Cleanroom Validating and Monitoring
Information | Understanding | Best Practice.
Validation of the cleanroom needs to encompass all potential sources of variation and contamination, demonstrate understanding and control in order to assure customers and regulatory bodies that products outputted from the cleanroom will meet quality, reliability and safety demands on a continual basis. Effective cleanroom validation is a fundamental necessity in pharmaceutical, biotechnology and medical device processing.Cleanroom Validation Standards:
US FDA, 21 CFR 210 and 211, Current Good Manufacturing Practice for Finished Pharmaceuticals, details the requirements for cleanrooms needed to assure the integrity of the finished product. CGMP regulations, 21 CFR 600 through 680 also provide additional requirements which focus on the processing of biological products.ISO 14644 Cleanrooms and Associated Controlled Environments. This standard details the classification of air cleanliness in terms of the concentration of airborne particles in cleanrooms and clean zones. The standard is sub-divided as follows:
EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines. EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use. Annex 1 Manufacture of Sterile Medicinal Products
IEST-RP-CC006: Testing Cleanrooms, prepared by Working Group 006 of the IEST Contamination Control Division (WG-CC006). (IEST refers to the Institute of environmental sciences and technology). This is a recommended practice standard which details test methods for the characterisation and performance of cleanrooms.
IEST-RP-CC001, HEPA and ULPA Filters. This Recommended Practice standard, IEST-RP-CC001.6, details requirements for HEPA (high efficiency particulate air/particulate arrestance) and ULPA (ultra-low penetration air) filter units based on customer needs.
IEST-RP-CC012, Considerations in Cleanroom Design. This recommended practice standard is focused on the typical environmental conditions which need to be considered in cleanroom design.
Of the above standards ISO 14644 is widely considered to be the prime standard in terms of cleanroom validation.
Product and Process Validation.
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Per ISO 14644, whenever a cleanroom is initially operated, or whenever a change is made in the primary purpose of the cleanroom then a validation needs to be performed. The standard identifies key phases when a validation should be performed, specifically:
Phase 1, as built testing, installation qualification. Here testing is performed when the initial installation is complete with all services installed.
Phase 2, operational qualification, here testing is performed when all process and testing equipment is in-situ (and operating where practical), however with no personnel present, and
Phase 3, performance qualification. In this phase testing is performed with the cleanroom operating as would be expected during routine production.
Where validations are performed, they need to extend over an appropriate period of time in order to capture routine variation, data will be collected and reviewed to confirm acceptability. The data will also be retained to provide a continually enhanced depository of proof of operational performance within the pre-determined acceptance criteria. The cleanroom will be certified to a particular cleanroom class, depending on the requirements of the product & process.
Testing to be performed to complete a cleanroom validation.
The ISO 14644 standard advises on the type and frequency of testing to be performed to demonstrate compliance with the standard. However, the extent of testing to be performed should be directly related to the process requirements, in order to assure the end quality, reliability and safety of the final product. This needs to be defined and justified by the process & product owners.
A typical cleanroom validation testing program will normally include the following tests:
Air particle count testing.The cleanroom will be designed to meet a particular classification based on the requirements of the product. The classifications define the limits allowed for the number of particles present within a cubic meter of air. Particle testing will need to consider particle size and sampling locations. When determining locations, guidance is provided in ISO 14644-1, where the minimum number of sample locations taken within the cleanroom is calculated by taking the square root of the area of the cleanroom in square meters. This number should be rounded up to the nearest whole number. The volume of air to be sampled can be determined by reference again to ISO 14644-1.
Analyzing samples.
For each particle size, the mean, standard deviation and 95% upper confidence limit (UCL) can be calculated. The greater the number of samples, the more accurate the 95% UCL will be. It is often necessary to take more than 10 sample locations.
Acceptance testing.
Per ISO 14644-1, if the average particle concentration at each sampling location is below the classification limits, or the 95% UCL is below the specified limit then the cleanroom has met the required classification. Acceptable particle limits for each particle size are detailed in the ISO 14644-1 standard.
By increasing the volume of clean air which passes into and through a cleanroom, the overall contamination level can be decreased. Clearly there is a limit with the level of air changes but the principle of continually flushing clean air into a room is easy to understand and relatively easy to implement. The optimum level of air changes (per hour) will need to be determined in advance of room build and will be influenced by product requirements, the number of personnel in the rooms, the type of equipment and processing to be performed on an on-going basis. Guidance on the level of air changes is provided by the FDA and EU GMP’s at air velocities of 0.45m/s+/- 20% and 0.36 – 0.54 m/s respectively.
HEPA (High Efficiency Particulate Arrestance), ULPA (Ultra Low Penetration Air) filter installation leak testing.
Pushing air into a cleanroom is only effective in driving down contaminate levels, if the air being introduced into the room is guaranteed clean. This is the role of the HEPA/ULPA filters. The filters need to be tested to ensure that they are capturing and removing contaminant particles from the air supply, and to ensure that there are no leaks within the filters or their housings.
