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Ronald A. Rader is senior director, Technical Research, at BioPlan Associates.
FDA inspections can create uncertainty. Supervision of the contract manufacturer is crucial in ensuring compliance.
FDA is often considered the ‘gold standard’ global regulator by many and the most rigorous and respected regulator of pharmaceutical products. Besides evaluating applications for new drugs, generics, and biologics, FDA regularly inspects manufacturing facilities for deficiencies. Because a great majority of drug substances (active agents), particularly generic drugs, are manufactured in foreign countries, primarily China and India, FDA inspections of pharmaceutical facilities manufacturing products for the US market are performed worldwide for both internal drug company manufacturing and outsourced contract manufacturing facilities.
When evaluating the source of inspection problems, most pharmaceutical industry reports suggest that facilities in India, China, and other emerging regions are receiving a greater percentage of Form 483s and warning letters from FDA compared with US-based facilities. The problems noted in these inspections, such as data fraud or inadequate sanitation, are often more dramatic, and get more press coverage than most inspection-related problems noted in the United States, Europe, and other developed regions. But regardless of geography, any problems noted may constitute violations of the US Food Drug and Cosmetic (FD&C) Act. FDA has less authority outside the US, such as limited ability to force halt of manufacturing, but it can halt imports into the US. The worst-case situations (e.g., Form 483s, warning letters, facility inspection-related recalls, and product withdrawals) happen in all geographies and with all types of companies, including the largest and sophisticated facilities.
FDA inspections can create fear and uncertainty for pharmaceutical companies when FDA finds and seeks correction of manufacturing-related problems. Also, warning letters are published on FDA’s website, and Form 483s are available through freedom of information (FOI) requests, both of which may have an adverse impact on a company’s stock prices. Negative regulatory actions may halt mergers, acquisitions, licensing, and other business deals, and in the worst case, could result in company financial failure.
FDA inspectors are primarily concerned that in-house quality systems are fully documented and followed. Categories of quality systems that are inspected include:
For bioprocessing facilities, typical violations are a lack of or altered documentation, or violations of set procedures, or products not meeting quality specifications.
Deficiencies noted in any area can trigger a Form 483; however, often, a problem can be discussed onsite with inspectors and resolved, avoiding the issuance of a Form 483. Each problem noted by inspections should be responded to specifically, including plans for remediation, generally within 15 days of Form 483 issuance.
Inspectional observations are cited by facility inspectors in the context violating a specific FDA regulation and generally are listed in presumed order of seriousness. FDA welcomes rapid, informal resolution of problems to avoid issuing a Form 483. After receiving a Form 483, the facility/company can use a formal two-step dispute resolution process within 30 days (1). If facility responses are found to be adequate, generally no further action is taken by the agency. If deficiencies noted are not rapidly or sufficiently fixed, a formal warning letter may be issued.
Warning letters are issued after significant compliance problems noted in one or more prior inspections or Form 483s have not been properly addressed and resolved. Warning letters can lead to closure of manufacturing operations; criminal charges; consent decrees potentially involving third parties assuming responsibilities for manufacturing; product recalls and seizures of products; withdrawal of approvals; or an “Import Alert” letter halting import of products into the US.
By issuing a warning letter, FDA is serving notice that major compliance violations must be corrected, and actions taken to prevent reoccurrence of the same problems. Warning letters identify specific problems and the related regulations violated. Generally, the problems noted in warning letters are considered more severe than noted in Form 483s.
Once the facility addresses problems cited in a warning letter, FDA will conduct another facility inspection. If unresolved problems noted are serious and affect product quality and/or safety, FDA may withdraw or recall related products, and even withdraw approvals.
The top 10 manufacturing facility-related problems reported in Form 483s in FY2018 were, in decreasing order of frequency:
In general, most problems noted involve:
Other common problems involve computer and data systems:
These computer/data-related problems can be expected to increase as ever more data are generated and many facilities/companies move data storage and management to third-party cloud facilities.
Regulatory inspections frequently occur without warning; manufacturing facilities should be ready for a formal FDA inspection at all times. Conducting internal audits of quality systems for compliance with US 21 Code of Federal Regulations Part 820 (Quality System Regulation) and hiring consultants for mock FDA facility inspections can better prepare facilities for the real thing.
Relevant facility staff should be familiar with Form 483s and warning letters. Most large companies have implemented rigorous internal auditing of facilities and procedures, and maintain internal groups to monitor internal issues and trends in FDA inspections. Reviewing Form 483s and warning letters can provide insight on typical infractions.
Inspections are relatively informal in the sense that facility managers can and should discuss disagreements, offer explanations, and challenge inspectors as needed while they are in the facility. The facility may prudently later seek meet with inspectors to make sure all issues are resolved, giving the facility more certainty that it is properly addressing problems.
Most employees, including process operators, manufacturing-, quality-, and safety-associated staff should ideally be briefed on how to respond to FDA inspectors, who may ask questions during inspections.
Drug companies have control over activities in their facilities and can respond to regulatory inspections. When contract manufacturing facilities are used, however, the drug company passes control of manufacturing control to another company, while maintaining responsibility for the quality and efficacy of the drug product. Therefore, supervision of the contract manufacturer is crucial.
Quality oversight of CMOs. CMOs currently commercially manufacture 30–33% of commercially manufactured biopharmaceutical products. The CMO is contracted to fully comply with GMP bioprocessing standards, SOPs, and everything else specified in biologic license applications (BLAs)/new drug applications (NDAs), with this including CMO-internal critical review and oversight. But it is ultimately the product developer, the ‘manufacturer’ in the eyes of FDA, that needs to take responsibility for control and oversight of its CMO’s manufacturing activities. It has been reported that the typical bioprocessing described in a BLA involves approximately 1200 distinct steps. Add in variability in materials, equipment performance, environmental control, sterility, staff doing tasks different ways, and other normal variables, and a lot can go wrong at the off-site CMO. Many aspects of bioprocessing execution and the supply chain are controlled by the CMO, not the sponsor. Obviously, this increases risks for problems in bioprocessing, and the client needs to devote a good amount of relevant staff time, effort, and expertise in oversight of its CMO. Generally, the more time, effort, and higher-level staff assigned to these tasks, the less risk of major regulatory inspection problems and failures.
Many more established manufacturer companies have over time learned that investing in onsite CMO quality oversight is both necessary and cost-effective, including preventing or lessening the extent of problems that may arise. Some ‘manufacturers have ‘man-in-plant,’ with one or more staff on the factory floor and in the labs, providing oversight of the CMO’s bioprocessing and testing of its product(s). It is also prudent for relevant client staff or hired consultants to regularly review the CMO’s documentation related to its products, conduct audits, and debrief CMO staff, including on the factory floor, to ideally spot problems before they develop. But most manufacturers rely mostly on periodic visits and increasingly on teleconferences and E-mail to keep up with project progress and problems. No matter what, the CMO client should seek to maximize the ease and amount of communications back-and-forth with the CMO and should seek a low barrier for the CMO to report problems and ask questions.
1. FDA, Guidance for Industry Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP (HHS, January 2006).
Volume 32, Number 4
When referring to this article, please cite it as R. Rader, "Bioprocessing Facilities and FDA Inspection Problems," BioPharm International 32 (5) 2019.