Toxicologic Pathology Forum: Opinion on Performing Good Laboratory Practice Histopathology Evaluation for Nonclinical Toxicity Studies in a Remote Location

Abstract

Toxicologic/veterinary pathologists are working remotely from Good Laboratory Practice (GLP) test facilities (TFs) in increasing numbers, most commonly in home-office settings. A study pathologist (SP) generating data on GLP-compliant nonclinical studies must be keenly aware of applicable national GLP regulations and comply with TF and protocol requirements. This Toxicological Pathology Forum Opinion Piece will summarize primary areas of emphasis for the SP generating GLP data using glass slides. Peer review and digital review of whole slide images are out of scope for this opinion piece. Key GLP considerations for primary pathology on glass slides are discussed with respect to SP location and employment status, including pathologist qualifications, specimen management, facilities, equipment, archive, and quality assurance. Notable differences between national GLP regulations of the United States, the United Kingdom, Germany, the Netherlands, France, Ireland, Switzerland, Italy, and Israel are presented. With the understanding that each combination of location and employment is unique, the authors provide a general overview of considerations for successful remote GLP work.

This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the authors. It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

Introduction

Good Laboratory Practices (GLPs) are a quality system intended to assure the quality and integrity of safety data through an organizational process and conditions under which nonclinical health and environmental safety studies are planned, performed, monitored, recorded, archived, and reported. ¹ Good Laboratory Practices compliance is governed by national regulations; therefore, there are differences in practices across countries. “The Organisation for Economic Co-operation Development (OECD) Principles of Good Laboratory Practice” and “Guidelines for the Testing of Chemicals” are harmonized international standards agreed upon by OECD GLP Mutual Acceptance of Data (MAD) member countries, facilitating GLP study acceptance among member countries.^{2 -4} The OECD Principles are based on the 1976 US Food and Drug Administration (FDA) Good Laboratory Practice for Nonclinical Laboratory Studies proposed regulations, 21 Code of Federal Regulations (CFR) Part 58. ⁵ The principles were created with input from many countries, providing a framework to implement compliance programs while allowing variation among national programs. The European Union (EU) requires member countries to adopt OECD Principles by Directive 2004/9/EC and Directive 2004/10/EC^6,7; other countries may choose to claim OECD compliance along with their national regulations. There are subtle but important differences in text and interpretation between OECD Principles and country-specific regulations which make harmonization across multinational test sites (TS) challenging. ⁸ Some countries have adopted the OECD Principles as their national regulations (e.g., Canada). National regulations supersede the OECD Principles, and in some countries, there are notable differences, for example, the United States. An exhaustive comparison of national GLP regulations is beyond the scope of this article; however, one key difference applicable to the practice of toxicological pathology in support of nonclinical safety studies involves laboratory certification. With the exception of the United States, OECD MAD member countries certify laboratories on a 2- to 4-year interval, issuing a GLP certificate to facilities meeting national regulations. The FDA does not require facilities be licensed as defined in the 1978 Preamble, comment #80; the US Environmental Protection Agency (EPA) follows the same approach.^5,9,10 The US authorities perform compliance inspections on a risk-based interval. Despite differences in GLP regulations, data generated under each country-specific compliance program should be of sufficient quality and integrity for their intended use.

To understand how GLP regulations are applied to the study pathologist (SP) generating data at a worksite geographically remote from the test facility (TF), the location of the TF and SP need to be known, and the organizational structure and employment status of the pathologist need to be defined. There are many possible combinations of SP employment and worksite location. The SP may be employed by the company sponsoring the study (sponsor), the TF (contract research organization or sponsor), or be self-employed/part of a consulting firm, contracted by either the TF or sponsor. The pathologist may work at the TF, from a remote worksite/home office, or a combination of both, taking slides home for review some days of the week. While the same rules apply regardless of where the pathologist works, employment status determines where oversight originates and “how” the pathologist operates. The remote worksite of a SP employed by a TF operates under the main TF oversight (quality assurance unit [QAU] and information technology [IT]) and is not organizationally distinct from the TF. The remote worksite of a TF pathologist may, therefore, be considered an extension of the TF. The remote worksite address is not recorded in the protocol for security reasons but maintained by the TF and made available upon regulatory request. A consulting pathologist, contracted by the TF (or sponsor), is both geographically remote and operating under distinct oversight mechanisms. In this case, the SP is the principal investigator in charge of the study phase, and their premises is considered a TS of a multisite study.

