Washington Report

Drug Specifications Under Scrutiny (continued)

Seeking understanding To address these shortcomings, FDA officials and industry leaders are seeking a proactive approach to measuring product quality and performance that involves establishing more useful and informative product specifications. They emphasize the importance of gaining a thorough understanding of the biopharmaceutical and physical–chemical properties of each drug substance and how product formulation and process factors affect product performance and design. Under the envisioned scenarios, a manufacturer identifies the preferred polymorphic or crystalline form, analyzes solubility, stability, and absorption properties, and then determines the preferred particle shape, size, and surface area to optimize absorption or dissolution. It may be that the dissolution rate itself is not critical to quality performance for a solid oral dosage. Or parametric release may be a viable alternative to routine release testing. Instead of assuming that particle size is a critical parameter, advises Hussain, one must understand how particle size affects product quality. As envisioned in FDA's "critical path" initiative to make drug development more productive, a modern quality assessment system also should link product specifications to clinical effectiveness. Instead of adopting a rigid set of release specifications just before filing a new drug application, FDA officials urge manufacturers to identify those product parameters that are most relevant to product safety and efficacy. This involves examining clinical trial data to determine whether evidence of efficacy and adverse events relate to individal patient variation or to variability in a product's pharmacokinetic properties. A low potency result may have little effect on product efficacy, and some specifications such as dissolution or crystal size may not be critical for all medication classes. The agency believes that earlier discussion of these issues with manufacturers will improve the new-drug review process, as well as product quality. FDA is asking companies to address drug specifications and other quality issues more formally at end-of-phase-II meetings, an approach that the agency hopes will encourage manufacturers to submit more data in a new drug application (NDA) to indicate the company's greater understanding of product and process. CDER's ONDC is reorganizing its chemistry reviewers into teams to free up CMC reviewers for earlier meetings with manufacturers (see Sidebar, "CDER eyes chemistry review teams"). Seeking harmonization Modernizing drug specifications also involves revising and updating the Q6a guideline developed by the International Conference on Harmonization (ICH). This five-year-old policy defines terminology and approaches for setting pharmaceutical acceptance criteria. It discusses the importance of collecting relevant data from batches used in clinical studies, including information from accelerated and long-term stability studies, and the use of pharmacopeial standards for establishing a reasonable range of expected analytical and manufacturing variability. But by encouraging manufacturers to set acceptance criteria on the basis of worst-case batch data to address regulatory concerns, the guideline may inhibit more sophisticated strategies for evaluating manufacturing processes. ICH participants from the United States, Japan, and Europe consequently are considering how to adapt Q6a definitions and concepts to reflect recent guidelines on process analytical technology (PAT) and risk-based regulatory approaches. As a first step, a new ICH policy instructs manufacturers to explain drug development and production processes more fully in regulatory submissions that follow the common technical document (CTD). The ICH Q8 initiative, now in draft form, outlines the contents for the CTD's pharmaceutical development section, including a summary of formulation design history, manufacturing process, and critical variables important for ensuring product quality. This proposed guideline also discusses terms and approaches for achieving greater understanding of product formulation and manufacturing approaches through quality by design strategies (see Sidebar, "Achieving the desired state through quality by design"). (continued)