This paper discusses the approach, methods, and content of work programs manufacturers in FDA regualted industries must consider to achieve validation of new or modified plant facilities.
When firms in industries regulated by the FDA construct new facilites, change equipment or processes, place new instruments in their laboratories, introduce new methods of electonic documentation, or introduce new sources of critical components into their manufacturing program, they have special requirements to validate such actions in accordance with federal regulations. In most cases the definition of what constitutes validation is quite clear in the regulations and the published guidelines are very helpful. However, for any significant sized project, the validation effort, impact on schedule, and the cost can be substantial. If internal resources are limited or not sufficiently experienced, assistance with validation compliance by an experienced consultant may be very cost effective. The regulatory basis for validation is given in several articles of 21CFR. Careful interpretation is needed to avoid excessive and cumbersome application. Validation is one of the criteria for satisfactory gmp compliance. As such; the extent, scope, and content of an appropriate validation program will vary with the relevant gmp. The range is from little or no validation in cosmetics (except perhaps for water systems) to rigourous and highly structured validation programs in sterile parenteral product plants.
The regulatory basis for validating processes to manufacture drugs in given in 21CFR211.110. While it provides a wide latitude for interpretation of the specific procedures and practicies, it is completely unambiguous as to the fact that the process must be validated. The Part 211.110 words are: To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes.... While this part is written specifically to drug products, the long standing interpretation of the FDA is that these regulations are equally applicable to bulk drugs. To implement a validation program consistent with this regulation there are four critical things that must be done. These are:
As in most business activities, proper planning is at the heart of every succesful undertaking. This is particularly true with validation programs. The principle document used to express the planning effort is the Validation Master Plan. The VMP sets the scope of the validation work and clearly defines all details of administering the program including work responsibilities, approval authorities, documentation standards, change control, and final disposition of the information collected in the program. The masterl VMP sets out the requirement for "qualification" and treats all the sub-parts of the validation work including; cleaning validation, laboratory controls validation, and process validation. Individual planning documents for each of these parts provide the focused requirements for that part of the program, i.e. cleaning, analytical instruments, water system, etc. A validation plan for each of these should be prepared
The Qualification Master Plan is a key document that defines the work of the DQ/IQ/OQ/PQ in terms of the specific protocols, aceptance criteria, and format for data recording. A critical understanding needed in validation programs is that qualification is a pre-requisite for validation. This is defined in the VMP. It is not sufficient to validate a plant process using a plant equipment system that has not been qualified. Indeed, such a "validation" is not adequate since there is no assurance that the plant equipment can perform consistently as designed and installed.
The validation program defined in the VMP must follow an assessment of needs. Volume 5 of the ISPE Pharmaceutical Engineering Guides for New and Renovated Facilities, titled Commissioning and Qualification provides a clear description of the rationale to be applied for this. The planning should distinguish between systems requiring validation in the context of FDA regulation and those that are satifactorily treated by traditional "good engineering practice". The determination of these needs follows from clear understanding of the basis. The ISPE guide lays out planning steps that sequentially evaluate needs and define criteria leading to validation. The process is inteded to ensure that only the critical operations are subjected to validation. The terms applied to these activities are:
The specific work entailed in qualification and validation is in the form of test procedures. Some of these entail real physical measurments and others are simply a verification of an information item. Whatever they are, the requirements must be documented in a written protocol. A properly structured protocol includes a clear description of the object to be tested, the measurements and observations to be recorded, statement of the expected value or outcome of the observation, and a determination of whether the test passed or failed. The protocol should make it clear as to what reference materials, calibrations, source documents, and the like are part of the test. The protocols must be executed exactly as written, or if changed the change is administered in accordance with the approved change procedure. Data entry must be made directly from the observations and should not be copied from other hand recordings. Data entry should be certified by signature of the responsible test person. The fully executed protocol is the formal record of validation and is an important part of the gmp documents to be retained for the facility. They are subject to review in a facility inspection and are an important element in granting approval for operations.
A validation SOP will provide detailed instructions for preparing protocols and establishing the format, change control requirement, approval process, and document management procedure to ensure that only official protocols are used in the validation program and the integrity of the data is maintained over the life of the facility or the process.
While the basic intent of protocol execution is the same in all phases of the qualification and validation program, the actual content of the work is markedly different in each phase.
The Design Qualification protocol is aimed at verifying that appropriate design documents exist for the process unit. Execution of the DQ may consist simply of a checklist of documents on file and a sign-off that the document was inspected and is appropriate for the procurement/installation work related to the item.
The Intallation Qualification protocol is aimed at verifying that the installation followed the design document. Execution of the IQ will consist of inspection of the installed equipment. The protocol format may comprise "green-lining" a drawing to indicate conformance or "red-lining" to show non-conformance.
The Operational Qualification protocol is aimed at verifying that each component of the system works as specified. Execution of the OQ calls for running equipment. This means powering rotating units, filling and emptying vessels, and exercising the operating cycles involved in each piece of equipment. The OQ protocol must incorporate criteria of the performance specifications associated with the equipment. In some types of equipment this will constitute a calibration of the unit. In such cases, attention to the accuracy of test gauges and validity of measurement methods is needed.
The Performance Qualification is aimed at verifying that the system can achieve the operating states needed to run the defined process. Since most drug manufacturing operations are batch processes this leads to a protocol that in effect simulates the batch cycle, temperatures, pressures, batching accuracies, and filling or emptying rates for a model fluid, usually water or a water solution. Succesful "water batching" or "solvent batching" runs will typically complete the qualification plan for a bulk pharmaceutical manufacturing unit.
Protocol execution in the validation phase also takes a somewhat different form depending on the specific object for validation. There is an essential difference between qualification and validation. Execution of the validation protocol entails running the actual process in question. In Process Validation the test data from the validation protocols are actual quality parameters, i.e. purity, physical properties, identity, for the manufactured product obtained from the defined process. The process in this case may be the entire manufacturing scheme, or a critical unit operation such as drying, or sterilizing, etc. In the Analytical Methods Validation the test data are results of analysis on a known sample of the actual product, i.e. correct identity spectra, correct purity level in terms of a chromatogram, wet chemistry method, or whatever the specified analysis entails, and correct detection of impurity at the limit of detection. Validation is aimed at demonstrating reliability and repeatability. Consistency of results through multiple batches is a pre-requisite to demonstrating validdation. For this reason most validation programs require repetitive runs. Typically process validation entails making three consequtive batches successfully without deviation from the defined process.
Implementing a validation program is viewed by many firms on the one hand as just a tedius excercise and by others an almost impossible task. Unquestionably for a plant unit of any size it is a significant amount of work. Firms that are not staffed adequately or not experienced with the details of protocol preparation and execution need assistance. Consulting firms and individual consultants are available to do this. Services offered include:
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