More Than You Need to Know about Manufacturing Pharmaceutical Proteins

Manufacturing of Pharmaceutical Proteins is a practical text based on author Stefan Behme's personal experience in the field. It emphasizes the intersections of various disciplines and functions that must communicate effectively to produce a successful protein. The book's title is misleading, however, because it focuses on biotechnologically derived proteins and does not discuss protein drugs that are extracted from plant, animal, and human cells.

Manufacturing of Pharmaceutical Proteins, Stefan Behme, Wiley, Hoboken, NJ, 2009, 390 pp., ISBN 978-3-527-32444-6

The book is divided into seven parts that describe topics such as technology, quality assurance, pharmaceutical law, production facilities, and economy. Each topic is broad enough to warrant a book of its own. Behme's treatment of the relevant subjects is superficial, but, strangely enough, he provides more detail about tangential topics. The information conveyed ranges from basic to highly technical.

Behme's introduction emphasizes several well-known facts. He notes that biotechnological-derived processes are difficult to control and present more risks than do small-molecule production processes. He also says that manufacturing is a pivotal step between the development of the protein and the sales and marketing of the final product, and this reviewer contends that manufacture plays a similar role in small-molecule processes. Readers with expertise in project management are familiar with the links between research, development, manufacturing, and marketing.

Throughout the book, Behme offers background information on each topic. The chapter about the "Basics of Biology" is a valiant effort to provide foundational information to students, but most of the information can be found in various biology books written for that purpose, and these texts should have been cited as references.

Several diagrams in the book's technology section provide a simplified view of the tools used to manufacture protein substances and finished products. The diagrams are a bonanza for individuals who prefer a visual approach to understanding complex processes. The technology section also discusses the critical factors to be used in evaluating a process. Cell-bank handling and the expression of proteins in various systems (e.g., microorganisms, and mammalian cells) are discussed.

The technology section covers much important ground, including topics such as cell disruption, solubilization, protein refolding, formulation, and final-product filling. A discussion of aseptic processing of the final product in appropriate containers is missing, however. This omission is perplexing because most proteins are heat labile and cannot be terminally sterilized. The omission is also unusual because the author intends the book to be comprehensive.

A later section compiles a plethora of analytical methods designed to establish identity, purity, potency, and quality of protein products. Methods such as amino-acid analysis, protein sequencing, peptide mapping, and protein content are reviewed in some detail. For each method cited, the author presents the purpose of each test and its working principles. This section is by far the most comprehensive discussion of these methods in a single book that I have seen.

The list of methods would not be complete without the methods for in-process control for fermentation, mammalian systems, purification, formulation, packaging, raw-materials testing, and environmental testing. These methods are described in great detail. Perhaps the structure of the book dictated that raw-materials testing and manufacturing environmental testing be described after the manufacture of the active ingredient or the finished product, but obviously this is not the order in which the testing is actually performed.

The section about quality assurance explains basic rules that are not specific to the biotechnology industry, but that constitute a framework for organizations that wish to manufacture high-quality products. Chapters focus on quality assurance in manufacturing and emphasize good manufacturing practice, equipment qualification, process validation, computer validation, documentation, and change control. This detailed section could be part of a book about manufacturing-process development, but has little application to quality control of protein-manufacturing processes.

The "Pharmaceutical Law" section would more aptly be titled "Regulatory Requirements" because it covers regulations from the US Food and Drug Administration, the European Medicines Agency, and from Japanese and German authorities. The section also lists nongovernmental organizations that indirectly regulate the manufacture of pharmaceutical proteins (e.g., the US Pharmacopeia, the World Health Organization, and the Parenteral Drug Association). The list gives the neophyte a general overview of the roles of these organizations in the development of mandatory and voluntary quality standards for these products. The section about drug approval is minimal and requires more comprehensive treatment.

One drawback of the book is its inclusion of several chapters that are not germane to the manufacture of pharmaceutical proteins. For example, the section titled "Pharmacy" examines pharmacokinetics, pharmacodynamics, various phases of clinical testing, the classification of side effects, and pharmacovigilance. A better place to discuss these topics is in a book about research and development.

A section about production facilities includes a detailed description of the design, planning, construction, and commissioning of production facilities. Although the discussion is interesting it is totally unnecessary in this type of book. In general, facilities are designed and constructed by specialized engineering organizations. Extensive treatment and exquisite detail are not necessary for biopharmaceutical production personnel.

Another interesting but inappropriate section is the one titled "Economy," which is essentially a treatise on profitability and investments. The section provides a nuanced view of the decisionmaking process of an organization that intends to manufacture pharmaceutical proteins, but it is out of place in a book about manufacturing.

Behme covers too much material in his book, including topics indirectly related to his stated focus. Some parts of the book are tedious; one can be overwhelmed by details and lose interest quickly. The stated audience for the book—libraries, biotechnology companies, technicians, and students—is too diverse, and the author cannot do justice to many of the topics he proposes to include.

Overall, the book is interesting because it provides general understanding that specialized personnel might not have. The book is intended as a practical tool and an academic text on the subject, but does not fully satisfy either purpose.

Roger Dabbah is a principal consultant for Tri-Intersect Solutions, Potomac, MD 20854, rdabbah@verizon.net. He is also a member of Pharmaceutical Technology's editorial advisory board.