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CLEANROOMS

Qualification of Cleanrooms for Injection Molding

Product specifications, regulatory guidelines, and ambient conditions all influence the fundamental design considerations for cleanroom facilities intended for injection molding applications.

Gernod Dittel and Erwin Bürkle

Facility qualification and process validation as well as cost-structure assessment are critical elements in the process of cleanroom engineering. The second in a two-part series, this article discusses the steps necessary for cleanroom planning and qualification. It also outlines the contents of the relevant specifications, describes the qualification procedures, and addresses risk assessment techniques and monitoring requirements for an established facility.

Specifications for each cleanroom facility must be established according to the procedures and products to be processed.

Because the quality of products manufactured under cleanroom conditions depends not only on the actual manufacturing techniques, but also on the manufacturing environment, cleanrooms and the related ventilation facilities must be qualified. Qualification entails checking cleanroom facilities for compliance with the relevant technical rules and regulations, and evaluating the facilities in terms of measurement and monitoring techniques. Specifications and acceptance tests are based on distinct criteria that depend on whether the cleanroom is to be used for pharmaceutical or another kind of manufacturing.

The qualification of cleanrooms encompasses all areas of cleanroom engineering. In facilities for pharmaceutical production, it is essential that relevant regulations (good manufacturing practices, and European Union commission guidelines concerning drug manufacturing) be observed. In facilities used for micromechanics, coating techniques, or the manufacture of printed circuit boards, the qualification of the manufacturing environment is a part of the certifying procedures outlined by ISO 9000. The specific parameters to be qualified, and the measuring and testing procedures to be used are subject to numerous regulations. Handbooks on cleanroom engineering can provide a comprehensive overview. The qualification and validation of facilities are standard prerequisites for the documented proof of safe manufacturing practices of medical or pharmaceutical products. In this way, a transparent manufacturing process can be demonstrated to the relevant authorities.

Increasing demands for high quality levels and advances in technology require facility qualification to be made a standard part of the production package that contract manufacturers offer their customers. To ensure completeness of the recorded proof, planning offices and facility contractors need to thoroughly understand the products to be processed.

Facility qualification will differ depending on whether the cleanroom already exists or whether a new one is being constructed. If an existing facility will be used for pharmaceutical manufacturing, a retrospective qualification should be performed. Performing a prospective qualification in the case of new facilities is usually simpler.

The procedures for qualifying a new cleanroom for pharmaceutical or medical device production can be divided into the following key issues:

• Feasibility study and concept planning.
• GMP review with FDA preapproval.
• Basic and detail engineering.
• Execution planning and realization.
• Start-up and operation.

It is useful to consider the qualification requirements early in the planning process, during the feasibility study. Current basic engineering principles suggest that the qualification procedure be completely integrated.

WRITING THE UTILIZATION DESCRIPTION

The first thing to be done is to write a utilization description. The layouts of the individual rooms and the processes to be performed within them should be planned simultaneously. This allows the required cleanroom classes and other parameters to be determined and incorporated into the specifications. The performance details are established on the basis of the utilization description, the specifications of the rooms, and the working environment. This process also provides the basis for cost estimates from component or system suppliers, allowing technical and cost factors to be compared. In pharmaceutical applications, it is essential to ensure that the offered components comply with the requirements, which is not always immediately apparent from a component's technical description.

CLEANROOM SPECIFICATIONS

There is no universally applicable cleanroom specification. On the contrary, each cleanroom—in fact the complete clean facility—must be specified according to the procedures and products to be processed. Reciprocal effects must be considered. In semiconductor manufacturing, for example, the ambient environmental conditions needed during the photolithography process and the appropriate vibration-sensitive exposure processes must be considered. In pharmaceutical applications, it is essential to keep germs from penetrating into any part of the cleanroom or open production area. When producing medical equipment, however, only particles >5 µm need to be considered a contamination risk.

Cleanrooms are subject to dynamic changes because of the facility environment. Specific parameters may change, causing limits to be exceeded or not reached.

This specification process considers individual measures with reciprocal effects. Consequently, only indirect conclusions with regard to the overall equipment features can be drawn from the specifications of individual procedures and product-specific factors. For this reason, the following criteria, while providing a basic guideline, should not be considered as being complete.

Overpressure. Cleanrooms are normally operated with overpressure so that no contaminants can penetrate from outside to the interior. Some exceptions exist, including rooms in bioengineering or nuclear engineering facilities. The degree of overpressure depends on the overall system and can range from 5 to 100 Pa. To prevent cross-contamination from unclean areas into cleanrooms, the appropriate pressure differences must be maintained at all times.

