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Qualification of Cleanrooms for Injection Molding

Medical Device & Diagnostic Industry Magazine MDDI Article Index Originally Published March 2000   CLEANROOMS Product specifications, regulatory guidelines, and ambient conditions all influence the fundamental design considerations for cleanroom facilities intended for injection molding applications.

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

Originally Published March 2000


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

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.


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.


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.


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?


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 (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.
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