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Developers of low-dose drugs in solid oral dosage forms will find theoretical considerations and practical advice in a new book.
Ensuring content uniformity, stability, and bioavailability and developing accurate analytical methods are particular challenges for low-dose oral delivery systems. Their extremely fine powders, highly specific surfaces, and low concentrations of active ingredients make these products more difficult to create than high-dose drugs.
Formulation and Analytical Development for Low-Dose Oral Drug Products, Jack Zheng, Ed., Wiley, Hoboken NJ, 2009, 461 pp., ISBN 978-0-470-05609-7
Written by a team of leading drug-development scientists, nearly all from Eli Lilly (Indianapolis, IN) and Pfizer (New York), Formulation and Analytical Development for Low-Dose Oral Drug Products sums up the key topics and regulatory perspectives for these medicines. The editor defines low-dose drugs as containing < 1 mg/dose unit or < 0.01% (w/w) drug load.
Various chapters advise manufacturers how they can fulfill the US Food and Drug Administration's new and stringent regulatory requirements for these therapies. The book's contributors discuss topics such as pharmaceutical quality risk management, process analytical technology guidance documents, design space of quality by design, target product profiles, and design of experiments.
One section reviews the formulation and process development of low-dose drugs. It covers topics such as theoretical considerations about the drug substance's particle size and content uniformity, micronization of the drug substance, and manufacturing platform technologies such as high-shear wet granulation, fluid-bed granulation, direct compression, and roller compaction. The book also discusses the quality and functionality of pharmaceutical excipients. This part is exhaustive and describes standard procedures such as wet granulation.
Another part of the book reviews challenges in analytical-method development, including control strategy (e.g. using an excipient-library approach), physical characterization of the micronized powder, and the solid state of the active ingredient in dosage forms. In addition, the book examines cleaning verification of manufacturing equipment. This part also is highly detailed and explains standard procedures such as dissolution rate testing.
Low-dose drugs tend to be highly potent, and a portion of the book is dedicated to containment technologies used in analytical laboratories and manufacturing plants. A good working practice is necessary to control the risks and to protect personnel from health dangers. The chapter is well written and fills a gap in standard textbooks about pharmaceutical technology.
The book divides potential hazards into categories according to occupational-exposure banding (i.e., a set of criteria to manage the risk of exposure and to decide what precautions such as personal protective equipment are needed).
A former FDA employee describes important regulatory considerations in one chapter that sums up the information FDA expects for low-dose products and the way that the agency currently requires results to be presented.
Although the book provides much useful information, it has a few shortcomings that should be mentioned. In general, the writing is not concise, and basic principles are repeated excessively throughout the book, even within individual chapters. These problems might result from the fact that the contributions were written as individual reviews, but the editor should have eliminated redundancies and established a consistent style for the text.
Also, the book would have benefited from a special list of abbreviations as an appendix. Mentioning the abbreviations in the the index is insufficient for the average reader.
Despite these flaws, the book provides a worthy contribution to formulation and analytical sciences. The publication should help pharmaceutical scientists, postgraduate students of pharmaceutical technology, and newcomers to the industry overcome the obstacles to developing solid oral low-dose drug products.
Heinz Sucker is professor emeritus at the University of Bern, Bernerring 70 CH-4054 Basel, Switzerland, tel. +41 61 281 0084, firstname.lastname@example.org. He also is a member of Pharmaceutical Technology's editorial advisory board.