A Guide to Good Validation Practices (Second Edition)
A Guide to Good Validation Practices (Second Edition)
Product Type: Market Report
Published Date: December 2004
Published By: Drug & Market Development
Page Count: 133
Order Code: R294-0124
Print Copy $395
The regulatory authorities, when examining the submissions from drug manufacturers for permission to proceed to clinical trial (e.g. USA IND), or to market the product (NDA), are placing increasing emphasis on adequate validation documentation. This documentation must demonstrate that all critical activities that may affect the safety, purity or efficacy of the product are properly defined, controlled and reproducible in performance. Validation requirements may be applied to the manufacturing facility, its critical services and systems, the manufacturing processes, and all analytical test methods used to demonstrate the conformation of the product with its pre-set specifications.
The major emphasis in drug product development in these competitive times is on the reduction of "time to market". It follows that delays to clinical trial initiation or product approval resulting from validation non-compliance will adversely affect the company's cash flow and competitive position. They will make the timely retrieval of the high development and clinical testing costs that much more difficult. In addition, the failure to provide satisfactory documentation of processes involved in the production and testing of a marketed product can result in product recalls and even legal action against the company by the regulatory authorities.
Although regulatory agencies in North America and Europe have issued guidelines on validation methods, this special legislation has been the subject of much discussion in the professional press and at specialist conferences. The means, whereby, validation may be achieved in particular cases, especially in the production of biopharmaceuticals, are not always clear. For these reasons, this guide is devoted to considering in greater detail the ways of complying with validation requirements at all stages of drug research, development and manufacture. The particular problems associated with the newer biopharmaceutical products are given special consideration.
The definitions currently accepted for the validation process may be summarized by stating that "validation provides documentary evidence that the operation of a system, process, or analytical test method produces the required result reliably and reproducibly, and that this fact can be well documented as a result of testing the performance". The problems associated with validation often revolve around the tests that must be performed in order to demonstrate this reliability, and the interpretation of the results. The problems are highlighted by the fact that "failure to validate" is a term often encountered in the FDA Form 483 reports which are written at the end of the inspection of a regulated facility. In fact, a recent report lists this problem as number 3 in the top 10 subjects for 483 citations.
Validation is now realized not to be a one-time event in the development and finalization of a particular process or analytical method. A proper program for validation, especially of processes, must include a "life cycle" approach. The ongoing monitoring of manufacturing processes is a key element in this process. Priorities in validation must be based upon an accepted risk evaluation process, with those processes posing the greatest potential for risk to the integrity of the product being given the highest priority. Three types of validation procedures are generally recognized. Their application is most often based upon the validation of production processes according to the stage of development of the drug product, but a similar approach may be taken to analytical test method validation.
Prospective Validation is the most valuable procedure. It is performed during the development of the product, before GMP manufacture commences. The validation plan is derived by performing an analysis of the potential for failure and risk to the product inherent in each proposed production process. Each individual production step is evaluated on the basis of past experience and knowledge of the engineering and science involved. Concurrent validation is performed during routine production, usually in the start-up phase. This method is acceptable if the development process has yielded a full understanding of all the production steps. At least three consecutive production-scale batches are monitored as comprehensively as possible.
Retrospective Validation involves the examination of past experience of production. It assumes that, during the period under examination, the materials, processes, and equipment involved have remained unchanged. This is in itself a dangerous assumption, unless the process has been extremely thoroughly documented and all batch records are absolutely reliable. Revalidation should be performed if any change capable of affecting product quality is introduced. Such changes may include those in raw materials, manufacturing processes, packaging components (especially containers and closures), equipment, in-process controls, or manufacturing areas and the specialized systems therein, such as purified water and filtered air supplies. An integral part of quality assurance is therefore the maintenance of an effective change control procedure.
Planning is the most important part of validation. The Validation Master Plan (VMP) provides a framework and operating procedures for the qualification of the facility's utilities and systems, the process and test equipment, the computer systems which may control the equipment, and the information management systems for laboratories and production facilities. It will specify the risk evaluation methods to be used. Or, if this has already been done, it will use the evaluation to place the systems, processes, and tests in some form of validation priority. Although the Good Practice regulations do not specifically require a VMP, the FDA usually expects to see one in place, as evidence of the company's overall commitment to compliance and of a rational, wellcontrolled approach to the validation task, with realistic time frames.
The specifications, designs, materials, and mode of operation of most pharmaceutical and biological manufacturing plants and their environmental control systems can be expected to affect areas or procedures involved in the quality of the product. As a result, validation will start with these. The systematic approach to this task is detailed in the following chapters. Emphasis is also placed on the validation of the cleaning and sanitization/sterilization of installed pipework. This is an area often given special attention by regulatory inspectors.
The most common requirement for validation procedures is that applied to the manufacturing processes. All GMP regulations and guidelines are directed towards assuring that every critical process affecting the integrity of the product is validated. This is particularly the case for biologicals and biopharmaceuticals, where final testing of the product is not sufficient to guarantee compliance with product specifications. Process validation must be based upon full understanding of the scientific and engineering principles involved in the process. This understanding is developed during the product development and process scale-up stages.
At this stage in the development process, scaled-down models can be used to examine the effect of various process parameters and to define the control limits. It must be shown, however, that the results of scaled-down experiments can be reliably applied to full-scale operations. By the time a process is to be validated, the process control parameters should have been defined and the process fixed. The scientific rationale for the validation protocol and acceptance criteria must be documented. A key objective of the validation should be to ensure that the process does not operate too close to the failure limits of any critical parameter.
The requirement to ensure adequate validation of analytical methods is a more recent addition to the North American and international GMP regulations. The accuracy, sensitivity, specificity, and reproducibility of test methods used by a manufacturer are now required to be validated and documented. And, the suitability of all testing methods used must be verified under actual conditions of use. The ICH guidelines and two new FDA guidances on the validation of analytical procedures have been used as the basis for the advice on method validation which is given in this guide.
All successful validation processes depend upon adequate documentation of the original plans, the validation protocols, the data obtained during the validation runs and the conclusions drawn from the analysis of these data. This dependency is recognized in every section of this work and sample forms and check-lists are provided to assist in the task of assembling the documents which will be generated.
To complete this comprehensive guide to validation and its problems, full texts are provided of the major guidelines issued by National and International regulatory authorities, along with the relevant abstracts from the GLP, GMP, and GCP regulations. Other references include Web sites for the retrieval of the text of regulations and guidelines, a list of useful publications, and of some well-known firms specializing in validation consulting.