1. What are the responsibilities of Test Facilities (TF) and sponsors with respect to overseeing the work and ensuring the qualifications of the full range of GLP service providers / subcontractors (e.g. those who supply commercial assay kits to Contract Research Organisations (CROs))?
The sponsor’s responsibilities for provided services are described in OECD Advisory Document No 11 (The Role and Responsibilities of the Sponsor in the Application of the Principles of GLP) and in the OECD GLP Principles Document No 1 paragraph 2.2, point no. 5. If a sponsor is a test facility, the test facility management’s obligations also include assessing the supplied services. (Posted on 28 February 2018).
2. Some TF activities may be performed by external suppliers (e.g. IT services, eArchive, metrology, computer system validation). What are the responsibilities of TFs with regard to these types of suppliers when these suppliers are not GLP certified (i.e. the suppliers are not included in a national GLP compliance monitoring programme)?
Test facility management has overall responsibility to ensure that the facilities, equipment, personnel and procedures are in place to achieve and maintain the validated status of computerised systems in order to establish “GLP compliant” study results. This includes the responsibility for internally as well as externally provided services (e.g. third parties, vendors, internal IT departments, service providers including hosting service providers). Depending on the provided services, a supplier’s facility need not be part of a GLP compliance monitoring program or conform to GLP regulations, but it must have a documented quality system verified as acceptable by test facility management with input from its quality assurance unit. (Posted on 28 February 2018)
3. Do the responsibilities of a TF include IT facilities/services and archive/e-archive facilities?
Elements of a Test Facility such as IT services and archives can be an integral part of the Test Facility or be outsourced by written agreements. Test Facility management should have an overview of all suppliers relevant for IT services. Electronic archiving is a GLP relevant service (OECD Document No 17, paragraph 34, 109 – 118 and OECD Document No 15). It is the responsibility of Test Facility management to evaluate the service and to estimate risks to data integrity and data availability. (Posted on 28 February 2018)
4. What are the roles and responsibilities of a TF and IT provider when GLP data are retained by an IT provider that is not part of a GLP monitoring program?
Written agreements (contracts, service level agreements) should define roles and responsibilities within a relationship between Test Facility management and a supplier (OECD Document No 17, paragraph 34). A documented risk-based approach should be used to assess suppliers providing a GLP-relevant computerised system infrastructure, platforms, or software to a test facility.
Vendor assessment is the responsibility of Test Facility management and may result in an audit of a supplier. Vendor assessment should be properly scaled, based upon a risk assessment and be performed by suitable personnel (input from the Test Facility management‘s quality assurance unit may be considered). The assessment should estimate risks to data integrity. (Posted on 28 February 2018)
The answer to questions 5 and 6 are detailed below question 6:
5. What are the responsibilities of a TF when third parties subcontract non-GLP hosting services with data acquisition systems used in GLP studies (e.g. data storage such as “e-archiving as a service”)? What is considered acceptable?
6. If a data centre uses an IT service provider to only provide infrastructure for the data centre (e.g. space, power, controlled environmental conditions, etc.) or hosting servers of a contracted GLP test facility (i.e. access to the GLP data is only possible via the Test Facility), is this data centre considered to be part of the TF (and not a third party)? Would such a data centre need to be part of the test facility audits?
Hosted services (e.g. platform, software, data storage, archiving, backup or processes as a service, cloud computing etc.) should be treated like any other supplied services (OECD Document No 17, paragraph 39). Written agreements are required which describe the roles and responsibilities of each party and proper documentation to ensure adequate risk control and risk mitigation. Uncontrolled use of hosted services may carry risks to integrity, availability, ownership, and confidentiality of data and may not be acceptable.
The need for, and extent of, vendor assessment should be based upon a risk assessment taking into account the complexity of the computerised system and the criticality of the business process supported by the computerised system. The need for an audit should also be based on a documented risk assessment. It is test facility management's responsibility to justify the requirement for and type of audits based on risk. (Posted on 28 February 2018)
7. Should an IT service provider that offers software as a service be considered a TF and therefore be included in a national GLP compliance monitoring programme?
