Validating a Pharmaceutical Research and Development Facility
A Case Study
Balancing the conflicting constraints of delivering a project within budget, in a timely manner and with the appropriate level of quality is a challenge in any project. What makes the management of a project in a pharmaceutical environment particularly challenging is the emphasis that must be placed on quality. A project can be delivered on time and within budget, but if the facility does not meet regulatory requirements at the time of inspection, the entire project will be perceived as a failure. Regulatory agencies have the power to stop the distribution of drugs produced in a facility that does not meet specific requirements. Ensuring that quality is built into a facility and all the equipment and utilities contained within this facility is referred to as “validation” in the pharmaceutical industry. Validation is such a crucial aspect of the construction project that it must be managed as a separate project, with its very own project manager, project team, project plan, and schedule. This paper demonstrates how the “validation master plan” used as a project plan is an essential project management tool in this context.
Our client is expanding its clinical supplies manufacturing facility by constructing a new building that will house, among other things, laboratories, storage space, and a small manufacturing area. This new facility is primarily dedicated to the formulation and development of solid dosage pharmaceutical products for use in clinical studies in the North American markets. The expansion has a total area of 41,000 square feet and a total cost of approximately $20 million US.
The research and development (R&D) department has outgrown its current available space and it is imperative that the turnover date of the project be met. The project has a two-year life and turnover is scheduled for June 2002. In order for this turnover date to be met and for the facility to be fully validated, the construction must be completed in April 2002. The success of this project is crucial to the overall success of the pharmaceutical site. It will allow the facility to distinguish itself among other international R&D sites within the same corporation and allow it to maintain a world-class status.
As validation consultants, our role within the scope of this project is to ensure that the facility is designed and built to meet current GMP while complying with all other governing codes, laws, and regulations. The steps required to achieve this are: develop the project plan—in the pharmaceutical industry called the Validation Master Plan, put together the validation team, manage this team throughout the entire life of the project and ensure that the validation effort ends on time and on budget. In this paper, “the project” will refer to the construction project, while we will use the term “validation subproject” to describe the collection of work packages we are responsible for as validation consultants.
In this project, the cost of validation represents 5%–10% of total project costs. Given the magnitude of this subproject, it is managed as a project of its own, with its own planning and control mechanisms, and adapted tools to document and support its management.
In order to understand the context in which this project takes place, we have to consider that there are regulatory requirements to document certain aspects of the project. Those requirements are spelled out in regulations or in guidance documents published by regulatory authorities such as the Food and Drugs Administration (FDA) in the United States. Depending on the location of the facility and on the markets on which a pharmaceutical product is sold, different national or transnational rules and regulations may apply to a facility. For manufacturing facilities, pharmaceutical companies must follow GMP. The terminology used by the FDA in the United States is “current Good Manufacturing Practices” (cGMP). The cGMP are part of Chapter 21 of the Code of Federal Regulations, easily found on the Internet. In this paper, we will only refer to American regulations since it was the reference used by our clients.
Following GMP is a matter of public health. These regulations were for the most part developed over time, following incidents where innocent consumers were sometimes harmed or killed by contaminated medication. These regulations explicitly state obligations of pharmaceutical companies with respect to building and facilities, equipment, control of drug component and packaging components, production and process control, packaging and labeling, holding and distribution, laboratory controls, records and reports, as well as returned and salvaged drug products. In the 1941 Sulfathiazole disaster, a poorly managed drug recall that left thousands of contaminated tablets on the market resulted in hundreds of injuries or deaths (Swann, 1999).
Exhibit 1. The “V” Diagram
One of the regulatory requirements is validation. Validation can be defined as the establishment of documented evidence, through systematic testing, that a facility, piece of equipment, system or process produces the output for which it was designed, and that this output is produced with the required quality characteristics. One may have to demonstrate that a purified water system in a pharmaceutical plant was installed according to manufacturer's recommendations (what we call installation qualification or IQ). In addition, one may have to demonstrate that the purified water system operates in the expected way over all normal operating ranges and that the equipment's documentation is available and up-to-date (what we call operational qualification or OQ). For example, we demonstrate that water conductivity after reverse osmosis filtration and demineralization is at the required level or that the system produces the required number of gallons per minute. When the system is automated, we also verify that the required alarms and interlocks function properly. Finally, one may have to demonstrate that the water system can produce water with the required characteristics under normal operating conditions (what we call performance qualification or PQ). For a pharmaceutical water system, this consists in testing water quality over 30 days and demonstrating that it meets industry standards.
