Foster Wheeler, Reading, Berkshire, U.K.
INTRODUCTION
The design, construction, and commissioning of a new facility for the pharmaceutical industry is a complex process that involves the interaction of a wide variety of engineering, process and QA, and control disciplines and may proceed through a series of different phases from a conceptual, feasibility study, through to the final detailed design, construction, commissioning, and final site vali- dation activities. The FDA’s risk-based approach to GMPs for the 21st century has changed the industry’s perspec- tive to validation and qualification. This new initiative allows the facility designer, constructor and commis- sioning group to take a risk-based approach to the qualification of facility and equipment. The basic require- ments for validation of facilities and equipment are defined in both the European community’s Guide to Good Manufacturing Practice Vol. IV (Medical Products) and the United States’s GMPs CFR Title 21 (1,2). These documents clearly define the need for a whole system that is based on QA. This is essential for pharmaceutical companies to ensure that products meet their quality and marketing authorization requirements. cGMP is a key element of an overall QA system and GMP extends through people, production, premises, and equipment. Both the U.S. GMP and the EC Guide emphasize that premises and equipment should be designed to be appropriate and fit for the purpose. Interpretation of this statement implies that it is essential that facilities must be built to standards that meet the requirements of the GMPs and be demonstrated to meet these require- ments. The process of validation is a key component within the concept of QA and GMP. The consequence of this for the facility designer is that he or she must use design and engineering methods that will comply with and demonstrate that the facility, when complete, does meet the requirements of cGMPs.
This chapter describes an approach that can be used by the designer to ensure that the design, engineering, and construction process can meet the GMP require- ments. This approach is sometimes referred to as Validation Master Planning. More commonly, industry develops a Validation Master Plan to cover all aspects of the validation of an operating unit such as: Process Validation, Cleaning Qualification, Automation Vali- dation, and Facility and Equipment Qualification. This chapter shall refer to it as the Facility and Equipment Qualification or FEQ plan. The key basis to successfully qualify a facility is to plan the qualification from the earliest stage of the facility design by the development of a clear validation strategy that will develop into a plan for validation throughout the project. The main focus of this chapter is on new facilities; however, a separate section discusses how this approach can be adapted to meet the needs of revamp or refurbishment projects. A complete section is devoted to the development of an FEQ Plan. The FEQ section outlines the whole of the qualification requirements both in scope and for all stages of the project.
THE ENGINEERING DESIGN PROCESS FOR A FACILITY
The engineering or feasibility design process typically follows a series of phases.
& Conceptual design
& Design development, front-end design or basic/pre-
liminary engineering
& Detailed engineering & Procurement
& Construction & Precommissioning & Commissioning
Each of these phases has its own engineering objectives and, consequently, the qualification require- ments have both a different scope and extent at each phase. The concepts for qualification will be described for each phase.
Conceptual Design Introduction
The actual process design commences at a much earlier phase than the engineering design. Pharmaceutical drug discovery, design, and production are key elements of the industry. At a stage during the drug development and clinical trial phases, it will become apparent Abbreviations used in this chapter: cGMP, current good manufacturing
practice; CIP, clean in place; DQ, design qualification; EC, European Commission; EMEA, European Medicines Evaluation Agency; FAT, factory acceptance test; FDA, Food and Drug Administration; FEQ, facility and equipment qualification; GMPs, good manufacturing practices; HVAC, heating, ventilation, and air-conditioning; IOQ, installation and operation qualification; IQ, installation qualification; NDA, new drug application; OQ, operationalqualification; PID, piping and instrument diagram; PQ, performance qualification; PV, process validation; QA, quality assurance; SIP, sterilization in place; SOPs, standard operating procedures; UK MCA, United Kingdom’s Medicines Control Agency; URS, user requirements specification; USP, United States Pharmacopeia; WFI, water for injection.
whether the company has a new product that it wishes to bring to the market. This is usually the point when first considerations for the engineering and manufac- turing needs for the production of the drug will be addressed.
