Essentials of Validation Project Management Part I

Pharmaceutical Technology

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 reviewBy 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).
During the design review stage, the engineer and owner should evaluate all critical specifications and drawings to ensure that regulatory compliance is achieved. In general, experienced vendors understand the requirements imposed by GMP regulations and design and construct their equipment and systems accordingly. Rarely are serious design and construction errors uncovered because a reputable vendor's knowledge and understanding of GMP-compliant design often exceeds that of the owner and engineer combined (2). Design reviews should be performed using a structured and systematic approach. For mechanical systems such as HVAC, the evaluation of drawing sets takes precedence over most other documents. Vendor submittals always should be reviewed. Although less beneficial, Division 15, 22, and 23 type construction specifications (3) also should be examined, even though these are often standard with little customization. Checklists and other reviewing aids may be valuable because they prove that the designs were evaluated and they may be used again for subsequent projects.
Three critical steps must be taken in a design review:
  • identify and evaluate any potential areas or items of noncompliance;
  • ensure that designs are modified to eliminate noncompliant features;
  • prepare a brief report that summarizes the design-review process and obtain appropriate approvals, including quality assurance.

Much of the current content in both domestic and foreign GMP regulations is limited and nonspecific. The owner is obligated to review all designs and verify conformance with industry standards and regulatory guidelines. In the absence of standard equipment specifications within the GMPs, logic dictates that process equipment and utilities must be designed to be:

Figure 1: Valve orientation (45° above horizontal) and nonchloride insulation in purified water, USP system.
Nonreactive. Materials of construction must be inert and non-additive. Type 304 and Type 316 stainless steel are commonly used. Hastelloy C frequently is used in reactor systems and condensers. Wood should be avoided, even for utensils, because it can generate unwanted particulates and is porous and difficult to clean. Gaskets must withstand attack by process fluids and be dimensionally stable under expected temperature conditions. Chloride-containing insulation should not be used with stainless steel components (see Figure 1).

Figure 2: Fluidized bed dryer showing mechanical components requiring maintenance located outside the process space (photo courtesy of Vector Corporation).
Cleanable. Equipment surfaces must be smooth and free of voids and crevices in which material can accumulate. Welds must be polished smooth, although mirror polishing is not always recommended where glare is a concern. Short-radius corners are preferred at joined surfaces. Threaded fittings usually are not permitted on sanitary systems. Diaphragm valves must be installed on horizontal lines at 45° angles to ensure complete drainage (see Figure 1). Labeling and packaging equipment must be designed to permit thorough inspection. If cut labels are used, equipment should permit stray labels to fall to the floor unimpeded. Seamless floor coverings should be installed where practical because they prevent the infiltration and exfiltration of water and contaminants from and to sublayers. Valves and flanges should be minimized in concealed-piping runs over critical process areas where leakage or failure could be problematic.

Figure 3: Duplex steam-trap assembly at a critical air-handling unit.
Maintainable. Through-the-wall designs should be used where serviceable mechanical components are located outside process spaces (see Figure 2). Such items include HVAC air-control valves and instrumentation, process filters, and operator workstations. Remote grease fittings should be installed on fan bearings to minimize air handler entry. Adequate clearance should be allowed at heat exchangers to permit coil removal and inspection. Redundancy should always be considered for mission-critical systems, including sanitary pumps, steam traps (see Figure 3), filter assemblies and regulators, and recorders on sterilizers. Ergonomics also should be considered

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