Cleanliness Classes of Air. Cleanliness classes of air currently are defined in Federal Standard 209 and VDI 2083, sheet 1. ISO 146441-1 is expected to be applied on a worldwide basis in the future.

Germs. In certain applications, including pharmaceutical plants, the number of germs in the air, on surfaces, and in liquids has a greater significance than nonviable particles. Acceptable limits for viable microorganisms are defined in accordance with GMPs. GMP requirements include a revised appendix that applies to the manufacturing of sterile products. The manufacturing requirements will be regulated by ISO/DIS 13408-1 in the future.

Air-Conditioning. Closed cleanroom systems are generally air-conditioned. Independent laminar-flow units have only partial air-conditioning, which must be subsequently absorbed by the ventilation of the surrounding room.

Air Volumes. Various air volumes—surrounding air, circulating air, and processed outgoing air—need to be defined during the planning stage, and must be reflected in the layout of the ventilation system.

Flow Velocity. This specification varies from 0.15 to 0.45 m/sec depending on the clean area involved. Velocities of about 25.0 m/sec are required in staff and materials chambers, depending on traffic flow.

Low-Turbulence Displacement Flow. A near-laminar flow of 0.2 to 0.5 m/sec results in an air exchange rate of approximately 200 to 600 times per hour.

Turbulence-Mixed Ventilation. Usually no flow velocity is defined in each room. The air displacement rate is up to 300 times per hour.

Direction of Flow. The direction of flow can be verified in cleanrooms with a low-turbulence displacement flow. The recommendations outlined in IES RP 6.2 call this exercise a test of parallelism.

Recovery Time. Recovery time depends on the air displacement rate and the particle sources in the room.

Particle Disposition. Particle disposition may be defined in cleanrooms with turbulent flow-through, with the critical particle size beginning at several microns.

Rules of conduct for personnel working within cleanrooms differ greatly from those for persons at normal workstations, and maintaining the proper mental attitude is important.

Sound Volume in the Cleanroom. Although target values are approximately 55 dB or less, the sound level is commonly influenced by the degree of comfort perceived by personnel in the room.

Luminous Intensity. Determination of luminous intensity is generally based on the kind of manufacturing to be performed and the equipment being used, among other factors.

Peculiarities. In microelectronics, electrostatic supercharging, electromagnetic field intensities, and vibrations may have a negative effect. Specific criteria must be determined for structures such as floors, walls, or ceilings because the requirements outlined in VDI 2083 sheet 3 or Federal Standard 209 have no appropriate specifications. Ventilation consistency is an important consideration. Ventilation systems should have an overpressure compared with the surrounding areas because leakage at this point may have a negative effect on air cleanliness. Leakage requires only a greater surrounding air quantity to ensure that pressure is maintained.

Figure 1 illustrates the typical steps that lead from initiation of a cleanroom project through qualification of the facility to the start of operation. The figure includes essential components and identifies the four key stages of the qualification process: design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). Planning for the qualification process includes three essential organizational components:

• Selecting the qualification team.
• Setting up the qualification master plan (QMP) and the validation master plan (VMP).
• Establishing a procedures plan.

The qualification team should be headed by at least one project manager who oversees the entire qualification process. The team should be composed of at least two persons in order to separate execution and control responsibilities, and the division of responsibilities for engineering and qualification should be agreed upon from the outset. From a general point of view, the details of the QMP and VMP describe a processing scheme, including definitions of terms, objectives and procedures, work materials used, and the organization of the quality project. The QMP must correlate properly with the VMP. Procedures planning includes a division of tasks into stages and construction groups, explains the function testing to be executed, and describes monitoring of the control systems.

Figure 1. Steps leading from cleanroom concept to qualification of the facility.

Time schedule regulates the entire project, including engineering, qualification, and validation. The time schedule exerts this broad influence because of the project-specific relationship of these three areas to the success of the overall project.

RISK ANALYSIS OF A CLEANROOM FACILITY

A risk analysis needs to be performed to determine the critical points and functions of the facility. Part of the process used to accomplish this is to test the functionality of the facility components. Both critical and noncritical systems and components should be included. Certain functional components of the cleanroom can be easily changed to minimize problems identified by the risk analysis process. Nevertheless, various key components may pose risks that may be reduced only with a considerable investment of time and money.

Ultimately, the risk analysis makes a comparison between the theoretical and practical measures in qualification procedures. When the results differ in terms of structure and statement, another comparison must be made. The key components of a risk analysis are:

• Risk assessment.
• Risk management.
• Risk communication.