Production of clinical trial material will have moved from laboratory facilities to pilot-scale operations. Experi- ence gained at this pilot-scale production will normally give sufficient information to enable a process definition to be prepared. The marketing organization will also have some early projections for demand levels and the type of formulations that will be required. These key elements will give a basis for a conceptual design study. The collection of process data for subsequent full-scale PV will also already have begun. Clearly, the current regulat- ory bodies emphasis on proof of drug equivalence, i.e., final production batches must be equivalent in biological and chemical activity to those used in the clinical trial and any subsequent submissions (typically for the NDA) will already have some significant effect on the manufacturing route, engineering design, and equipment selection.
The conceptual study must consider all these aspects and incorporate their requirements into this early design. Consequently a plan is required to ensure that GMP, qualification, and process requirements are incorporated. Purpose
The main purposes of a conceptual study is to provide: 1. An agreed basis for the design philosophy to be able
to proceed to the next phase of development (frequently called Front-End Design by the engin- eering contracting organization or sometimes known as Design Development or Basic Engineering). 2. To provide an initial capital cost estimate, usually for a preliminary budget sanction by senior manage- ment. Often a conceptual study is used as a feasibility study (i.e., should we proceed or not?).
3. Deliverables.
The typical deliverables of this phase are as follows:
& Statement of basis of design & GMP statement
& Process block flow diagrams or schematics & Major equipment item list
& Conceptual layout and accommodation schedule & Building and HVAC philosophy
& Outline of utility systems & Outline of control philosophy & Safety considerations
& Budget estimate
Approach
Usually, the conceptual study will be run as a mixed disciplinary team bringing together research and development, production, and engineering disciplines led by a study manager. Although QA does not have a major role to play at this stage, it is important that the team has access to appropriate personnel.
In the design of a pharmaceutical facility, one of the most important aspects of the development is the layout. A typical approach that has been useful is to develop an accommodation schedule (Fig. 1), which shows a typical example for an aseptic suite.
This shows the flow of personnel, materials, and products. Figure 2 shows the variety of data that goes into the development of this schedule, which usually brings together specialist disciplines, including an engin- eer who understands layout development. This early process is an iterative phase during which all disciplines will have their input into the accommodation schedule, although it is best if a single individual, skilled in layout development, coordinates the activities and provides the preliminary drawings for review by the team. Once a first layout is agreed on, it must then be formally reviewed for GMP compliance. Figure 3 shows such a preliminary layout. The process may be repeated as the layout is developed and, consequently, GMP principles are built into the design from an early stage. The whole process
Vial Washer Vial Sterilizer Vial Filler Stopper Washer Sterilizer Dry Heat Sterilizer Capping
Machine Inspection Labeling Cartoner
Transfer to Fibreless Trays Vials from Warehouse Stoppers from Warehouse Machine Parts Product Sterile Caps To Warehouse
ensures that the final layout meets GMP and is docu- mented. This is part of the qualification of the design and is key “DQ documents” and must be approved by the appropriate team members.
Qualification Activities
At this stage, the qualification of the facility is in its earliest phase and the emphasis must be on the qualifica- tion of the design. This can be completed by reviews of the proposed design against defined user requirements
criteria. The preliminary nature of the study limits the depth of review. It should address critical issues against the user specification and the GMP requirements. Qualification Cost
Clearly if the conceptual phase is to provide a cost estimate for the project, then the qualification must be similarly estimated at this stage. Some form of qualifica- tion statement and policy is required to at least determine Accommodation Schedule
Establish Concepts Identify Priorities Estimate ‘Building Blocks’
Conceptual Layout
Preliminary Arrangement of Rooms Adjacency of Areas
Initial Building Concepts Personnel Access/ Egress Utility Distribution Concepts Defined Provisional Constructability Assessment Influences
Guidelines Building Regulations Process Design Basic Equipment List Architectural Treatment Existing Site Influences
GMP Material and Personnel Flow Charts Statement of Fitness for Purpose Regulatory Authority Requirements Containment
Room Data
Conceptual Layout Challenged with Established Priorities and Recycled to Include Identified Improvements
Front-End Design Figure 2 Conceptual layout development.