Whether or not an IT service provider is considered to be part of a test facility by a GLP compliance monitoring authority will depend on various factors including the extent of the service provider’s involvement in GLP studies. If they are part of a test facility then the GLP compliance monitoring authority may also decide that they will be subjected to GLP inspections.
Depending on the services provided, audits by test facility management may be necessary for the contracted IT service. These may include the assessment of its computerised systems management, in general, and of the specific computerised systems, where such systems impact a study (e.g. risk assessment, validation approach and qualification). Suppliers are addressed in detail within OECD Document No 17, paragraphs 34 – 40. (Posted on 28 February 2018)
1. Is it possible to harmonise retention times for archived records?
Retention period harmonisation across countries is not anticipated given that the periods “defined by an applicable regulatory authority” are based on: country-specific legal requirements of the registration receiving organisation, the nature of the specific GLP program (human health, animal health, agricultural chemicals, GMO etc.) and approaches aimed at minimising burdens on the regulated industry.
Study records must be retained in compliance with the requirements of receiving authorities. Study records and other supporting material should be retained for as long as regulatory authorities might request GLP audits of the respective studies. (Posted on 28 February 2018)
2. What are the responsibilities of TF management with respect to support records?
See sections 4.2 and 7.2.2 within OECD GLP Document 15 “Establishment and Control of Archives that Operate in Compliance with the Principles of GLP” (2007).
GLP records and materials include both the study and the facility records. Facility records (support records, or related records and materials) would include non-study specific records such as equipment maintenance, staff training, organisational charts, SOPs, Master Schedules, Quality Assurance inspections, validation for computerised systems, environmental monitoring, and archiving processes (record transfers, specimens or electronic media disposals). (Posted on 28 February 2018)
1. How should hosted services (“cloud” computing) and the retention of electronic data be treated in the context of GLP.
Hosted services (cloud services, e.g. platform, software, data storage, archiving, backup or processes as a service) should be treated like any other supplier service and require written agreements describing the roles and responsibilities of each party. It is the responsibility of test facility management to evaluate the relevant service and to estimate risks to data integrity and data availability. Test facility management should be aware of potential risks resulting from the uncontrolled use of hosted services. (OECD Document No 17, paragraph 39). Written agreements (contracts) should exist between the test facility and the supplier. These agreements should include clear statements outlining the responsibilities of the supplier as well as clear statements about data ownership. (OECD Document No 17, paragraph 34) (Posted on 28 February 2018)
2. For some national GLP compliance monitoring programmes, it is acceptable to archive electronic data in a primary database with the use of appropriate access rights (i.e. read only permission for the study director / the study staff/QA and full rights for the archivist etc.). For other national programmes, data can be physically transferred to another location or to a storage medium (also with the corresponding access right modifications) for archiving. Are both acceptable?
Archived electronic data should be protected physically and logically in order to meet the requirements of a GLP archive. Electronic data should be accessible and readable, and its integrity maintained, during the archiving period (OECD Document No 17, paragraph 112).
Electronic records may be moved from the production part of a computerised system to a discrete, secure archive area on the same computer system (e.g. physically separated file record systems), or explicitly marked as archived (e.g. logically separated database record systems). Records should be locked such that they can no longer be altered or deleted without detection. Records archived in this way must be under the control of a designated archivist and be subject to equivalent controls to those applied to other record types (OECD GLP Document 15 Section 8.3). (Posted on 28 February 2018)
3. If a GLP inspector requests information retained in an archive, can a test facility respond by retrieving electronic records from a company’s global electronic archiving system (physically located in another country)?
The response would be satisfactory as long as all required records can be retrieved from the archive. All electronic records should be verifiable on screen in human readable format and retained (OECD Guidance Document 17, paragraph 79).
The GLP Principles for archiving must be applied consistently to electronic and non-electronic data. It is therefore important that electronic data is stored with the same levels of access control, indexing and expedient “retrieval” as non-electronic data (OECD Guidance Document 17, paragraph 110).