In order to write the required qualification protocols, and to determine the acceptance criteria for all tests to be carried out during qualification, one must refer to specifications. Specifications can be written at different levels: user requirements, functional requirements, design requirements. The user requirements describe what the system must do and state criteria that must be met for system acceptance. Functional requirements are a detailed description of system functions. These two sets of requirements are often combined in a single document for small systems. Design specifications include design plans for all systems components (hardware, software, instrumentation) as well as drawings, electrical schematics, process, and instrumentation diagrams (P&ID). Requirements and qualification protocols are intimately linked in a documentation system that is best illustrated by the “V-diagram” (see Exhibit 1).
Validation activities are carried out in a standard sequence. Following the preparation of a validation master plan, specifications are prepared. Qualification protocols are then written, based on the specification documents. The validation master plan cannot be closed out until the all protocols have been executed and closed out individually. This sequence is illustrated in Exhibit 2. We refer to this sequence as the “life cycle.”
In the field of validation, we often refer to the concept of “living document.” Documents that describe the system are kept up-to-date throughout the life of the system (often applied to validation master plan and specifications), from the time at which the system is designed until it is decommissioned.
Systems must be maintained in a “state of control.” In practice, this means that, at all times, an update-to-date set of documents describing the system exists, that there is a change control system that defines how changes to the system will be made, tested, and documented, and that operating procedures exists and are accurate. Maintaining a “state of control” is also often referred to as maintaining the “validated state” of the system. A practical benefit of this requirement is that accurate information is available for system or equipment repair or upgrade and that there would never be a need to “backward engineer” the system.
Exhibit 2. Sequence of Validation Activities
Looking back on the definition of validation, we see that validation applies to a facility, piece of equipment, system or process. Validation activities are quite similar no matter what is the focus, with the exception of a facility, which is deemed to be validated when all the systems that is contains are validated, as defined in the Validation Master Plan (VMP). A more detailed discussion of the contents and the role of the VMP later in the paper.
When a system does not require validation, it will be commissioned according to good engineering practices. Commissioning can be defined as “a well-planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the End-User that results in a safe and functional environment that meets established design requirements and stakeholders expectations” (ISPE 2001,19). Drawing the line between systems that must be validated and systems that will only be commissioned is not always easy. There exists a gray zone where decisions must be made based on whether the particular piece of equipment or utility can directly affect product quality. Such decisions must be documented as well.
The Validation Master Plan: A “Living Document”
The validation master plan or VMP is the first deliverable of the validation subproject. The VMP can and should be written once the scope of work and the basis of design for the construction project is determined. The VMP is the game plan for the validation portion of the project. It is a “living document” and as such must be kept current for the life of the project.
The following list of elements is typically found in a VMP:
• Description of the project management strategy
• Scope statement
• Work breakdown structure
• Responsibility matrix
• Major milestones and target dates for each
• Key staff members
• Constraints and assumptions
• Open issues and pending decisions.
Exhibit 3. Project Milestones
The VMP ensures that a clear direction is given to the project, the deliverables are well understood, and that the key players in the construction project agree upon their responsibilities. It also protects the manager of the validation subproject against lack of up-to-date information on his own project. The “living document” nature of the VMP ensures that project documentation is held to the same standards as validation documentation. This is of particular interest in an industry where documentation is a key element of all activities related to manufacturing, be it of products for commercial distribution or clinical supplies.
The VMP, in this context, plays the same role as the project plan, as defined in the PMBOK® Guide. The PMBOK® Guide says of the role of the project plan that it is “used to: guide project execution, document project planning assumptions, document project planning decisions regarding alternatives chosen, facilitate communications among stakeholders, define key management reviews as to content, extent, and timing, provide a baseline for progress measurement and project control” (PMI, 2002, p. 43). In the same way as the VMP, the “project plan is a formal, approved document used to manage project execution” (PMI, 2002, p. 44). The project plan plays a crucial role in the coordination of project resources and in the achievement of project goals. The VMP is similarly at the heart of the validation subproject.
The first step in producing a good VMP is to identify the members of the validation team and to include them in the development if the document. For our project, the validation team consists of the construction project manager, the facility owner, and quality assurance personnel. These individuals are responsible for the initial approval of the VMP and sign the closeout of the VMP at the end of the validation subproject. The closeout of the VMP will indicate that all project deliverables listed in the document have been produced.
During the development of the VMP, weekly meeting were held, over the course of approximately two months, to discuss the VMP content. Issues discussed in these meetings included: what utilities require validation in this new facility and to what extent will they be tested, who will sign off on the documents produced, who is responsible for all training aspects of new equipment, what equipment must be validated and to what extent, etc. Other important GMP issues in the overall facility were discussed in the course of preparing the VMP (e.g., what should room temperature and humidity setpoint be, how will change control for equipment relocation be handled and many other issues which directly affect the regulatory compliance of the facility).
