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To qualify and validate a pharmaceutical manufacturing facility, one must carefully review the facility design for compliance with good manufacturing practices and manage project scope definition, labor and cost estimating, and master-plan development.These activities, properly implemented, help deliver a validated facility on schedule, at the estimated cost, and with expected quality.
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:
Part 2 will continue with a discussion of the following validation-related subjects:
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).
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:
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:
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 1: Valve orientation (45Â° above horizontal) and nonchloride insulation in purified water, USP system.
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 2: Fluidized bed dryer showing mechanical components requiring maintenance located outside the process space (photo courtesy of Vector Corporation).
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.
Figure 3: Duplex steam-trap assembly at a critical air-handling unit.
Reliable and controlled. Control systems such as programmable logic controllers (PLCs) should be used to control equipment. Automation allows processes to be replicated without variability, a fundamental principle on which GMPs are based. Mechanical-type (cam) controllers should be avoided because regulations require that current and modern technology be used. Manual control also should be avoided where possible because replication is inherently difficult. Any system that may alter batch-to-batch uniformity, and ultimately the product therapeutic response, must be very carefully considered.
Correct for application. The correct design criteria must be specified. For example, clean compressed air must have a dewpoint temperature of approximately –40 °F to prevent condensation. Refrigerated air driers cannot meet this requirement. Oil-free compressors should be used to exclude oil contamination unless several levels of filtration are used (4). Industry standards allow no more than 1 ppm (1 mg/m3 ) of oil/hydrocarbon in compressed air.
Besides developing some original standards for process equipment design and construction, the pharmaceutical industry has borrowed standards from industries that produce similar consumer products, most notably the dairy industry. The 3-A Sanitary Standards are voluntary guidelines followed by dairy equipment vendors and dairy operators. The standards provide material specifications, design criteria, and other necessary information for the construction of dairy equipment to satisfy public health concerns. The ultimate objective is to safeguard public health from contaminated dairy products.
To meet this objective, 3-A Sanitary Standards and 3-A Accepted Practices ensure that dairy, food, and other microbial-sensitive products are protected from contamination; that all product contact surfaces can be cleaned in place or easily dismantled for manual cleaning; and that all product contact surfaces can be easily inspected to confirm cleaning effectiveness (5). The purpose of these standards and their application to pharmaceutical manufacturing are readily apparent. The 3A Sanitary Standards should be consulted when equipment such as holding tanks, clean-in-place systems, valves, and pumps are undergoing GMP compliance review. Design errors are uncommon, however, because most equipment vendors already fully understand and comply with these standards.
For high-value projects and facilities intended to manufacture sterile products, it is often required and worthwhile to contact the local FDA district office. This alerts the agency that inspections must be scheduled, often to coincide with critical construction milestones and events. FDA Office of Regulatory Affairs Field Management Directive (FMD) 135 also encourages manufacturers to contact FDA when facility and equipment designs are being prepared (6). The following is a summary of FMD 135, which can be found on FDA's Web site:
Providing [FDA] review and comment is desirable because it may reveal [design] defects early and prevent costly construction errors which could lead to defective operations and products. It also affords FDA the opportunity to become aware of future work load obligations and, in some cases, new technologies. Early field involvement with new or modified facilities will increase efficiency and result in the timely processing of applications (6).
Companies should understand and recognize that partnering with FDA to review proposed designs is beneficial to both parties. Costs and delays associated with rework can be avoided if problems are detected early. Definitive dates for facility inspections can be established, which serve as endpoints that motivate project completion. Current agency inspectional focus also may be apparent, foretold by the types of questions that are asked. Overall, early dialogue and FDA involvement may expedite facility completion, reduce engineering and construction costs, and lead to a smooth transition from start-up to operation. These results are desirable for all manufacturers, regardless of company size or complexity.
Scope definition, organization, and planning
Successfully implemented validation projects all begin with a well-defined scope (i.e., the set of activities and deliverables that must occur to complete the project). Scope definition is critical if contracted validation resources are used because it becomes the basis for cost estimates and assessing job completion.
Validation project scope definition usually begins by reviewing the following drawings and documents (7):
Figure 4: Typical air-flow diagram for an API facility.
These four types of documents are common and essential to all validation projects, although the level of detail and content may vary. Design-document quality is usually closely associated with cost; the greater the upfront engineering costs, the more detail that can be found in drawings and lists. Because facility construction and protocol preparation require drawings that are detailed, accurate, and thoroughly checked, increased funding for engineering services is usually money well spent. In general, one can expect that the cost of facility-design services will be approximately 10–12% of the facility's total installed cost.
