Encyclopedia of Pharmaceutical Technology 

Encyclopedia of Pharmaceutical Technology

The introductory paragraph of the preface to both the first and second editions of this encyclopedia, published in 1988 and 2002, respectively, notes that pharmaceutical science and technology have progressed enormously in recent years, and that significant advances in therapeutics and an understanding of the need to optimize drug delivery in the body have brought about an increased awareness of the valuable role played by the dosage form in therapy. In turn, this has resulted in an increased sophistication and level of expertise in the design, development, manufacture, testing and regulation of drugs and dosage forms.

This statement is as true today as it was back in 1988 and 2002—and perhaps more so, given the increasing emphasis being placed on the discovery, development, and use of large molecular entities as therapeutic and diagnostic agents. The pace at which these advances are being made is reflected in the fact that, after only four years, it has been felt necessary to publish this, the third edition, of the Encyclopedia of Pharmaceutical Technology.As with the second edition, the third edition is available in print and also online.

The third edition continues the focus on the discovery, development, design, manufacture, testing, regulation, and commercialization of drugs and dosage forms. Areas of emphasis include pharmaceutics, pharmacokinetics, analytical chemistry, quality assurance, drug safety, and manufacturing processes. Both more traditional and newer technologies and processes are included, with an increased emphasis on biotechnology and large molecule development. Current trends relating to solid state aspects of drug entities are also included, reflecting again the advances made in this area.

While of primary interest to pharmaceutical scientists and management in the pharmaceutical and related industries, including regulatory agencies, the encyclopedia will be of value to those in academia undertaking pharmaceutical research and those responsible for the education and training in pharmaceutical science and technology of graduate and undergraduate students.

The print version of the third edition consists of six volumes totaling about 4400 pages, an approximately 45% increase in content compared to the second edition. The number of articles has increased to almost 300 titles arranged alphabetically by subject and the number of contributors has risen by over 50% to in excess of 500 individuals. The new edition now contains a Topical Table of Contents, whose purpose is to group article titles into categories and subcategories, thereby making the reader aware of other related and relevant articles.

As was the case with the second edition, the online version includes everything in the print version and also offers the convenience of a keyword search engine as well as the inclusion of color illustrations. New and revise articles will be digitally posted quarterly and available to all subscribers of the electronic version.

Preparation of the third edition began under the auspices of Marcel Dekker, Inc. before it became part of In forma Healthcare USA, Inc. last year. I would be remiss therefore if I did not acknowledge the fantastic support received from Carolyn Hall, Managing Editor of the Encyclopedia Department of Marcel Dekker, Inc. prior to the merger. At the same time, it is a pleasure to acknowledge to contributions to the development of this third edition from staff in The Encyclopedia Group of Informa Healthcare USA, Inc., in particular Louisa Lam, Claire Miller, and Yvonne Honigsberg.

I must note the absence of Jim Boylan’s name as an editor on the third edition. Jim and I worked closely in partnership as co-editors on both the first and second editions. After 17 years commitment to the encyclopedia Jim decided to relinquish his role as co-editor,a move that both I and the publisher greatly regretted. And so, it is fitting that this new edition, which relies in large part on Jim’s past contributions, is dedicated to him.

Finally, you the readers are to be thanked for your support and comments. I trust you will find that the third edition continues the high standards set by the previous editions. As always, I welcome your comments and suggestions for new titles.

Chromatographic Methods

The introduction of GC as an analytical technique has had a profound impact on both qualitative and quantitative analysis of organic compounds. Identification of compounds by GC can be accomplished by their retention times on the column as compared to known reference standards, by inference from sample treatment prior to chromatography,[11] or by the concept of retention index.[12] The latter method and tables of retention indices[13] with associated conditions have been reported.[14] Although qualitative data and analytical techniques for identification of compounds are well-established[15,16] and relative retention data for over 600 substances also have been published,[17] the main utility of GC undoubtedly lies in its powerful combination of separation and quantitative capa-bilities. Use in quantitative analysis involves the implementation of two techniques being performed concurrently, i.e., separation of components and sub-sequent quantitative measurement.

