Essentials of Validation Project Management - Part 1 (Reprint)

The Industry’s Authoritative Source ® Essentials of Validation Project Management Part I William Garvey T he qualification and validation of complex pharmaceutical manufacturing facilities requires the careful coordination VECTOR CORPORATION 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 To qualify and validate a pharmaceutical departments must be notified of impending increased workloads. manufacturing facility, one must carefully review And finally, the manufacturer should alert the local US Food and the facility design for compliance with good Drug Administration district office that a new facility is planned. manufacturing practices and manage project Considering all these activities, careful planning and cautious man- scope definition, labor and cost estimating, and agement will increase the likelihood of a successful project out- come, no matter how difficult or complicated the project. Success- master-plan development. These activities, ful project completion is never guaranteed, but by implementing properly implemented, help deliver a validated proven techniques and the programs described in this article, a fa- facility on schedule, at the estimated cost, and vorable end-result is much more likely. with expected quality. Parts 1 and 2 of this article will examine seven critical components of a comprehensive validation program for new and reno- William Garvey is Validation Consultant at vated manufacturing facilities. The programs and procedures ex- Millipore Corporation (Billerica, MA). plained are appropriate for all commonly manufactured dosage Phone: (781) 533-2407. forms (e.g., tablets and capsules, active pharmaceutical ingredients Email: William_garvey@millipore.com [APIs], parenterals). Given that the design, construction, and qual- Submitted: Aug. 16, 2005. Accepted: Sept. 9, 2005. ification 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

DATA AND REVIEW 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 ren- Figure 2: Fluidized bed dryer showing ovated facility and the purchase and installation Figure 1: Valve orientation (45 above mechanical components requiring maintenance horizontal) and nonchloride insulation of mechanical equipment and process systems located outside the process space (photo in purified water, USP system. constitute a project. All projects have basic, com- courtesy of Vector Corporation). mon 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 understanding of GMP-compliant design often exceeds that of process is common to all facility projects. All facilities start with a the owner and engineer combined (2). Design reviews should design, about which engineers, owners, scientists, and other stake- be performed using a structured and systematic approach. For holders confer to determine how the facility will appear and op- mechanical systems such as HVAC, the evaluation of drawing erate and what equipment and systems are needed. The usual se- sets takes precedence over most other documents. Vendor sub- quence starts with the development of a conceptual design by an mittals always should be reviewed. Although less beneficial, Di- engineering firm, from which preliminary decisions are made about vision 15, 22, and 23 type construction specifications (3) also facility layout and size, utilities required, and equipment capacity should be examined, even though these are often standard with and material of construction. The process then continues into the little customization. Checklists and other reviewing aids may preliminary and detailed engineering stages, in which costs are fi- be valuable because they prove that the designs were evaluated nalized and designs are completed and approved. It is at this point and they may be used again for subsequent projects. when the conceptual design transitions to preliminary engineer- Three critical steps must be taken in a design review: ing that formal review to verify GMP compliance begins. • identify and evaluate any potential areas or items of noncom- In general, process equipment and utility systems affecting prod- pliance; uct quality or contacting product are the subject of design review. • ensure that designs are modified to eliminate noncompliant fea- Typical reviewed utilities include heating, ventilation, and air-con- tures; ditioning (HVAC), compendial waters (e.g., water-for-injection, • prepare a brief report that summarizes the design-review process purified water, clean steam), and compressed gases such as nitro- and obtain appropriate approvals, including quality assurance. gen and compressed air. At present, regulatory expectations for Much of the current content in both domestic and foreign GMP other utilities such as chilled water or plant steam are minimal, regulations is limited and nonspecific. The owner is obligated to and these may be omitted. Design review is mandatory for highly review all designs and verify conformance with industry standards customized or unique process equipment, particularly when the and regulatory guidelines. In the absence of standard equipment unit is custom manufactured. Equipment for critical processes specifications within the GMPs, logic dictates that process equip- such as aseptic filling and packaging, lyophilization, and final pu- ment and utilities must be designed to be: Nonreactive.Materials of construction must be inert and non- rification also requires rigorous evaluation. Because the GMP regulations are interpretive and nonspecific for equipment design and additive. Type 304 and Type 316 stainless steel are commonly construction, the design engineer and owner are responsible for used. Hastelloy C frequently is used in reactor systems and con- assessing compliance (1). densers. Wood should be avoided, even for utensils, because it During the design review stage, the engineer and owner can generate unwanted particulates and is porous and difficult should evaluate all critical specifications and drawings to en- to clean. Gaskets must withstand attack by process fluids and sure that regulatory compliance is achieved. In general, experi- be dimensionally stable under expected temperature conditions. enced vendors understand the requirements imposed by GMP Chloride-containing insulation should not be used with stain- regulations and design and construct their equipment and sys- less steel components (see Figure 1). Cleanable. Equipment surfaces must be smooth and free of voids tems accordingly. Rarely are serious design and construction errors uncovered because a reputable vendor’s knowledge and and crevices in which material can accumulate. Welds must be 2

