cleanroom design, construction, and qualification

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Cleanroom Design, Construction, and QualificationEd White

“The Aseptic Core” discusses scientific and regula-tory 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 e-mail your suggestions to journal coordinating editor Susan Haigney at [email protected].

KEY POINTSThe following key points are discussed in this article:

• Construction and qualification of a new aseptic pro-cessing area is a complex project involving multiple disciplines

• Good upfront strategic planning is critical for an effective qualification effort. All involved disci-plines should be involved in planning for an aseptic facility.

• Construction and qualification of a new aseptic pro-cessing facility can be divided into several phases: planning, design, construction, commissioning, quali-fication, 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) 14644-4 can serve as useful references during design reviews

• Cleanrooms are generally designed using a pressure cascade that maintains a minimum differential pres-sure of 10–15 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 14644 series of standards

• Some cleanroom reclassification activities can be satisfied with routine monitoring data.

INTRODUCTIONIn this issue, we move from the topic of high efficiency particulate air (HEPA) filters to the larger topic of clean-room 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 PROCESSA typical cleanroom or aseptic facility design and construc-tion 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, commis-sioning, and qualification process.

ABOUT THE AUTHOREd White is a senior principal validation engineer at Baxter Healthcare in Thousand Oaks, California. He may be reached by e-mail at [email protected].

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The Aseptic Core.Coordinated by Ed White

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Figure 1: Facility design, commissioning, and qualification process.

Journal of Validation technology [Autumn 2009] 31

The Aseptic Core.

Planning PhaseBecause of the cost, duration, and complexity of a clean-room construction project, some form of project manage-ment is typically used. The planning phase for a clean-room 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, includ-ing 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 dura-tion of the project.

Design PhaseThe first phase covered in this flow chart is the design phase, which begins with the preparation of formal pro-cess 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 oxygen-sensitive 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? Con-sideration should be given to whether the product dosage is low enough to cause concern with clean-ing 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 specifica-tions (URS) for the equipment, utilities, and facilities that are included in the project. These requirements

will give generic requirements for the equipment, utili-ties, 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 auto-matically 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 assess-ment 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 14644-4 (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-

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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 appropri-ate CGMP requirements. The design review should be updated if any design changes are implemented after the detailed design is approved.

Construction PhaseOnce 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 stan-dard construction management techniques for the facili-ties, utilities, and equipment. Special attention should be given to items such as welded piping such as water-for-injection (WFI) piping, and cleanroom construction during this phase. The construction phase concludes when the equipment, facilities, and equipment are con-structed 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 PhaseOnce the construction phase is complete, the project moves into the commissioning phase. In this phase, the equip-ment, 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 commis-sioning, 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

• Verification of materials of construction for equip-ment, utilities, and cleanrooms, if not verified during the construction phase

• Cycle development for various component, equip-ment, and material preparation processes such as steam sterilization processes, clean-in-place and steam-in-place, closure washing, siliconization (if necessary) and sterilization processes, depyrogena-tion 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 pro-fessional 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 equip-ment, facilities, or utilities are ready for qualification.

Qualification PhaseThe qualification phase begins with completion of com-missioning 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 verifi-cation 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 PhaseThe 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 manu-factured during the submission phase is held pending approval of the submission.

Operational PhaseOnce approval is received, the cleanroom can be con-sidered to be operational. Product being held pending submission may be released, assuming it meets its pre-determined specifications.


The Aseptic Core.

POINTS TO CONSIDER FOR CLEANROOM DESIGNThere 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 14644-4, 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 construct-ed 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 main-tain operator comfort when gowned and main-tain 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 per-sonnel, 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 unidi-rectional 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 prob-lems 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 10-15 Pascal to all surrounding zones of lower classi-fication. 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 con-cept is shown in Figure 2.

• When setting up pressure monitoring in an exist-ing building monitoring system (BMS) or when installing a new BMS, consider where the refer-ence 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 QUALIFICATIONQualification of an aseptic processing facility is a complex project including qualification of the clean-rooms 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 qualifica-tion of the cleanroom itself.

Installation QualificationInstallation qualification activities for a new clean-room 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 han-dling 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.


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Operational QualificationOperational 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 man-agement system (BMS) or other control system for the cleanroom

• Measurement of vibration and noise in the cleanroom

• Cleanroom classification activities.

