GLP Quality Consulting



GLP Hot Topic- Recent FDA 483 Trends -Test Site GLP Qualification Procedures for Study Directors at Test Facilities

Scott C. Rumsey, RQAP-GLP

GLP Quality Consulting, LLC

In a recent series of U.S. FDA GLP site inspections, test facilities have been either cited-- or verbally notified --that FDA will be expecting more robust procedures for the qualification/evaluation of subcontracted/test sites used for GLP compliant activities. While the industry has been working in accordance with the guidance for multi-site studies (OECD Guidance No. 13), this is a new enforcement focus for the U.S. agency. Specifically, The agency had concerns related to the integrity of data provided to Study Directors and clearly was looking to determine what they knew about the test site(s) contributing to the overall study.

Background:

The U.S. FDA maintains a GLP inspection program to support the safety testing requirements of human and animal drugs, medical devices, biological products, and food and color additives under FDA GLPS (21 CFR Part 58). FDA is also a member of the Organization for Economic Cooperation and Development (OECD) GLP working group, which has a separate set of GLPs entitled, ‘Principles on Good Laboratory Practice No.1’ and a series of consensus documents on various aspects of GLP—including multi-site studies (GLP Consensus Document No. 13 ‘The Application of the OECD Principles of GLP to the Organisation and Management of Multi-Site Studies.’)

In addition, the U.S. FDA has Memorandum of Understanding (MOUs) with various countries under which each country agrees to accept GLP data that is considered compliant with the other counties’ GLP program.

The FDA conducts a surveillance inspection program which typically includes site inspections that are targeted for biennial site visits. Sites appear on the FDA inspection list by the submission of applications for new product approvals (IND, NDA, BLA etc.) and based upon prior experience. The Agency also conducts targeted inspections for studies supporting applications that are under review. However, unlike various European agencies, the FDA does not issue/renew Certifications to GLP facilities. Rather, the FDA has relied upon industry statements in submissions as to the compliance status of work performed---and then utilized surprise inspection, periodic re-inspection and reactive enforcement actions to verify compliance.

However, as there is no certification process for GLP facilities in the United States, and newer facilities may not yet have been inspected by the FDA, it becomes difficult for sponsors or larger CROs which sub-contract aspect of a study to other ‘test sites,’ to determine the compliance status. In the U.S. you cannot ask for a copy of a ‘GLP Certificate’ as evidence of passing an inspection by the FDA. The best that can be done is to ask for a copy of any previous FDA inspection documents, such as Form 482

“Notice of Inspection’ or Form 483 ‘Inspectional Observations.’ These would at least verify that the FDA had visited the facility. However, there are many facilities that have not been inspected by the agency, but that may be suitable for GLP compliant work. Absent a GLP certificate, how do you demonstrate ‘due diligence’ in determining the suitability of a test site for your GLP study? This is the question the FDA is now investigating.

Upcoming U.S. FDA GLP Revision:

The FDA has been working on a revision to the 21 CFR Part 58 regulations, first implemented in 1978 and revised in 1987 and 1991. Industry comments have been collected and a draft version could be published in the Federal Register at any time. Two of the aspects that may be changed are clarification of multi-site study requirements, and the concept of GLP certification. Will the FDA continue the current ‘self-qualification followed by surprise inspection’ system? This is uncertain. However, the revision process has been delayed and the timeline for any change could be extended.

In the meantime, testing facilities should have procedures in place to verify the GLP compliance status of their contractors. And some CROs, depending upon study design, will need to verify the GLP compliance status of their sponsors--- a touchy situation. If a sponsor is paying CROs to perform a study and wants to perform some aspect of the work (e.g. formulation analysis or perhaps bioanalytical assays), how does a CRO verify---as a testing facility with the Study Director in-house--- that a sponsor test site is actually GLP compliant? And do this without a conflict of interest?

Some definitions:

It is important to clearly define the question and the resulting roles and responsibilities for GLP compliance. First, a few definitions, which I will obtain from the OECD principles and multi-site consensus document, as they have more clearly defined the roles and responsibilities:

The Study Director- means the individual responsible for the overall conduct of the nonclinical health and environmental safety study.

The Principal Investigator- Means an individual who, for a multi-site study, acts on behalf of the Study Director and has defined responsibility for delegated phases of the study. The Study Director’s responsibility for the overall conduct of the study cannot be delegated to the Principal Investigator(s); this includes approval of the study plan and its amendments, approval of the final report, and ensuring that all applicable Principles of Good Laboratory practice are followed.

