The qualification and validation of complex pharmaceutical manufacturing facilities requires the careful coordination of multiple
activities. Conceptual, preliminary, and detailed designs must be reviewed to ensure compliance with current good manufacturing
practices (CGMPs); protocol and standard operating procedure (SOP) formats must be developed; and project resources must be
identified and obtained. A validation schedule must be created and integrated with the facility construction schedule. The
Quality Assurance and Calibration–Metrology departments must be notified of impending increased workloads. And finally, the
manufacturer should alert the local US Food and Drug Administration district office that a new facility is planned. Considering
all these activities, careful planning and cautious management will increase the likelihood of a successful project outcome,
no matter how difficult or complicated the project. Successful project completion is never guaranteed, but by implementing
proven techniques and the programs described in this article, a favorable end-result is much more likely.
Parts 1 and 2 of this article will examine seven critical components of a comprehensive validation program for new and renovated
manufacturing facilities. The programs and procedures explained are appropriate for all commonly manufactured dosage forms
(e.g., tablets and capsules, active pharmaceutical ingredients [APIs], parenterals). Given that the design, construction, and qualification
and validation of a major facility are relatively infrequent events in most corporate life cycles, some of these project components
are not well known or understood. For this reason, Part 1 of this article examines the following areas:
- facility- and equipment-design review to ensure compliance with CGMP regulations;
- project scope definition, organization, and planning;
- project labor requirements and budget;
- validation master plan development.
Part 2 will continue with a discussion of the following validation-related subjects:
- protocol and SOP development, scheduling, and implementation;
- design- and construction-document collection (turnover package);
- evaluation of deviations and discrepancies.
Facility- and equipment-design review
By definition, the construction of a new or renovated facility and the purchase and installation of mechanical equipment and
process systems constitute a project. All projects have basic, common features: a logical start, a logical end, and little
or no possibility of recurrence (i.e., the project will not repeat at some future time). In addition, the design process is common to all facility projects. All
facilities start with a design, about which engineers, owners, scientists, and other stakeholders confer to determine how
the facility will appear and operate and what equipment and systems are needed. The usual sequence starts with the development
of a conceptual design by an engineering firm, from which preliminary decisions are made about facility layout and size, utilities
required, and equipment capacity and material of construction. The process then continues into the preliminary and detailed
engineering stages, in which costs are finalized and designs are completed and approved. It is at this point when the conceptual
design transitions to preliminary engineering that formal review to verify GMP compliance begins.
In general, process equipment and utility systems affecting product quality or contacting product are the subject of design
review. Typical reviewed utilities include heating, ventilation, and air-conditioning (HVAC), compendial waters (e.g., water-for-injection, purified water, clean steam), and compressed gases such as nitrogen and compressed air. At present,
regulatory expectations for other utilities such as chilled water or plant steam are minimal, and these may be omitted. Design
review is mandatory for highly customized or unique process equipment, particularly when the unit is custom manufactured.
Equipment for critical processes such as aseptic filling and packaging, lyophilization, and final purification also requires
rigorous evaluation. Because the GMP regulations are interpretive and nonspecific for equipment design and construction, the
design engineer and owner are responsible for assessing compliance (1).