Traditionally, when performing GLP work, TF pathologists worked at the TF, and consulting pathologists worked at their privately owned business. Over the past 10 to 15 years, greater numbers of SP have been working remote from a TF, a trend which was noticeably accelerated by the COVID-19 pandemic. How an SP maintains GLP compliance at a remote worksite has been a point of conversation within the toxicologic pathology community.

Discussion

Good Laboratory Practices regulations span all aspects of study conduct from planning to archiving. Study activities are performed according to standard operating procedures (SOPs) and the study protocol, following GLP principles of attributable, legible, contemporaneous, original, and accurate, complete, consistent, enduring, and available. Primary areas of emphasis for the SP at a remote worksite may be divided into four categories: (1) qualification, (2) specimen management, (3) facilities, and (4) equipment.

1. Qualifications: The SP (or designee) is responsible for maintaining documentation of training, education, and experience to perform the role. Most commonly, these requirements are met through an up-to-date curriculum vitae (CV), job description (JD), and training records (including training on GLP regulations), maintained in the SP training record. Documentation is regularly updated and reviewed by management who has the responsibility to ensure qualifications of personnel. This documentation is available for review by auditors and regulators.

2. Specimen management: The SP (or designee) is responsible for maintaining the chain of custody of specimens from receipt to return to the TF (or other protocol directed TS/archive). Most commonly, this is achieved through a commercial courier service with a secure record of shipment and receipt. Methods for specimen receipt, storage, and inventory vary and are directed by the applicable SOPs of the TF, sponsor, and/or the pathology consultant.

3. Facilities: SP facilities include a designated space for performing study-related duties and the security of study specimens/raw data. There are a wide variety of setups designed to ensure specimen/data security at a remote worksite, typically defined by SOP, which may include either a lockable cabinet or a room with restricted access. Security may include, but is not limited to, protection from fire, theft, damage (water, pests, natural disasters, etc.), and manipulation of the raw data. Protection from fire may include a smoke/fire alarm, fire extinguisher, sprinkler systems, and/or fire-proof cabinets/safes. Protection from theft may include home security systems, locks, and/or safes. Protection from damage may include restricting access to the site and implementation of pest control. It is desirable to have a disaster recovery plan in place describing how to limit and/or recover damage in case of calamities. Insurance (covering human injury, professional, and public liability) should be considered, and clarity between personal liability and employer liability should be defined.

4. Equipment: The SP requires an adequately functioning and maintained light microscope. Additional considerations are necessary for digital review of whole slide images. The SP is responsible for compliant use of a data-capture system. Some TFs/sponsors provide dedicated computers that have direct, secure access to the company server and data-capture programs for histopathology data entry via a virtual private network (VPN) or a similar secure, validated and compliant connection. Maintenance and/or performance qualification should be directed by TF/TS SOP. Access to an IT resource is helpful as electronic record management is an evolving area of GLP regulations. Awareness of network privacy and training to avoid hacking/phishing is critical to ensuring data security and may be included in the employee training record.

In addition, to maintain GLP compliance, the SP must have access to archive facilities and a QAU. At the end of a study, all study materials should be transferred to a GLP archive (as defined in the protocol and SOPs). Facility records should similarly be maintained under GLP archivist control. The SP must have access to a QAU, responsible for various duties (including study conduct, facility, and process-based audits) to help ensure that the study goes smoothly, is documented thoroughly, and follows all applicable GLP regulations.

• SP employed by the TF: The remote worksite may be assessed for compliance by TF QAU via on-site audits, questionnaires (including photographic documentation), and/or video calls. Remote audits evaluate requirements (as outlined by SOP) and demonstrate equipment function (such as VPN access). System-based audits may be performed by TF QAU, the frequency of which differs by TF and country. Study conduct audits may be performed if selected by the QAU.

• Organizationally distinct (consulting) SP: TF QAU may audit the TS of remote and organizationally distinct SP; sponsor QAU may also perform facility, process, and study conduct audits. An independent, contracted commercial QAU or company may conduct periodic facility or process-based audits for consultant SP as part of their company compliance plan.