polished smooth, although mirror polishing is not always recom- mended where glare is a concern. Short-radius corners are pre- ferred at joined surfaces. Threaded fittings usually are not permit- ted 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. Seam- less floor coverings should be installed where practical because they prevent the infiltration and exfiltration of water and con- Figure 3: Duplex steam-trap assembly at a critical air-handling unit. taminants 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. of these standards and their application to pharmaceutical man- Maintainable. Through-the-wall designs should be used where ufacturing are readily apparent. The 3A Sanitary Standards should serviceable mechanical components are located outside process be consulted when equipment such as holding tanks, clean-in- spaces (see Figure 2). Such items include HVAC air-control valves place systems, valves, and pumps are undergoing GMP compli- and instrumentation, process filters, and operator workstations. ance review. Design errors are uncommon, however, because most Remote grease fittings should be installed on fan bearings to min- equipment vendors already fully understand and comply with these imize air handler entry. Adequate clearance should be allowed at standards. heat exchangers to permit coil removal and inspection. Redun- For high-value projects and facilities intended to manufacture dancy should always be considered for mission-critical systems, sterile products, it is often required and worthwhile to contact the including sanitary pumps, steam traps (see Figure 3), filter assem- local FDA district office. This alerts the agency that inspections blies and regulators, and recorders on sterilizers. Ergonomics also must be scheduled, often to coincide with critical construction should be considered. milestones and events. FDA Office of Regulatory Affairs Field Man- Reliable and controlled. Control systems such as programmable agement Directive (FMD) 135 also encourages manufacturers to logic controllers (PLCs) should be used to control equipment. Au- contact FDA when facility and equipment designs are being pre- tomation allows processes to be replicated without variability, a pared (6). The following is a summary of FMD 135, which can be fundamental principle on which GMPs are based. Mechanical- found on FDA’s Web site: type (cam) controllers should be avoided because regulations re- Providing [FDA] review and comment is desirable because it quire that current and modern technology be used. Manual con- may reveal [design] defects early and prevent costly construc- trol also should be avoided where possible because replication is tion errors which could lead to defective operations and prod- inherently difficult. Any system that may alter batch-to-batch uni- ucts. It also affords FDA the opportunity to become aware of formity, and ultimately the product therapeutic response, must be future work load obligations and, in some cases, new technolo- gies. Early field involvement with new or modified facilities will very carefully considered. increase efficiency and result in the timely processing of appli- Correct for application. The correct design criteria must be spec- cations (6). ified. For example, clean compressed air must have a dewpoint temperature of approximately –40 F to prevent condensation. Re- Companies should understand and recognize that partnering frigerated air driers cannot meet this requirement. Oil-free com- with FDA to review proposed designs is beneficial to both parties. pressors should be used to exclude oil contamination unless sev- Costs and delays associated with rework can be avoided if prob- eral levels of filtration are used (4). Industry standards allow no lems are detected early. Definitive dates for facility inspections can more than 1 ppm (1 mg/m3) of oil/hydrocarbon in compressed air. be established, which serve as endpoints that motivate project com- Besides developing some original standards for process equip- pletion. Current agency inspectional focus also may be apparent, ment design and construction, the pharmaceutical industry has foretold by the types of questions that are asked. Overall, early di- borrowed standards from industries that produce similar con- alogue and FDA involvement may expedite facility completion, re- sumer products, most notably the dairy industry. The 3-A Sani- duce engineering and construction costs, and lead to a smooth tary Standards are voluntary guidelines followed by dairy equip- transition from start-up to operation. These results are desirable ment vendors and dairy operators. The standards provide material for all manufacturers, regardless of company size or complexity. specifications, design criteria, and other necessary information for Scope definition,organization,and planning the construction of dairy equipment to satisfy public health con- cerns. The ultimate objective is to safeguard public health from Successfully implemented validation projects all begin with a well- contaminated dairy products. defined scope (i.e., the set of activities and deliverables that must To meet this objective, 3-A Sanitary Standards and 3-A occur to complete the project). Scope definition is critical if con- Accepted Practices ensure that dairy, food, and other microbial- tracted validation resources are used because it becomes the basis sensitive products are protected from contamination; that all prod- for cost estimates and assessing job completion. uct contact surfaces can be cleaned in place or easily dismantled Validation project scope definition usually begins by reviewing for manual cleaning; and that all product contact surfaces can be the following drawings and documents (7): easily inspected to confirm cleaning effectiveness (5). The purpose • air-flow diagrams (see Figure 4); 3

