The authors, part of the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium),
explore and define common industry approaches and practices when applying GMPs in early development. A working group of the
consortium aims to develop a set of recommendations that can help the industry identify opportunities to improve lead time
to first-in-human studies and reduce development costs while maintaining required quality standards and ensuring patient safety.
This article is the second in the paper series and focuses on method validation in early-stage development.
The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ) was formed in 2010 as an association
of over 25 pharmaceutical and biotechnology companies with a mission to advance science-based and scientifically-driven standards
and regulations for medicinal products worldwide. In the June 2012 issue of Pharmaceutical Technology, a paper was presented which described an overview of IQs consolidated recommendations from the Good Manufacturing Practices
(GMPs) in Early Development working group (WG) (1). The focus of this IQ WG has been to develop recommended approaches on
how to apply GMPs in early phase CMC development activities covering Phase I through Phase IIa. A key premise of the GMPs
in Early Development WG is that existing GMP guidances for early development are vague and that improved clarity in the definition
of GMP expectations would advance innovation in small-molecule pharmaceutical development by improving cycle times and reducing
costs, while maintaining appropriate product quality and ensuring patient safety.
A consequence of the absence of clarity surrounding early phase GMP expectations has been varied in interpretation and application
of existing GMP guidances across the industry depending on an individual company's own culture and risk tolerance. Internal
debates within a company have frequently resulted in inappropriate application of conservative "one-size-fits-all" interpretations
that rely on guidelines from the International Conference on Harmonization (ICH) that are more appropriate for pharmaceutical
products approaching the point of marketing authorization application. In many cases, erroneous application of these commercial
ICH GMP expectations during early clinical development does not distinguish the distinct differences in requirements between
early development and late-stage development (Phase IIb and beyond). A key objective of this IQ WG, therefore, has been to
collectively define in early development—within acceptable industry practices—some GMP expectations that allow for appropriate
flexibility and that are consistent with existing regulatory guidances and statutes (2).
As outlined in the previous introductory paper, the efforts of the GMPs in Early Development WG have focused on the following
four areas of CMC activities: analytical method validation, specifications, drug-product manufacturing, and stability. The
initial scope of these efforts has been limited to small-molecule drug development which supports First in Human (FIH) through
Phase IIa (Proof-of-Concept) clinical studies. A series of papers describing a recommended approach to applying GMPs in each
of these areas is being published within this journal in the coming months. In this month's edition, the authors advocate
for a life-cycle approach to method validation, which is iterative in nature in order to align with the evolution of the manufacturing
process and expanding product knowledge space.
A pharmaceutical industry collective perspective on analytical method validation with regard to phase of development has not
been published since 2004 (3). Genesis of the 2004 paper occurred during a set of workshops sponsored by the Analytical Technical
Group of the Pharmaceutical Research and Manufacturers of America (PhRMA) in September 2003. The referenced paper summarized
recommendations for a phased approach to method validation for small-molecule drug substance and drug products in early clinical
development. Although a few other reviews on method validation practices have been published (4), this paper provides a current,
broad-based industry perspective on appropriate method validation approaches during the early phases of drug-product development.
This broad industry assessment of method validation also uncovered the need to clearly differentiate the context of the terms
of "validation" and "qualification." Method qualification is based on the type, intended purpose, and scientific understanding
of the type of method in use during the early development experience. Although not used for GMP release of clinical materials,
qualified methods are reliable experimental methods that may be used for characterization work, such as reference standards
and the scientific prediction of shelf-life.
A perspective on some recent analytical method challenges and strategies, such as genotoxic impurity methods, use of generic
methods, and methods used for testing toxicology materials or stability samples to determine labeled storage conditions, retest
periods and shelf life of APIs and drug products are also presented. The approach to method validation described herein is
based on what were considered current best practices used by development organizations participating in the IQ consortium.
In addition, this approach contains some aspects which represent new scientifically sound and appropriate approaches that
could enable development scientists to be more efficient without compromising product quality or patient safety. These science-driven
acceptable best practices are presented to provide guidance and a benchmark for collaborative teams of analytical scientists,
regulatory colleagues, and compliance experts who are developing standards of practice to be used during early phases of pharmaceutical
development. The views expressed in this article are based on the cumulative industry experience of the members of the IQ
working group and do not reflect the official policy of their respective companies.