Electronic data should be accessible and readable, and its integrity maintained, during the archiving period (OECD Guidance Document 17, paragraph.112). (Posted on 28 February 2018)
4. Would such global archives need to be declared by each test facility to their national GLP compliance monitoring authority?
The use of a global archive should be included in the appropriate SOPs. Test Facility SOPs must define and describe the archive facilities and processes, including contracted archiving services or storage at a different physical location. Routine Quality Assurance inspections and audits should be conducted of the services provided.
In the event of the closure of a test facility or an archive contracting facility, any data transfer to an archive within another country should include informing both GLP monitoring authorities in order to ensure the coverage by the GLP compliance monitoring program if required by that country [OECD Guidance Document 15 Section 11]. (Posted on 28 February 2018)
1. Which Test Facility “area of expertise” should be used for Biologicals/GMOs?
GLP studies on biologicals/GMO test items that are currently performed in accordance with the OECD Principles of GLP can be assigned to one of the existing nine areas of expertise, as defined in the OECD Guidance Document No. 2 - “Guidance for GLP monitoring authorities - Revised Guides for compliance monitoring procedures for GLP“, Appendix to Annex III, No. 4.
These areas of expertise are of a general nature and can be used for many product types (e.g. industrial chemicals, pharmaceuticals, plant protection pesticides etc.). In general, a product type will not have a specified area of expertise.
The existing areas of expertise are therefore sufficient to also describe studies conducted using biologicals/GMOs which may be either in vivo, in vitro or concern environmental toxicity, behaviour in the environment or bioaccumulation. There may also be GLP studies on safety testing of biologicals/GMOs (e.g. of gene therapy medical products).
The area of expertise No. 9 - “Other, specify“ is being increasingly used to specify study types in connection with molecular biology, genetic engineering or GMOs (e.g. cell-based systems for the detection of biological parameters, bioactivity testing, immunogenicity testing, patch clamp test, cell culture based biocompatibility test, test for microbial contamination, DNA sequencing for genotyping, etc.).
Biologicals/GMOs are a new test item type, albeit different to conventional chemicals, however GLP studies on biologicals/GMOs are neither a specific type of GLP study nor a specific area of expertise. They are no different to other “new” products such as nanomaterials or medical devices. It is therefore reasonable to regard biologicals/GMOs as just another product type. (Posted on 28 February 2018)
2. Should new OECD Test Guidelines be developed for Biologicals/GMOs?
In every area of expertise listed in the OECD Guidance Document No. 2 - “Guidance for GLP monitoring authorities - Revised Guides for compliance monitoring procedures for GLP“ Appendix to Annex III, No. 4 - there may be many kinds of studies that can be performed. For example, the area of expertise No. 2 - “Toxicity Studies” - includes studies conducted using the OECD Test Guidelines No. 401- 453, listed in Section 4 “Health Effects“.
The development of new OECD Test Guidelines for specific tests involving biologicals/GMO may help to reduce the use of area of expertise No. 9 - “Other, specify“. However, the OECD Working Group of the National Coordinators of the Test Guidelines Programme (WNT) is responsible for the development of Test Guidelines, not the OECD Working Group on GLP.
Biologicals/GMO can be listed in the table indicating the scope of a national GLP compliance monitoring programme and it is not necessary to create additional areas of expertise for one product type.
The OECD Advisory Document No. 14 - “The Application of the Principles of GLP to in vitro Studies“- is very comprehensive and applicable to biologicals/GMO. The revised OECD Advisory Document on the Characterisation of Test Items – currently under development - will also address some specific aspects of biological test items. (Posted on 28 February 2018)
3. Are Biologicals/GMOs test items or test systems?
Biologicals/GMOs can serve both as a test item and as a test system, depending on the circumstances, and this distinction can only be made on a case-by-case basis. For example, there are studies in which a GMO is used as a test system for characterising properties of a chemical test item, e.g. an Ames test under area of expertise No. 3 - “Mutagenicity testing“.
