Guide to Good Validation Practice

The major emphasis in drug product development in these competitive times is on the reductionof "time to market". It follows that delays to clinical trial initiation or product approval resulting,for example, from validation non-compliance, will adversely affect the company's cash flow andcompetitive position. They will make the return on the high development and clinical testing coststhat much more difficult. In addition, the failure to provide satisfactory documentation ofprocesses involved in the production and testing of a marketed product can result in productrecalls and even legal action against the company by the regulatory authorities.

Moreover, the regulatory authorities are placing increasing emphasis on adequate validationdocumentation in new drug applications. This is being applied to the submissions from drugmanufacturers for permission to proceed to clinical trial (e.g. USA IND), as well as those to marketthe product (NDA),. This documentation must demonstrate that all critical activities that mayaffect the safety, purity or efficacy of the product are properly defined, controlled andreproducible in performance. Validation requirements may be applied to the manufacturingfacility, its critical services and systems, the manufacturing processes, and all analytical testmethods used to demonstrate the conformation of the product with its pre-set specifications.

Although regulatory agencies in North America and Europe have issued guidelines on validationmethods, the means whereby validation may be achieved in particular cases, especially in theproduction of biopharmaceuticals, are not always clear. The Process Validation Guideline from1987 is being revised by the FDA and a new draft is expected soon. The revision will be basedupon the concepts of the revised Compliance Policy Guide 7132c.08 Sec. 490.100: "ProcessValidation Requirements for Drug Products and Active Pharmaceutical Ingredients subject to Pre-Market Approval", issued in March 2004.

Validation is now considered not to be a one-time event in the development and finalization of aparticular 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 keyelement in this process. Priorities in validation must be based upon an accepted risk evaluationprocess, with those processes posing the greatest potential for risk to the integrity of the productbeing given the highest priority. This will involve the application of the concept of Quality byDesign, emphasized in new guidances on Quality Management Systems and Process AnalyticalTechnology. Life-cycle validation will be achieved by gathering complete product/processknowledge, establishing a "continuous quality verification system" and a successfulmonitoring/assessment program to address effective process control and continuousimprovement as the key factors for reducing the risk to the product quality.

For these reasons, this guide is devoted to considering in greater detail the ways of complyingGood Validation Practice with validation requirements at all stages of drug research, development and manufacture. Theparticular problems associated with the newer biopharmaceutical products are given specialconsideration.

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 analyticaltest method produces the required result reliably and reproducibly, and that this fact can be welldocumented as a result of testing the performance". The problems associated with validation oftenrevolve around the tests that must be performed in order to demonstrate this reliability, and theinterpretation of the results. The problems are highlighted by the fact that "failure to validate" is aterm often encountered in the FDA Form 483 reports which are written at the end of the inspectionof a regulated facility. In fact, a recent report lists this problem as number 3 in the top 10 subjectsfor 483 citations.

Three types of validation procedures are generally recognized. Their application is most oftenbased upon the validation of production processes according to the stage of development of thedrug 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 ofthe product, before GMP manufacture commences. The validation plan is derived by performingan analysis of the potential for failure and risk to the product inherent in each proposedproduction process. Each individual production step is evaluated on the basis of past experienceand knowledge of the engineering and science involved. Concurrent validation is performedduring routine production, usually in the start-up phase. This method is acceptable if thedevelopment process has yielded a full understanding of all the production steps. At least threeconsecutive production-scale batches are monitored as comprehensively as possible.

Retrospective Validation involves the examination of past experiences of production. It assumesthat, during the period under examination, the materials, processes, and equipment involved haveremained unchanged. This is in itself a dangerous assumption, unless the process has beenextremely thoroughly documented and all batch records are absolutely reliable.

Revalidation should be performed if any change capable of affecting product quality isintroduced. Such changes may include those in raw materials, manufacturing processes,packaging components (especially containers and closures), equipment, in-process controls, ormanufacturing 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 aframework and operating procedures for the qualification of the facility's utilities and systems, theprocess and test equipment, the computer systems which may control the equipment, and theinformation management systems for laboratories and production facilities. It will specify the riskGood Validation Practice evaluation methods to be used. Or, if this has already been done, it will use the evaluation to placethe systems, processes, and tests in some form of validation priority. Although the Good Practiceregulations do not specifically require a VMP, the FDA usually expects to see one in place, asevidence of the company's overall commitment to compliance and of a rational, well-controlledapproach to the validation task, with realistic time frames.

The specifications, designs, materials, and mode of operation of most pharmaceutical andbiological manufacturing plants and their environmental control systems can be expected to affectareas or procedures involved in the quality of the product. As a result, validation will start withthese. The systematic approach to this task is detailed in the following chapters. Emphasis is alsoplaced on the validation of the cleaning and sanitization/sterilization of installed pipework. Thisis an area often given special attention by regulatory inspectors.

The most common requirement for validation procedures is that applied to the manufacturingprocesses. All GMP regulations and guidelines are directed towards assuring that every criticalprocess affecting the integrity of the product is validated. This is particularly the case forbiologicals and biopharmaceuticals, where final testing of the product is not sufficient toguarantee compliance with product specifications. Process validation must be based upon fullunderstanding of the scientific and engineering principles involved in the process. Thisunderstanding 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 ofvarious process parameters and to define the control limits. It must be shown, however, that theresults of scaled-down experiments can be reliably applied to full-scale operations. By the time aprocess is to be validated, the process control parameters should have been defined and theprocess fixed. The scientific rationale for the validation protocol and acceptance criteria must bedocumented. A key objective of the validation should be to ensure that the process does notoperate too close to the failure limits of any critical parameter.

The requirement to ensure adequate validation of analytical methods is a more recent addition tothe North American and international GMP regulations. The accuracy, sensitivity, specificity, andreproducibility of test methods used by a manufacturer are now required to be validated anddocumented. And, the suitability of all testing methods used must be verified under actualconditions of use. The ICH guidelines and two new FDA guidances on the validation of analyticalprocedures have been used as the basis for the advice on method validation which is given in thisguide.

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 drawnfrom the analysis of these data. This dependency is recognized in every section of this work andsample forms and check-lists are provided to assist in the task of assembling the documents whichGood Validation Practice will be generated.

To complete this comprehensive guide to validation and its problems, full texts are provided ofthe major guidelines issued by National and International regulatory authorities, along with therelevant abstracts from the GLP, GMP, and GCP regulations. Other references include web sitesfor the retrieval of the text of regulations and guidelines, a list of useful publications, and of somewell-known firms specializing in validation consulting.