COVID-19. A separate risk assessment of the viral control strategy should be conducted considering SARS-CoV-2 (aka COVID-19). The assessment should include, but not necessarily be limited to, the following:
- Does the host cell line(s) support the replication of the virus?
- Will cell bank and/or harvest testing for the virus detect SARS-CoV-2?
- Evaluate the effectiveness of viral clearance and inactivation steps with regard to this virus.
- Are controls in place for open systems such as buffer preparation and media preparation?
In addition to the above requirements, firms should also do the following to prevent person to person transmission of the virus:
- Clean and sanitize nonproduction areas more frequently
- Update existing procedures to support more frequent cleaning and sanitization of surfaces in the production area. The guidance specifically mentions door handles, equipment latches, and control panels.
- Consider modifying procedures to include gloves and face masks or gowning where they were not previously required.
- Consider additional restrictions on employee access to any manufacturing area to limit potential contamination
In the case where potential or actual viral contamination is identified, the FDA provides guidance on what actions should be taken prior to resuming manufacturing operations.
- Documentation within the quality management systems: Drug manufacturers should ensure that all assessments, changes and processes, and procedures are documented and managed within the quality management system and approved by the quality unit. The FDA reminds manufacturers that “a drug that is not manufactured, processed, packed, or held in conformity with current good manufacturing practice to assure that the drug meets certain quality and purity standards is considered adulterated.”
Similar to the June guidance, the September guidance was issued without the opportunity for public stakeholder comment “because the Food and Drug Administration…has determined that prior public participation for this guidance is not feasible or appropriate.” While the June guidance addresses precautions and controls to be implemented during the pandemic, the September guidance “describes how to evaluate and prioritize the remediation of CGMP activities that were necessarily delayed, reduced or otherwise modified during the public health emergency in order to maintain production and the drug supply.” The September guidance provides a level of granularity not included in the 2011 guidance Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products. While the 2011 guidance was limited to the manufacture of medically necessary drugs, the September 2020 guidance applies to all manufacturers of drugs and biologic products and includes more granularity in requirements that should be considered and met.
The FDA acknowledges that certain GMP activities may have been modified or delayed in response to the COVID-19 pandemic. This guidance provides three recommendations for identifying and remediating these modifications, along with the return to more normal business processes. We will cover each in additional detail, but they include identifying any deviations or remediations necessary, evaluating and prioritizing activities using quality risk management principles, and prioritizing the actions necessary to resume more normal activities.
- Address deviations from established GMP activities. Firms should identify where GMP activities were “delayed, interrupted, or reduced in frequency.” If critical activities were delayed or modified, this might mean that batches of material must remain in quarantine until activities that provide assurance of drug quality and patient safety can be completed. Manufacturers should consider that changes may have been made by their suppliers, and they should actively seek out this information. The FDA provides examples of these types of delayed activities, including:
- An investigation into non-critical deviations or discrepancies that may currently remain open
- A delay in testing or testing under conditions where the accuracy of the tests may have been at risk
- Changes made at suppliers and vendors that may impact the product or services provided
- Facility and equipment maintenance, cleaning, calibration, and servicing that may have been implemented on a reduced schedule
- Use a risk-based approach to return to normal activities. Most firms that have an effective disaster recovery plan will have already incorporated this into their return to business plans. The FDA asks firms to include prioritizing return to business for drugs that may be at risk of shortage in their overall plan. Each firm should develop a plan that includes the following elements:
- Documentation of remediation activities commensurate with the operations and types of remediation necessary
- Management leadership is important to the effective execution of plans
- A timeline to track implementing actions
- Where a product recall may be necessary, the local FDA district should be notified
- Field Alert Reports (FARs) and Biologic Product Deviation Reports (BPDRs) should be filed as appropriate
- If the firm decides to permanently discontinue a product, it should notify the FDA
The plan should be updated as new information becomes available or as conditions associated with the COVID-19 pandemic require additional mitigation.
- Return to normal activities should be prioritized. The FDA recognizes that the return to normal activities is a “fluid process” where priorities may change with newly available information. It recommends firms should update their return to business plans as appropriate.
The two guidances represent the FDA’s current thoughts on ongoing manufacture during the COVID-19 pandemic and will likely be further modified as the conditions change. The approach does not appear to implement new requirements but offers a common-sense way to assure product quality and patient safety during these difficult times. Firms should be aware of both guidances, even though they may not manufacture or distribute COVID-related drugs or devices.
About The Author:
Barbara Unger formed Unger Consulting, Inc. to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry, including general GMP auditing and auditing and remediation in the area of data management and data integrity. Her corporate auditing experience includes leadership of the Amgen corporate GMP audit group for APIs and quality systems. She also developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen. This included surveillance, analysis, and communication of GMP related legislation, regulations, guidance, and industry compliance enforcement trends. Unger was the first chairperson of the Rx-360 Monitoring and Reporting work group that summarized and published relevant GMP and supply chain related laws, regulations, and guidance. In addition, she was previously co-lead of the Rx-360 Data Integrity Working Group. You can contact her at email@example.com.