There are also other studies in which biologicals/GMO, or parts thereof, are used as test items such as when environmental or health effects of a biological/GMO are being investigated. Some other examples include wild-type biological agents in virus validation studies, environmental fate studies of a GMO product and feeding studies. Another example of a biological/GMO being used as a test item would be in a study to determine the concentration of a known gene product of a transgenic sequence.
The identification of the test item is one of the pivotal aspects of GLP studies. Due to the biological nature of such test items (e.g. stem cells or viral vectors) the unequivocal identification may require a more complex analysis than for a chemical substance. Nevertheless, the characterisation of a biological test item would not qualify for a new area of expertise.
It should also be noted that it is not within the remit of the OECD Working Group on GLP to give guidance on the expectations of regulators with regard to biologicals/GMOs. The national/local receiving authority should be contacted regarding this. It is however acknowledged that some countries have established rules on the content of dossiers for the authorisation of novel foods or GMO (e.g. Regulation (EU) Nr. 503/2013 of the European Commission). (Posted on 28 February 2018)
1. Why are there still inconsistencies in the way different national GLP compliance monitoring programmes inspect multi-site studies?
Where inconsistencies continue to arise, these may be the result of a country’s specific regulatory requirements and should be discussed with the Compliance Monitoring Authority (CMA) concerned. (Posted on 28 February 2018)
2. How should the frequency of QA audits be determined?
The OECD GLP Principles require that every study plan is verified by QA and every report audited. A definitive frequency for other audits is complicated as it will depend on many factors including: the different types and number of studies conducted, the complexity of a study, staff, etc.
When developing the QA Program, facilities may wish to apply any relevant quality assurance tools such as corrective and preventive action processes and risk based auditing. (Posted on 28 February 2018)
3. How can the GLP compliance status of a test facility or test site be checked?
Many CMAs have publicly available information with details of facilities that are in their GLP programs. (Contact points for national CMAs can be found here.) Some CMA’s also issue GLP certificates; however, this is not a requirement of the Principles. (Posted on 28 February 2018)
4. What is a physical/chemical test system?
The OECD GLP Principals define a physical/chemical test system as an “apparatus used for the generation of physical/chemical data”. It is the equipment or apparatus to which the test item or reference item is applied during the conduct of a study. Due to the number of different types of studies that are conducted, a complete list is not possible. However, some examples of physical/chemical test systems which may be used to evaluate the physical/chemical properties of a test item may include basic equipment such as pH meters, spectrophotometers and other analytical equipment and/or highly sophisticated and complex equipment such as gas chromatography–mass spectrometry, or those which utilise amplification and analysis of genetic material. (Posted on 28 February 2018)
5. Is there a standard format and content for the Study Director’s statement?
The OECD GLP Principles only require that the statement clearly describes what aspects of the study have been conducted in accordance with the Principles (or not) and, where applicable, what other standards/ guidelines were used (if the Principles were not). It should be noted that some CMAs may also have their own requirements due to national requirements. (Posted on 28 February 2018)
6. Can GLP studies be done in facilities that utilise other quality standards (GMP, GCP, ISO etc.)?
The implementation of other standards within a facility (cGMP, GCP etc.) should not preclude the use of the OECD GLP Principles within that facility. Most quality standards contain requirements which are compatible with the OECD Principles. Test facility management must ensure, however, that for any GLP studies that are conducted, the OECD GLP Principles are fully adhered to. Sponsors who commission the study with the CRO should also be aware of their role in ensuring that the facility complies with the Principles for GLP. (Posted on 28 February 2018)
1. Do software programmes which have been developed by outside vendors or academia to support calculations by test facilities using an OECD Test Guideline, and are referenced in OECD Test Guidelines, need to be validated by test facilities?
It is important to note that use by test facilities of the software programmes for these Test Guidelines is voluntary. That is, a test facility is not required to use the programmes to complete a test. However, if a test facility uses such a programme it must have the appropriately scaled validation documentation of risk assessment, user requirement specifications, acceptance testing records, and a listing in the computerised systems inventory.