Table I: Estimated labor hours for commissioning and qualification. Protocol Standard operating Commissioning Protocol preparation execution procedures Final System Doc. rev. Procedure Implement Doc. rev. IQ OQ IQ OQ Oper. Clean. Mainten. Reports Utilities Cold glycol 2 16 20 Hot glycol 2 16 20 Steam (50 lb.) 2 16 20 Instrument air 2 16 20 Process water 2 16 24 20 16 16 16 16 Nitrogen (50 PSIG) 2 16 24 20 16 16 16 16 Chilled water 2 16 20 Tempered glycol 2 16 20 Breathing air 2 16 20 Scrubber 2 16 20 Tempered water 2 16 20 HVAC 2 24 40 32 40 20 16 16 Vacuum pump LP2 2 16 20 Vacuum pump LP4 2 8 20 Subtotal 22 168 220 6 56 88 72 72 52 48 0 48 Process equipment T-4000 mix tank 2 16 16 24 24 16 16 16 12 Mixing vessel (T-501) 2 16 16 20 16 16 16 16 12 Mixing vessel (T-502) 2 8 8 20 16 16 T-500 reactor 2 24 24 24 24 16 16 16 16 T-504 receiver 2 16 16 20 16 16 16 16 16 T-1003 mix tank 2 8 8 20 16 16 Transfer panel system 2 16 16 24 20 12 16 16 16 Walk-in hood 2 16 20 24 24 16 16 16 16 Subtotal 16 120 124 176 156 124 96 96 88 Total 22 168 220 22 176 212 248 228 176 144 96 136 Grand total 1848 Abbreviations: Doc. rev. is document collection and review; IQ is installation qualification; OQ is operational qualification; Oper. is operation; Clean. is cleaning; and Mainten. is maintenance. • piping and instrumentation diagrams; qualification. Column headings and subheadings usually consist • utility-flow diagrams; of the following: • equipment lists. • document collection and review (to develop protocols and SOPs); These four types of documents are common and essential to • calibration and metrology; all validation projects, although the level of detail and content • protocol preparation (installation qualification [IQ], operational may vary. Design-document quality is usually closely associated qualification [OQ], performance qualification [PQ], and clean- with cost; the greater the upfront engineering costs, the more ing); detail that can be found in drawings and lists. Because facility • protocol execution (IQ, OQ, PQ, and cleaning); construction and protocol preparation require drawings that are • final reports; detailed, accurate, and thoroughly checked, increased funding • turnover packages (contain construction test reports, as-built for engineering services is usually money well spent. In general, drawings); one can expect that the cost of facility-design services will be ap- • SOPs (operation, maintenance, cleaning). proximately 10–12% of the facility’s total installed cost. A checkmark is placed in each cell for which a specific activity It is useful to identify project activities on a spreadsheet when is required. This checkmark may be replaced eventually with the establishing project scope. Systems and equipment requiring name of the individual responsible for the activity. Assigning labor qualification and validation are first determined by reviewing the hours to each checkmark is even more useful because this provides project documents described previously. Then, the spreadsheet an estimate of the labor required for each activity and for the en- is created and the first column is reserved for each identified sys- tire project (see Table I). tem and piece of equipment. Adjacent columns become a ma- trix of activities necessary to complete system and equipment 4

Figure 4: Typical air-flow diagram for an API facility. Project labor requirements and budgeting thus requiring that outside validation services be contracted. As- By revising the spreadsheet to include labor hours, and then total- signing a dollar amount (e.g., $75) to each hour of labor provides ing each row and column, a project labor estimate per activity and an estimate of validation project costs, which often is used to jus- system can be derived (7). Dividing total project hours by 2080 tify requests for financial resources and to support the annual budg- h/year provides an estimate of personnel required to complete all eting process. activities. Total project headcount will vary depending on project Industry experience has shown that validation costs (excluding duration, however. Anticipating the number of labor hours is im- commissioning and process validation) typically range from 2.5–5% portant because the labor involved may exceed available resources, of the total installed cost of the facility. Aseptic-filling and biotech- 5

