Product file process validation

Validation data should be generated for all products to demonstrate the adequacy of the manufacturing process. The process validation data may not always be available, however, where the manufacturing process uses a nonstandard method of manufacture. Data demonstrating the validity of that method should be submitted in the marketing authorization file. 

A program to ensure control of critical system documentation will be established. The files will be controlled by QA. Validation and centralized for easy retrieval. Equipment validation data such as operating and service manuals, purchase orders, manufacturer specifications, as-built drawings and schematics, spare parts lists, and any other information pertaining to the system will be included in the file. Separate validation files for Facility, Systems, and Process validation of each product, including all related data, will be maintained. Procedures will be developed to create files for new equipment, update information for existing equipment, control, removal, and return of information, etc. 

C3 Be able to draw up drug-preparation protocols and product files that meet the technical, biopharmaceutical and other relevant quality standards C4 Be able to design, set up and validate (including shelf-life tests) non-sterile, aseptic and sterile preparation processes and implement them... 

This part of the product file contains information about the validation of the preparation process and the method of analysis. It gives the rationale for the method of preparation, with validation data and any changes that have been carried out, and describes, where applicable, the background for the quality specifications of the preparation. 

Validation is the process of collecting documented evidence that the method performs according to the intended purpose. " The validation characteristics and the acceptance criteria to be applied in validation of HPLC methods for MAA/NDA filings and marketed products should comply with the international guidelines on method validation. Table 11 details validation activities to be conducted for type 1, type 2, and type 3 methods ... 

FDA inspectors are instructed to look for any differences between the process filed in the application and the process used to manufacturer the bio/clinical batch. Furthermore, one of the main requirements of a manufacturing process is that the process will yield a product that is equivalent to the substance on which the biostudy or pivotal clinical study was conducted. Validation of the process development and scale-up should include sufficient documentation so that a link between the bio/clinical batches and the commercial process can be established. If the process is different after scale-up, the company has to demonstrate that the product produced by a modified process will be equivalent, using data such as granulation studies, finished product test results, and dissolution profiles. 

As a potential product moves through the various developmental stages, information is continually generated and incorporated into a master documentation file. When the validation runs are planned for the final process, they will be based on the master documentation file contents. The information generated during the validation runs is usually the last major item to go into the master documentation file. 

A fundamental objective of a computer system applied to automate a pharmaceutical GMP operation is to ensure the quality attributes of the drug product are upheld throughout the manufacturing process. It is therefore important that quality-critical parameters are determined and approved early in the validation life cycle. The exercise should be undertaken to a written procedure with base information from the master product/production record file examined and quality-critical parameter values and limits documented and approved for the process and its operation. In addition, the process and instrument diagrams (P IDs) should be reviewed to confirm the measurement and control components that have a direct impact on the quality-critical parameters and data. This exercise should be carried out by an assessment team made up of user representatives with detailed knowledge of both the computer system application and process, and with responsibility for product quality, system operational use, maintenance, and project implementation. This exercise may be conducted as part of an initial hazard and operability study (HAZOP) and needs to confirm the quality-related critical parameters for use in (or referenced by) the computer control system URS. 

The garments used by the workers should be made of synthetic fabrics that minimize contamination risks. Operators should be trained for their work and also for the maintenance of clean conditions and hygiene. Cleaning is a key factor in the maintenance of good conditions and reduces or eliminates potential contaminants that can affect the product. Contaminants can have various sources live particles, inert particles (dusts, glass, file dust, lubricants, etc.) or cross-contamination when different processes or products share the same clean area. To avoid problems, the cleaning procedures should be written and approved, validated, and executed by trained operators. 

Regarding the validation of computerized spreadsheets used for in process and finished product analytical calculations (FDA-483, 4), your response states fiiat current spreadsheets were challenged using the proposed revisions to SOP 644, QA/QC Computer Spreadsheet Validation. However, your response does not indicate if computerized spreadsheets for all products which use file spreadsheets were challenged using the proposed revisions to SOP 644. 

Regarding the failure to use fully validated computer spreadsheets to calculate analytical results for in-process and finished product testing (FDA-483, item 5), your response states fiiat old spreadsheets will be revalidated according to file proposed revisions to SOP 644 prior to being implemented into use. You identify that SOP 644 will not be revised until July 20, 2001. 

Profile This privately held company was founded in 1972. It is a full-service drug synthesis and chemical services company that performs a variety of laboratory, process scale-up, and manufacturing tasks including development of processes and synthesis routes for new medicinal products, validating bulk pharmaceutical processes, and authoring Drug Master Files. The company also has a pilot plant/small volume manufacturing site in North Andover, Massachusetts. 

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