It is useful to identify project activities on a spreadsheet when establishing project scope. Systems and equipment requiring qualification and validation are first determined by reviewing the project documents described previously. Then, the spreadsheet is created and the first column is reserved for each identified system and piece of equipment. Adjacent columns become a matrix of activities necessary to complete system and equipment qualification. Column headings and subheadings usually consist of the following:
A checkmark is placed in each cell for which a specific activity is required. This checkmark may be replaced eventually with the name of the individual responsible for the activity. Assigning labor hours to each checkmark is even more useful because this provides an estimate of the labor required for each activity and for the entire project (see Table I).
Table I: Estimated labor hours for commissioning and qualification.
Project labor requirements and budgeting
By revising the spreadsheet to include labor hours, and then totaling each row and column, a project labor estimate per activity and system can be derived (7). Dividing total project hours by 2080 h/year provides an estimate of personnel required to complete all activities. Total project headcount will vary depending on project duration, however. Anticipating the number of labor hours is important because the labor involved may exceed available resources, thus requiring that outside validation services be contracted. Assigning a dollar amount (e.g., $75) to each hour of labor provides an estimate of validation project costs, which often is used to justify requests for financial resources and to support the annual budgeting process.
Industry experience has shown that validation costs (excluding commissioning and process validation) typically range from 2.5–5% of the total installed cost of the facility. Aseptic-filling and biotechnology facilities frequently have the highest validation cost, whereas API facilities tend to be the least expensive. Care must be taken not to apply these guidelines too tightly because the percentage validation cost will vary with project size. As an example, the purchase and installation of a small steam sterilizer might have a total installed cost of $150,000; however, the validation costs may exceed $50,000 (33%), when protocol preparation and implementation, SOP development, and laboratory supplies are considered.
On validation projects, personnel are often subdivided into teams, with one team preparing SOPs, another team preparing protocols, and so forth. Alternately, one person may be assigned to a specific system, taking full responsibility for protocol and SOP preparation, implementation, and final-report development. The spreadsheet described previously helps with this decision. Either method is satisfactory, but the one chosen must account for personnel availability and future operational needs. Often, contractors are employed to prepare protocols and SOPs only, while implementation is reserved for company personnel. This approach has several benefits. First, the contractor travel expenses are minimized because all document development can occur in the contractor's home office. Second, protocol implementation is performed by those who will ultimately operate and maintain the validated equipment and systems. This process may reduce the transition time from start-up to manufacturing, and if properly documented, can satisfy GMP training requirements.
Validation master plan development
The validation master plan complements the project scope. Although master plans are not officially required by some regulatory agencies, these documents may be submitted to FDA as part of the preoperational review program (FMD 135) discussed previously. Master plans typically describe the project scope in detail and include preliminary validation acceptance criteria. They also contain a description of all programs that collectively make the facility GMP compliant. A well-conceived and well-written master plan reduces the likelihood that a critical activity or program will be omitted and provides regulators with a sense that the company is quality-minded and operating in a state of control.
Once the project scope is determined and reduced to spreadsheet format, the spreadsheet may be imported into the draft validation master plan. Master plans usually are focused on project deliverables, not costs. Therefore, estimated costs and labor hours do not need to be presented. There is no standard format for validation master plans, although the concept has evolved so that many features are standard from company to company. Each master plan is an analysis and evaluation of a manufacturing facility's validation and compliance requirements. Typical master plan contents include the following:
If possible, special or unique features should be emphasized in the master plan, especially those that ensure product uniformity or the elimination of contamination and cross-contamination. These features might include a description of extract booths, personnel showers, and isolators used during toxic materials processing. Room air-change rates, personnel gowning practices, and decontamination with formaldehyde or vaporized hydrogen peroxide also are worth mentioning. It is important to convey quality and attention to detail in the master plan because this document is approved by the Quality Assurance department and often is reviewed by FDA.
Other programs to describe in the validation master plan are the facility revalidation program, turnover package development, and system or equipment commissioning. With the publication of the International Society for Pharmaceutical Engineering's Baseline Pharmaceutical Engineering Guide: Commissioning and Qualification in March 2001, greater emphasis has been placed on system and equipment commissioning (8). Until recently, commissioning was an activity often performed without any involvement of quality assurance or validation personnel. The construction team or an agent hired by the project manager usually performed system commissioning. Commissioning documents were often prepared and executed without any review or oversight by the Quality Assurance department. In many instances, validation often repeated common commissioning tests and verifications, thereby increasing costs and creating inefficiencies. In addition, systems often were commissioned and validated where commissioning would have satisfied operational requirements. It is worthwhile to identify and describe the interaction between commissioning and validation in the master plan. The plan may include a description of required commissioning documents and how they support the validation effort. In general, systems that have no product contact are good candidates for commissioning only, although there are occasional exceptions to this rule.
