A Frequently Asked Question in Non-Clinical Development: Is there a Need for (Bio)Analytical Method Validation under GLP Conditions?
By Roman Goetz
Regardless if early, mid or late stage of pharmaceutical development: it is all about time, cost and quality. Given the plethora of uncertainties of development success, who may not want to strip off any “nice-to-have’s” for the sake of time and cost, particularly at early stage?
Here, we are discussing a question pertaining to analytical and bioanalytical methods that are used in pivotal nonclinical studies conducted under Good Laboratory Practice (GLP): it goes without saying that validated methods are needed for that purpose. However, a frequently asked question is if method validation also needs to be conducted in compliance with GLP (vs. GLP being a “nice-to-have” on that end). We are addressing this question separately for bioanalytics and for dose formulation analysis.
Bioanalytics: Validated Methods
The requirement for using validated
methods for analysis of bioanalytical samples from safety-relevant pivotal non-clinical studies is clear from the applicable guidance documents in the ICH geographies of Europe, the United States and Japan:
- Guideline on Bioanalytical Method Validation; EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2; EMA 2011
- Bioanalytical Method Validation; Guidance for Industry; FDA 2018
- Japanese Guideline on Bioanalytical Method Validation in Pharmaceutical Development (2013)
- ICH draft guideline M10 on bioanalytical method validation (Step 2b);
EMA/CHMP/ICH/172948/2019; March 2019
Furthermore, it is consensus that bioanalytical samples from regulatory relevant studies should be analyzed under GLP.
Need for GLP in Bioanalytical Method Validation
When it comes to the need for GLP for method validation, regulatory perspectives are different:
Under the EMA jurisdiction, the guideline on bioanalytical method validation states the requirement for GLP in that “[…] normally, the validation of bioanalytical methods used in non-clinical pharmaco-toxicological studies that are carried out in conformity with the provisions related to GLP should be performed following the Principles of Good Laboratory Practice
. Aspects of method validation not performed according to GLP should be clearly identified and their potential impact on the validation status of the method indicated. […]”.
The FDA guideline on bioanalytical method validation does not state a requirement for GLP. Conversely, the US legal framework states that GLP applies to “non-clinical laboratory studies” that are defined as “in vivo or in vitro
experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. […]” (Code of Federal Regulations (CFR) 21 Part 58, Section 58.3 (d)). A method validation study is in an obvious way not a study determining the safety of a test article. Thus, US-based bioanalytical labs are considered not to be in a legal position to claim GLP for method validation studies to whatever highest standards of quality they may be conducted. A typical compliance statement for a method validation in a US laboratory would indicate that the work does not fall under the scope of 21 CFR Part 58 but that the work was performed at a facility that follows GLP regulations.
Indeed, FDA’s Guidance for Industry: Good Laboratory Practices / Questions & Answers (FDA 1981 (editorial changes 1999 & 2007)) underpins that by answering the question: “do the GLPs apply to validation trials conducted to confirm the analytical methods used to determine the concentration of test article in animal tissues and drug dosage forms?” with “No”.
The Japanese guideline on bioanalytical method validation in pharmaceutical development does not state a requirement for method validation under GLP compliance either. Neither is such requirement stated in the ICH M10 draft guideline. With regard to the latter (ICH M10 (draft)), it might be assumed that a harmonized regulatory view might be adopted in that GLP will not be mandated for bioanalytical method validation. However, at current stage the EMA guideline stays different from FDA and Japanese regulations.
In summary, while according to current guidance, bioanalytical method validation should be conducted under GLP in the EMA jurisdiction, US-based bioanalytical laboratories should not formally claim the method validation as a GLP study as the studies do not fall under the definition of non-clinical studies to which GLP is applicable. Practical experience tells that, nonetheless, some US-based labs state GLP-compliance for their validation studies, while others do not. In any case, when performing a validation study with a US-based lab, care should be taken that validation activities are conducted following the bioanalytical method validation guideline and the principles of GLP, while formal GLP compliance might not be stated. With regard to regulatory submissions in Europe, for validation studies conducted in the US and in compliance with US regulatory framework, the formal absence of GLP claim does not pose a roadblock. ICH M10 may resolve the ambiguity on GLP-compliance in Europe vs. US.
Dose Formulation Analysis (DFA): Validated Methods
It is common understanding that methods for dose formulation analysis, supporting GLP studies, should be validated.
The expectation for analysis of study samples
of dose formulations (from GLP studies) is the same as for bioanalytics in GLP studies: it should be done under GLP. According to the “OECD GLP Advisory Document (No. 19) on the Management, Characterization and Use of Test Items” (ENV/JM/MONO(2018)6)), “there is an expectation that data on homogeneity, concentration and stability of the test item in a vehicle are generated in compliance with the Principles of GLP.” In line with that, according to the previously mentioned FDA’s Guidance for Industry: Good Laboratory Practices / Questions & Answers (FDA 1981), “the GLPs apply to the chemical procedures used to characterize the test article, to determine the stability of the test article and its mixtures, and to determine the homogeneity and concentration of test article mixtures.”
Need for GLP in DFA Method Validation
According to this same FDA’s Guidance for Industry: Good Laboratory Practices / Questions & Answers (FDA 1981), “the GLPs do not apply to the work done to develop chemical methods of analysis […].”).
It should be noted that validation of analytical methods for DFA is not specifically addressed in EMA guidance. Industry’s practice on DFA method validation, both in Europe or North America, is either way, being conducted under GLP compliance or not. Thus, GLP compliance might add a level of formal adherence to highest quality standards but is not an explicit requirement.
MC Toxicology Consulting has been engaged in many non-clinical programs so far. Regulatory compliance questions such as the ones discussed above are just one part of our broad experience in non-clinical development, toxicology and non-clinical regulatory strategies, ready to share with clients.
Take Home Messages:
- Bioanalytical samples from GLP regulated studies should be analyzed under GLP. The bioanalytical method should be validated.
- The expectations on method validation under GLP are different in the regulatory geographies of Europe, USA and Japan: EMA regulatory guidance requires validation under GLP. Conversely, under the US regulatory framework formal GLP compliance is neither a requirement nor a legally applicable attribute. Japanese guidance does not state a requirement for GLP either.
- Regardless, method validation should be conducted following GLP principles and highest quality standards in compliance with bioanalytical method development guidelines and should be formally conducted GLP-compliant when required by regional guidance.
- The requirements might be harmonized upon guideline ICH M10 coming into force.
Dose Formulation Analysis
- Dose formulation samples from GLP regulated studies should likewise be analyzed under GLP, using validated methods. A requirement for method validation under GLP is not stated in guidelines.