The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium) is an association of
pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals
through scientifically driven best practices and standards. The consortium seeks to contribute to the improvement of the safety
and efficacy of pharmaceuticals for patient benefit. The consortium was formed in early 2010 with the goal of collectively
addressing the scientific, technical, and regulatory challenges facing the development of both small- and large-molecule derived
medicines. The advancement of global, science-based and scientifically driven standards and regulations is a key enabler towards
achieving this goal.
Current industry practice and CMC standards
An overarching driver during all phases of drug development is assuring product quality to minimize risk to patient safety
during clinical assessment. During the late stage of development, Chemistry, Manufacturing, and Control (CMC) efforts focus
primarily on the establishment of processes and controls that have been demonstrated to continually meet the target product
profile for the new drug, thereby underwriting its continued safety, efficacy, and quality throughout the commercial lifecycle.
This development knowledge is summarized in the documentation assembled to support the commercial license.
A large body of guidance and recommendations exist to clarify the associated regulatory requirements at the time of submitting
the commercial marketing application. For example, International Conference on Harmonization (ICH) consensus guidelines and
extensive regional regulatory guidance all provide clear expectations, in particular, on how the critical attributes of the
commercial product should be identified, understood, and controlled (1). Similarly, FDA guidance on the CMC requirements to
support Phase 2b/3 clinical studies, which aim to demonstrate the long-term safety and efficacy of the new drug in the targeted
patient population, provides clarity on these late phase expectations (2). ICH guidance on the application of GMP for APIs
provides clarity on specific information required for the manufacture of new drug substance for investigational clinical use,
which may be applied to earlier clinical phases (3).
From an industry perspective, it is common to consider the "early" phase of development as covering Phase 1 and 2a clinical
studies. During this phase, there is a high rate of product attrition and a high probability for intentionally introducing
change into synthetic processes, dosage forms, and the corresponding analytical methods and specifications. For example, simple
clinical formulations may be employed during Phase 1/2a that are not intended for the commercial dosage form, but instead
are utilized primarily to demonstrate safety and initial proof of concept in the clinic. In addition, these early-stage fit-for-purpose
formulations may provide valuable information relating the physico-chemical properties of the drug substance to in vivo pharmacokinetic performance, which in many instances is used to design formulations for late-phase clinical studies and commercial
use. Likewise, some information generated from scale-up and characterization of the drug substance can contribute to the overall
drug substance knowledge base. This formation and collection of knowledge is consistent with the concepts of the quality by
Developing an understanding of the scope and extent of CMC information required and how GMP is applied during this early stage
of development continues to be discussed across the industry. Consulting available guidance is the first step towards this
understanding. Activities carried out in support of early development are clearly not in the scope of the ICH guidance, as
clarified in the preamble introducing these documents. A rare exception of current regulatory guidance that clarifies compliance
expectations during the early phases of development is the FDA guidance on defining GMP requirements for manufacturing and
testing of materials intended for early clinical use (4). Some insight on CMC activities associated with the early phase of
product development can also be gleaned from historical guidance on the content of regulatory documents for Phase 1 clinical
studies (5). Because many aspects of the Phase 2a clinical studies that follow on from a successful Phase 1 program are similar
in their scope and expectations, the opportunity exists to formally make this comparison and clarify whether these approaches
and expectations can be aligned across early phase studies. The authors strongly believe that additional clarity regarding
best practices related to the application of GMPs in early development would greatly assist worldwide regulatory agencies
in adapting consistent expectations for the content of original INDs and other early regulatory documents.