Cleanroom Design, Construction, and Qualification

Transcription

1 [ The Aseptic Core. Coordinated by Ed White Cleanroom Design, Construction, and Qualification Ed White The Aseptic Core discusses scientific and regulatory aspects of aseptic processing with an emphasis on aseptic formulation and filling. This column has been developed to provide practical advice to professionals involved in the qualification of aseptic processes and the myriad support processes involved. Reader comments, questions, and suggestions are needed to help us meet our objective for this column. Please your suggestions to journal coordinating editor Susan Haigney at KEY POINTS The following key points are discussed in this article: Construction and qualification of a new aseptic processing area is a complex project involving multiple disciplines Good upfront strategic planning is critical for an effective qualification effort. All involved disciplines should be involved in planning for an aseptic facility. Construction and qualification of a new aseptic processing facility can be divided into several phases: planning, design, construction, commissioning, qualification, submission, and project closeout. Detailed design reviews should be performed on vendor design documents. These reviews should be repeated for any design changes. The US Food and Drug Administration s aseptic processing guideline, the European Commission s GMP Annex 1, and International Organization for Standardization (ISO) can serve as useful references during design reviews Cleanrooms are generally designed using a pressure cascade that maintains a minimum differential pressure of Pascal positive to adjacent areas of lower classification Cleanrooms and aseptic complexes should be designed for optimum flow of material, equipment, personnel, and waste streams so that raw materials and waste streams cannot cross over finished goods, personnel cannot move from less clean to cleaner areas without gowning, clean and dirty equipment cannot mix, and multiple products are segregated Cleanroom classification is performed per the ISO series of standards Some cleanroom reclassification activities can be satisfied with routine monitoring data. INTRODUCTION In this issue, we move from the topic of high efficiency particulate air (HEPA) filters to the larger topic of cleanroom design and classification. The construction of a new cleanroom is a complex project, involving multiple disciplines and extending over several years. As this topic is quite complex, this article gives a broad overview of the topic, with a focus on the design process and cleanroom classification. Future articles in this column will give more detail to specific qualification activities. CLEANROOM DESIGN, CONSTRUCTION, AND QUALIFICATION PROCESS A typical cleanroom or aseptic facility design and construction process can be divided into several phases: planning, design, construction, commissioning, and qualification. On completion of the qualification phase, a submission is prepared and submitted to one or more regulatory agencies for approval. On receipt of approval, the facility enters an operational phase in which product is manufactured for sale and routine quality controls are in place. Figure 1 shows a flow chart of a typical facility design, commissioning, and qualification process. For more Author information, go to gxpandjvt.com/bios [ ABOUT THE AUTHOR Ed White is a senior principal validation engineer at Baxter Healthcare in Thousand Oaks, California. He may be reached by at ed_white@baxter.com. 30 Journal of Validation Technology [Autumn 2009] ivthome.com

2 Ed White, Coordinator. Figure 1: Facility design, commissioning, and qualification process. gxpandjvt.com Journal of Validation Technology [Autumn 2009] 31

