The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ) formed in 2010, and is an association
of more than 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 written by the IQ Consortium's GMPs in Early Development Working Group described the desire and rationale for more
clear and consolidated recommendations for GMPs in early development (Phase 1 through Phase 2a) (1). A consequence of the
absence of clarity surrounding early phase GMP guidances has been varied interpretation and application of existing GMP guidances
within different companies according to its own culture and risk tolerance. Internal debates often result in conservative
"one-size-fits-all" interpretations that rely on International Conference on Harmonization (ICH) guidelines that are mostly
relevant to commercial product development and do not distinguish differences in requirements between early development and
later stage development (Phase 2b and beyond). A key driver of this working group (WG), therefore, has been to collectively
define the minimum acceptable practices within the industry regarding GMP expectations in early development that allow for
added flexibility, are consistent with existing guidance and statutes, and which assure product quality and patient safety
The second paper in this series addressed recommendations for analytical method validation of both drug substances (DS) and
drug products (DP) (5). In this third article of the series, the authors address the application of GMPs in early development
as they pertain to drug-product manufacturing.
As noted previously in the introduction to the paper series, due to high attrition in early development, most companies try
to minimize the resource required to advance compounds into human clinical trials by employing simple formulations and manufacturing
processes (1). For example, drug substance filled in bottle, drug in capsule, or simple powder blends filled in capsule are
frequently used. Even for more challenging molecules, for example, those with low aqueous solubility, prototype formulations
designed to investigate bioavailability enhancement (e.g., amorphous solid dispersions, lipid-based drug delivery systems,
nanosuspensions) are evaluated in as simple a manner as possible. For example, on-site preparation at the clinic site of an
amorphous solid dispersion by weighing into a capsule, or by suspension in a suitable vehicle may be utilized instead of a
finished tablet or capsule dosage form. Whatever approach to formulation/process is taken, there is a need for flexibility
in manufacturing due to limited product and process understanding in early development.
Based on the collective industry experience of the members of this working group, the authors believe that pharmaceutical
companies could be making better use of available guidances as they pertain to drug-product manufacturing in early development.
This belief was reflected by the mixed responses to a survey of IQ member companies conducted in late 2011 (see Table I). Accordingly, in this article, the authors provide pragmatic recommendations related to GMP drug-product manufacturing focusing
on those areas where it is believed there is opportunity for added clarity and flexibility, without added risk to product
quality and patient safety.
Table I. Survey results of IQ member companies related to drug-product manufacturing in early development. A total of 10
Following a brief explanation of the role and importance of quality systems, the areas highlighted in this paper include facilities,
equipment, materials (receipt and approval for use), and batch documentation. Not covered is cleaning verification/validation,
as this is a topic that is addressed in detail in the industry (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 position, it is recognized
that each company needs to evaluate these recommendations for drug-product manufacturing practices based on individual business
needs and risk culture.