Test Facility- means the persons, premises, operational unit(s) that are necessary for conducting the nonclinical health and environmental safety study. For multi-site studies, those which are conducted at more than one site, the test facility comprises the site at which the study director is located and all individual test sites, which individually and collectively can be considered to be test facilities.

Test Site-means the location(s) at which a phase(s) of a study is conducted.

The takeaway: The study director, located at the test facility, is responsible for the GLP compliance of the entire study—including all test sites at which phases are conducted. This means testing facilities must have some type of procedure (i.e. SOP) to describe how the study director is enabled to make an informed determination that each test site is GLP compliant. Ideally, this will involve documentation that can be presented to the FDA during an inspection.

Potential solutions: There are a number of procedures that, in combination, may indicate to the study director that a test site is GLP compliant. Some of these are proactive, and others involve activities during the conduct of the study that are in common practice today. Here are a few suggestions:

● if available (in certain countries) obtain a copy of the GLP certification for the test site to demonstrate GLP acceptance by the local regulatory authority

● for test sites in the United States, obtain a copy of FDA Form 482 and any Form 483s which demonstrates a previous inspection by the U.S. FDA and any actions taken to address findings

● periodically conduct a GLP site audit by either in-house QAU or a qualified 3rd party GLP QA Consultant to determine the GLP status of the test site and provide a summary sheet (minus any specific findings) to show the regulators the date(s) of inspection, who conducted the inspection, the scope of the inspection, and if the facility was considered in compliance with the GLP regulations

● sponsor companies—with no regulatory audit history, who wish to perform some aspect of the overall study as a Test Site, should be prepared to allow an audit by the Test Facility CRO, contract for an independent audit (with results/evaluation provided to the study director at the CRO testing facility) or to establish the study director in-house and conduct audits of the test site(s) contractors for GLP compliance.

● written quality agreements between the test facility and the test site(s) that define expectations including regulatory compliance requirements, and roles/responsibilities of Test Sites, principle investigator(s) study director, QAU, management(s)

● study protocols/plans that define roles and responsibilities and include the reporting of test site QAU audit findings to the test facility study director and management (be prepared to share coversheets, or summaries with FDA to demonstrate Study Director awareness of test site QAU audit reports)

● visit(s) by the study director to the test site(s) either before or during the study, documented

● test facility QAU/ QA Consultant audits of test site study activities, if no test site QAU available

● documented correspondence between the study director and test site personnel, including the principal investigator, during the conduct of the study

● review of data and draft reports at the test site by the study director, test facility QAU, or independent QA Consultant prior to finalizing a contributing scientist/PI report. A coversheet/summary of the conduct of this review to be available to the FDA (excluding any confidential QA findings)

Summary: Absent a U.S. GLP Certification program, there are challenges to testing facility study directors to ascertain (i.e. due diligence’) the compliance status of test sites which conduct GLP activities. The FDA has begun investigating the procedures that are used to provide this assurance as evidenced by recent 483 citations and verbal statements that have been made by FDA inspectors during several recent inspections. Organizations should review their procedures for the use of contractors, and for how test sites are evaluated, to ascertain whether increased oversight and documentation needs to be implemented. Sponsors and CROs will have challenges in the areas of conflicts of interest (sponsors pay the CRO, so how can the CRO perform an unbiased ‘audit’ of a sponsor test site?), confidentiality (one CRO may not want another CRO to audit them / review confidential procedures, etc.) and even partnerships between one sponsor company and another. Some of these conflicts might be resolved by the use of a 3rd party audit, or other combinations of the suggested solutions above.

The upcoming revision to U.S. GLPs may provide some clarification around the use of test sites by test facilities and to possible changes to FDA oversight. However, as the timing of GLP revision is uncertain, each organization should review their current procedures and make appropriate changes to demonstrate that the study director has the information to enable a reasonable determination of test site GLP compliance.

References:

FDA Good Laboratory Practices Regulation 21 CFR Part 58:



OECD Principles of GLP: (98)17&doclanguage=en

Consensus Document of the Working Group on Good Laboratory Practice No. 13 “The application of the OECD Principles of GLP to the Organisation and Management of Multi-Site Studies”:

(2002)9

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