Risk assessment is used to determine the probability of one or more problems occurring, as well as to identify the potential consequences of such a system failure. While emphasizing the risk assessment component of the risk analysis process, manufacturers and planners can address the following points.

Process initialization.

• Process analysis.
• What are the requirements and who determines them?
• Which products are affected?
• How are the products manufactured?
• Which materials are included in the process, and where do they come from?
• Where does the product go, and what purpose does it have?
• What is checked and why?

Identification of risk.

• What could happen?
• What problems may come up?
• What potential consequences exist?

Probability of malfunction.

• Evaluation of malfunction (high, medium, or low risk).
• Probability in terms of risk to the referred area.
• Probability of exposition or transfer.
• Probability of spreading.
• Description of chemical, physical, or microbiological risk.

Consequences of a malfunction.

• Are consequences chemical, physical, or microbiological?
• Description of chemical, physical, or microbiological consequences.
• Description of immediate financial loss caused by the event.
• Description of direct economic consequences caused by the event.
• Description of indirect economic consequences, such as loss of the firm's reputation.

Assessment summary.

• Description of uncertainty of data used in the assessment.
• Summary of all risks with probability, effect, and degree of uncertainty.

Decision-making process.

• What ought to be done? Importance of ensuring proper results must be considered in relation to the factors involved and the cost required for risk minimization.

Risk communication.

• When risks are identified, who informs whom? When, and how often?

DESIGN QUALIFICATION

The actual qualification process starts with the execution of design qualification (DQ). This entails gathering systematic and recorded proof that the facilities and equipment have been designed in accordance with the requirements for construction, process equipment, control, and specifications—especially the GMP requirements. It also encompasses compliance with the requirements for ensuring general quality in addition to environmental and work safety. The process should be based on the concept that quality must be planned, developed, and produced—not endlessly tested. Basic design characteristics from the view of GMPs include:

• Easy cleaning.
• Easy accessibility.
• Integrated control and logging systems.
• Available user documentation.
• Available qualification documentation.
• Flow simulation to the computer.

The testing and acceptance criteria used in this step are the standardized rules and regulations, or the requirements included as part of in-house work instructions.

Design qualification procedures must determine the extent to which the individual systems and facilities are to be tested. The DQ checklist includes only key words that must be adapted for use in the respective facility.

INSTALLATION QUALIFICATION

Installation qualification (IQ) is the gathering of systematic and recorded proof that the facilities and equipment have been built and installed in accordance with the specifications, installation regulations, and other standardized rules and regulations. As soon as an order for individual machinery has been placed with the suppliers, the step-by-step installation process begins. At this point, paperwork and checklists must be set up so that a consistent IQ can be executed. Included in this process is the delivery paperwork with details of component types and possibly serial numbers. This is critical for ventilation systems, sensors, or filters. IQ begins as soon as the facility has been set up. The contractor must have approved the IQ plan, and the paperwork, including protocols and documentation that have been included by the supplier, must be checked. Completion of the IQ entails generation of a report that, among other things, includes a list of defects. Key concerns during this stage are:

• Calibration of measuring equipment and documentation of machinery.
• Supplier audits (including nonmaterials services).
• Staff and materials flowchart.
• Media and equipment installation, as specified.
• Automation technique, as specified.
• Operation and maintenance manuals for all installed systems and facility components, including spare-parts lists.
• Compliance with local manufacturing codes and requirements.
• Factory setting, wiring, and surfaces.
• Definition and detailed listing of acceptance criteria.

OPERATIONAL QUALIFICATION

Operational qualification (OQ) is the gathering of systematic, recorded proof that the facilities and equipment will operate continuously as planned and specified, over the total range of the set parameters. It is thus the first operational test of the facility. The OQ planning stage calls for checking and identifying the operational tests that should be executed for specific facility components. Included are all functional systems that have a direct influence on the specified parameters of a cleanroom. OQ also includes the acceptance measurements of the cleanroom (discussed later). The OQ check involves the following:

• Operation under normal and cleanroom conditions.
• Reaction to malfunctions.
• Heat-loss performance, static charge, and leakage.
• Proof of airflow behavior.
• Normal and manual functioning (function qualification).
• Alarm interfaces to other systems.

PERFORMANCE QUALIFICATION

Performance qualification (PQ) is the last stage of qualification and encompasses the gathering of systematic and recorded proof that the facility's critical systems and equipment defined during risk assessment will function continuously with the components and materials as planned and defined. It also determines that the manufacturing process will be within the specified parameters. After the general systems of the facility have been checked during OQ, the facility is checked under operational conditions with a full staff and during running production. Facility parameters, such as climate or cleanroom classes, are introduced artificially. The parameters are measured during this process to assess the facility performance. The only systems tested are those that have been identified and determined as critical during risk analysis.

