Quality auditing is the systematic examination of a quality system and audits form an important part of Good Manufacturing Practice (GMP). Auditors need to be knowledgeable about cleanroom operations, and have an understanding of microbial contamination as well as being trained specifically as auditors. Ideally, they should have complete independence from the functions they are auditing.1
The audit approach within GMP is designed to verify objective evidence of processes and to provide evidence of action to eliminate or reduce problem areas. Quality auditing should not only report non-conformances and corrective actions, it should also highlight areas of good practice. Risk assessment plays an important part because one aim of the audit is to assess vulnerability. Risk assessment tools are available to the auditor to help structure the audit. These include approaches such as Failure Modes and Effects Analysis (FMEA) and Hazard Analysis and Critical Control Points (HACCP).2
Audit considerations
Space and design: To begin with, the auditor should consider whether the cleanroom is suitable for the intended purpose.3 Is it large enough? Is the layout logical? What are the key issues relating to space and design? One of the key concerns is whether there is sufficient space for carrying out operations and if such areas are correctly segregated to prevent mix-ups and to contain contamination.
Process flow: The auditor should examine the material flow throughout the building with a particular focus on how items are transported into and out of cleanrooms, and on how product is moved around the facility. The auditor should assess what control measures are in place to protect the process and product from contamination.
Certification: The auditor should consider if the types of cleanrooms, and their grades or classes, are suitable for the activities taking place within the areas. Here, both EU GMP cleanroom grades and ISO 14644 cleanroom classes should be considered. With this the auditor will wish to establish:
- When the cleanroom was last certified for HVAC operations? Is the frequency of certification adequate (that is a minimum of six-monthly for aseptic filling areas and 12-monthly for other grades of cleanrooms)?
- Are HEPA filter certificates available? Do they conform to standard?
- Was particle counting performed to ISO 14644? How were locations selected? Was the correct volume of air taken?
Physical control: While certification is important, on-going operation is arguably most important. The physical operation of cleanrooms is centred upon the Heating Ventilation and Air Condition (HVAC) system. The primary concern is with contamination control and ensuring that the cleanrooms have a suitable air supply, through High Efficiency Particulate Air (HEPA) filters. This is to maintain the correct pressure differentials and to provide air of a low enough particulate level appropriate to the class or grade of cleanroom. Perhaps the first issue that the auditor should check is the cleanroom certification, focusing on when this was performed, if it was undertaken to an approved standard (such as ISO 14644) and whether all of the requisite tests have been completed.
These cleanroom certification tests fall within the following areas:
a) Control of airborne particulates,
b) Sufficient airflow and air changes,
c) Positive pressure differences,
d) Testing of HEPA filters,
e) Temperature, humidity and lighting.
The auditor should check that the tests have been completed by competent engineers, that the tests have been conducted at a suitable frequency and that the test results meet the acceptance criteria required by an approved standard.
In relation to the above test criteria, and taking into account other aspects of the physical operation of cleanrooms and clean air devices, points that an auditor should consider are:
- Are laminar flow hoods/unidirectional airflow devices and HVAC system which serve the aseptic operations areas validated and within date?
- Which department performs the validation?
- Was the validation approved by QA?
- Was the report issued? If yes, was the report forwarded for QA for review?
- Filters represent a critical part of the cleanroom operation and are discussed in more detail below.
All filters have an efficiency rating and should be tested periodically for leaks. In addition, filters are studied for particulate penetration. The type of filter used in a cleanroom will be selected and justified by the cleanroom manager. A common type of HEPA filter is one with an efficiency rating of 99.997%. The rating is based on particle sizes 0.3µm and larger (i.e. theoretically only 3 out of 10,000 particles at 0.3µm size can penetrate the filter). The auditor should review this.
In addition to particulates penetration, filters that form part of unidirectional airflow devices need to be examined for air velocity. Here the auditor should ask:
- What is the frequency for measuring air velocity through a filter?
- How often are air velocities measured?
- Are airflow velocities within operating parameters? (Here it should be noted that EU GMP defines an air velocity range at the working height: 0.45m/s +/-20% (unidirectional). However, the FDA does not specify criteria and instead requires air velocities to be justified by the user; and to be sampled six inches from the filter face).
- Where, in relation to the filter face, are air velocities measured from? (that is, near the filter face or at the working height?)