3 The Aseptic Core. Planning Phase Because of the cost, duration, and complexity of a cleanroom construction project, some form of project management is typically used. The planning phase for a cleanroom construction project should include definition of costs, timelines and deliverables, and identification of constraints and risks. Careful attention should be taken in the planning phase, as effective planning can make the difference between a project that is delivered on time and on budget and meeting strict quality standards compared to one that is late, over budget, and fails to meet quality standards. Involving all involved disciplines, including manufacturing, engineering, quality, validation, environmental monitoring, cleaning, sterilization, etc., will make it more likely that the critical requirements are captured in the planning stage, reducing additions to the cleanroom design that increase the cost and duration of the project. Design Phase The first phase covered in this flow chart is the design phase, which begins with the preparation of formal process and product requirements. These requirements should answer the following questions: Will the facility be dedicated to a single product or will it be a multiproduct facility? Will the product(s) include any lyophilized products, any moisture-sensitive products, or any oxygensensitive or light sensitive products? Are any of the products temperature-sensitive? Do any of the products have special containment requirements, such as cytoxic products? How will the product(s) be presented to the consumer (e.g., vials, syringes, ampoules, cartridges, etc.)? Are any devices included in the presentations that will require additional equipment in the cleanroom? Can the products be terminally sterilized or must they be aseptically filled? Do the processes require dedicated or disposable equipment, or can equipment be shared between some products with appropriate precautions? Consideration should be given to whether the product dosage is low enough to cause concern with cleaning validation. The project team working on the product and process definitions will need to answer many more questions than the examples presented. The product and process definitions should lead to user requirements specifications (URS) for the equipment, utilities, and facilities that are included in the project. These requirements will give generic requirements for the equipment, utilities, and facilities that are detailed enough to prepare more detailed specifications. The URS should focus on what should be done, not how it is done, as follows. For example: The cleanroom should be designed to provide a Grade A environment over all filling and closing equipment and should be at least 15 Pascal positive to any area of lower classification. Sufficient space should be provided for aseptic filling and stoppering equipment, as well as associated conveyors, and for transfer of sterilized vials from a depyrogenation tunnel located external to the cleanroom. Sufficient Grade B space should be provided in the cleanroom for production operators and for environmental monitoring operations; or The filler shall be capable of aseptically filling and closing vials from 5 ml to 20 ml at consistent speeds from 15,000 vials per hour for 5 ml vials to 7,500 vials per hour for 20 ml vials. The filler will be capable of fully or partially inserting 20 mm stoppers into the vials at these speeds. The filler will automatically check-weigh the vials so that each filling head is checked at least once every 15 minutes. The filler will be capable of displaying actual fill weights and control charts of the fill weights, and will be capable of exporting the fill weight data through a standard data interface. Once the URS is complete, the preliminary risk assessment should be performed to identify risks that need to be addressed in the design, and a preliminary design should be prepared (typically by an architectural and engineering [A&E] firm). A preliminary design review should be performed on the preliminary design to ensure that the user requirements are met, and that the design complies with current good manufacturing practice (CGMP) requirements, as outlined in the appropriate reference such as the US Food and Drug Association s aseptic processing guideline (1) or the European (EU) GMP Annex 1 (2). The International Organization for Standardization (ISO) Standard (3) is also a useful reference for preliminary design review. After the preliminary design has been reviewed and approved, the A&E firm will prepare a request for quotes, which the various vendors and contractors will use to prepare basis of design and quotation documents. Once the vendors and contractors have been selected, functional specifications are typically written for the equipment and utilities (functional specifications can be written as part of the bid package in some cases). Functional specifica- 32 Journal of Validation Technology [Autumn 2009] ivthome.com

