FDA INSPECTIONS: PAST, PRESENT AND FUTURE
The globalization of the pharmaceutical supply chain and the quality issues that have arisen because of that globalization, the FDA initiative "Pharmaceutical Quality for the 21st Century" and resource constraints that all Health Authorities are feeling are all changing the way FDA is viewing their mission to protect the American consumer. This article discusses the past, present and potential future of non-US FDA inspections.
Past state
In the past, FDA did many fewer inspections outside the United States than within1. If you were a non-US manufacturer of an API, you might only be inspected once by FDA as part of the drug pre-approval process. Drug product manufacturers were inspected more frequently by FDA, but other than those sites producing drug products aseptically, still would only be subject to an FDA inspection on average every 14 years1.
Additionally, each Center within FDA had their own inspection model. The inspections performed by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) followed a different format (compliance program), with different models for how to select investigators for non-US inspections.
In general, CDER investigators performing non-US inspections were pulled from the Districts around the US. These investigators were senior in their Districts, and generally 90 - 100% of their work was related to drug inspections. These investigators used the System based inspection approach. How much the investigator interacted with the CDER personnel was highly variable, dependent both on the Center contact and the investigators preferences. A small number of inspections were conducted by CDER Compliance Officers, which also led to variability in the conduct and outcome of the inspection.
For CBER, the model was different. For the most part, CBER inspections were performed by Team Biologics, a national team of highly trained specialists. They did not follow the systems based inspection approach. In addition, the investigators and Center contacts were generally in close communication before, during and after inspections. Because Team Biologics investigators were all trained together, and because they performed inspections with all members of the team, there was generally less variability in their inspections.
Recommendation
Berlin, Germany4/5 December 2024
Root Cause Analysis
With the transfer of the review and approval of therapeutic proteins from CBER to CDER in 2003, the FDA began the process of harmonizing inspections of large and small molecule entities described above. Current initiatives and programs have continued the process.
Current Initiatives
Development of the Pharmaceutical inspectorate.2
The Pharmaceutical Inspectorate is CDER's version of Team Biologics. While the program has existed since 2003, the FDA is just now starting to see a real impact from this program. These investigators are all highly trained, Level III certified drug inspection specialists. They perform both US and non-US inspections of highly complex or high risk sites. Because the members of this cadre are trained as a group, the variability on inspection conduct is decreased.
Dedicated non-US inspection cadre.3
FDA traditionally has had difficulty resourcing non-US inspections. The trips are very demanding on the investigators and there is / was little or no incentive to perform these inspections. FDA is addressing this issue, in part, by the implementation of a dedicated non-US inspection cadre of approximately 30 members. These investigators only perform non-US inspections, and are experienced not only in their program area, but in the logistical and cultural challenges of non-US inspections. Since they are managed out of the Office of Regional Affairs (ORA), they maintain a close relationship with both the Center contact and the FDA International Office of Compliance.
Issuance of an updated Compliance Program on Pre-Approval Inspections (CPGM 7346.832).4
The new program also harmonizes the performance of PAIs performed for both large and small molecules, taking the best aspects from both the CDER and CBER inspection models. The program requires much more involvement of the NDA / BLA reviewers in the inspection process, and substantially increases the guidance around inspections of drug substance manufacturers.
Establishment of overseas offices.5
The goal of establishing liaisons in foreign countries is to provide support for development of regulatory capacity, promote information sharing and regulatory collaboration, administer certification and verification programs, and to facilitate and coordinate foreign inspections within a given country. By obtaining useful information and intelligence from foreign regulatory counterparts, FDA will be able to more effectively analyze risk to target foreign inspection resources and inspections will be easier to facilitate, coordinate and conduct.
Resource sharing.6
Both the FDA and EU recognize that they inspect each others facilities too much, and that there are opportunities to leverage inspection information. Initiatives such as Joint inspection Program are an attempt to begin this process.
PIC/S Membership.7
FDA has been accepted into the Pharmaceutical Inspection Co-operation Scheme (PIC/S), which fosters cooperation among pharmaceutical inspection authorities and training of competent authorities (in particular inspectors). Upon acceptance, PIC/S membership will enable the exchange of inspection reports and other inspection information with regulatory authorities. While the admission of FDA to PIC/S is an important milestone, there are still legal hurdles (see below) that must be overcome before FDA would be allowed to accept member nation inspections in lieu of their own inspections. However, having access to member state inspection reports will allow FDA to make better risk based decisions regarding when a non-US facility should be inspected.