Air Flows Assessment.
The path followed by air moving into, within and out of the cleanroom is influenced by the room design, rate of air changes, airflow velocity and directions, HEPA/ULPA design, equipment design and layout, locations of product storage, flow of people into and out of rooms with consequent doors opening & closing, etc.. FDA advice is that appropriate design needs to ensure unwanted air turbulence and build-up of pockets of stagnant air needs to be avoided. The objective in designing the cleanroom must be to ensure that potential airborne contamination is pushed away from cleanroom staff, work areas and product. An analysis of airflows needs to be performed to identify undesired air flow directions, potential air stagnation pockets, ensuring that the air flows as desired under expected operating conditions.
Room Recovery testing.
If an area within the cleanroom becomes contaminated, how fast will it take to recover to the desired acceptable state. This test will establish minimum time limits within which production cannot occur after a potential contamination is detected. Clearly, where a contamination in excess of acceptable limits is identified, then it is advisable to identify the cause of the process breakdown and to ensure that the predefined particle count limits are achieved before any recommencement in product processing.
Pressurization differentials within the cleanroom areas.
Cleanrooms operate at a positive pressure versus the outside environment via a greater level of air being pushed into the cleanroom, than can escape. This leads to a build-up of pressure within the cleanroom and whenever a door or hatch is opened into the cleanroom air escapes out into the outside environment ensuring contamination cannot flow into the cleanroom. In a cleanroom where there are multiple rooms, then the area with the highest “clean” requirements will have the highest-pressure levels. Pressure differentials will then follow-on based on the cleanliness requirements. As personnel and product moves within the cleanroom and ultimately out into the non-cleanroom work areas, air will flow from the cleanest area through areas with less clean requirements until ultimately flowing into the outside environment. The FDA suggest that positive pressure differentials of 10-15 Pa should be maintained between adjacent areas of different classifications. The ISO standard ISO 14644 proposes that positive pressure differentials of 5-20 Pa should be maintained.
Testing needs to be performed to confirm that the designed pressure differentials are continually achieved.
Microbial testing.
This form of testing is particularly important within the pharmaceutical, biotechnology and medical device industries. Microbial testing needs to be performed during the “process qualification” phase, and should include testing during the worst case situations, i.e. at those times where the maximum number of personnel allowed are present and when processing is also at a maximum. Testing should consider the levels of both viable and non-viable particulates, in-addition to the levels of microbial contamination on process equipment, floors, walls, doors, work surfaces, etc..
Process specific testing.
Testing on the relative humidity, lighting levels, vibration, temperature, etc. may be appropriate depending on the nature of the process and the potential impact on the quality of the final product.
On-going particulate monitoring.
A routine sampling and test regime to measure the particulate levels needs to be implemented to ensure ongoing adherence with the cleanroom classification. The frequency of sampling, the sample locations should be determined via a risk assessment, taking into account the history of previous sampling results, combined with the costs (financial, customer, product, etc.) associated with the detection of “out of specification” results. ISO 14644 provides guidance on the types and frequency of routine testing to be performed to assure continued compliance to the standard.
Ongoing environmental monitoring standards.
Widely utilized guidelines are the FDA Aseptic Processing Guide, IS EN ISO 14698 (Bio-Contamination Control in Cleanrooms), the European Guide to Good Manufacturing Practice, Annex 1 (Manufacture of Sterile Medical Products) and USP 1116 (Contamination Recovery Rates). These standards do not demand specific requirements as any monitoring should be based on risk appropriate to the products being processed.
Types of sample testing.
The widely-utilized sampling methods are air sampling, surface sampling and personnel sampling. For sampling of surfaces such as equipment, floors, doors, work surfaces “agar” plates can be used. Where access may be difficult, i.e. within an item of process equipment, moistened swabs may be appropriate. A map detailing the proposed sampling locations should be predefined, based on a risk analysis, again frequency and extent of all sampling should be risk based.
Product and Process Validation.
- The Validation Master Plan. Performing a Gap Analysis. Validation in the Design Process. Etc..
- How to ensure Validation efforts are aligned with potential Risks.
- How to ensure that Validation activity is appropriately documented, reviewed and aligned with requirements.
- Information | Understanding | Best Practice >>>
FDA, Guide To Inspections of Validation of Cleaning Processes.
EC, “The Rules Governing Medicinal Products in the European Community,” Volume IV, Good Manufacturing Practices for Medicinal Products.
Health Canada, Cleaning Validation Guidelines (GUIDE-0028).
WHO, “Appendix 3, Cleaning Validation,” WHO Expert Committee on Specification for Pharmaceutical Preparation, World Health Organization, Fortieth Report.
ICH Guidance for Industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.
PIC/S, Recommendations on Cleaning Validation. Document PI 006- 1, Pharmaceutical Inspection Cooperation Scheme, Geneva, Switzerland.