FINAL REPORT

The final report summarizes all listed qualification steps. The report serves as the formal release of systems and equipment for the manufacturing process, once qualification and validation have been completed.

DOCUMENTATION

Documentation, which is an essential part of quality security and GMP principles, includes all qualification plans, test plans and instructions, and the final report. The documentation should also include all machine documentation, relevant electrical and mechanical switching and facility plans, and user documentation containing operation instructions and detailed maintenance manuals.

Figure 2 illustrates the principles of cleanroom engineering that must be considered. Any subsequent modifications require repeating the entire qualification and validation process. The documentation also addresses and provides specific recommendations for staff education and training and in-house implementation of the continuous tasks.

Figure 2. Cleanroom engineering principles.

CLEANING VALIDATION

Performed after a facility is operational, cleaning validation involves gathering recorded proof that planned hygiene measures have been successfully implemented. This validation process must be completed for all systems in which risk analysis identified product contact as being a critical factor, even if the product contact is indirect or transient. Sources of potential product contact include the staff. Validation should take into consideration the following examples:

• Staff screening for specific diseases.
• Cleanroom clothing.
• Wrapping and containers.
• Transportation and duct systems.
• Systems for media.

Depending on the application, tests must be done for microbiological and particulate cleanliness, and to eliminate cross-contamination.

REQUALIFICATION

Requalification may sometimes be required. This involves the technical and operative repetition of the qualification process in the various levels and areas up to the initial operation for manufacturing.

ACCEPTANCE MEASUREMENTS

In principle, the acceptance of a cleanroom is merely a formal act that is preceded among other things by acceptance measurements and tests. The acceptance measurements and tests are often based on various recommendations. Several recommendations include details on the methods and measuring devices to be used. Consideration must be given to the differences that exist in the details concerning the described methods and measuring devices. To minimize possible disagreements within the scope of the acceptance measurements, the cleanroom manufacturer and cleanroom user should specify the parameters to be tested. To implement the acceptance measurements, it is necessary to define the extent and kind of measurements to be made, and to define the necessary operational mode of the cleanroom during measurement. The basis for these measurements is VDI 2083, sheet 1. The operational modes are restricted to three conditions:

• As built—cleanroom facility systems in operation, without built-in production equipment, and without staff.
• At rest—cleanroom facility systems in operation, with built-in production equipment running, and without staff.
• In operation—cleanroom facility systems and production equipment in operation, with intended staff.

MONITORING

As soon as the cleanroom acceptance measurements have been completed and the cleanroom is being used for the manufacturing process, it should be continuously monitored according to a defined plan. The monitoring of the cleanroom systems and the parameters of the cleanroom are not defined in VDI 2083. General monitoring details are left to the user. The monitoring plan may include system components other than those described in the listed parameters defined in VDI 2083, sheet 3. If appropriate, or if respective parameters have been defined, ventilation systems (sheet 3), surfaces (sheet 4), and media (sheet 7) are included. In addition to the list on sheet 3, parameters for the other areas should be defined. These parameters should be monitored continuously or cyclically after acceptance. Among other details, a monitoring plan should include:

• Layout with precise details concerning the monitoring sequence of the equipment, including facility plans.
• List of the required equipment for the individual measurements.
• Instructions for executing the measurements and evaluations.
• Time intervals between measurements.
• Type of evaluation and description of the results.

Monitoring requires consideration of several specific aspects, including recording the dynamics of the systems, and obligatory measurements, including documentation.

Dynamic Behavior of Facilities. Cleanrooms and their systems (outside/recirculated air, manufacturing equipment) are subject to dynamic changes. This means that specific system parameters may constantly change, causing limits to be exceeded or not reached.

The cleanliness class of air depends, for example, on the particle generation in the cleanroom and the particle concentrations brought in from outside areas. The aerosol concentration can vary even under normal circumstances by a factor of 10, and can increase dramatically on extreme summer days or as a result of particle sources in the area immediately surrounding the facility (a nearby construction site, for example). Clearly the dynamic fluctuations of a new facility must be recorded in general. Commonly recognized critical parameters should be recorded over a longer time period. With these results, an initial monitoring plan can be set up. After a period of time, the plan should be revised—the defined measuring intervals or measuring points must be tested and redetermined if needed.