4 Ed White, Coordinator. tions are used by the vendors to prepare detailed design specifications that undergo a detailed design review and design qualification in which the vendor design is reviewed to ensure it meets user requirements and the appropriate CGMP requirements. The design review should be updated if any design changes are implemented after the detailed design is approved. Construction Phase Once the detailed design reviews are complete the project moves to the construction phase, in which the facilities, utilities, and equipment are built. This phase uses standard construction management techniques for the facilities, utilities, and equipment. Special attention should be given to items such as welded piping such as waterfor-injection (WFI) piping, and cleanroom construction during this phase. The construction phase concludes when the equipment, facilities, and equipment are constructed and installed. Equipment typically undergoes a factory acceptance test (FAT) before it is shipped. An FAT is intended to verify that the equipment meets its approved design specifications and functional specifications before it ships. The contract with the vendor typically specifies that successful completion of an FAT is required before the equipment may ship. An FAT is typically executed using an FAT protocol that is approved by representatives from the vendor and customer. Once the FAT is approved, the equipment may ship and may be installed at the customer site. A site acceptance test (SAT) may be performed once the equipment is installed in the cleanroom to ensure that the equipment has been installed properly. Commissioning Phase Once the construction phase is complete, the project moves into the commissioning phase. In this phase, the equipment, utilities, and facility are tested to ensure they meet design specifications, functional specifications, and user requirements. The commissioning phase differs from the subsequent qualification phase in that a less formal change management system is typically in place during commissioning, allowing changes to be made and documented with lower levels of approval than would be necessary during the qualification phase. Typical activities that occur during the commissioning phase may include the following: Redlining of equipment, facility, and utility drawings to ensure they reflect the actual systems as installed Verification of field interconnects, if not performed as part of a site acceptance test Verification that equipment and utilities operate as designed gxpandjvt.com Verification of materials of construction for equipment, utilities, and cleanrooms, if not verified during the construction phase Cycle development for various component, equipment, and material preparation processes such as steam sterilization processes, clean-in-place and steam-in-place, closure washing, siliconization (if necessary) and sterilization processes, depyrogenation processes, sterile filtration, etc. Preparation of forms and procedures for equipment, facilities, and utilities, and many other activities Air balancing of the facility to ensure proper air flows and pressure cascades. This is typically done by professional air balancing firms that are certified by the National Environmental Balancing Bureau (NEBB). The commissioning phase is typically closed out by a formal commissioning report, which evaluates whether the equipment, utilities, and facilities are properly installed and properly operating, and whether or not the equipment, facilities, or utilities are ready for qualification. Qualification Phase The qualification phase begins with completion of commissioning of the equipment, facilities, and utilities and continues through aseptic process simulations (media fills) and process validation (conformance) runs. Some installation qualification (IQ) activities, such as verification of piping, wiring, or materials of construction, may begin in the commissioning phase or even in the construction phase, continuing into the qualification phase. Operational qualification (OQ) and performance qualification (PQ) activities are almost totally contained in the qualification phase, although some OQ activities may be performed during commissioning if no changes are made to the equipment subsequent to the OQ activities. It is in the qualification phase that cleanroom certification activities are typically performed. Submission Phase The submission phase consists of the preparation of regulatory submissions once qualification activities are completed. These submissions are sent for approval to one or more regulatory agencies. Any product manufactured during the submission phase is held pending approval of the submission. Operational Phase Once approval is received, the cleanroom can be considered to be operational. Product being held pending submission may be released, assuming it meets its predetermined specifications. Journal of Validation Technology [Autumn 2009] 33

