Quality control pharmaceutical manufacture

Engineering, Marketing, Packaging, Pharmaceutical Manufacturing, Quality Control, and Sales. 

Contracting out of activities previously only conducted in-house is already becoming quite common and will probably continue to develop. In the past a so-called full-service pharmaceutical company took direct responsibility for all the activities required for the formulation, manufacture, quality control, and regulatory approval of its drug products. Nowadays the use of specialist contract houses to perform activities such as formulation, analytical methods development, manufacture of clinical trials supplies, supervision of the assembly of an NDA, postmarketing surveillance, and even troubleshooting may be contracted for even by some of the largest companies. 

Detecting known substances, and determining their quantity, is also important. In synthetic research, it is essential to know the relative proportions of various reaction products. In manufacturing, it is important to detect any impurities in the product and to determine whether they are present in a significant amount. Analytical characterization is critical in pharmaceutical products, for instance. Products for practical uses—paint or adhesives, for example—will typically consist of several components. For proper and reliable performance it is important to measure the amounts of each of the components as part of a manufacturing quality control system. Manufacturers also commonly need to analyze the raw materials they receive, measuring the amounts of various substances in them to be sure that the material meets their requirements. Before it can be correctly processed into steel, iron ore must be analyzed to determine how much of other components need to be added to produce a metal alloy of the desired composition and properties. 

Peroxidation and free-radical formation should be considered as important aspects of pharmaceutical stability and quality of parenteral nutriton and intravenous drugs. Peroxidation and free-radical formation depend on environmental factors, such as storage conditions and container material, but are also influenced by formulation components or additives such as tocopherols and metabisulfite. Since the generation of these harmful species occurs generally at the time of use, manufacturing quality controls fail in demonstrating their existence. 

The apparatus used to measure membrane bubble points is shown in its simplest form in Figure 7.7 [4], Bubble point measurements are subjective, and different operators can obtain different results. Nonetheless the test is quick and simple and is widely used as a manufacturing quality control technique. Bubble point measurements are also used to measure the integrity of filters used in critical pharmaceutical or biological operations. 

Pharmaceutical Purity. A safety profile of a generic drug can differ from that of the brand-name product because different impurities may be present in each of the drugs (154). Impurities can arise out of the manufacturing processes and may be responsible for adverse interactions that can occur. For example, serious adverse reactions (Lyell syndrome) were observed upon the use of isoxicam in 1985. These seemed to have resulted from trace elements of a manufacturing by-product that was within the manufacturing quality control specifications. 

As a minimum, the personnel responsible for inspecting manufacturing sites should have relevant qualifications and experience in pharmaceutical manufacturing, quality assurance, GMP, performing inspections and audits, chemistry and quality control. Ideally they should have an inspection background from working with a regulatory authority. 

Parenteral Drug Association (PDA). 3 Bethesda Metro Center, Suite 1500, Bethesda, MD 20814, U.S.A. Phone +1 301-656-5900, Fax +1 301-986-0296. E-mail info pda.org. URL http //www.pda.org. PDA is a non-profit international association of more than 10,500 scientists involved in the development, manufacture, quality control, and regulation of pharmaceuticals/biopharmaceuticals, and related products. The association also provides educational opportunities for government and university sectors that have a vocational interest in pharmaceutical/biopharmaceutical sciences and technology. The association publishes the PDA Journal of Pharmaceutical Science and Technology. It holds an annual meeting and sponsors several symposia and educational programs. 

Figure 6.1. Schematic showing the various departments in pharmaceutical research discovery research, chemical and pharmaceutical development, drug metabolism and pharmacokinetics (DMPK), and manufacturing quality control. Diagram Courtesy of Waters Corporation.

Nowadays, in the pharmaceutical industry, the need to obtain accurate and rehable analytical data faster and more cost-effectively, has meant that approaches to method development are becoming simpler and more straightforward. These sinpler approaches have the benefits of more consistent methods, lower method diversity, reduced inventory costs for separations consumables and more easily transferable methods from R D laboratories to manufacturing quality control (QC) laboratories. Many pharmaceutical companies have adopted this approach. 