Currently, software programmes have been developed for four OECD Test Guidelines:
While these software programmes were not developed by OECD, they are referenced in the Test Guidelines, and can be downloaded for free on the OECD public website. These software programmes are provided as a courtesy of the developers of the test methods, but have not been validated, reviewed or approved by OECD. The developer, and not the OECD, should be described as the supplier of the software. In addition, the maintenance of the software or of the calculation sheets is not guaranteed by OECD.
If a test facility does use one of these products, and if that facility wishes its test results to be compliant with OECD GLP, it must follow the guidance as described in Advisory Document 17 Application of GLP Principles to Computerised Systems.
These software programmes are considered “Commercial Off-The-Shelf products (COTS)”, as described in OECD Advisory Document 17. Therefore, they require appropriate validation depending on the risk and the complexity of any customisation. If an application (e.g. a spreadsheet) is not complex, it might be sufficient to verify functions against user requirement specifications. In addition, user requirement specifications should be written for any application that is based on a COTS product. Documentation supplied with a COTS product should be verified by test facility management to ensure it is able to fulfill user requirement specifications.
A test facility should perform a validation of a COTS software programme to ensure that it meets their needs, depending on prior validation by the provider. There must be documentation from the supplier that they have done the validation. Documentation must be available on the validation performed by the test facility.
Therefore, if a test facility uses one of the software programmes to support data intended for a regulatory submission or to support a regulatory decision, and a validation has not been conducted by the vendor or documentation to support that validation is not available, there would be an expectation that the test facility would perform a full validation to ensure that it meets their needs as described in Advisory Document 17. Even if a validation has been conducted by the vendor, and documentation exists, it is still the test facilities' responsibility to determine whether that is sufficient and, thus, further validation is not necessary. As mentioned above, the extent of the validation would likely depend upon prior validation (and documentation to support such a validation) as well as adaptation by the test facility (configuration) to meet their individual needs. And, if the user modifies the software programmes (customisation), there would be an expectation that the test facility would perform a full validation to ensure that it meets their individual needs. Documentation must be available on the full validation performed by the test facility.
Software programmes available for Test Guidelines on OECD's Public Websites:
(Posted on 27 March 2017)
1. Section 2.5 of OECD Advisory Document Number 16 (Guidance on the GLP Requirements for Peer Review of Histopathology) indicates that all correspondence regarding the histopathological evaluation of the slides used for peer review between the sponsor and the representative of the test facility and the peer reviewing pathologist should be retained in the study file. Could the interpretation of this requirement be clarified?
The clarification is as follows: Correspondence refers to any communication that is needed to reconstruct how slides were selected and reviewed. This should include communications regarding the interpretation of any observations (preliminary or final) on adverse or non-adverse effects made during the review.
(Posted on 27 March 2017)
2. Section 2.8 of OECD Advisory Document Number 16 (Guidance on the GLP Requirements for Peer Review of Histopathology) indicates that where the peer reviewing pathologist’s findings were significantly different from the original interpretation of the study pathologist, a description of how differences of interpretation were handled and changes made to the study pathologist’s original interpretation should be discussed in the final report. Does this apply to both retrospective and contemporaneous peer review?
The clarification is as follows: Section 2.8 relates specifically to a retrospective peer review. For a contemporaneous peer review, there is an expectation that all correspondence (letters, e-mail etc.) relating to differences in the interpretation (preliminary or final) of slides between the original pathologist and the peer reviewing pathologist which may impact on the conclusions of the study (e.g. NOEL/NOAEL) are to be retained in the study file.
(Posted on 27 March 2017)
The OECD Principles of Good Laboratory Practice (GLP) provide provisions for errors in the final report to be corrected and admissions to be addressed by issuing a study report amendment. However, it would not be appropriate to use a study report amendment to facilitate the reanalysis of data or add new data to a final report except under exceptional circumstances.
Exceptional circumstances will include requests from receiving authorities to reopen a GLP study. Such requests are usually made so that data can be reanalysed. For example, studies may be reopened to reassess statistical analyses or to review histology findings.