New Proposed Legislation.8
There is currently legislation in front of Congress affecting the FDA. Some of the draft legislation provisions include:
- A requirement for manufacturers to develop and maintain quality management plans subject to inspection by FDA,
- Maintenance of drug pedigrees throughout the supply chain,
- Development and implementation of a system to track drug substance and drug product manufacturers,
- Providing FDA the authority to mandate a recall of drug substance and drug products,
- A requirement that FDA provide a report on agreements it enters into with foreign regulatory authorities to mutually recognize assessments of industry compliance with manufacturing standards and
- Provides FDA authority to share information with other regulatory bodies.
Future state
FDA has stated publicly at several meetings that they intend to significantly increase the number of non-US inspections they perform in the coming years. What the impact of that increase is to Europe is not yet clear. As stated previously, both the FDA and the EMA have indicated that, based on their risk assessments, they inspect each other far too much and are looking for opportunities to leverage resources. I believe you should not expect to see a significant increase in inspections within the EU, but will see a significant increase in China, India and other countries manufacturing drug substance and drug product for the US market that have not yet developed mature regulatory systems.
Areas of Focus for FDA In addition to the traditional areas of focus for FDA investigators, which includes areas such as batch review and release, change control, discrepancy management, corrective and preventative action (CAPA) management, process validation and equipment qualification, two new areas of focus are currently being emphasized during inspections: supply chain and complaint management. For the supply chain, FDA wants to see that you understand your end to end supply chain and have appropriate controls to detect both unintentional and intentional contamination. You should also be prepared to be asked about measures you are taking to secure your supply chain to prevent diversion and counterfeiting.
For complaints management, FDA wants to see that you make every effort to get as much information as possible from the complainant, that you thoroughly investigate complaints (and do not accept complaints as "normal") and that your product and medical complaints are viewed together and not as separate entities.
In addition to the above, you should anticipate FDA will continue to increase their focus on a company's quality system during inspections, with emphasis on senior management review and accountability, risk management, a global versus local quality system, timely event reporting (MDR / ADE / BPDR) and, based on recent warning letters and FD-483s, that the FDA will renew their focus on the quality reporting structure - Quality reporting to Quality versus Quality reporting to Site Heads in multi-site companies.
Recommendation
22/23 January 2025
HPLC Data Integrity - Live Online Training
Finally, FDA will increase their already significant emphasis on integrity. As outlined in the new Compliance Program Guide for Pre-Approval Inspections, the pre-approval inspection has three primary objectives: to determine if a site is ready for commercial manufacturing, to determine if the process, controls and facility conform with what was filed, and to verify the data submitted in the application is accurate and complete. You should also expect data integrity will be a focus during routine GMP inspections.
Author:
Mark Tucker, Ph.D.,
... is Senior Director, GMP Compliance at Genentech Inc., South San Francisco, USA, where he has the full strategic responsibility for GMP Compliance.
Source:
1 United States Government Accountability Office Report to Congressional Requesters, "DRUG SAFETY Better Data Management and More Inspections are Needed to Strengthen FDA's Foreign Drug Inspection Program", September 2008.
2 "Memorandum of Understanding Between The Office of Regulatory Affairs and The Center for Drug Evaluation and Research on the Pharmaceutical Inspectorate", August 2003.
3 Department of Health and Human Services Food and Drug Administration, Report to Committee on Appropriations, "Report on FDA's Approach to Medical Product Supply Chain Safety In Response to The Joint Explanatory Statement to Accompany H.R. 1105 The Omnibus Appropriations Act, 2009", July 2009.
4 Compliance Program Guide CPGM 7346.832, Pre-Approval Inspetions, May 2010.
5 FDA's Action Plan for Import Safety, Chapter 9, Operations in a Global Environement, September 2008.
6 FDA, "Update on a pilot project to collaborate on international GMP inspection activities", FDA Website, May 2009.
7 FDA, "Pharmaceutical cGMPs for the 21st Century, International Collaboration."
8 US Congress, "The Drug Safety and Accountability Act of 2010."
