CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS
Process validation is required, in both general and specific terms, by the Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211. Examples of such requirements are listed below for informational purposes, and are not all-inclusive.
A requirement for process validation is set forth in general terms in Section 211.100 -- Written procedures; deviations -- which states, in part:
"There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess."
Several sections of the CGMP regulations state validation requirements in more specific terms. Excerpts from some of these sections are:
Section 211.110, Sampling and testing of in-process materials and drug products.
(a) "....control procedures shall be established to monitor the output and VALIDATE the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product." (emphasis added)
Section 211.113, Control of Microbiological Contamination.
(b) "Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include VALIDATION of any sterilization process." (emphasis added)
VI. GMP REGULATION FOR MEDICAL DEVICES
Process validation is required by the medical device GMP Regulations, 21 CFR Part 820. Section 820.5 requires every finished device manufacturer to:
"...prepare and implement a quality assurance program that is appropriate to the specific device manufactured..."
Section 820.3(n) defines quality assurance as:
"...all activities necessary to verify confidence in the quality of the process used to manufacture a finished device."
When applicable to a specific process, process validation is an essential element in establishing confidence that a process will consistently produce a product meeting the designed quality characteristics.
A generally stated requirement for process validation is contained in section 820.100:
"Written manufacturing specifications and processing procedures shall be established, implemented, and controlled to assure that the device conforms to its original design or any approved changes in that design."
Validation is an essential element in the establishment and implementation of a process procedure, as well as in determining what process controls are required in order to assure conformance to specifications.
Section 820.100(a) (1) states:
"...control measures shall be established to assure that the design basis for the device, components and packaging is correctly translated into approved specifications."
Validation is an essential control for assuring that the specifications for the device and manufacturing process are adequate to produce a device that will conform to the approved design characteristics
VII. PRELIMINARY CONSIDERATIONS
A manufacturer should evaluate all factors that affect product quality when designing and undertaking a process validation study. These factors may vary considerably among different products and manufacturing technologies and could include, for example, component specifications, air and water handling systems, environmental controls, equipment functions, and process control operations. No single approach to process validation will be appropriate and complete in all cases; however, the following quality activities should be undertaken in most situations.
During the research and development (R& D) phase, the desired product should be carefully defined in terms of its characteristics, such as physical, chemical, electrical and performance characteristics.(3) It is important to translate the product characteristics into specifications as a basis for description and control of the product.
Documentation of changes made during development provide traceability which can later be used to pinpoint solutions to future problems.
The product's end use should be a determining factor in the development of product (and component) characteristics and specifications. All pertinent aspects of the product which impact on safety and effectiveness should be considered. These aspects include performance, reliability and stability. Acceptable ranges or limits should be established for each characteristic to set up allowable variations.(4) These ranges should be expressed in readily measurable terms.
The validity of acceptance specifications should be verified through testing and challenge of the product on a sound scientific basis during the initial development and production phase.
Once a specification is demonstrated as acceptable it is important that any changes to the specification be made in accordance with documented change control procedures.
VIII. ELEMENTS OF PROCESS VALIDATION
Prospective validation includes those considerations that should be made before an entirely new product is introduced by a firm or when there is a change in the manufacturing process which may affect the product's characteristics, such as uniformity and identity. The following are considered as key elements of prospective validation.
The equipment and process(es) should be designed and/or selected so that product specifications are consistently achieved. This should be done with the participation of all appropriate groups that are concerned with assuring a quality product, e.g., engineering design, production operations, and quality assurance personnel.
a. Equipment : Installation Qualification
Installation qualification studies establish confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. After process equipment is designed or selected, it should be evaluated and tested to verify that it is capable of operating satisfactorily within the operating limits required by the process.(5) This phase of validation includes examination of equipment design; determination of calibration, maintenance, and
adjustment requirements; and identifying critical equipment features that could affect the process and product. Information obtained from these studies should be used to establish written procedures covering equipment calibration, maintenance, monitoring, and control.
In assessing the suitability of a given piece of equipment, it is usually insufficient to rely solely upon the representations of the equipment supplier, or upon experience in producing some other product.(6) Sound theoretical and practical engineering principles and considerations are a first step in the assessment.
It is important that equipment qualification simulate actual production conditions, including those which are "worst case" situations.
Tests and challenges should be repeated a sufficient number of times to assure reliable and meaningful results. All acceptance criteria must be met during the test or challenge. If any test or challenge shows that the equipment does not perform within its specifications, an evaluation should be performed to identify the cause of the failure. Corrections should be made and additional test runs performed, as needed, to verify that the equipment performs within specifications. The observed variability of the equipment between and within runs can be used as a basis for determining the total number of trials selected for the subsequent performance qualification studies of the process.(7)
Once the equipment configuration and performance characteristics are established and qualified, they should be documented. The installation qualification should include a review of pertinent maintenance procedures, repair parts lists, and calibration methods for each piece of equipment. The objective is to assure that all repairs can be performed in such a way that will not affect the characteristics of material processed after the repair. In addition, special post-repair cleaning and calibration requirements should be developed to prevent inadvertent manufacture a of non-conforming product. Planning during the qualification phase can prevent confusion during emergency repairs which could lead to use of the wrong replacement part.
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This should be done with the participation of all appropriate groups that are concerned with assuring a quality product, e.g., engineering design, production operations, and quality assurance personnel.
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