Preparation, manufacturing, quality control and dispensing of medicinal products have always been associated with the pharmacist. Traditionally the pharmacist has therefore been trained in pharmaceutical analysis, focusing on analytical measurement of quality characteristics (identity, strength and purity) but the pharmacist was marginally trained in statistical quality control that is related to manufacturing processes. 

Quality Control Records. Accurate quality control records are of utmost importance and may be required by law, as in the pharmaceutical industry. A few years ago, mandatory Good Manufacturing Practices were proposed for the cosmetic industry. Although the proposal was later dropped, many manufacturers go by the rules worked out at that time for laboratory testing and record keeping. The food industry also requires extensive testing and record keeping. 

Pharmaceutical microbiology may be defined as that part of microbiology which has a special bearing on pharmacy in all its aspects. This will range fiom the manufacture and quality control of pharmaceutical products to an understanding of the mode of action of antibiotics. The full extent of microbiology on the pharmaceutical area may be judged fiom the chapter contents. 

The first chapter in this section provides a unique account of the ecology, i.e. distribution, survival and life-style, of microorganisms in the factory environment, and should enable process designers, controllers and quality control personnel to comprehend, trace and eradicate the sources of failure due to extraneous microbial contaminants in the finished product. Much of the information given here is applicable to hospital manufacture also, and this is extended in a contribution (Chapter 19) dealing with contamination in hospital pharmaceutical products and in the home. 

Pharmaceutical products are used in a variety of ways in the prevention, treatment and diagnosis of disease, hi recent years, manufacturers of pharmaceuticals have improved the quality of non-sterile products such that today the majority contain only a minimal microbial population. Nevertheless, a few rogue products with an unacceptable level and type of contamination will occasionally escape the quality control net and when used may, ironically, contribute to the spread of disease in patients. 

If the product is to be used for pharmaceuticals the GMP rules must be obeyed during plant operation. All chemicals to be tested in clinical studies with humans must be prepared according to GMP. This leads to very detailed documentation since if you haven t documented it, you haven t done it . All procedures for manufacturing and changes in procedures are subject to approval by quality control departments. This decreases the flexibility in process development. Products that are contaminated too much must be reprocessed according to the GMP guidelines. All equipment to be used in the pilot plant must be validated before use. 

Quality control tests or improvement of existing processes. Raw materials from various sources can be used in the manufacture of fine chemicals and pharmaceuticals. The raw materials can contain different impurities at various concentrations. Therefore, before the raw material is purchased and used in a full-scale batch its quality should be tested in a small-scale reactor. Existing full-scale procedures are subject to continuous modifications for troubleshooting and for improving process performance. Laboratory reactors used for tests of these two kinds are usually down-scaled reactors or reactors being a part of the full scale-reactor. 

One disadvantage of soft gelatin capsules is that such products often must be contracted out to a limited number of firms having the necessary filling equipment and expertise. Materials must be shipped to the soft gelatin capsule facility, and products must be shipped back to the pharmaceutical manufacturer for final packaging and distribution. Additional quality control measures may be required. 

Good Manufacturing Practices for Pharmaceuticals A Plan for Total Quality Control, Second Edition, Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV Formulation of Veterinary Dosage Forms, edited by Jack Blodinger Dermatological Formulations Percutaneous Absorption, Brian W. Barry... 

Good Manufacturing Practices for Pharmaceuticals A Plan for Total Quality Control, Third Edition, edited by Sidney H. Willig and James R. Stoker... 

A Sponsor submits a clinical trial application to the Competent Authority in each member state where the trials are to be conducted. The Competent Authority has 60 days to review and approve or reject the application. Application is in prescribed forms and covers the proposed clinical trial protocol, manufacturing, and quality controls on the drug, and supporting data, such as (1) chemical, pharmaceutical, and biological data, (2) nonclinical pharmacological and toxicological data, and (3) clinical data and previous human experience. The supporting data are submitted in the Common Technical Document (CTD) format (see Section 7.11). 

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