GLP Hot Topic- FDA GLP Modernization Status

Quality Solutions for the Life Sciences Industry

GLP Hot Topic- FDA GLP Modernization Status Quality Solutions for the Life Sciences Industry Scott C. Rumsey, RQAP-GLP GLP Quality Consulting, LLC

The FDA Good Laboratory Practice (GLP) Regulations, first implemented in 1978, have been in place for over 30 years. As the first of the GLPs, they were followed by similar regulations in the US (EPA) and then by Japan, the OECD and other countries. While these regulations were substantially similar, minor differences were resolved through the issuance of Memoranda of Understanding (MOUs) between countries, whereby data were considered acceptable if conducted under the member countries GLPs. Over the years, the FDA GLPs were revised in 1987 to make minor clarifications to test article characterization, protocol and retention period requirements. However, as pre-clinical testing and industry R&D practices have evolved, including greater use of outsourcing, computers and multi-site studies, questions over interpretation of FDA GLP have arisen. Additionally, OECD GLP guidance documents have been issued to clarify the practices for multi-site studies and other aspects of compliance with GLP. These guidance documents contain terminology and designate responsibilities which are missing from FDA GLP.

In recent years the FDA has implemented a review of regulation and has revised the Good Manufacturing Practices (GMP) to more accurately reflect current practice and technology. These revisions have placed an increased emphasis upon risk-based approaches and upon quality systems. As part of this ongoing regulatory review process, the GLPs are also being considered for potential future revision and comments from the industry have been solicited by FDA. The Society of Quality Assurance (SQA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) are two groups which have implemented working groups and provided comments for suggested changes. The following is an overview of the major comments from these organizations:

Pharmaceutical Research and Manufacturers of America (PhRMA)

Define the Role of the Principle Investigator to align with OECD:

FDA GLPs do not define the role of a principle investigator, who, under OECD GLP is responsible for activities on a multi-site study at a location remote from the overall study director. FDA GLP does mention “contributing scientists” (and their reports), but does not define other responsibilities.

Master Schedule Maintenance:

A requirement for QA to maintain a copy of the master schedule is currently required by FDA GLP. It is proposed that QA only be required to have access to the master schedule. Industry practice allows for electronic maintenance of a master schedule and it may be more appropriate for it to be maintained by other business units (which schedule the work, assign the study personnel, etc.)

Contributing Scientist Reports: Quality Solutions for the Life Sciences Industry PhRMA would like to remove the requirement to have separate signed contributing scientist reports. Contributing scientists, who reside within an organization, should be allowed to sign an integrated final study report. Current FDA expectation is that all contributing scientist sign their own report, which is appended to the final report.

Test Article Characterization:

PhRMA believes that a GMP certificate of analysis should be sufficient to characterize materials used on GLP studies. Current FDA GLP regulations state that characterization must be conducted to GLP, although industry practice is more aligned to GMP (i.e. no protocol, study director, etc.)

Remove requirement for Final Study Reports for Compounds terminated prior to IND:

The requirement to write a final report for compounds which are not submitted to FDA is unnecessary and does not reflect a good use of resources. Data are archived for any subsequent review/analysis. It is recommended that a protocol amendment indicating reason for study termination be issued as an alternative.

Society of Quality Assurance (SQA)

The SQA solicited comments from its membership and convened a committee to provide recommendations. Overall, the SQA believes that the GLPs currently provide a good quality systems approach to regulation. Major changes may not be needed as the regulation covers the basics and allows for flexibility under different circumstances. There were several areas of agreement with PhRMA and a couple areas of disagreement as follows:

Define the role of Principle Investigator to harmonize with OECD:

SQA agrees with PhRMA that this role should be defined. A requirement to specify names, addresses and delegated activities of contributing scientists should be included.

Master Schedule Maintenance:

SQA agrees with the PhRMA position that the QAU does not need to maintain the master schedule. QAU access to the master schedule should be sufficient. Ensuring the maintenance of the Master Schedule should be a responsibility of management. Also, removal of reference to a “sheet” will reflect modern practice of optional electronic systems for master schedules.

QA retention of copies of the Protocol:

The QAU is currently required to maintain copies of all protocols. While it is necessary to maintain copies of protocols for which the QAU is responsible during the conduct of studies, it is not necessary to separately archive duplicate copies of protocols and amendments at the close of the study. It is recommended that this requirement be removed from the QAU and added to materials for archival.

Contributing Scientist Reports: Quality Solutions for the Life Sciences Industry SQA supports the requirement for separate signed contributing scientist reports as a method to ensure accountability for scientific interpretation and results. This is a different view-point from the PhRMA comments. SQA expressed concern that it would be difficult to determine accountability of various scientific interpretations in a combined report (i.e. who said what) and expressed confusion over what would happen with report amendments, etc. Additionally, SQA would also like to define the required content for individual scientist reports.

Test Article Characterization:

SQA would be supportive of allowing for GMP characterization of test article. However, the issue is the rigor of testing and the responsibility of the party performing the testing should be defined.

Test Article Storage Containers:

The current requirement to retain empty test article storage containers for the duration of studies should be removed. This requirement requires the use of extra storage space and does not add value to the quality/integrity of studies.

QAU is not responsible for protocol and SOP deviations; this is the responsibility of the Study Director:

Current FDA GLPs states that the QAU will “Determine that no deviation from approved protocols or standard operating procedures were made without proper authorization and documentation.” While the QAU does provide this function as part of the auditing process, the ultimate responsibility for protocol and SOP deviations resides with the study director. Regulatory citations are often made to the effect that the QAU failed to assure these deviations were addressed. A proper accountability would be to cite the study director, as the FDA does not review the QAU records to determine that the QAU has failed to cite these deviations. Both SQA and PhRMA agree that this requirement should be moved to the study director responsibilities.

Remove requirement for Final Reports for compounds terminated prior to IND:

SQA agreed with PhRMA to support the removal of the requirement for a Final Report if the reason for termination is included in the protocol amendment.

Computerized Data Systems:

SQA would like the “raw data” definitions to be updated to include electronic records. Also, the inclusion of a reference to computerized systems in the equipment section of the GLPS should be added.

Use of Guidance documents to reflect FDA current expectations for the following activities:

● Multi-site study best practice ● Use of Process inspections by the QAU ● Roles and responsibilities of sponsors

Quality Solutions● Test for and the Lifecontrol article characterization Sciences● Method Industry Validation best practices ● Processes around contribution scientist reports ● Application of GLPs to Medical Device studies ● GLP Compliance in Academic settings

Additional Considerations

Additional discussion has been conducted on the role of study-specific inspections vs. process-based inspection. Current FDA expectation is that each nonclinical study be inspected at least once during the course of activities. Process-based inspection may be conducted to supplement study inspection; however it is not clear that it can take the place of a minimal study-specific inspection program. Review of documentation (i.e. protocols and data/reports) on a study may not be considered an in-process inspection to meet the requirement. There is some support in industry to allow for the implementation of a risk-based process inspection program to cover the activities in a facility without necessarily inspecting each study once. This approach may be appropriate for activities of a short duration and of a repetitive nature (i.e. genotox studies, etc.) No consensus has been reached on this topic.

Current Status

The FDA has implemented a GLP Working group with Dr. C. T. Viswanathan as the Chair. The group is in the process of soliciting input from the various FDA Centers, as well as industry. The group will then begin the process of how to modernize the GLPs. FDA will publish preliminary information to the public and, after a comment period, a new GLP regulation may emerge. At this time, there is no firm timetable for the activities to be completed.

Scott Rumsey can be contacted at (734) 222-6285 or at [email protected]