Dr R. Williams, United States of America

Good quality starting materials, including both drug substances and excipients, are critical for safe, effective, and good quality medicines. Failure to assure this quality has been the reason for many product failures, including recurring episodes of morbidity and mortality from the inadvertent use of diethylene glycol (DEG) in pharmaceutical formulations.

The most recent of these occurred in Haiti in 1995-1996, with prior episodes in Argentina, Bangladesh, India, Nigeria, South Africa, and the United States. To avoid recurrence of DEG and similar problems, pharmaceutical manufacturers must develop a rigorous understanding of the quality attributes of pharmaceutical products and exert careful control of all materials used in their manufacture. Using good manufacturing practices (GMPs) and other approaches such as appropriate specifications, strict control of a starting material including the drug substance, excipients and other materials used in manufacturing must be maintained from the primary source to final utilization in the manufacturing process.

The overall objective is to develop and manufacture a pharmaceutical product that will reliably yield an established pattern of safety and efficacy over time and with multiple administrations of the finished dosage form. Pioneer manufacturers usually expend considerable resources to assure the quality of a marketed pharmaceutical product. Prior to approval, a key objective is to characterize the drug substance and drug product so that their quality attributes are known and appropriately controlled.

For small molecules and simple pharmaceutical products, the effort may not be especially difficult. For larger molecules, complex drug substances, and complex pharmaceutical products, the challenge to a pioneer manufacturer in characterizing the drug substance and product may be formidable. For pharmaceutical products where sterility assurance is needed, special approaches are critical.

Agreement between a manufacturer and regulatory authority on a set of specifications for a finished dosage form is a critical time. Some aspects of a set of specifications for an approved drug product may become part of a drug substance or drug product pharmacopoeial monograph. These drug substance/product specific standards may thus become a public standard for use by all pharmaceutical manufacturers in assuring the quality of a pharmaceutical product. General pharmacopoeial tests are also useful to all pharmaceutical manufacturers. For manufacturers who intend to market in more than one country, harmonization of pharmacopoeial standards is important to avoid the need for different procedures and/or acceptance criteria to assure the quality of a product intended for different markets.

ICH and WHO have worked over the years to develop a set of guidelines that may be used by pharmaceutical manufacturers to assure the quality of starting materials and of the finished dosage form. While ICH guidance becomes part of the regulatory requirements and/or recommendations of participants to the ICH process, WHO documents are more generally available but are not necessarily part of any nation’s or region’s regulatory machinery’.