Cleanroom QualificationClassification of a cleanroom is typically performed according to ISO 14644-1 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

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 sup-ply 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 guide-line recommends a minimum of 20 air chang-es/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:

Figure 2: Cleanroom cleanliness cascade (adapted from ISO 14644-4).


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a. Supply volume = 520 ft3/min x 9 filters x 60 min/hr = 280,800 ft3/h

b. Room volume = 30 ft x 35 ft x 10 ft = 10,500 ft3

c. Air Changes/Hour = Supply Volume/Room Volume = 280,800 ft3/h / 10,500 ft3 = 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 m3/s x 3600 s/h x 24

filters = 24,192 m3/hb. Room Volume = 15 m x 4.5 m x 3 m = 202.5

m3

c. Air Changes/Hour = Supply Volume/Room Volume = 24,192 m3/h / 202.5 m3 = 119.5 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 10–15 Pascal (0.04–0.06 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 14644-1 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/m3) than the limit for the same particle size class in ISO 14644-1 (29 particles/m3). 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 identi-cal 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 NL= A1/2; where NL = the minimum number of sam-pling point locations, rounded up to a whole number, and A1/2 = 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 deter-mine which points within the cleanroom should be tested. Special attention should be given to points

Table: EU grades and equivalent ISO classes.

ActivitiesEU grade ISO Class

Non-viable particulate (particles/m3)

At rest In operation

0.5 μm 5.0 μm 0.5 μm 5.0 μm

The local zone for high-risk operations (e.g., filling zone), stopper bowls, open ampoules and vials, making aseptic connections.

A 4.8 3520 20 3520 20

For aseptic preparation and filling, this is the background environment for the grade A zone.

B 5 at rest, 7 in operation

3520 29 352,000 2900

Clean areas for carrying out less critical stages in the manufacture of sterile products.

C 7 at rest, 8 in operation

352,000 2900 3,520,000 29,000

Clean areas for carrying out less critical stages in the manufacture of sterile products.

D 8 at rest, not defined in operation

3,520,000 29,000 Not defined Not defined


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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 NL= A1/2 , the minimum number of sampling locations in the Grade A zone is determined to be nine sampling locations. The Grade B area is (11.4–4.6) m x 15.2 m, or 103.4 square meters. Using the formula NL= A1/2, the mini-mum number of sampling locations is determined to be 11 sampling locations.

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 m3 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 sequen-tial sampling procedure listed in ISO 14644-1, Appendix F.

d. All samples were taken in the “At Rest” condi-tion, 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

Figure 3: Pressure cascade in typical cleanroom complex.


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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 nor-mal 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 visualiza-tion will be the topic of an upcoming column.

CONTINUING CLEANROOM COMPLIANCEOne final item to discuss is the periodic tasks for demon-strating continued compliance of a cleanroom with ISO

14644 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 clean-room is usually performed under “at rest” conditions. Retrospective review of in operation particle counts may be used to demonstrate compliance under “in operation”

Figure 4: Sampling locations for Grade A/B cleanroom.


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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 monitor-ing 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 IMPLICATIONSThis 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.

REFERENCES1. US Food and Drug Administration, Guidance for Industry:

Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, 2004.

2. European Commission: Enterprise and Industry Director-ate-General, EudraLex–The Rules Governing Medicinal Prod-ucts 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), 2008.

3. International Organization for Standardization (ISO), ISO14644-4, Cleanrooms and Associated Controlled Environ-ments–Part 4: Design, Construction and Startup, 2001.

ADDITIONAL REFERENCESISO, ISO 14644-1, Cleanrooms and Associated Controlled Envi-

ronment–Part 1: Classification of Air Cleanliness, 1999.ISO, ISO 14644-2, Cleanrooms and Associated Controlled Envi-

ronment–Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1, 2000.

ISO, ISO 14644-3, Cleanrooms and Associated Controlled Environ-ment–Part 3: Test Methods, 2005. JVT

ARTICLE ACRONYM LISTINGA&E Architectural and EngineeringBMS Building Monitoring SystemCFD Computational Flow DynamicsCGMP Current Good Manufacturing PracticeDPC Discrete Particle CounterEU European CommissionFAT Factory Acceptance TestFDA US Food and Drug AdministrationHEPA High Efficiency Particulate AirNEBB National Environmental Balancing BureauIQ Installation QualificationISO International Organization for

StandardizationOQ Operational QualificationPQ Performance QualificationSAT Site Acceptance TestULPA Ultra-Low Particulate AirURS User Requirements SpecificationWFI Water-for-Injection


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