5 The Aseptic Core. POINTS TO CONSIDER FOR CLEANROOM DESIGN There is not a single right way to construct an aseptic processing facility or cleanroom, as each should be designed to accommodate the processes and products contained in the cleanroom. There are, however, general principles of design that should be followed in constructing a cleanroom or aseptic processing facility. Many points to consider can be found in ISO , the FDA aseptic processing guideline, and in EU Annex 1. I highly recommend these references. The following points should be considered: Floors, walls, and ceilings should be constructed of materials that are smooth, hard, and easy to clean. Transitions between floors and walls should be designed with a smooth transition (coved) to allow for easy cleaning. Temperature and humidity controls in cleanrooms and supporting areas should be sufficient to maintain operator comfort when gowned and maintain adequate humidity for the process. Consider humidity and temperature loads from operating equipment such as autoclaves, CIP/SIP, etc., when designing temperature and humidity controls. Cleanrooms should be designed to facilitate personnel, equipment, and material flows to prevent microbial contamination of sterilized or sanitized equipment and facilities, sterilized components, and sterile filtered drug product. Personnel should enter the cleanroom through gowning facilities. Equipment and materials should either enter through sterilization or depyrogenation equipment or through airlocks using a validated sanitization procedure. Multiproduct facilities should be designed to eliminate or minimize instances where product streams cross. Pay careful attention to locations of return ducts in Grade A/B rooms, as they can affect the unidirectional airflow over critical processing zones. Investing in a computational flow dynamics (CFD) analysis of the cleanroom design may be worthwhile, as this can reveal unforeseen problems in the design. CFD analysis will require accurate representation of the equipment as installed, accurate locations of HEPA filters and returns, and accurate estimates of supply volumes of the HEPA filters. The cleanroom should be positive by at least Pascal to all surrounding zones of lower classification. This is accomplished by a cascade-type design, in which the cleanroom is surrounded by areas of lower classification, which are then surrounded by areas of even lower classification, eventually leading to an external unclassified area. Illustration of the cleanliness cascade concept is shown in Figure 2. When setting up pressure monitoring in an existing building monitoring system (BMS) or when installing a new BMS, consider where the reference area for differential pressures is located. It is important that a stable reference point is used to ensure good control of differential pressures. Referencing one clean zone to another clean zone can be problematic, as it can cause fluctuations in one clean zone to cascade to other clean zones. CLEANROOM QUALIFICATION Qualification of an aseptic processing facility is a complex project including qualification of the cleanrooms in the facility, IQ/OQ/PQ of the equipment and utilities in the facility, airflow visualization studies, personnel training and qualification, aseptic process simulations, process validation, conformance runs, and other validation activities. This article focuses on the activities involved in certification and qualification of the cleanroom itself. Installation Qualification Installation qualification activities for a new cleanroom typically include the following items: Verification that the materials of construction are as specified (e.g., Epoxy Terrazzo flooring, smooth hard walls compatible with cleaning chemicals such as phenolic compounds or sodium hypochlorite, etc.) Verification of adequate lighting (typically defined in user requirements) at work height Verification of appropriate installation of air handling units and ductwork or laminar flow units Verification that air handling ductwork has been adequately cleaned. This is very important, as improperly cleaned ductwork can cause HEPA leaks in some cases. Verification that the specified HEPA or ultra-low particulate air (ULPA) filters have been installed and installed properly Verification of location and size of returns Verification of instrumentation type, location, and installation Verification of installation of air handling units or laminar flow units. 34 Journal of Validation Technology [Autumn 2009] ivthome.com

6 Ed White, Coordinator. Figure 2: Cleanroom cleanliness cascade (adapted from ISO ). Operational Qualification Operational qualification for a clean room might include the following: Verification of proper operation of air handling units, humidifiers and dehumidifiers, duct heaters, smoke alarms, dampers, and other controls Verification of proper operation of the building management system (BMS) or other control system for the cleanroom Measurement of vibration and noise in the cleanroom Cleanroom classification activities. Cleanroom Qualification Classification of a cleanroom is typically performed according to ISO and its supporting documents. Typical activities involved in classification of a cleanroom include the following: Certification of HEPA filters, as discussed in the previous column. Measurement of airflow velocity and airflow volume. For Grade A areas, airflow velocity is measured using an anemometer or micromanometer at several points gxpandjvt.com across each filter. The average velocity for each filter may be multiplied by the average velocity for that filter to obtain an airflow volume for that filter. The airflow volume for each filter is added to the airflow volume of the other filters to obtain the total air supply volume for a room. Outside of Grade A areas, airflow volume is typically measured directly using a device such as a flow hood. The volume readings for each filter are summed to provide the total supply volume for the room. Air changes per hour are calculated by dividing the supply volume in cubic feet or cubic meters per hour by the room volume in cubic feet or cubic meters. The FDA aseptic processing guideline recommends a minimum of 20 air changes/hour for class 100,000 (ISO 8) cleanrooms, with significantly higher rates for cleanrooms with lower particulate classifications, as follows: Example 1: A 30-ft by 35-ft component preparation area with a 10-ft ceiling height is supplied by nine HEPA filters, each with an average supply velocity of 520 ft/min. The air changes per hour are calculated as follows: Journal of Validation Technology [Autumn 2009] 35