DATA AND REVIEW nology facilities frequently have the highest validation cost, whereas portation into corresponding protocols); API facilities tend to be the least expensive. Care must be taken not • preliminary acceptance criteria (for each system and piece of to apply these guidelines too tightly because the percentage vali- equipment); dation cost will vary with project size. As an example, the purchase • SOP listing; and installation of a small steam sterilizer might have a total in- • other GMP-required activities (document control, training, en- stalled cost of $150,000; however, the validation costs may exceed vironmental monitoring, and so forth); $50,000 (33%), when protocol preparation and implementation, • drawings, particularly facility layouts, piping and instrumenta- SOP development, and laboratory supplies are considered. tion diagrams, and air-flow diagrams. On validation projects, personnel are often subdivided into If possible, special or unique features should be emphasized teams, with one team preparing SOPs, another team preparing in the master plan, especially those that ensure product unifor- protocols, and so forth. Alternately, one person may be assigned mity or the elimination of contamination and cross-contami- to a specific system, taking full responsibility for protocol and SOP nation. These features might include a description of extract preparation, implementation, and final-report development. The booths, personnel showers, and isolators used during toxic ma- spreadsheet described previously helps with this decision. Either terials processing. Room air-change rates, personnel gowning method is satisfactory, but the one chosen must account for per- practices, and decontamination with formaldehyde or vapor- sonnel availability and future operational needs. Often, contrac- ized hydrogen peroxide also are worth mentioning. It is impor- tors are employed to prepare protocols and SOPs only, while im- tant to convey quality and attention to detail in the master plan plementation is reserved for company personnel. This approach because this document is approved by the Quality Assurance has several benefits. First, the contractor travel expenses are min- department and often is reviewed by FDA. imized because all document development can occur in the con- Other programs to describe in the validation master plan are tractor’s home office. Second, protocol implementation is per- the facility revalidation program, turnover package develop- formed by those who will ultimately operate and maintain the ment, and system or equipment commissioning. With the pub- validated equipment and systems. This process may reduce the lication of the International Society for Pharmaceutical Engi- transition time from start-up to manufacturing, and if properly neering’s Baseline Pharmaceutical Engineering Guide: documented, can satisfy GMP training requirements. Commissioning and Qualification in March 2001, greater em- phasis has been placed on system and equipment commission- Validation master plan development ing (8). Until recently, commissioning was an activity often per- The validation master plan complements the project scope. Al- formed without any involvement of quality assurance or though master plans are not officially required by some regulatory validation personnel. The construction team or an agent hired agencies, these documents may be submitted to FDA as part of the by the project manager usually performed system commission- preoperational review program (FMD 135) discussed previously. ing. Commissioning documents were often prepared and exe- Master plans typically describe the project scope in detail and in- cuted without any review or oversight by the Quality Assurance clude preliminary validation acceptance criteria. They also con- department. In many instances, validation often repeated com- tain a description of all programs that collectively make the facil- mon commissioning tests and verifications, thereby increasing ity GMP compliant. A well-conceived and well-written master plan costs and creating inefficiencies. In addition, systems often were reduces the likelihood that a critical activity or program will be commissioned and validated where commissioning would have omitted and provides regulators with a sense that the company is satisfied operational requirements. It is worthwhile to identify quality-minded and operating in a state of control. and describe the interaction between commissioning and val- Once the project scope is determined and reduced to spread- idation in the master plan. The plan may include a description sheet format, the spreadsheet may be imported into the draft val- of required commissioning documents and how they support idation master plan. Master plans usually are focused on project the validation effort. In general, systems that have no product deliverables, not costs. Therefore, estimated costs and labor hours contact are good candidates for commissioning only, although do not need to be presented. There is no standard format for val- there are occasional exceptions to this rule. idation master plans, although the concept has evolved so that The facility revalidation program also should be described in many features are standard from company to company. Each mas- the master plan because the validation life cycle continues long ter plan is an analysis and evaluation of a manufacturing facility’s after the facility is mechanically complete and handed over for op- validation and compliance requirements. Typical master plan con- eration. Revalidation usually takes two forms: time or event based tents include the following: (9). Time-based revalidation is the practice in which a system or • approval page (quality-assurance approval is required); process is recertified at a specified interval. Time-based assessments • introduction and facility description; also can include a review of historical system performance data. • project organizational chart (optional); Event-based revalidation is implemented whenever physical or op- • descriptions of component and material storage areas, produc- erational changes are made to the system outside the scope of the tion areas, quality assurance areas, critical utility systems (HVAC, original validation. All such modifications are the subject of the purified water, water-for-injection, building management sys- facility’s change control program, which also should be described tem); in detail in the master plan. • spreadsheet (described previously); Turnover package (TOP) development also can be described • system and equipment descriptions (in sufficient detail for im- in the master plan. Turnover package is a system for organiz- 6

