Practices to mitigate the spread of COVID-19 have begun. Many people in pharma and biotech companies are working from home, and on-site staff is often severely limited to those performing business-critical activities. A serious concern of many is the security of their supply chain based on its complexity and global nature. We have already seen this play out in unexpected ways.
While the initial shortage in testing kits was severe, now that more of these are available another supply chain issue has appeared. A shortage in the reagents to extract RNA from clinical samples may now be limiting the number of tests that can be performed. And while alternatives are identified and implemented, this takes time and effort. The most recent shortage is now the swabs used to take samples from potentially ill individuals. Bottom line, supply chain issues will be with us in unexpected ways during this public health crisis.
Supply chain security for the pharmaceutical industry is a broad topic with many components. One of these components is the GMP audit program and ongoing GMP oversight of raw material and component suppliers, contract manufacturers, and contract laboratories. Supply chain security and its various components should be an essential part of a corporation’s disaster planning. We’re going to look at the GMP audit program and some options that may be able to help mitigate risk in this area, as well as explain choices made that may be asked during the next health authority inspection.
Health Authority Actions
Health authorities recognize the challenges of operating during this pandemic. The MHRA Inspectorate Blog reported on “Advice for Management of Clinical Trials in Relation to Coronavirus.” While I’m extrapolating a bit, it’s clear that regulators understand that outside activities are going to require modifications during this public health crisis. That’s good news.
Some key recommendations from this blog are relevant to the management of a GMP audit program under these conditions. Three suggestions, with some heavy paraphrasing, stood out to me. These include:
- Documentation of deviations that occur during this period.
- The conduct of a risk assessment to document the impact of the deviation.
- Prioritization of critical activities.
Similarly, the FDA issued guidance regarding the FDA’s enforcement discretion regarding supplier verification on-site audit requirements required by the FDA Food Safety Modernization Act. The enforcement discretion described in the guidance identifies the circumstances where FDA will not enforce the requirement for on-site audits. These are primarily in the areas of inability to travel and finding alternative verification methods.
In the GMP inspection area, the FDA has ceased conducting routine foreign inspections until at least the end of April 2020. They have also announced that they have temporarily postponed routine domestic surveillance inspections in order to concentrate on product safety.
In light of that, the FDA posted a statement identifying the steps they are taking to ensure the quality of foreign products. In the absence of on-site inspections, they have additional tools available to monitor and control products entering the US. Among these tools is one where FDA may request records from firms “in advance of or in lieu of” drug inspections. The authority to request these records is reasonably new for FDA and is found in section 706 of FDASIA amendments of 2012 to the FD&C Act.
And finally, for now, the Therapeutic Goods Administration of Australia announced that overseas inspections have been impacted and “inspections in some countries have been suspended until further notice.” They acknowledge that their regulatory partners in other countries are also delaying and deferring inspections due to the public health crisis.
GMP Audit Schedule Challenges and Potential Options
Most companies audit two general categories of firms that include: suppliers/vendors of raw materials and components and contract manufacturers/contract laboratories. Service providers, such as outsider calibration and maintenance services, are generally included in the suppliers/vendors group. In general, each of these categories is risk ranked, with some suppliers and providers deemed to be more critical to product quality and patient safety than others.
For example, a contract aseptic manufacturing site is more critical to product quality and patient safety than is a contract site that packages and labels solid oral dosage form products. In the area of raw materials, an excipient is generally more critical than a salt or solvent used early in the manufacturing process. And it is essential to remember that all of these suppliers of products or services should have been initially qualified through a rigorous process. In addition, they should be supported by Quality Agreements and be subject to ongoing oversight that includes active monitoring of the quality and acceptability of purchased products in addition to periodic audits.
With the above prioritization in mind, audit groups are going to delay or defer GMP audits as part of COVID-19 mitigation efforts with the imposition of travel restrictions and other practices. And just as important, auditee firms are limiting visitors from the outside, sending staff home to work whenever possible, and on-site personnel may be limited to business-critical activities and staff. And hosting an audit will not begin to make the list of business-critical activities, in my opinion.