7 The Aseptic Core. Table: EU grades and equivalent ISO classes. Activities The local zone for high-risk operations (e.g., filling zone), stopper bowls, open ampoules and vials, making aseptic connections. For aseptic preparation and filling, this is the background environment for the grade A zone. Clean areas for carrying out less critical stages in the manufacture of sterile products. Clean areas for carrying out less critical stages in the manufacture of sterile products. EU grade ISO Class Non-viable particulate (particles/m 3 ) At rest In operation 0.5 μm 5.0 μm 0.5 μm 5.0 μm A B C D 5 at rest, 7 in operation 7 at rest, 8 in operation 8 at rest, not defined in operation , , ,520,000 29,000 3,520,000 29,000 Not defined Not defined a. Supply volume = 520 ft 3 /min x 9 filters x 60 min/hr = 280,800 ft 3 /h b. Room volume = 30 ft x 35 ft x 10 ft = 10,500 ft 3 c. Air Changes/Hour = Supply Volume/Room Volume = 280,800 ft 3 /h / 10,500 ft 3 = 26.7 Air Changes/Hour. Example 2: An aseptic filling room measures 10m x 4.5m x3m, and is supplied by 24 HEPA filters, each supplying an average volume of 0.28 m3/s at a velocity 0.45 m/s, as follows: a. Supply Volume = 0.28 m 3 /s x 3600 s/h x 24 filters = 24,192 m 3 /h b. Room Volume = 15 m x 4.5 m x 3 m = m 3 c. Air Changes/Hour = Supply Volume/Room Volume = 24,192 m3/h / m 3 = Air Changes/Hour. Measurement of differential pressures between rooms. This is typically accomplished using an electronic micromanometer or differential pressure gauge. Differential pressures are measured between reference points in the higher-pressure room and the lower pressure room. Generally, cleaner areas should be Pascal ( inches of water column) positive to less clean areas. Figure 3 shows a pressure cascade in a typical cleanroom. Particulate classification is performed per ISO and its associated documents, using a standard discrete particle counter (DPC). Each room in the complex should be verified as meeting the ISO Class or EU Grade for the activities performed in that room. The Table lists the activities and associated cleanroom grades in a typical cleanroom. As shown in the Table, the EU Grade and associated ISO Class recommended by FDA are equivalent except for EU Grade A, which recommends a lower particle limit for the 5.0 µm particle size class (20 particles/m 3 ) than the limit for the same particle size class in ISO (29 particles/m 3 ). I personally prefer certifying to the EU limits, as these limits are more stringent than the ISO limits; a clean zone certified to EU grade A will automatically meet ISO class 5 requirements the other limits are identical to the equivalent ISO class. One drawback to the EU classification scheme is that EU does not allow for sequential sampling in Grade A zones. EU Annex 1 requires that at least 1 cubic meter is sampled at each site during classification activities. The minimum number of sampling point locations in each cleanroom is determined using the formula N L = A 1/2 ; where N L = the minimum number of sampling point locations, rounded up to a whole number, and A 1/2 = the area of the cleanroom or clean zone in square meters. Once the number of sample sites is determined, the room should be examined to determine which points within the cleanroom should be tested. Special attention should be given to points 36 Journal of Validation Technology [Autumn 2009] ivthome.com

8 Ed White, Coordinator. Figure 3: Pressure cascade in typical cleanroom complex. in the room where returns are located, and points where critical operations are occurring, and to points where particle ingress could occur, such as portals between adjoining rooms. Example 3 shows the calculation of the number of sample sites for a filling room containing both EU Grade A and EU Grade B zones. Example 3. An aseptic filling room containing Grade A and B zones is to be classified. The overall room size is 11.4 m by 15.2 m, with a Grade A zone 4.6 m x 15.2 m (see Figure 4). The area of the Grade A zone is 4.6 m x 15.2 m, or 69.9 square meters. Using the formula N L = A 1/2, the minimum number of sampling locations in the Grade A zone is determined to be nine sampling locations. The Grade B area is ( ) m x 15.2 m, or square meters. Using the formula N L = A 1/2, the minimum number of sampling locations is determined to be 11 sampling locations. gxpandjvt.com For the Grade A zone, critical sites such as the portal to the capping room, stopper hopper, conveyor belt, filling needles, in feed turntable, and operator stations are selected as the sampling locations, as follows: a. For the Grade B zone, the sampling sites were evenly distributed throughout each side of the room, with an additional sampling site at the double door leading to the room. b. A 1 m 3 air sample was taken at each Grade A location using a discrete particle counter (we have a 100 liter per minute counter) c. Smaller air samples (100 liters per site) were taken in the grade B zones, using the sequential sampling procedure listed in ISO , Appendix F. d. All samples were taken in the At Rest condition, as this was an initial qualification of the room. In Operation samples were taken at a later phase in the validation project, during performance qualification studies. The In Journal of Validation Technology [Autumn 2009] 37

