New bioanalytical quality standards initiative reduces risk

By Synomics Pharma

Over the course of the last year, Synomics Pharmaceutical Services has been leading the initiative to develop an industry acceptable guideline applicable to standardizing acceptable laboratory and quality management practices for Bioanalytical studies supporting clinical trials. Participating in the initiative are representatives from 8 of the leading Generic Pharmaceutical companies, accounting for a majority of generic activity in the United States, as well as a leading Washington Law Agency specializing in US FDA compliance. The initiative was born out of the industry wide recognition that neither the US FDA or EMEA regulation nor ICH harmonized guidelines address laboratory analysis in support of clinical trials.

The FDA and OECD good laboratory practices for non-clinical laboratory studies regulations clearly address the quality principles for safety studies prior to clinical trials. The FDA regulations for Bioavailability and Bioequivalence Requirements do provide that methods must be demonstrated to be accurate, sufficiently sensitive and have appropriate precision, but do not address any current thinking regarding quality principles beyond requiring that the drug products under consideration are manufactured according to appropriate levels of GMP. The collection of regulations that fall within the scope of FDA good clinical practices do not address quality systems or guidelines for laboratory studies, with the exception of 21CFR314 – applications for FDA approval to market a new drug, which requires that the non-clinical data is generated according to GLP regulations and the drugs are manufactured according to GMP regulations. The EMEA guidance on the investigation of bioavailability and bioequivalence, 140198en states that the studies “should be conducted according to the applicable principles of GLP, however, the studies fall outside the formal scope of GLP”. The recent FDA guidance on Bioanalytical Method Validation, and the subsequent AAPS/FDA Bioanalytical workshops, resulting in the whitepaper “Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays” represents the most proactive effort to address the existing regulatory gap for Bioanalysis supporting clinical trials.

Even with the recent efforts of the joint AAPA/FDA Bioanalytical workshops and publications, adequate guidance for the industry is still absent. The current methodology for Bioanalysis is not uniformly applied in labs, examples include the implementation of incurred sample reanalysis, repeat analysis and “event resolution” (investigation of unexpected or unforeseen circumstances, and the resultant corrective and preventative actions). The roles of Sponsor, Study Director and contributing scientists, as well as the role of the quality unit is not addressed in this publication, leaving the application of the “best practices” to the individual labs.

As a result of the inconsistencies in the application of the various regulatory standards and guidance documents, regulatory agencies have had to apply a higher level of scrutiny to the bioanalytical results submitted in support of NDA and ANDA submissions. Further, the lack of uniform application of the regulations and absence of clear guidance has resulted in inconsistent regulatory enforcement applied to studies and the organizations conducting the Bioanalysis for clinical studies. Until the industry has developed a coordinated approach to identifying and adopting the best practices for quality management systems applicable to the laboratory execution of clinical studies, the regulatory agencies will necessarily have to establish standards through the issuance of non-conformance reports and warning letters.

Synomics Pharma invited professionals working in Bioanalysis, Quality, Regulatory and Procurement, primarily from the Generic Pharmaceuticals industries, to participate in the initial phase of the initiative. Because of the high level of outsourcing by Generic Pharmaceutical companies for execution of the Bioavailability and Bioequivalence studies required for FDA marketing approval, Generic Pharmaceutical companies are most vulnerable to the inconsistent practices and applications of regulatory principles during the execution of the studies. The team assembled became the “expert working group” for this initiative, with the goal to develop an industry wide acceptable standard comprising the “best practices” and the principles of the regulations and guidelines.

The Bioanalytical Quality Standard Initiative under development is based on the quality management system that is fully, and effectively, implemented by Synomics Pharmaceutical Services, LLC. The Standard completely integrates the best practices from the core regulatory requirements of the FDA, GMP for drug products and medical devices, GLP and Bioavailability and Bioequivalence, as well as the ICH guidelines for quality, including recently adopted Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality Management). The quality standard also addresses the major issues noted in FDA warning letters and 483’s issued over the last couple of years; the top non-conformance relating to inadequate or failure to perform or complete event resolution (investigation along with appropriate corrective and preventative actions in response to unexpected for unforeseen circumstances). Other significant areas addressed in the Bioanalytical Quality Standard include the responsibility of Executive Management in the quality planning process and ongoing assessment and evaluation of the effectiveness of the quality system, through both internal auditing and annual review of key metrics and system indicators.

The format of the standard follows that provided by the ICH Q7A standard, providing guidance appropriate for a Bioanalytical Laboratory for each of the 19 sections. For example, each clinical trial is unique, and as such, the specific laboratory activities are best provided in a protocol that is specific to the study, reviewed and approved by a study director or project manager, the sponsor, and consistent with the principles of GMP, the quality unit. On the other hand, a Bioanalytical Laboratory should perform studies consistently, and standard operating procedures for development of the protocol, coordinating work flow through the laboratory, communication with the sponsor, resolving events and reporting results should be developed. In keeping with the principles of GMP and ICH, the quality assurance unit has greater responsibility for the development of the quality management system and for ensuring overall compliance with the system and the principles of the regulatory requirements; however, everyone has responsibility for quality and compliance to the quality management system. The quality unit is responsible for ensuring that events are resolved, and the study director is responsible for the investigation and the subsequent corrective and preventative actions that are implemented as a result of the event.

The primary objective when Synomics Pharma started the initiative was to develop a broad standard that would be adopted by the laboratories performing the analysis for the clinical trials, resulting in consistent approach and application of the best practices and principles of the regulations. Sponsor companies could expect comparable execution, data and results obtained from different laboratories. When required, sponsor companies could assess compliance against the standard in advance of contracting with the laboratory and potentially reduce exposure to risk. If appropriate, third party certification to the standard could be considered. An appropriate, comprehensive, industry accepted and adopted standard would contribute to more consistent enforcement by the regulatory agencies, moving the industry once again in the direction of self regulating to the highest quality standards and current “best practices”.

Ultimately, the goal of any increased control or standardization of the processes is to reduce risk, to both the company and the consumer. The clear guidance provided by this critical initiative moves in the direction of reducing risk while providing greater benefits. Studies executed under the guidelines established by this standard are expected to withstand the increased scrutiny by the agencies, provide process transparency and highest levels of accuracy and integrity in the results. This could, in fact, lead to reduction in the registration approval cycle due to fewer issues or concerns resulting from the bioanalytical results in the clinical trials.