Stability studies to support early phase development
Early in development, pharmaceutical research organizations develop products with a primary focus on patient safety. Data
are generated at appropriate storage conditions to demonstrate or support the stability of the drug substance and product
to assure product quality through the clinical study period. Guidance documents are available to indicate the type of information
needed to support clinical trials (3, 6–8). Although ICH stability guidelines outline the stability data needed to support
storage conditions and shelf life for commercial submissions, these guidelines are not applicable to early stages of development
when less is known about new drug substances and products (9). However, there must be appropriate data to support storage
of the products being proposed for clinical use.
If a product is intended for human use, the concepts of cGMPs apply. For stability, this application often results in a written
stability study plan or protocol, fit-for-purpose test methods, traceable and reliable documentation, and appropriate SOPs.
Most compounds in early development end up being discontinued, for safety and/or efficacy issues and/or inadequate commercial
viability. Therefore, efficiently assuring the quality of products being used in early human clinical trials is a challenge
facing every pharmaceutical research organization involved in early trials. The common challenges faced in supporting drug
substance (also referred to as API) and drug-product stability are discussed here. The authors offer some risk-based approaches
for collecting data for small molecule, solid oral dosage forms used in Phase 1 and Phase 2a clinical trials, in hopes of
guiding companies and health authorities towards harmonized strategies and best practices.
In early phase development, CMC requirements include generation of appropriate stability data at suitable storage conditions
to support filing the IND (or IMPD/CTA) and use of the clinical material through the end of the clinical study. These scientific
and regulatory objectives for stability must be met while at the same time minimizing nonvalue-added operational expenses.
Several factors from a business, regulatory, and scientific perspective need to be taken into account when designing early
phase development stability studies:
- The risk tolerance of the sponsoring organization and their approach to the scientific mitigation of the risks.
- The inherent stability of the drug substance or product, and prior product, process and stability knowledge.
- The regulatory environment in the countries where the clinical trial will be conducted. For example, some countries may request
stability data on multiple batches or actual clinical batches or may not accept extrapolation to justify use-date assignments.
- The projected future use of the product. Development teams may have some idea of the likelihood that a project will continue
into Phase 2b. If a product is expected to be used for many months or multiple years through several development phases, then
a use-date extension proposal based on additional long-term data may be necessary and further knowledge gathering may be warranted
(3). This information may influence the scope of the initial stability study in the form of additional time points, additional
conditions, and/or additional tests.
Considering these factors, the industry must work to balance the perceived expectations of the regulators in the countries
where clinical trials will be conducted using a science- and risk-based approach to generating and providing stability data
in the regulatory filings.
Discussed in this article are recommendations with regard to generating stability data for drug substance and solid oral dosage
forms used for Phase 1 and Phase 2a (early phases of development). This paper presents a framework and guiding principles
to this end. The examples presented are not meant to be a "how to" guide, but rather illustrations of the principles being
discussed. Other study designs and conditions may also be feasible with the appropriate justification.
The product development efforts for early clinical supplies often are simple formulations with limited development history.
The early small-molecule oral products can be placed into one of two categories: drug-substance (DS) based products and formulated
products. DS-based products include the use of neat DS (e.g., powder-in-bottle [PIB], powder-in-capsule (PIC), or DS shipped
in bulk to clinical sites for on-site compounding). These products almost always have the same stability characteristics as
the bulk DS, and DS stability data may be used to support the product use dating. Formulated products can be powders formulated
with excipients, capsules filled with formulated granulation, or a tablet formulation. These formulations take more effort
and are normally used because of a specific clinical need, a shortcoming of the DS-based product, or a desire to use the same
formulation in Phases 1 and 2 studies. In most cases, they will be fairly simple formulations meant to have a short lifecycle.
If the product advances further into development, more elegant formulations will need to be developed. Not covered in this
paper are formulations that are extemporaneously prepared at the clinical site. These formulations are consumed quickly and
long-term stability studies are not warranted.
In the following sections, DS and drug product (DP) stability considerations for early development are discussed.