The use of GC was first included in the United States Pharmacopoeia (USP) in the sixteenth edition[18] in 1960, and became an official method of the British Pharmacopoeia (BP) in 1968.[19] GC has found wide-spread use in pharmaceutical analysis by virtue of its applications to purity and control analysis of raw materials, content and quality assessment of dosage forms (including product stability), and in the quanti-tative measurement of drugs in biological fluids. The latter application is important for therapeutic drug monitoring, pharmacokinetic studies, and bioavailabil-ity assessments. In fact, in a survey on GC use,[20] a major application of this technique was in the field of pharmaceuticals.

Electroanalytical Methods

Voltammetry is a term that encompasses all measure-ments based on controlled electrolysis at a microelec-trode. Polarography, first introduced by the Czech electrochemist Jaroslav Heyrovsky in 1922, is voltam-metry at a special form of mercury microelectrode, the dropping mercury electrode (DME). Mercury elec-trodes can only be driven to negative potentials because otherwise, the metal dissolves in aqueous solutions as Hg2þ. Consequently, polarography is an electroanalytical method based on the cathodic reduction of electroactive species, either metal cations or electroreducible organic species, in an electrically conducting solution. By contrast, voltammetry is based on electroanalysis involving anodic oxidation, prefer-ably in a flowing system in which a self-cleaning action prevents fouling of the solid electrode surface by the products of the electrochemical reaction, thereby lead-ing to non-reproducible current/voltage curves.

Analytical Procedures: Validation 

To the pharmaceutical world, the meaning of analyti-cal methods validation is the process to confirm that a method does what it purports to do, that is, to docu-ment through laboratory studies that the measurement procedure can reliably assess the identity, strength, and/or quality of a bulk drug substance, excipient, or finished pharmaceutical product. To provide consis-tent, worldwide regulatory expectations, previously unavailable, the International Conference on Harmo-nization (ICH,[1]a) has defined the methods validation process for the release and stability testing of all new products. This chapter interprets these ICH regulatory definitions and requirements,[2,3] as well as provides direction toward rational and efficient validation.

Regulatory methods can be compendial or non-compendial. Wherever possible, methodologies are to be employed which are documented, generally recog-nized as official pharmacopoeia or compendial. Com-pendial methods are considered valid; however, suitability must be verified under actual conditions of use. Non-compendial methods require validation, and must be selected if a compendial method does not exist. A non-compendial method can be chosen over an existing compendial method, if it can be demonstrated to be superior to the compendial test.

Before a product dossier has been submitted to an agency for regulatory market approval, analytical laboratories have utilized validated methods to sup-port toxicological, clinical, stability, development, scale-up, optimization, process, and cleaning valida-tion studies. Unreliable data for any of these studies have the potential to completely undermine the speed and success of approval. A method’s ‘‘life cycle’’[9] parallels the drug development process. Starting with early (preclinical) development projects, the related methods for drug substance and finished drug product require only some rudimentary validation to provide sufficient confidence in the results, eventually leading to a complete methods validation package for the final stages of product development and commercialization (see section ‘‘Validation During Drug Development and Manufacturing’’). The methods life cycle con-cludes with methods transfers, monitoring of routine quality control (QC) usage, and revalidation. We define revalidation as repeating those parts of valida-tion that are affected by a modification, for example, specificity, if the column has changed. Repeating the whole validation periodically is superfluous; instead, continuous monitoring of the performance of the ana-lytical procedure should be performed (see section ‘‘Maintenance of the Validation Status’’). Many tests may be specified in the early development of a product or process that will not be ultimately selected for routine release testing. Clearly not all products reach the approved and marketing stage, due to toxicology, efficacy, or even business conditions. Multiple other changes can occur along the way toward approval such as active pharmaceutical ingredient (API, drug substance), synthetic route changes, drug product formulation, and process changes, as well as newly identified degradation pathways. All of these affect the method applied. Therefore, methods (development) validation requires efficient planning of resources to match the accuracy and precision requirements needed to assess product quality.