For the most part, GLP activities and oversight are the same across countries; however, nuances of national GLP regulation are extensive, and the interpretation by national monitoring authorities (MAs) is evolving. National MAs inspect domestic facilities according to their country-specific regulations; additionally, each country’s MA may conduct joint mutual visits to TF/TS in other MAD countries, led by the host country. What follows are key learnings on national regulations applicable to the pathology phase of GLP studies that the authors are aware of. Performing peer review on GLP studies is out of scope for this discussion, but is also impacted by country-specific regulations and TF-specific policies.

The United States

In the United States, the FDA is responsible for assuring GLP regulations are followed, promulgated in Title 21 CFR Part 58: “Good Laboratory Practice for Nonclinical Laboratory Studies”, and subsequently amended. The EPA is responsible for assuring GLP regulatory standards are followed, promulgated in 40 CFR Part 792, pursuant to the Toxic Substances Control Act and Clean Air Act (Part 111), and 40 CFR Part 160, Part IV, pursuant to the Federal Insecticide, Fungicide, and Rodenticide Act. As described above, the United States will audit and inspect facilities but not certify for GLP compliance.

The United Kingdom

The UK GLP Monitoring Authority (UK GLPMA), part of the Medicines and Healthcare products Regulatory Agency (MHRA) enforces GLP requirements in-line with the OECD Principles. The UK GLP Compliance Monitoring Program will inspect TF/TS on a risk-based interval, approximately every 2-3 years, and issue a statement of GLP compliance. Within the UK if a TF pathologist is geographically remote from the TF, the MHRA interprets the remote worksite to be an extension of the TF, subject to periodic TF QAU monitoring and assessment in line with OECD advisory document 23 at the remote worksite ¹¹ . If the study pathologist is geographically and organizationally distinct from the TF, their premises could be considered a TS of a multi-site study, in line with OECD consensus document 13 for multisite studies ¹² . In this case, the SP would be required to join the UK GLP compliance program and be subject to UK GLPMA inspections (additional information on this process can be obtained from the MHRA GLP website). In addition to the SP’s CV and JD, mandatory annual continuing education (CE) to maintain licensure as a veterinarian is required in the UK. Additional hours of annual CE are needed to maintain specialist qualification as a pathologist. Records of CE are included in the SP GLP training files.

The Netherlands

The Health and Youth Care Inspectorate of the Ministry of Health, Welfare and Sport performs GLP inspections of TF and TS every 2 to 3 years, and the results are published on their site (https://english.igj.nl/). If the TF/TS is in compliance, a GLP endorsement statement is issued. Unlike other geographies, Dutch inspectors require a signed study report for review as a part of the site inspection. Therefore, when the SP is not employed by the TF, best practices include producing two original signed reports, one sent to the TF and one to be maintained in the SP’s archive for a period of at least 3 years. After this time, the second report is returned to the TF. If a TF accepts electronic reports, then only one signed report will be created and maintained in the archive of the SP.

Germany

Good Laboratory Practices requirements follow the German Law for Chemicals and are enforced by the German Federal Institute for Risk Assessment. Every three years, a consulting SP must apply for an official GLP site inspection to maintain his/her TS GLP certification. A list of TF/TS in the monitoring program of Germany in specialty fields of toxicology is published by the German Federal Institute for Risk Assessment (https://www.bfr.bund.de/cm/349/good-laboratory-practice-GLP-test-facilities-in-the-monitoring-programme–germany.pdf). To obtain certification, a TS must have an appointed “head” that is not the SP and a QAU. Similar to the United Kingdom, CE is required to maintain specialist qualification as a pathologist, and documentation of CE is included in the SP training files.

France and Other Countries

National GLP requirements are enforced by the Agence nationale de sécurité du médicament et des produits de santé in France, the Federal Office for the Environment (FOEN) and Swiss Medic in Switzerland, the Italian Ministry of Health in Italy, the Irish National Accreditation Board in Ireland and the Israel Laboratory Accreditation Authority in Israel. The authors are not aware of notable differences between OECD Principles and the national regulations of these countries.

Conclusion

It is our opinion that GLP-compliant histopathology (including light microscopic evaluation of glass slides, data interpretation, and report writing) may be successfully performed from a remote worksite. The SP must be keenly aware of national GLP regulations and those of the countries they work with. It is essential to comply with applicable regulations, the protocol, SOPs, and the TF/TS GLP program. When designing a GLP program, consulting pathologists should consider how they are going to comply with requirements for documentation of SP qualification, sample management, facilities, equipment, archive, and quality assurance. It is our opinion that a strong QAU and IT support are key to the success of a remote SP.