9 The Aseptic Core. Figure 4: Sampling locations for Grade A/B cleanroom. Operation samples were taken using the same procedure as the At Rest samples, excepting that a full complement of operators were in the room and all equipment was operating per normal procedures. In Operation samples were taken during practice runs for aseptic process simulations (Media Fills). Airflow visualization. This is performed in all Grade A processing areas to demonstrate that the airflow is appropriate for aseptic processing. Airflow visualization will be the topic of an upcoming column. CONTINUING CLEANROOM COMPLIANCE One final item to discuss is the periodic tasks for demonstrating continued compliance of a cleanroom with ISO standards. These tasks include the following: HEPA filter leak testing: every 6 months for ISO Class 5 and lower classifications, every 12 months for classifications >ISO 5 Particle classification: every 6 months for ISO 5 and lower, every 12 months for >ISO 5 Airflow volume or airflow velocity: every 12 months Air pressure difference: every 12 months. Because of the routine particle counts in operational conditions, verification of the classification of a cleanroom is usually performed under at rest conditions. Retrospective review of in operation particle counts may be used to demonstrate compliance under in operation 38 Journal of Validation Technology [Autumn 2009] ivthome.com

10 Ed White, Coordinator. conditions. Review and trending of viable and non-viable particle counts should be part of a quality system for any aseptic processing facility. Air pressure difference can also be satisfied by review and trending of routine monitoring results most building monitoring systems have the capability of trending differential pressures. With in operaton particle counts and differential pressures satisfied by routine data, periodic recertification activities are limited to HEPA filter leak testing, at rest particle counts, and airflow volume or airflow velocity. VALIDATION IMPLICATIONS This column has discussed the cleanroom qualification process through the classification phase. At this point, the cleanroom is far from validated. The additional validation tasks will be discussed in future columns. REFERENCES 1. US Food and Drug Administration, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, European Commission: Enterprise and Industry Directorate-General, EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1: Manufacture of Sterile Medicinal Products (corrected version), International Organization for Standardization (ISO), ISO , Cleanrooms and Associated Controlled Environments Part 4: Design, Construction and Startup, ADDITIONAL REFERENCES ISO, ISO , Cleanrooms and Associated Controlled Environment Part 1: Classification of Air Cleanliness, ISO, ISO , Cleanrooms and Associated Controlled Environment Part 2: Specifications for testing and monitoring to prove continued compliance with ISO , ISO, ISO , Cleanrooms and Associated Controlled Environment Part 3: Test Methods, JVT ARTICLE ACRONYM LISTING A&E Architectural and Engineering BMS Building Monitoring System CFD Computational Flow Dynamics CGMP Current Good Manufacturing Practice DPC Discrete Particle Counter EU European Commission FAT Factory Acceptance Test FDA US Food and Drug Administration HEPA High Efficiency Particulate Air NEBB National Environmental Balancing Bureau IQ Installation Qualification ISO International Organization for Standardization OQ Operational Qualification PQ Performance Qualification SAT Site Acceptance Test ULPA Ultra-Low Particulate Air URS User Requirements Specification WFI Water-for-Injection gxpandjvt.com Journal of Validation Technology [Autumn 2009] 39