Validation documentation

Ensure that the management level approvals have been secured for the appropriate validation documents. 

In the Validation Documentation Inspection Guide, US Department of Health and Human Services, Food and Drug Administration, 1993 the process validation is defined as ... 

Extraction, Isolation, and Purification Process Types Process Validation Documentation Validation... 

There can be e.g. a master list of all valid documents together with their revision status in the quality manual (or in a separate document)... 

The method validation procedure should always be documented in order to give evidence of method performance. Proper documentation has an influence on the consistency and subsequent reproducibility, which, at the final stage affect the uncertainty contribution. The information in the validation documents should be clear and easily understood by everyone who uses the method. 

System validation documentation has been collected, including evidence of requirements and design approvals, testing, and implementation. Emphasis is placed... 

If all requirements have been satisfied and all validation documents have been approved, the quality assurance managers may release the water system for production use. 

The purpose is to provide guidelines for keeping the record of literature cited in validation documents. 

Validation Documentation Inspection Guide, Interpharm Press, Buffalo Grove, IL, 1993-... 

Record Management Describe the format, numbering sequence, revision, version control, and storage of the validation documentation. 

For simple analytical instruments, a simple table to summarize the qualification testing, acceptance criteria, results, and pass/fail decision of the tests will be sufficient since there are fewer tests that are required and the tests are usually relatively simple. For complex analytical systems, a more complex table often referred to as a traceability matrix which traces the requirements, testing, acceptance criteria, test results, and storage locations of the validation documents, test data, and other supporting documents is usually included in the summary report for easy reviewing and quick references. 

Documentation Validation documents are current and the requirements are being met by the instrument, SOPs, operation manuals, business continuity plan, and location of the documents. 

Validation Team A well-defined validation team with a well-written description of responsibilities is required and assures the adequate realization of the validation tasks. A validation team should be composed by different responsibilities responsible-of-validation team, team leader, archive manager, test coordinator, quality assurance member, tester, and witness. The responsible-for-validation team elaborates and approves the VMP, protocols, and reports. The team leader should be responsible for the computer system validation and utilization. An archive manager is responsible for the management of all computer system validation documents. The test coordinator is responsible for the computer system test and coordinates the elaboration and operation of tests for evaluating the performance of the computer system. A quality assurance member is required to periodically inspect and train the personnel and review all the validation documents. The tester is responsible for the execution of the tests required to perform the validation protocol. The witness is responsible for observing and reviewing the operations of the tester. 

Limit of detection (LOD) sounds like a term that is easily defined and measured. It presumably is the smallest concentration of analyte that can be determined to be actually present, even if the quantification has large uncertainty. The problem is the need to balance false positives (concluding the analyte is present, when it is not) and false negatives (concluding the analyte is absent, when it is really present). The International Union of Pure and Applied Chemistry (IUPAC) and ISO both shy away from the words limit of detection, arguing that this term implies a clearly defined cutoff above which the analyte is measured and below which it is not. The IUPAC and ISO prefer minimum detectable (true) value and minimum detectable value of the net state variable, which in analytical chemistry would become minimum detectable net concentration. Note that the LOD will depend on the matrix and therefore must be validated for any matrices likely to be encountered in the use of the method. These will, of course, be described in the method validation document. 

How do you prepare for an audit of the environmental chambers In preparing for an audit, it is necessary that all validation documents be readily available for inspection. If these documents are stored off-site, arrangements should be made to retrieve these documents in time for the inspection. In addition, all chamber deviations should be identified and summarized in an annual report, if necessary. Also, the chamber inventory should be verified against existing records to ensure accuracy. An explanation should be available to explain any inventory discrepancies. 

Documentation must be complete. On completion of equipment qualification and system validation, documentation should be available that consists of the following ... 

The primary focus during validation is validation of the content of the spreadsheet itself. Nevertheless, items such as location of storage, security of cells and file, as well as access to the file have to be taken into account. The general validation approach for spreadsheets is not different from other validation approaches and can be arranged in three general sections (1) validation plan, (2) execution of the plan, and (3) validation documentation (protocol). 

The review and approval (system acceptance) will include information about the approvers. All validation documents have to be reviewed and approved with involvement of the quality assurance unit. Figure 18.12 is an example. 

The categories listed above require qualification and validation documentation. It is advisable that process automation and companion computer-integrated manufacturing operations not be initiated until sufficient prospective and concurrent validation studies have been completed. 

Unfortunately, there is still much confusion as to what process validation is and what constitutes process validation documentation. At the beginning of this introduction several different definitions for process validation were provided, which were taken from FDA guidelines and the CGMPs. Chapman calls process validation simply organized, documented common sense [6], Others have said that it is more than three good manufactured batches and should represent a lifetime commitment as long as the product is in production, which is pretty much analogous to the retrospective process validation concept. 

In-process monitoring of critical processing steps and end-product testing of current production can provide documented evidence to show that the manufacturing process is in a state of control. Such validation documentation can be provided from the test parameter and data sources disclosed in the section on retrospective validation. 

The reader should realize that there is no one way to establish proof or evidence of process validation (i.e., a product and process in control). If the manufacturer is certain that its products and processes are under statistical control and in compliance with CGMP regulations, it should be a relatively simple matter to establish documented evidence of process validation through the use of prospective, concurrent, or retrospective pilot and/or product quality information and data. The choice of procedures and methods to be used to establish validation documentation is left with the manufacturer. 

The focus then shifts to a discussion of transdermal process validation. This particular discussion will share a method for completing this critical step. Although the method for completing validation for transdermals is important, there are two other items that must not be forgotten validation documentation and the establishment of a solid change control program. Later sections of this chapter will discuss each area in adequate detail. As the chapter draws to a... 

For example, most companies would rather reference their supporting documents than have FDA ask whether or not a particular document exists. Further, this practice will assure that the company has actually taken sufficient time and prepared the document referenced. There are those companies that prefer to voluntarily attach the documents rather than just reference them. This may not be in the best interest of CGMP manufacturers for two clear reasons. First, attaching every development report, every batch record, every analytical method, every support protocol/report and so forth will make a process validation document—a hefty document to begin with—too big to read. Second, volunteering any information is considered very dangerous, as it is very rare for a company to have no dirty laundry. Why hang it out for FDA or any audience to see ... 

Therefore, the recommendation is that the process validation document be used as a guide document, referencing support documents as appropriate, as illustrated in Figure 16. 

Figure 16 Schematic detailing how process validation document references other support documents. 

Labeling. The labeling section simply discusses how labels will be prepared and with what information. Typically the batch number, the validation document number, the validation sequence or event number (run x of y), the sample number (or other descriptive information e.g., sample type and/or time), and of course the date that sampling occurred are recorded on a validation label. 

Theoretically, every unit operation conducted in the plant comes under the CGMP umbrella, and is therefore subject to the need for validation documentation requirements. This includes not only the final API but also the manufacture of the final intermediate(s) (or main reactants), key intermediates that are used to prepare the final intermediate(s), all the way back to commercial starting materials that enter the plant, as well as the pivotal intermediates thereafter. 

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