Monitoring authorities will usually not allow a study to be reopened if the test facility or study sponsor wants to reanalyse or add data. However, most monitoring authorities will assess each request to reopen a study on a case-by-case basis.
If a GLP study is reopened, any changes to the original text or the addition of new text must be presented in the form of a report amendment. All the original data must be retained in the final report and the reason for reopening the study should be documented in the amendment. If additional work is performed that was not required in the original study plan, it should be covered by a study plan amendment.
As detailed in Section 9, Part 9.1 (5) of The OECD Principles of GLP, reformatting of the final report to comply with the submission requirements of a national registration or regulatory authority does not constitute a correction, addition or amendment to the final report (posted on 21 January 2016).
The early termination of a study may occur prior to, or after, the completion of the experimental phase of the study, but before the data has been assessed or incorporated in a final report. In both situations, a study plan amendment must be produced in order to provide an explanation of why the study was terminated. Some compliance monitoring authorities may expect that the key findings up to the point of termination are summarised and that the summary report is subject to a Quality Assurance (QA) audit (posted on 21 January 2016).
There is no requirement to finalise the validation of all methods that will be used to conduct a GLP study before the initiation of the study. However, there is an expectation that methods are fully validated before the results of the study are considered to be valid (posted on 21 January 2016).
Unless stipulated in national regulations, there is no requirement to perform method validation in compliance with GLP. Since parameters of the validated method are used in the GLP study (for example threshold, linearity, accuracy, precision, stabilities, equipment settings, etc.), data should be accurately recorded and stored in a manner that protects its integrity. Validation data may be required for study reconstruction and, consequently, it should be retained for an appropriate period of time.
The quality assurance statement should clearly identify the study and include all the types of inspections that are relevant to the study (including inspections performed as part of a study phase(s)). Associated information should include the dates the inspections were performed and the dates inspection results were reported to management, the study director and if applicable the principal investigator. Some monitoring authorities will require the quality assurance statement to include confirmation that facility audits have been performed.
The statement should confirm that the final report reflects the raw data and some monitoring authorities will require this fact to be clearly stated in the statement.
Verification of the study plan by QA personnel should be documented (see OECD Principles on Good Laboratory Practice, Doc. No. 1). This would also apply to study plan amendments. The GLP Principles do not formally require that these verifications are included in the quality assurance statement but this is often the case (posted on 15 July 2014).
The OECD Principles on GLP (Section II, Par. 2.2.1.f) require QA personnel to sign the statement. The Principles do not restrict this responsibility to specific QA employees such as, for example, the manager of a QA department. However, the procedures for compiling the statement and the responsibility for signing the statement should be described in QA procedures (posted on 15 July 2014).
As is the case for all operative procedures covered by the GLP Principles, the QA programme of inspections and audits should be subject to management verification. What constitutes verification will differ from one monitoring authority to another. In some cases verification will include a requirement for the independent inspection of QA activities. In all cases both QA staff and management should be able to justify the methods used for the conduct of the audit programme (posted on 15 July 2014).
National GLP monitoring authorities may request information relating to the types of QA inspections conducted and the dates they were performed and reported to management. They may also request the names of the QA auditors who performed specific activities so that their training records can be reviewed. However, QA inspection findings will not normally be examined by inspectors as this is likely to have a negative impact on the way in which some QA personnel report findings. Nevertheless, some national monitoring authorities may occasionally require access to the contents of inspection reports in order to verify the adequate functioning of QA or to verify that management has received and acted upon reports from QA concerning problems that are likely to seriously affect the quality or integrity of the facility or a study.
Under no circumstances should QA reports be inspected as an easy way to identify inadequacies within the facility or problems associated with a specific study.
Compliance monitoring authority inspectors will need to verify the effectiveness of QA activities as part of the inspection of QA. In order to do this it is highly likely that they will routinely review QA procedures and other supporting records (with the exception of the inspection report). These documents will be used to verify key requirements including the independence of QA from study specific activities, that critical study phases are monitored in accordance with the facility’s policies and that the frequency of audits is sufficient etc. (posted on 15 July 2014).