The facility revalidation program also should be described in the master plan because the validation life cycle continues long after the facility is mechanically complete and handed over for operation. Revalidation usually takes two forms: time or event based (9). Time-based revalidation is the practice in which a system or process is recertified at a specified interval. Time-based assessments also can include a review of historical system performance data. Event-based revalidation is implemented whenever physical or operational changes are made to the system outside the scope of the original validation. All such modifications are the subject of the facility's change control program, which also should be described in detail in the master plan.
Turnover package (TOP) development also can be described in the master plan. Turnover package is a system for organizing all documents related to facility and system design, construction, and start-up relevant to the eventual commissioning and qualification of systems and equipment (10). Turnover packages are usually prepared by the construction manager and turned over to the owner at project completion. TOP documents construction activities and contributes to system IQ, OQ, and PQ and usually is a prospective or concurrent activity (i.e., design, construction and start-up documents are compiled as system construction proceeds). Turnover packages will be discussed in detail in Part 2 of this article.
This article provides a basic introduction to four components that are fundamental to all successful validation projects. Part 2 will describe three additional programs that should be considered and implemented. Before undertaking any validation project, careful planning to arrive at a logical, uncomplicated approach is required. All projects are labor and capital intensive, and incorrect or inefficient use of either resource ultimately escalates cost and extends the schedule.
All validation projects must begin with a comprehensive design review and include FDA assistance if necessary. Once a compliant design is finalized, validation project scope must be established and properly communicated to all project stakeholders. Concurrent with project-scope definition is the development of a labor estimate, and by extension, a cost estimate. Knowing labor requirements and costs early helps identify potential shortfalls in personnel and permits appropriation of sufficient funding to complete the project. Accurately defining project scope also avoids misunderstandings, errors, and omissions when work is assigned to contractors and company personnel. A comprehensive validation master plan follows design review and scope definition in the project timeline. The master plan identifies critical project activities, communicates expectations, and conveys a quality mindset and state of control to regulators. Each of these project components, in conjunction with the guidelines and programs described in Part 2 that follows, helps assure that the project is completed on time and within budget. More importantly, quality is built into the project from the start, regulatory compliance is realized, and the transition from start-up to operation is optimized. In the current environment of cost control, expedited product introductions, and increased regulatory oversight, the benefits of efficient validation project management should be evident.
William Garvey is a senior advisor at Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, tel. 860.715. 2277, fax 860.715.7806, firstname.lastname@example.org
1. US Food and Drug Administration, Code of Federal Regulations, Title 21 (FDA, Washington, DC, April 1, 2005), pp. 120–141.
2. W. Garvey, "Integrated Validation Programs for Solid Dosage Facilities—Part 1," Am. Pharm. Rev. 2 (2), 33–39 (1999).
3. The Construction Specifications Institute (Alexandria, VA).
4. Department of Health, Education and Welfare, "Human Drugs—Current Good Manufacturing Practice in Manufacture, Processing, Packing or Holding of Large Volume Parenterals, and Request for Comments Regarding Small Volume Parenterals," Fed. Regist. 41 (106), 22022–22115 (June 1, 1976).
5. 3-A Sanitary Standards Inc., McClean, VA.
6. FDA, "ORA Field Management Directive 135, Pre-Operational Reviews of Manufacturing Facilities" (FDA, Washington, DC, Dec. 4, 1995).
7. W. Garvey, "Effective Validation Project Management," oral presentation given at Interphex Conference 2005, New York, NY, April 26–28, 2005.
8. ISPE Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engineering Guides for New and Renovated Facilities, Vol. 5, Commissioning and Qualification, (International Society for Pharmaceutical Engineering [ISPE], March 2001), pp. 11–15.
9. ISPE Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engineering Guides for New and Renovated Facilities, Vol. 5, Commissioning and Qualification, (ISPE, March 2001), p. 111.
10. M. Chin, "TOP: A Rational Approach For Ensuring Proper Biopharmaceutical Plant Construction," in proceedings from PharmTech Conference '87 (Aster Publishing Corporation, Eugene, OR, 1987), p. 73.