The parameters acquired during the recording of both the initial monitoring and normal monitoring should be retained in graph form for evaluation. Only with recordings in graph form over a period of time can time-based performance be clearly recognized. Although recording the dynamic fluctuations of facilities is recommended by FDA, they are not part of the agency's required measurements.

Obligatory Measurements. Because of existing recommendations and regulations, continuous measurements of the cleanliness class of air are required to be performed during filling processes in the pharmaceutical industry. Measuring points in the air are defined below the air entrance surface, and samples are taken continuously or by means of a measuring point switch.

The measurements must be recorded and archived. Class limits ought not to be exceeded in the case of obligatory measurements for proof of cleanliness. If measurements are performed below the air entrance surface within a distance of approximately 30 cm, influx from the cleanroom or the systems are seldom recorded, if at all. For this reason, the measurements for optimizing manufacturing must be done separately. In other words, additional measurements must be taken in the immediate surroundings of the product or in the manufacturing area. Only then are the changes in cleanroom class caused by the staff or modified operation conditions of the manufacturing facilities visible. On the other hand, changing staff behavior, correcting flow direction, or modifications in the process or the manufacturing facilities can reduce elevated particle concentrations.

COSTS

Unfortunately, implementation costs have a higher priority for many contractors than planning or quality of implementation. As far as qualification and validation go, however, it can be difficult to estimate implementation costs in advance. Experience has shown that these two stages make up most of a project's costs, accounting for approximately 8–15% of total investments.

The required quality management includes the control of modification and malfunction management. It is important to note that any modifications made within the described project stages may have barely noticeable consequences because of the relationships that exist between individual cleanroom subsystems. In many cases, these consequences are first visible during running production, which is why some experts refer to them as second-priority defects. If such modifications are nevertheless required, the entire process for identification and determination of the parameters must be repeated. Because this inevitably has an adverse impact on tight cost calculations, planning is critical for the development of budget allowances for subsequent corrective measures.

Qualification and validation generally require substantial staffing levels. For individual project stages, as well as in critical stages, staff employment often increases, and staff costs must be calculated accordingly.

BALANCING RISKS AGAINST
SAVINGS

Certain concepts apply to cleanroom engineering perhaps more than to many other technical areas. Prerequisites for conceiving and constructing an economical cleanroom facility include the specific knowledge and experience of the planner and the contractor—and close cooperation with the manufacturer who will be using the facility. The user of a cleanroom manufacturing facility must be aware that such a complex facility is expensive. Setting up cleanroom production in a smaller space to save costs can entail considerable risk. Such a decision requires that a precarious balance be maintained between safety precautions, quality monitoring, and the need for validation on the one hand, and efforts to realize cost savings on the other. The expected cost optimization is usually not realized.

One principle of cleanroom engineering is that the product determines the environment. For example, in terms of employing cleanroom engineering in plastics processing, the necessary efforts are relative. In other words, plastics processors should not develop cleanroom plans based on conditions existing in the pharmaceutical or microelectronics industries. The requirements in such industries are considerably higher than those for plastics manufacturing. In terms of technical aspects and costs, planning and construction of a cleanroom facility always depends on the demands of the user.

CONCLUSION

Cleanroom technology is now fully established in the production of articles for the medical, pharmaceutical, cosmetics, electrical, and electronics industries, as well as biotechnology. In all these industries, dust- and germ-free production is a matter of course. It is not just the aspect of production cleanliness that matters. The controlled climatic conditions also play an important part in many instances. On a production line subjected to defined and consistent ambient conditions (climate and ventilation, temperature, pressure, and relative humidity) there also always exists a thermal balance between processing partners. Product quality can thus be increased because repeatability can be kept at a much higher level than is possible with a conventional production plant.

An often undervalued side effect of clean production is the relationship between contractor and customer. As a rule, contractors that have maintained an excellent reputation for their consistent production philosophy have an advantage over their competitors. A pragmatic approach is recommended for the planning of a cleanroom production plant. New challenges, such as coping with dust, difficult processing sequences, and the requirements of a high-tech installation, should not be viewed as discouraging. An analysis should be made to establish what kind of cleanroom specifications (category of cleanliness) the article to be produced requires. Taking essential peripherals into account, such as those needed for assembly and packing, the next step is to establish suitable premises. In principle, it is expedient to begin working with experts early in the planning stage in order to develop the most economical solution and have them ultimately be involved in its implementation.

Gernod Dittel, Dipl. Ing., is the managing director of Dittel Cleanroom Engineering (Benediktbeuern, Germany). Erwin Bürkle, Dr. Ing., is director of the research and development center for Krauss-Maffei Inc. (Munich).