Assay: An assay specification of 90.0–110.0% is normally attainable and controllable for most tablet and capsule formulations used in early development and ensures dosage integrity and patient safety. Additionally, this acceptance criteria provides reasonable formulation process control while accounting for typical assay variability and formulation inconsistencies in early development given the higher levels of impurities/degradation products normally observed at this stage.

Impurities and degradation products: Similar to the earlier proposal for DS, it is proposed that identification and qualification thresholds of three times those listed in ICH Q3B guideline (regardless of maximum daily dose), be applied for both impurities and degradation products in DP in the early stage. The proposed limit for unspecified individual degradation products in early development is NMT 1.0%. The limit of 5.0% for total degradation products in early phase DPs is higher than the corresponding limit of 3.0% for total impurities in DS due to the additional variability contributed by the formulation excipients, DP manufacturing process, and DP analytical methods.

In early development, these limits are justified because clinical studies are of limited size and duration and stability information on early drug candidates with respect to sensitivities to moisture, hydrolysis, and oxidation is still being acquired. Later in development, process control, formulation design, and product protection strategies to minimize product degradation can be implemented after the compound sensitivities are better understood and thus tighter degradation product controls are justified.

Water content: As described for DS, a DP specification only needs to be established to control moisture levels in an investigational capsule or tablet dosage if the product quality or performance is known to be sensitive to water. As development progresses and additional knowledge is attained about product performance and stability in the presence of water, a specification may be applied, as necessary for release, shelf life, or both.

Dissolution and disintegration: For rapidly dissolving immediate release formulations, it is recommended to include disintegration as a regulatory filed specification. Dissolution may be performed as an internal specification (i.e., report results without defined acceptance criteria) to gather product knowledge during early development (e.g., for poorly soluble drugs). As additional knowledge is gained toward establishing an in-vitro–in-vivo correlation (IVIVC), dissolution acceptance criteria should be established in later development (i.e., Phase 2b and beyond).

Other tests to consider. Other tests may be added to the DP specification as required. For example, residual solvents should be tested if solvents are used in the DP manufacturing process. Similar to DS, microbial testing may be considered, although a risk assessment may be performed to justify not including this test in the specification for solid oral dosage forms in early development.

Some in-process control tests such as hardness and/or friability may have a critical impact on drug product quality (e.g., chewable tablets). In these cases, acceptance criteria should be included in the specification.

Conclusions

A standard, risk-based approach has been presented for setting DS and DP specifications in early development for conventional solid oral dosage forms intended for US regulatory submissions. The recommendations herein are aimed at ensuring patient safety while allowing the flexibility to adapt to the frequent product and process changes that occur early in development. The authors' goal is to promote clarity and consensus within the pharmaceutical industry and to establish a more detailed approach to specifications in early development that are aligned across the industry and regulatory agencies. To further stimulate discussions on these approaches within the industry and with worldwide health authorities, this IQ working group is planning on conducting a workshop in the near future to promote robust debate and discussion on these proposed specifications in early development. In closing, it is recognized that each company needs to evaluate these early development recommendations based on the objectives of their individual drug development programs and may choose not to adopt this industry proposal on phase appropriate specifications.

Michael Coutant works in Analytical Research and Development at Pfizer Inc. (Groton, CT); Zhihong Ge works in Analytical Chemistry at Merck & Co. Inc. (Rahway, NJ); James S. McElvain* works in Analytical and QC at Kythera Biopharmaceuticals (Calabasas, CA); Scott A. Miller works in Analytical and Bioanalytical Development at Bristol-Myers Squibb Company (New Brunswick, NJ); Dennis O'Connor works in Quality & Records Management and Frank Swanek works in Analytical Development, both at Boehringer Ingelheim Pharmaceuticals Inc. (Ridgefield, CT); Michael Szulc works in Analytical Development at Biogen Idec (Cambridge, MA); Mark D. Trone works in Analytical Development–Small Molecule at Millennium Pharmaceuticals, Inc. (Cambridge, MA); Kirby Wong-Moon works in Analytical Research and Development at Amgen Inc. (Thousand Oaks, CA); Mehran Yazdanian works in Pharmaceutical Development at Teva Global Branded Products R&D (West Chester, PA); Peter Yehl works in Small Molecule Analytical Chemistry and Quality Control at Genentech (South San Francisco, CA); and Shuhong Zhang works in Process R&D, Global Pharmaceutical R&D at Abbott Laboratories (North Chicago, IL).

*To whom all correspondence should be addressed.