Figure 3 Preliminary conceptual layout.
its future scope. At this stage, this may involve only a flowchart (Fig. 4). Some may prefer to develop a very preliminary facility and equipment plan (see the section entitled Facility Qualification Plans). The decision of which route to take may be determined by the extent of the study and company policy. Without significant details of the facility and its contents, specific costs for the key qualification tasks cannot be easily determined unless access to similar projects’ costs is available. At this stage, it is probably more normal to make an allowance based on in-house or the design engineers’ experience. It is important to have an estimate that reflects that of the study. If the study is G25%, then it is reasonable for the qualification estimate to fall within similar limits. Design Development
Introduction
Usually, by this phase of the project, the pharmaceutical company believes that it is highly probable that the project will proceed subject perhaps to certain restrictions, usually based on schedule and total final cost. The first key decision is (i) should this phase be done in house? (ii) involve an external design construction consultancy? (iii) an Engineering Management Contractor? Frequently, the choice is very dependent on organization culture.
Clearly, whatever the choice, some key questions are “Can the designer meet and demonstrate that the design complies with GMP?” “Are you going to use a single engineering organization to manage the project through design, procurement, construction, commissioning, and qualification?” “Are the systems in place to aid qualifica- tion?” Choosing your contractor is discussed in more detail elsewhere (3). The answers to these questions have significant bearing on the route adopted.
Purpose of Design Development
The main objectives of this design development phase are as follows:
1. To establish a basis for detailed design
2. To progress the design to establish the technical, capability, and safety aspects of the project
3. To provide the necessary design data to evaluate and, subsequently, comply with the regulatory, environ- mental, and planning requirements of a project with the relevant authorities
4. To provide an improved cost estimate and so enable sanction of the project.
Deliverables
Typical design development deliverables are as follows:
& Process flow diagrams
& Process and equipment specifications & Utility specifications
& Control and automation user requirements
specification
& Preliminary process PID
& Floor plans and equipment layouts & Facility and equipment qualification plan & List of systems
& Building evaluation & Building finishes
& HVAC schematics and routings & Safety and GMP reviews & Environmental considerations & Project schedule
& Estimate
Approach
Once the choice of management for the project is made, a team must be assembled under a project manager, who
Identify Items
to be Qualified FDA Life Cycle
Approach Approved Design Documentation Specification Standard Operating Procedures SOPs Records Identify Systems & Subsystems Process Qualification of Products & Processes Includes Dust Control Preventative Maintenance Plan Personnel •Training •Experience Change Control •Project •Engineering •Process •Etc. Validation Master Plan
Computer Qualification List Items to be Qualified Design
Qualification QualificationInstallation Calibration Identify Items to be Calibrated Cleaning Qualification Identify Systems to be Qualified Operation Qualification
will preferably see the project through all the subsequent phases to provide a high degree of continuity. This is an important factor to consider for this key position.
The key areas of development during this phase are the following:
1. The layout, to define and fix the building size 2. Define all major items of equipment
3. Define piping and instrument requirements, as shown in the PID
4. Identify the key process services to equipment (e.g., pure steam, WFI, air, nitrogen, and so on)
5. Establish philosophy for process control and auto- mation, containment, and safety
6. Identify the utility services, HVAC, drainage, elec- tricity, and others
7. Identify preliminary architectural details and building structure and foundations
8. Identify any long-lead items: usually equipment (e.g., major items can be on delivery times as long as 12 months)
9. Ensure the design meets GMP and can be demon- strated (validated) to do so
10. Develop a cost estimate at a defined accuracy (usually 10–15% is required at this stage)
Layout Development
From the conceptual design, the materials, personnel and product flows will have been agreed on, and the philosophy determined. During this phase, each of these needs to be challenged and developed in detail. Once completed, no further changes should be made during detailed design other than minor accommodations to permit interfacing with final equipment installation requirements.