So, are we at a standstill for potentially the rest of 2020, or do options exist that we might consider in the interim? We will discuss some options in the rest of the article, but whichever path the firm chooses, sound documentation and justification for actions are essential. But first, firms should ensure they have options in their audit SOP(s) that permit changes in schedule when supported with appropriate documentation and approvals.
Some options that firms might consider include but are not limited to the following:
Some audits of lower risk suppliers and contractors might reasonably be deferred until later this year, or longer. Consideration should be given to the past performance and compliance history of the auditee and product(s) they supply that justify a delay beyond the scheduled timing. The justification should be in writing consistent with the firm’s SOP that permits a delay of GMP audits and should consider the potential impact on product quality and patient safety.
For items and suppliers where companies would prefer not to defer audits entirely, companies might consider purchasing a recent GMP audit report from Rx-360 if they include one for the site in question.
Questionnaire as Part of Vendor/Supplier Qualification
For other items and suppliers, it might be reasonable to provide a questionnaire, something that many firms routinely employ for certain categories of suppliers and as part of vendor/supplier qualification. This may be coupled with purchase of an audit from Rx-360 mentioned above. This approach might suffice as an interim control until an on-site audit can be scheduled if the performance history of the site has been satisfactory.
Consider, however, whether questions need to be modified or added in light of the current COVID-19 impact on manufacturing staffing. For example, are firms fully staffed for manufacture, testing, packaging, or distribution, or have reductions in personnel occurred? And if so, has the number of units produced or tested decreased to reflect the decreased staffing? What other controls have the auditee implemented to ensure that product quality is not negatively impacted?
In some cases, remote/paper audits can be conducted with documents provided electronically in advance of the audit, and perhaps having staff interviewed over secure video-conferencing links. Remote audits might best also include the completion of a questionnaire. WHO routinely conducts what they refer to as “desk reviews,” similar to the process described in section 706 of FDASIA (2012). For some vendors, such as software vendors and SaaS providers, this may well be adequate. Again, questionnaires for these software audits may be found in the Rx360 website audit manual for software and hardware providers.
For audits of manufacturing and testing operations, this is not as effective because walk-throughs of the areas often prompt the most meaningful questions and serve to identify the most serious problems. In my personal experience, critical and many major findings are frequently a result of something seen on the tour that led to the additional investigation of features that may not have been identified with exclusively a document review. These audits might best work for audits within a company where the auditors are familiar with the facility and the overall quality systems and could focus on data or follow up from previous audits.
Using this approach becomes more difficult for Contract Manufacturing Organizations and Contract Laboratory sites. It does, however, provide a legitimate alternative to on-site audits in this current pandemic.
A potential worst-case one-year hiatus in on-site audits of GMP suppliers should not signal impending disaster in ensuring the integrity of the supply chain and continued production of quality products. Options are available to mitigate the cancellation and deferment of GMP audits scheduled in 2020. Procurement departments and others should also be involved in working with suppliers during this challenging time. Routine audits are only one tool that companies should use to ensure the security and integrity of their supply chains. Even on-site audits represent only a snapshot in time, and all are limited in the number of auditors allowed and their duration. At best, they are a component of ongoing supplier management.
The conditions we face with the COVID-19 pandemic make the supplier and CMO/CLO selection process even more critical. Evaluation of potential suppliers should include a focus on disaster preparedness/mitigation and recovery plans and whether they have existing plans for events such as the one we are living through now. If not, or if the plans are rudimentary or weak, the ultimate cost of partnering with such a supplier in the face of a disaster may be extreme. The importance of rigorous, multi-functional evaluation of potential providers cannot be overestimated when viewed through the lens of the COVID-19 pandemic. It also identifies that some elements of disaster mitigation and recovery may well be necessary to include in Quality Agreements.
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