These meetings are the core of a successful plan and ultimately a successful validation project. The project team should take the time to fully examine all issues that are raised. Supplementary information obtained from investigating these issues can be integrated into the document before all stakeholders sign it. For example, an important issue was the design of the formulation cubicles. Expert advice from FDA inspectors was sought out and the issue was resolved prior to the signing off of the document. Including this team in the development of the plan helps with document and deliverable approval later on in the process because all stakeholders know what deliverables to expect. If the planning is well done and well documented up-front, then all that remains is the execution of the detailed plan.
But what if the plan changes? The VMP was described earlier as a “living document.” In practical terms, this means that there are mechanisms inherent in the structure of the VMP that make it possible to keep it current and up to date. There is a change log in the appendix of the document that is used to record changes to the document and allow for a natural evolution of the project. The changes are managed as follows. The first revision of the VMP is signed-off by the project managers and validation team members. It is the responsibility of the project manager for the validation subproject to ensure that the VMP is followed and kept up to date. A mistake often made if to neglect validation and leave it to the end of the project without a detailed plan and no real direction. The validation manager ensures that the plan is being followed and that changes are being documented properly. For example, two years ago when the plan was first developed, team members decided that the security system would be validated following the full life-cycle methodology described above. One year into the project, the entire site philosophy changed and it was decided that the security system would only be commissioned by the vendor and not fully validated as described in the VMP. A memo describing the change signed by all validation team members was appended to the VMP and listed in the change log. Several similar changes were handled in the same way. This makes the closeout of the VMP two years down the road much easier because everyone will have been informed to these changes and no one will be searching for those deliverables at the end of the project and demanding an explanation for their absence. Communication and team member approval of these changes is essential in the management a large validation project.
Time, Money, and Risk in the Validation Project
In this project, the VMP was developed around the same time the project scope was finalized. It therefore became the appropriate basis to develop the budget for the validation effort and the work breakdown structure of the entire validation project. The validation subproject's schedule is also dependent on the construction project's schedule and cannot be determined and managed independently. The VMP therefore only contains critical milestone dates based on the project's construction schedule. For example, all quality assurance plans, configuration management plans, requirement specifications and design specifications for the various system, utilities, and equipment must be prepared and approved during the facility's construction. The schedule allowed for three months to prepare the IQs, OQs, and PQs and to get them approved. Three more months are needed to actually execute all the testing required to close out the protocols. The milestones in the VMP were expressed in the following way.
Using these milestones as a guide, the validation project manager develops a more detailed project schedule using traditional tools such as Microsoft Project or even Excel for smaller projects. This detailed schedule planning is done outside the scope of the VMP because any small change in the schedule would require an update of the VMP and consequently, another approval of the document. There is no value added in keeping such a detailed schedule in the VMP. The detailed planning, however, does help the validation subproject manager to determine resource requirements.
At this point, all stakeholders approve the VMP. The required documents and deliverables are known. When validation consultants are used, a contract is normally awarded to write the VMP and then a separate contract is awarded to actually do the work. Using the VMP as a guide, a proposal to do the work is prepared. The proposal is very detailed and each of the required deliverables becomes an element in the work break down structure (WBS). The benefit of this approach is twofold: (1) once the contract is awarded the project WBS is already determined and, (2) the construction project manager can use this to determine how much money should be budgeted in order to complete the validation requirements as specified in the VMP.
Change control is another important element that must be considered in a renovation or expansion project. It must be included at least in general terms in the VMP and must be thought out in more detail for the purpose of cost estimation. Usually the VMP contains a general statement, such as “Any changes made to a validated utility, system or piece of equipment will follow the approved site Change Control procedure.” Most pharmaceutical facilities have one and when expanding a facility it must be followed. It is almost impossible to capture all the change control elements required at the time when the VMP is first produced, but a good brainstorming session must be carried out in order to include an estimate that is as realistic as possible in the validation budget. A detailed list of all the systems and equipment that must undergo the change control procedure are included in the VMP and as the project progresses this list must be updated in the VMP to keep it current. Change control is an important element of risk in a validation project. A good way to attain this estimate is to go through every utility, system and piece of equipment in the facility. For example, determine how many pieces of validated equipment will be moved in to new facility, whether change control will in all likelihood be required, and budget for it. For utilities such as medical compressed air or United Stated Pharmacopoeia (USP) grade water, we must consider whether the utility will be stand-alone or connected to an existing validated network. The experience we have had with this project is that the heating and air-conditioning ventilation (HVAC) systems required the greatest number of change controls. Several change control procedures were required to connect to the existing validated ventilation systems during construction, before finally achieving the final ductwork configurations. At the end of the project, a summary list of all the change control documents that were produced within the scope of the project is included in the VMP.