Typically decisions made affect both the DQ and the subsequent validation process. We consider two examples: aseptic changing facilities and the options that might be chosen for sterile stoppers used for vials.
Three schematic options are shown for aseptic changing facilities (Figs. 5–7); all have an appropriate use, depending on specific requirements. The designer must be aware of the implications of their choice. The simplest (Fig. 5) is suitable only for low-traffic-flow areas and may need some form of traffic control to prevent an exiting operator passing an ingoing operator at a critical point. The option in Figure 6 is straightforward and preferred (i.e., separate in and out), but is more expensive to build, whereas Figure 7 is a compromise, but reuse of the garments will require validating. The option in Figure 5 requires validation of the traffic flow procedures and cleanup rates between exit and reentry; perhaps automatic systems may be considered to prevent personnel who are moving in opposite directions from meeting; more normally the firm would rely on procedure. The option in Figure 6 clearly eliminates this potential adverse consequence and so makes the sub- sequent validation of operations simpler. Each option presents its specific challenge in design and in sub- sequent validation requirements, and an evaluation of capital cost versus validation costs should be a part of the decision process.
Again, two options are shown schematically in Figures 8 and 9, for handling stoppers for an aseptic vial filling process. The designer’s choice has significant effect both on layout and subsequent validation require- ments. The option in Figure 8 may initially appear very attractive, the use of prewashed and sterilized stoppers reduces the need for expensive equipment to be purchased and installed. However, QA must audit the supplier, and the designer must devise an aseptic means of transfer to the filling line. The solution is frequently a manual transfer by a pass-through hatch and manual loading into the stopper bowl. Each operation will have to be validated. The route shown schematically in
Factory Change Remove Factory Clothing Remove Clean Room Garments Air Lock Wash Scrub Up Don Clean Room Garments Air Lock Clean Corridor
Figure 6 Aseptic changing facilities—separated flow in and out. Outer Change Air Lock Clean Corridor Scrub Up Step Over
Figure 9 shows stoppers being washed and sterilized on site and then being transferred from the clean side of the stopper washer–sterilizer to the vial stopper hopper. This can be achieved in closed containers minimizing manual contact and operations. Options are available from some suppliers that make use of isolation technology. Clearly, this latter route has very significant influence of vali- dation requirements and design.
The two examples demonstrate that the develop- ment of the design choices at this stage has implications for the layout, the layout’s qualification, and the valida- tion requirements to be later conducted by the operations group. These requirements can be covered in the GMP review that is a key part of the DQ and can be used as part of an evaluation of the options.
Equipment
Usually, within the scope of this phase, the major equip- ment specifications are developed. These specifications will form part of the DQ and should be related to the user requirements specification. For some major items, with long-lead times, it may be necessary to develop these into requisitions or tender documents to meet the overall project schedule. The requirements for validation must be developed concurrently with these specifications and requisitions. These requirements include identifying all types of documentation that will be necessary to execute the qualification. This documentation will typically include the following generic topics:
& Equipment suppliers’ documents and drawings & Engineer’s documents and drawings
& FAT documents
& Delivery and installation documents and drawings & Protocols IQ, OQ, PQ, and associated documents.
An approach that can be used to assemble the list of detailed documents and drawings is to develop the lists in a matrix form (Fig. 10). It is important to incorporate the document drawing requirements into a requisition, for this can represent a significant proportion of the cost. Negotiating for documents post- delivery of an item can prove costly and, in some circumstances, result in no documentation being received. The implications of this for the completion of qualification are potentially severe. Many of the vendor documents are also essential to commence and complete the IQ and OQ protocols.
Further details on the protocol contents and asso- ciated documents are found in the section entitled Facility Qualification Plans. Ensuring availability of relevant documents at the correct time in the program is critical