- What is the equipment used to measure air velocities and is this equipment calibrated?
- For air filters, is there a written procedure specifying the frequency of inspection and replacement?
- Does the facility have separate air handling systems, if required, to prevent contamination (for example, where antibiotics are produced)?
The auditor should review the airflow visualisation studies to determine that areas requiring unidirectional airflow are protected.
Positive pressure is an essential operational feature of cleanrooms. To maintain air quality in a cleanroom, the pressure of a given room must be greater relative to a room of a lower grade. This is to ensure that air does not pass from ‘dirtier’ adjacent areas into the higher grade cleanroom. The facility will set appropriate limits for pressure differentials (as guidance 15–20 Pascals relative to lower grade rooms is commonly used). The auditor should request to see a map of pressure differentials, with the pressure cascade clearly marked out.
Furthermore, the auditor should ask for example measurement data for pressure differentials between each room and all surrounding spaces, and between two rooms.
Personnel: During the audit the auditor should check if the right number of appropriately trained staff are present. The auditor should also examine how personnel enter cleanrooms and the change procedures. This will also include an inspection of the changing rooms.
Cleanliness levels relate to correct changing procedures. For example, Annexe 1 of the EU Guide (paragraph 20) states that changing rooms in which outdoor clothing is worn should not be used to access Grade C/ISO class 8 (dynamic) and Grade D/ISO class 9 (dynamic) areas. For entering aseptic filling areas a two-change procedure should be in place.
Staff must also be able to demonstrate that they are aware of good cleanroom practices; for example, they need to comply with good hygiene and sanitation practices./p>
Environmental monitoring and microbial control: Environmental monitoring is applicable to all types of cleanrooms within the life science sector. The auditor must review whether a systematic and comprehensive environmental monitoring programme is in place (and that such a programme is documented).
Important points to examine include:
- Is there an environmental monitoring programme for the cleanrooms? Are Standard Operating Procedures (SOPs) in place and in date?
- What is the frequency of monitoring?
- How are monitoring locations selected? Are the sites that have been selected suitable – has reference been made to airflow visualisation studies for the selection of environmental monitoring locations? The auditor should review the environmental monitoring sampling plan.
- Does monitoring cover all locations, including areas that are hard to clean such as walls, floors and ceilings?
- Is the monitoring programme able to indicate if the cleaning and disinfection frequencies are appropriate?
- Is monitoring undertaken in the operational or non-operational state? (here, the operational state is deemed to be more representative of processing conditions).
- Has the culture media been subject to growth promotion testing?
- For media manufactured in-house, are there standardised and validated autoclave loads for nutrient media used for environmental monitoring?
Cleaning and disinfection: An essential aspect of cleanroom management is the cleaning and disinfection programme, and one applicable to all types of cleanrooms and controlled environments. The auditor must consider if the facility has written procedures that describe in sufficient detail the cleaning schedule, methods, equipment and material. It is important to check that cleaning agents and disinfectants are suitable and compatible.
In summary, this article has examined the activity of auditing in general and the application of good auditing practices to cleanrooms. However, it is important to note that there is no universal checklist that can simply be picked up and used. Each cleanroom or cleanroom suite is different and the auditor will need to have a firm grasp of the activities and operations within the specific cleanroom to conduct an effective audit. The key focus should always be upon contamination control.
References
1. Sandle, T. (2013). Preparing for Regulatory Inspections of Sterile Facilities: the Focal Points. In Saghee, M.R. (Ed.) Pharmaceutical Regulatory Inspections, Euromed Communications: Passfield, UK, pp361–462
2. Sandle, T. (2003) The use of a risk assessment in the pharmaceutical industry – the application of FMEA to a sterility testing isolator: a case study, European Journal of Parenteral and Pharmaceutical Sciences, 8(2): 43–49
3. Sandle, T. and Saghee, M.R. (2012). Compliance Aspects of Sterile Manufacturing. In Saghee, M.R. (2012) Achieving Quality and Compliance Excellence in Pharmaceuticals: A Master Class GMP Guide, New Delhi: Business Horizons, pp517–560
This article is an edited extract from the book Cleanroom Microbiology written by Tim Sandle and R.Vijayakumar. The book is published by DHI/PDA and is available from: https://store.pda.org/ProductCatalog/Product.aspx?ID=2474#