Radiochemical Methods

Enzyme immunoassay, a bioanalytical method incor-porating an antigen–antibody reaction to capture the analyte of interest and an enzyme reporter system to detect the captured analyte, is one of the most widely used immunoassay formats. The method is sometimes applied only qualitatively to indicate the presence of an antigen in a matrix. However, in the more common quantitative implementation, a calibration (standard) curve is incorporated, from which the concentration of the analyte in unknown samples is interpolated. In the decades since the development of a radioimmu-noassay for insulin by Yalow and Berson,[1] immu-noassays have been widely applied in support of medical practice and drug development. However, in recent years, there has been a decline in the application of immunoassays to the quantitation of low-molecular-weight xenobiotics, primarily due to the advent of liquid chromatography–mass spectrometry (LC–MS) methods, which have high sensitivity and specificity. This is particularly so for support of early drug dis-covery, where assay development times of as little as a day and analytical run times of only a few minutes per sample make LC–MS ideally suited to fast delivery of results to discovery scientists. Nonetheless, the remark-able specificity of antibodies allows their application in well-characterized immunoassays to the support of Phase III and Phase IV clinical trials as a cost-effective alternative to LC–MS methods. In addition, these meth-ods are still widely used for therapeutic drug monitoring and analysis of low-molecular-weight hormones, such as steroids, in support of medical diagnostics. Immunoas-says remain the method of choice for the quantitation of protein macromolecules and antibodies in complex matrices. Another major application of immunoassays is in the detection and quantitation of biomarkers, which are evolving to be of pivotal importance in the evaluation of pharmacological, toxicological, and clinical activities of candidate drugs.[2]

Immunoassays generally vary in the type of critical antibody binding reagent or the detection and reportersystems used to monitor the end-point of the binding reaction. These different types of immunoassays have many characteristics in common; therefore, this chap-ter will include discussions of both enzyme immunoas-says and other closely related methods. The enzyme immunoassay technique has been the subject of several textbooks, monographs, and review articles, including an excellent, comprehensive discussion in an earlier edition of this series.[3] Thus, this chapter does not provide an in-depth review of the mechanistic details for producing and processing antibodies as reagents or on assay conditions for enzyme immunoassay. Rather, the intent is to present this technique in the context of several primary topics, namely the range of bioanalytical applications, the different, and some-times additional, validation considerations imposed upon an enzyme immunoassay and its fraternal immu-noassay methods, and some newer techniques that are complementary to enzyme immunoassay and offer potential performance enhancements. The chapter is written from the perspective of bioanalysis in biologi-cal fluids and does not address in any detail other applications of enzyme immunoassay, such as support of process control or product release, although such topics have been addressed elsewhere.

Radiochemical Methods

The use of flame photometry as a quantitative tool can be traced to work by Kirchhoff and Bunsen in the early 1860s.[1] Its modern history begins, however, in the 1940s, when instruments became available that successfully addressed the problems of repro-ducible sample introduction and detection. Flame photometry soon developed into a reliable analytical technique for the determination of several cations of pharmaceutical interest, notably sodium, potassium, and lithium. The technique is useful in the analysis of bulk drugs, dosage forms, and clinical samples such as blood and urine.

This article focuses primarily on ‘‘traditional’’ low-temperature flame photometry. High-temperature flame photometry has evolved into separate tech-niques, typically identified by their temperature sources (e.g., inductively coupled plasma-atomic emission spectrometry, ICP-AES[2]). Some references to other related analytical tools, including high-temperature flame photometry, are made here to establish perspective.

Thermal Methods

within a material that are either manifested as exother-mic (heat liberating) or endothermic (heat consuming) events (Table 1). Changes in energy (not absolute energies) are conventionally determined, and quantitative measurements may be made if the mass of the sample(s) is accurately known. Recently, nanocalorimetry or calorimetry microarrays[1–3] are expanding the application of calorimeters to high throughput screen-ing (HTS), providing high throughput thermodynamic measurements at the microgram scale. Preliminary studies using these microchip calorimeters have shown interesting potential for their applications in studying biological macromolecules in solution, such as protein ligand binding and measuring heat capacities on samples as small as 10 mg.[2] Additional applications could include the study of the thermal properties of drug molecules in HTS.

The most common applications of calorimetry in the pharmaceutical sciences are found in the ‘‘subfields’’ of differential scanning calorimetry (DSC) and microca-lorimetry. State-of-the-art DSC instruments and micro-calorimeters are extremely sensitive and are powerful analytical tools for the pharmaceutical scientist.

Differential scanning calorimetry usually involves heating and/or cooling samples in a controlled manner, whereas microcalorimetry maintains a constant sample temperature. The DSC instruments are considered to be part of the ‘‘Thermal Analysis’’ armamentarium; for additional information, the reader should refer to the Thermal Analysis section of this Encyclopedia.


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