Drug Specifications Under ScrutinyJill Wechsler

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.

Jill Wechsler

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.

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, analyses 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 an 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").

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").

Achieving the desired state

Biologics, too

As pharmaceutical companies are weighing revisions to Q6a, biotech manufacturers are examining similar options for Q6b, the ICH guideline on setting specifications for biotechnological products. The need to develop a rational approach for establishing and using specifications through the biotech product life cycle was examined this past October at a workshop sponsored by FDA, industry, and the American Association of Pharmaceutical Sciences. Some 200 attendees explored the purposes of specifications and challenges in identifying clinically relevant measures. The session clarified that specifications are important parameters that a product must meet, although limits apply to less critical measures that a product should meet.

Participants acknowledged that specifications may not be needed for certain product attributes that demonstrate little batch-to-batch variation or sensitivity to manufacturing change, explained Keith Webber, director of CDER's Office of Biotechnology Products. He noted that critical quality attributes could include identity, strength, quality, purity, and potency. At registration, a manufacturer may estimate assay variability and proposed shelf-life. Continuous product improvement is the goal of postmarketing activities that provide additional understanding of a product and process. Webber noted that current standards encourage the use of batch data to calculate shelf life and other specifications and that further discussion by FDA and industry is needed to resolve key issues related to using specifications to ensure quality throughout a product's lifetime.

Concerns and confusion

The PQRI March workshop generated considerable discussion about these issues but appeared to fall short of its original goals. Meeting organizers had hoped to gain some consensus about how manufacturers could identify the most critical parameters for a safe and effective drug product as well as less vital measures. The three-day discussion exposed some 500 attendees to innovative concepts, but in the end, most participants had difficulty moving away from more traditional approaches to ensuring product quality.

Some manufacturers questioned whether it's worth the time and cost to reach a still unclear "desired state" of pharmaceutical development within a somewhat vague "design space." And, they expressed fear that innovative approaches will draw more regulatory scrutiny. There appears to be a strong reluctance to shift from specifications determined by clinical batch data or to loosen up tight acceptance criteria that ensure the process is under control. Some of these issues were discussed at the May meeting of FDA's Advisory Committee for Pharmaceutical Science and further deliberations are expected in coming months. If anything, the PQRI workshop revealed how important specifications are to drug development and quality control, which are key issues in any effort to modernize prescription drug manufacturing and production.

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