About three months before construction of the facility is complete, all validation protocols (IQ/OQ/PQ) must be complete and approved. This time frame, determined by the client at the outset, is rather independent of the size of the project. Whether there are three new utilities or ten, execution of the protocols cannot start until the systems are installed. And operational qualification cannot start until the systems have at least been started up. What will vary in the three-month period that has been allotted for execution of the protocols is the size of execution team. What works best in these projects is to keep the team writing protocols small but composed of experienced validation specialists or engineers. Then, depending on the size of the project, execution of the protocols can be done by a slightly larger team of lesser experience.
In our case study, a team of two experienced validation engineers prepared about a dozen protocols (IQ/OQ/PQ) of varying complexity in six months. Of course all other pertinent documentation, quality assurance plan, configuration management plans, design specifications, etc. were already produced and approved according to the life-cycle methodology. The validation project manager was able to produce these documents as well as handle the change control activities over the course of the year-and-half construction period. The last three months of the project require three full-time resources to execute the dozen or so protocols. As mentioned before, depending on the number of protocols to be executed and their complexity, it is the size of this execution team that will vary considerably from project to project. It can also happen that the construction of the facility is delayed but that the turnover date of the facility does not move. Where did those three months the project manager had allowed for validation execution go? They might be cut down to a month and a half. The validation project manager must add resources to the team, to get execution done in half the time. This is why having all the protocols ready and approved and ready to go when the project manager says “go” is so crucial. Members of the team cannot write and execute at the same time. It is neither efficient nor practical.
In addition to the validation resources, the services of a training specialist were also used to ensure that the client's training requirements were met and fully documented. The training specialist helped define training requirements for the various site groups: electricians, plumbers, technicians, end users, etc. This same individual worked with suppliers to develop training plans and training materials. All too often, training requirements are left to the end of the project. This often leads to dissatisfaction of the client and ultimately delays for project turnover. Training is a crucial element of validation, and until training requirements are met and proof that training was dispensed properly is provided, validation protocols cannot be closed out. A major part of the success of the project came from having a resource whose sole responsibility on the project was ensuring that training needs were met.
Closing-Out the Validation Subproject
The most effective way to close out protocols after execution is to have a sign-off meeting. During the meeting, one protocol or a set of similar protocols (e.g., three identical HVAC systems) is reviewed and all deviations encountered during execution are discussed. The validation subproject manager explains how the deviations were resolved and presents the final closeout report. She prepares a closeout list and when the protocol for a particular system, utility, or piece of equipment is closed out, it is added to the list. The closeout process can take several weeks. After all protocols have been closed out, all that remains is to close out the VMP. The closeout of the VMP represents the official turnover of a validated facility to the client. The closeout list prepared while closing out each of the individual protocols will demonstrate that each of the required deliverables has been approved. Normally, the closeout of the VMP is a formality at this point. The hard part is closing out each of the individual protocols.
In this paper, we have shown how the validation master plan or VMP plays the role of a project plan and contains the essential elements of a project plan as defined by the PMBOK® Guide. Using as an example an expansion project for a clinical supplies manufacturing facility, we showed that the VMP documents the scope of the validation subproject, the responsibilities of the various stakeholders, the specific deliverables of the validation subproject, as well as the major milestones and target date for each. We explained how the VMP is kept a “living document” such that, at all points in time, it reflects the scope of the project and the current thinking about the assumptions and the constraints affecting the validation subproject. Finally, we explained how the successive closeout of the validation protocols leads to the closeout of the validation master plan itself, as all deliverables are completed to the stakeholders’ satisfaction.
ISPE. 2001. Baseline Pharmaceutical Engineering Guides for New and Renovated Facilities: Volume 5. Commissioning and Qualification.
ISPE. 2001. GAMP Guide for Validation of Automated Systems, 4th edition.
Project Management Institute. 2000. A Guide to the Project Management Body of Knowledge (PMBOK® Guide) – 2000 Edition. Newtown Square, PA: Project Management Institute.
Swann, John P. 1999. “The 1941 Sulfathiazole Disaster and the Birth of Good Manufacturing Practices.” PDA Journal of Pharmaceutical Science & Technology, 53 (3): pp. 148–153.
Proceedings of the Project Management Institute Annual Seminars & Symposium
October 3–10, 2002 • San Antonio, Texas, USA