Washington Report

Drug Specifications Under Scrutiny

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com

Officials at the US Food and Drug Administration are working with industry and academia to develop more efficient and reliable drug production processes that can ensure a consistent supply of high-quality therapies. A modern manufacturing system based on harmonized regulatory policies across global regions is critical for meeting public demand for safe and effective medicines, while also reducing production costs and eliminating waste. A central aspect of this process is to revise rules and guidelines that now encourage manufacturers to set overly conservative product specifications and inhibit a manufacturer's ability to adapt marketed therapies to meet changing needs and technological advances. Appropriate specifications are important for ensuring drug supplies and for meeting good manufacturing practices through a product's life cycle. Overly rigid or irrelevant standards may lead to out-of-specification results and raise costs if finished products must be discarded. Under a more rational, risk-based approach to specification setting, manufacturers and regulators would establish tighter standards for critical product parameters and be more flexible for less relevant measures. The aim is to develop pharmaceutical products that will serve patient needs and not simply fit dissolution criteria. Leaders in industry and at FDA believe that a new approach is needed for establishing product specifications that reflect appropriate product design and changing needs throughout the product life cycle. The main problem with the current system is that most quality assessment relies on end-product testing, which has severe limitations in a modern, mass production environment, according to FDA Acting Deputy Director Janet Woodcock. Companies set limits on quality attributes primarily to ensure that production batches resemble batches tested in the clinic. Nevertheless these measures fail to explain the relationship between those specifications and desired clinical outcomes. Such limits often are too wide, too tight, or inappropriate for clinical performance, Woodcock says. Instead, specifications should be determined by a mechanistic understanding of how product formulation and manufacturing processes affect product performance, explained Steven Galson, acting director of the Center for Drug Evaluation and Research (CDER), at a March workshop on setting drug specifications for the twenty-first century cosponsored by FDA and the Pharmaceutical Quality Research Institute (PQRI). The meeting examined how specifications help ensure safe and effective pharmaceutical products and the process for establishing more-relevant global standards that may improve drug specifications. Reactive process A specification is a document stating the requirements to which a product must conform as part of a "total control strategy" for ensuring product quality and consistency, explained CDER Office Pharmaceutical Science Deputy Director Ajaz Hussain. The specification-setting process begins by determining a set of tests, analytical procedures, and acceptance criteria that may be used to measure product parameters such as chemical properties, polymorphs, particle size, impurities, and microbial contamination. Then the manufacturer identifies in-process controls, product design features, and process validation procedures to ensure that the product will meet maximum and minimum tolerance ranges and conform to compendial criteria through numerous production batches during a period of years. Unfortunately, the current testing process focuses on controlling variability and end process results to establish a shelf-life specification. The process seldom reflects a clear understanding of product design and the sources of production process variability. And, because such empirical approaches encourage manufacturers to define acceptance criteria as narrowly as possible, it frequently leads to out-of-specification results. End-product testing seldom identifies the root cause of a problem or the needed corrective action, said Moheb Nasr, director of CDER's Office of New Drug Chemistry (ONDC), but merely indicates that the product or batch failed to meet specifications. Moreover, specifications that are too tight discourage manufacturers from upgrading production processes or improving a formulation after the drug is on the market. A related issue is whether quality standards established by pharmacopeias in Europe and the United States discourage innovation and change. The current system relies heavily on adherence to compendial standards to document a process control strategy. Nonetheless, drug monographs set broad, minimal standards that are applicable to many product formulations and manufacturing processes and leave little room to recognize when a manufacturer gains greater process understanding. New approaches for establishing specifications challenge compendial standards and put pressure on pharmacopeias to revise monographs, which is a long and difficult process. (continued)