Biotech firms can validate buildings even before completion, and equipment; VMP suggested.

SAN DIEGO -- A biopharmaceutical manufacturing facility manager and consultant advised a conference here Nov. 1 how to control and document the CBER validation process, beginning well before the building is open for business.

Addressing the WilBio Facilities for Mammalian Cell Products conference, Ernest A. Bognar, VP of manufacturing of AppTec in Philadelphia, said "a production facility doesn't need to be finished to begin the GMP validation process." (See related AppTec 483, page 11.)

Bognar said he was responsible for the construction of AppTec's 75,000-square-foot facility housing testing laboratories for biopharmaceuticals, as well as a mammalian cell culture GMP production facility for monoclonal antibodies and therapeutic proteins.

The basis for building a facility designed to meet FDA standards is a comprehensive validation master plan (VMP), he noted. Bognar said this document should cover testing and production operations, and is developed with construction sequencing in mind. He said it should be used as a "driver for required documentation, scheduling and sequencing for both construction and start-up."

To ensure clean utilities and production equipment that meet validation standards, Bognar recommended using equipment validation master plans (EVMP) as part of the VMP for the facility.

He said each EVMP should document the specified equipment, system (such as, the building HVAC system), or process in sufficient detail to define its indicated use and boundaries. It should provide the validation approach and acceptance criteria as guidance for generating procedural and inspection protocols. "The sooner you can establish acceptance criteria, the sooner you can execute your plan," Bognar said.

Validating a new manufacturing facility can involve thousands of test articles to demonstrate that its physical plant as well as its processes for personnel, manufacturing, cleaning, packaging, storing, etc., meet all applicable FDA requirements, such as, the agency's electronic records rule (21 CFR Part 11). Bognar said: "Logistics and planning play a major role in minimizing errors and lost time in all areas, including procurement, execution and documentation. Support documentation is absolutely critical for cleaning, training and equipment logs."

Jesse Gillikin, president and CEO of cGMP Validation, Mission, KS, acknowledged that manufacturers employ many approaches and strategies in the commissioning and qualification of a new facility in his remarks on Nov. 3.

Gillikin advised biotech companies to "keep it simple and leverage pre-validation data" in documentation where appropriate and applicable.

He stressed that appropriate documentation starts pre-construction--during the design phase. Changes made to the design during construction are almost inevitable and must be documented.

Besides defining the flow of personnel, materials, waste and air in the facility, as well as specifying room classification, the VMP must define "mechanically complete" for the plant. Not only does this mean that equipment has been installed and is secure, but also that all valves have been tagged with appropriate IDs, and all instruments have been tagged and calibrated. If these items are left pending, argued Gillikin, they can cause deviations and delays during commissioning and validation.

Pre-validation activities may include factory acceptance testing (FAT)--typically performed for large equipment and automation systems, such as spray ball testing for tank systems.

When site acceptance testing (SAT) is performed, Gillikin advised repeating some of the FAT, especially if there are concerns that something could have changed or been altered during shipment.

Commissioning assures that equipment is installed and functions properly. I/O points verification and loop tuning is standard. "Poor commissioning negatively impacts the validation effort and can result in persistent compliance problems," Gillikin said.

During start-up, studies determine how well equipment meets functional specs; assess operating range, "warm up" times and cycle times; and load configurations for certain equipment, such as autoclaves, depyrogenation ovens and tunnels, lyophilizers, etc.

"Commissioning and startup schedules must be realistic," said Gillikin. The various disciplines must have adequate tools to monitor progress. Quality assurance should be involved and approve the test procedures and results.

"Good documentation practices must be maintained, especially if results of these tests are to be used in lieu of validation," noted Gillikin. "All pre-validation activities must have pre-approved test procedures, training and operator protocols, and acceptance criteria. If these are written correctly, performed correctly, and test results pass acceptance criteria, then a lot of this data may be used in lieu of validation."

Lastly, during validation of installation qualifications, operational qualifications, and performance qualifications, there must be formal protocols to test, and documentation should include manuals, drawings, etc. Process validation should be performed after utilities, equipment and computers have been validated.