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 fifth paper in the series and focuses on specifications.
The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium) 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 previous issues of Pharmaceutical Technology, papers written by the IQ Consortium's "GMPs in Early Development Working Group" described the desire and rationale for more
clear and consolidated recommendations for Good Manufacturing Practices (GMPs) in Early Development (Phase 1 through Phase
2a) (1–4). In this issue of Pharmaceutical Technology, the IQ Consortium presents a proposal for the analytical assessment and control of both drug substances (DS) and drug products
(DP) in early development specifications. These recommendations take into consideration the differences in clinical trials
in early development versus those in later development and provide a starting point to stimulate discussion on specifications
in early development.
Previous industry position(s) on the topic of science-based specifications have not addressed early development needs or differentiated
the role of specifications in early versus late development (5). During preclinical and early development, the primary focus
is to progress the product into the clinic for safety and preliminary efficacy assessment. Due to the high attrition rate
in early development, consistent specifications that ensure patient safety are desirable. During late development, specifications
evolve as the clinical focus expands from safety to include efficacy, and as the product and corresponding synthetic and formulation
process undergo significant transformations (e.g., synthetic route changes during scale-up, evolution of dosage forms from
fit-for-purpose to robust formulations and processes suitable for commercial manufacturing). Therefore, early development
specifications should also focus on those tests and acceptance criteria determined to be critical for the control of product
quality with an emphasis on patient safety and supported by preclinical and early clinical safety studies.
Based on the cumulative industry experience of the members of this IQ working group, the authors of this paper have proposed
standardized early phase specification tests and acceptance criteria for both DS and DP, which are discussed herein. In addition
to release and stability tests, consideration is given to internal tests and acceptance criteria that are not normally part
of formal specifications. These tests can be performed to collect information for product and process understanding, or to
allow for tighter control (i.e., target criteria tighter than the release testing criteria), to ensure product quality will
be maintained throughout the product's retest period. Based on the information obtained in early development, additional tests
and acceptance criteria for other attributes (e.g., water content) can be included as the late development focus shifts to
process and product performance and consistency; eventually aligning with the available ICH guidelines (6).
The scope of this position paper has purposely been limited to traditional small molecules that are formulated into solid
oral dosage forms intended for US regulatory filings with the desire to build consistency across all worldwide regulatory
regions. However, it is believed that the concepts presented can be easily adapted to other dosage forms and routes of administration.
Although designed as an industry proposal, it is recognized that each company needs to evaluate these DS and DP specification
recommendations based on their individual business needs.