Pharmaceuticals process validation procedure

Process validation is the procedure that allows one to establish the critical operating parameters of a manufacturing process. Hence, the constraints imposed by the FDA as part of process control and validation of an SMB process. The total industrial SMB system, as described, is a continuous closed-loop chromatographic process, from the chromatographic to recycling unit and, with the use of numerical simulation software allows the pharmaceutical manufacturer rapidly to design and develop worst-case studies. 

In a pharmaceutical laboratory environment, system validation for analytical instrumentation is certainly both a value and a burden. Albeit a valuable procedure, it is a process that requires considerable time and resource expenditure. Part of the latter concern is exacerbated by the fact that many laboratories are not quite sure about what exactly is required. In this chapter, the system validation terms will be defined, the responsibilities and requirements will be brought into better focus and recommended procedures will be described. This is intended to help relieve the actual burden of the process for those on-site individuals who are directly involved with the drafting and implementation of the validation procedures. The recommendations herein are provided as guidance to help streamline the actual procedures in an effort to keep both the time and financial expenditures to a minimum. 

This procedure provides the information required to support the sterility assurance of the drug product (product name), USP, manufactured by ABC Pharmaceutical Industries. It references the FDA Guidance titled Guidance for Industry for the Submission of Documentation for Sterilization Process Validation in Applications for Human and Veterinary Dmg Products prepared by the Sterility Technical Committee of the Chemistry Manufacturing Controls Coordinating Committee of the Center for Dmg Evaluation and Research (CDER) and the Center for Veterinary Medicine (CVM) in November of 1994. 

In the present chapter, the pharmaceutical industry validation system has been reviewed. To have an appropriate validation system it is first required to define which equipment, facilities, and processes will be validated, when they will be validated, and by whom this must be performed. This definition is based on a risk assessment priority and is written in a specific document, the so-called MVP. In order to generate an adequate validation report, all the validation activities should be described in the validation protocols, SOPs, and specific procedures. 

Syed Imtiaz Haider has a Ph.D. in chemistry and is a quality assurance specialist with over 10 years of experience in aseptic and nonaseptic pharmaceutical processes and equipment validation, in-process control, and auditing. Dr. Haider is the author and co-author of more than 20 research publications in international journals dealing with products of pharmaceutical interest, their isolation, and structure development. He is a professional technical writer and author of more than 500 standard operating procedures based on FDA regulations, ISO 9000, and ISO 14000 standard. 

This introduction was written to aid scientists and technicians in the pharmaceutical and allied industries in the selection of procedures and approaches that may be employed to achieve a successful outcome with respect to product performance and process validation. The authors of the following chapters explore the same topics from their own perspectives and experience. It is hoped that the reader will gain much from the diversity and richness of these varied approaches. 

The concept of validation came up in the 1970s in association with sterilization procedures and was extended to all steps of pharmaceutical manufacturing procedures. Validation means proving that any and all procedures, processes, equipment, material, operations, and systems comply with the expected performance. Well-planned and well-conducted validation studies constitute GMP principles once they guarantee a consistently safe and efficacious final product. Validation is important for companies, first for QA, and also for cost reduction, decreasing failures, rejection, reworks, recalls, and complaints. The positive aspect of validation is an increase in productivity, as a consequence of a well-controlled process. Validation is required by the regulatory agencies of many countries. 

The best approach to assessing problems with respect to a terminal sterilization method (i.e., moist heat, dry heat, radiation, and chemical methods) is to first establish the qualification, validation and stability of the pharmaceutical process prior to conducting a given sterilization procedure. 

In the area of pharmaceutical industries in most countries, validation of manufacturing processes and supporting functions is the fundamental issue for the quality assurance of products. Analytical methods and procedures are associated with most evaluation activities in this field. Analytical validation is an essential prerequisite for any evaluation work during process validation,... 

Cleaning validation tests are performed to ascertain the effectiveness of the procedure used to clean pharmaceutical processing equipment (e.g., blender,... 

In the study of thermal stability, accelerated testing in the form of elevated temperatures has been used by many pharmaceutical companies to minimize time involved in the testing process. This procedure is only valid for simple formulations in which the single major ingredient is broken down by a thermal reaction. In practice, regulatory authorities demand that a shelf-life determined by extrapolation of accelerated test data should be supported by actual stability data obtained by normal temperature storage (Carstensen, 1995). This is because degradation of a product by microbial contamination may well be inhibited at elevated temperatures. 

Elucidation of how the general principles underlying the concept of validation should be expressed in practice is an evolving process, as exemplified by the ongoing evolution of validation requirements for bioanalytical assays in the pharmaceutical industry (Shah 1992, 2000 FDA 2001 Viswanathan 2007). The complementary principle of fitness for purpose (Section 9.2) applies not only to the assay method but also to the validation process itself. Procedures that are considered to be fit for purpose in validation of an analytical method to be used in drug development, for example, need not necessarily apply to, e.g., methods used to screen pesticide residues in foodstuffs. As noted in Section 9.2, this point of view appears to be consistent with the definition of validation applied to all measurements (ISO 1994) Validation Confirmation by examination and provision of objective evidence that the particular requirements for a specified intended use are fulfilled. Of course, some basic principles are common to all validation schemes. 

In one respect, decontamination following freeze-drying of a known pathogen is a more simple procedure than general decontamination of a freeze-drier for pharmaceutical processing since the nature of the pathogen or toxin will be known and its sensitivity to a particular biocide can be experimentally validated. 

Comprehensive physicochemical characterization of any raw material is a crucial and multi-phased requirement for the selection and validation of that matter as a constituent of a product or part of the product development process (Morris et al., 1998). Such demand is especially important in the pharmaceutical industry because of the presence of several compounds assembled in a formulation, such as active substances and excipients, which highlights the importance of compatibility among them. Besides, variations in raw materials due to different sources, periods of extraction and various environmental factors may lead to failures in production and/or in the dosage form performance (Morris et al., 1998). Additionally, economic issues are also related to the need for investigating the physicochemical characteristics of raw materials since those features may determine the most adequate and low-cost material for specific procedures and dosage forms. 

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. 

Several key issues have to be addressed in the downstream processing of biopharmaceuticals regardless of the expression system. The removal of host cell proteins and nucleic acids, as well as other product- or process-related or adventitious contaminants, is laid down in the regulations and will not differ between the individual expression hosts. The identity, activity and stability of the end product has to be demonstrated regardless of the production system. The need for pharmaceutical quality assurance, validation of processes, analytical methods and cleaning procedures are essentially the same. 

In addition to equipment, many processes/procedures undertaken during pharmaceutical manufacture are also subject to periodic validation studies. Validation of biopharmaceutical aseptic hlling procedures is amongst the most critical. The aim is to prove that the aseptic procedures devised are capable of delivering a sterile bnished product, as intended. 

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