ing all documents related to facility and system design, con- municates expectations, and conveys a quality mindset and state struction, and start-up relevant to the eventual commissioning of control to regulators. Each of these project components, in con- and qualification of systems and equipment (10). Turnover junction with the guidelines and programs described in Part 2 that packages are usually prepared by the construction manager and follows, helps assure that the project is completed on time and turned over to the owner at project completion. TOP docu- within budget. More importantly, quality is built into the project ments construction activities and contributes to system IQ, OQ, from the start, regulatory compliance is realized, and the transi- and PQ and usually is a prospective or concurrent activity (i.e., tion from start-up to operation is optimized. In the current envi- design, construction and start-up documents are compiled as ronment of cost control, expedited product introductions, and in- system construction proceeds). Turnover packages will be dis- creased regulatory oversight, the benefits of efficient validation cussed in detail in Part 2 of this article. project management should be evident. Summary References 1. US Food and Drug Administration, Code of Federal Regulations, Title 21 This article provides a basic introduction to four components that (FDA, Washington, DC, April 1, 2005), pp. 120–141. are fundamental to all successful validation projects. Part 2 will de- 2. W. Garvey,“Integrated Validation Programs for Solid Dosage Facilities— scribe three additional programs that should be considered and Part 1,” Am. Pharm. Rev. 2 (2), 33–39 (1999). implemented. Before undertaking any validation project, careful 3. The Construction Specifications Institute (Alexandria, VA). planning to arrive at a logical, uncomplicated approach is required. 4. Department of Health, Education and Welfare, “Human Drugs—Cur- rent Good Manufacturing Practice in Manufacture, Processing, Packing All projects are labor and capital intensive, and incorrect or inef- or Holding of Large Volume Parenterals, and Request for Comments Re- ficient use of either resource ultimately escalates cost and extends garding Small Volume Parenterals,” Fed. Regist. 41 (106), 22022–22115 the schedule. (June 1, 1976). All validation projects must begin with a comprehensive design 5. 3-A Sanitary Standards Inc., McClean, VA. review and include FDA assistance if necessary. Once a compliant 6. FDA, “ORA Field Management Directive 135, Pre-Operational Reviews of Manufacturing Facilities” (FDA, Washington, DC, Dec. 4, 1995). design is finalized, validation project scope must be established 7. W. Garvey,“Effective Validation Project Management,” oral presentation and properly communicated to all project stakeholders. Concur- given at Interphex Conference 2005, New York, NY, April 26–28, 2005. rent with project-scope definition is the development of a labor 8. ISPE Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engi- estimate, and by extension, a cost estimate. Knowing labor require- neering Guides for New and Renovated Facilities, Vol. 5, Commissioning ments and costs early helps identify potential shortfalls in person- and Qualification, (International Society for Pharmaceutical Engineer- ing [ISPE], March 2001), pp. 11–15. nel and permits appropriation of sufficient funding to complete 9. ISPE Baseline Pharmaceutical Engineering Guide, Pharmaceutical Engi- the project. Accurately defining project scope also avoids misun- neering Guides for New and Renovated Facilities, Vol. 5, Commissioning derstandings, errors, and omissions when work is assigned to con- and Qualification, (ISPE, March 2001), p. 111. tractors and company personnel. A comprehensive validation mas- 10. M. Chin,“TOP: A Rational Approach For Ensuring Proper Biopharma- ter plan follows design review and scope definition in the project ceutical Plant Construction,” in proceedings from PharmTech Confer- ence ’87 (Aster Publishing Corporation, Eugene, OR, 1987), p. 73. PT timeline. The master plan identifies critical project activities, com- © Reprinted from PHARMACEUTICAL TECHNOLOGY, December 2005 Printed in U.S.A. 7

Essentials of Validation Project Management - Part 1 (Reprint)

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