When is regulatory compliance necessary when talking about a cleanroom? If you're new to the pharmaceutical industry, you may think you can build a cleanroom and apply for a regulatory license with no prior work required. However, compliance is necessary throughout the whole lifecycle of the cleanroom.
The new EU GMP Annex 1 revision for Sterile Medicinal Products introduced the principles of a Contamination Control Strategy (CCS). This overarching concept should be implemented to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical, and organisational).
The CCS should be a living document relevant to all aspects of your processes and facility. But you can't begin to think about creating your CCS when you're ready to use the cleanroom! Part of the CCS must consider the facility you will be using, and this is where cleanroom compliance begins.
So, you need a new cleanroom or to upgrade your current facility. The first step to consider when it comes to compliance is the generation of a User Requirement Specification (URS) for the cleanroom. When planning a URS, regulatory requirements must be considered, along with process requirements. The URS must be prescriptive to ensure critical parameters are met yet allow for compliant variables. You must also ensure that what is included is essential. Is the requirement nice to have or need to have? Consider the initial works to be carried out and any requalification requirements. The URS is the critical document your cleanroom constructor must follow to qualify the facility, so the earlier this document is generated and approved, the sooner the qualification process can begin.
When looking at cleanroom construction companies, assessing their understanding of GMP is beneficial. Do they have any in-house regulatory expertise to support the qualification process, with an understanding of the regulatory requirements you need to work to, along with the implications of quality and GMP? Do they have experience building GMP-compliant facilities where contamination control has been suitably addressed as part of the design?
Providing the URS to the cleanroom constructor at the earliest available opportunity will allow for a review period
Providing the URS to the cleanroom constructor at the earliest available opportunity will allow for a review period, where the constructor will be able to outline the scope of their works, indicating the areas they're able to support and whether you would require a third-party or subcontractor for specialist requirements outside of their remit.
Once the URS is approved, the cleanroom constructor will use the document to develop the qualification programme, where your requirements are evidenced and qualified throughout the design, installation, and validation stages. Qualification must be carried out while the project is ongoing and run in parallel with the construction timeframe.
As part of the pre-project compliance stage, you must consider designing a compliant layout. Ensuring the correct flows for personnel, materials, final product, and waste is critical. Do you require unidirectional flow when entering higher-grade areas? Do you need cubicles for staff privacy when removing outer clothing to enter a grade C or higher area?
Along with the flow of physical activity, the pressure cascade must be factored into the design early to create a suitable regime. A minimum of 10 Pa pressure difference between rooms of differing grades is required from a regulatory point of view. However, do you have any process requirements requiring negative pressure containment or bubble and sink arrangements?
The cleanroom construction materials must be suitable for use with the specified cleaning and disinfection programme
Another factor to consider is the cleaning and disinfection you will be introducing once the room is operational. The cleanroom construction materials must be suitable for use with the specified cleaning and disinfection programme. You must think ahead! Engaging with a consumables supplier early in the project will allow you to collate the technical data required to make an informed decision on the materials of construction and the cleaning/disinfection agents you plan to use in the future.
Do you have any critical parameters that require monitoring? For example, suppose the product you're producing is temperature-sensitive. In that case, you must ensure the monitoring system you plan to use can monitor the room temperatures as required and provide alarms if excursions occur.
Once the pre-project compliance stage is complete, you will find yourself at the point of design. The constructor will begin to generate design drawings while execution of Design Qualification (DQ) against the URS will commence. Execution of the Functional Design Specification (FDS) will also happen at this stage, if required. For example, the verification of suitable materials for construction.
Understanding where validation and qualification of the URS requirements will occur throughout the qualification lifecycle is necessary to ensure all requirements are covered. A protocol tracker is a useful tool to provide an overview of the scope of each qualification stage.
Running in parallel with the cleanroom's construction, installation, and commissioning is the Installation Qualification (IQ), where verification of the correct installation against design drawings and specifications is carried out, including verification of architectural and functional components.
Using commissioning data to support the qualification process will reduce the need for repeat testing
Using commissioning data to support the qualification process will reduce the need for repeat testing if the commissioning reports are suitable for standard use in a GMP document.
Once the installation is complete, Operational Qualification (OQ) — testing the room with equipment in place but not running — must be performed. OQ could include qualifying the room in the "At Rest" state. Performance Qualification (PQ) — testing of the room with equipment running and routine personnel simulating work — is then completed to ensure the cleanroom operates to the required specifications in the most challenging state.
During these stages, ensure the constructor or validation company understands how GMP and ISO 14644 interact. Suitably trained engineers must carry out the testing, which must be witnessed. An additional benefit of software such as TEAMs is the capability for a live review of documents by QA, providing real-time insight into how the progress of the qualification work without having to be on-site and in the cleanroom.
The scope of testing must consider regulatory requirements (airborne particulates, pressure differences, recovery testing, etc.) and process-driven requirements (temperature, relative humidity, and containment). Annex 1 now provides a detailed list of cleanroom and clean air qualification requirements where relevant to the design and operation of the installation.
Servicing and requalification
The approach to the requalification of the facility should factor in regulatory and process-driven requirements. Annex 1 details the minimum testing requirements – note the word minimum. Additional testing may be required, and a risk assessment should be performed to determine additional requirements.
You can always requalify more often, but not less often
Annex 1 also details the maximum time interval for requalification for A & B areas (6 months) and C & D areas (12 months). Again, note the wording as the maximum time.
You can always requalify more often, but not less often.
Servicing of the cleanroom should be in accordance with a Planned Preventative Maintenance (PPM) schedule to ensure the facility runs correctly. However, with a new facility, creating a schedule without previous data can be a challenge. Utilising recommendations from the cleanroom constructor on expected servicing requirements should provide the initial servicing schedule.
However, trending the cleanroom performance will allow the PPM to develop and deliver assurance your facility is continually operating as expected. Combine this information with known shutdown periods for other maintenance works to reduce your facility's overall downtime and the impact on your business.
Compliance during use
Once the cleanroom is qualified, does the room stay compliant? No!
Compliance cannot be guaranteed if a cleanroom is not used correctly, using best practices and following procedures.
- Ensure your team is adequately trained - is the training provided independently, and how do you evidence this?
- Staff must be appropriately gowned – are the gowning consumables fit for use and has gowning qualification been carried out?
- A validated cleaning and disinfection programme must be in place – suitable agents must be used, and their efficacy must be demonstrated through a full cleaning validation programme.
- Microbial environmental monitoring must be performed with the cleaning programme to demonstrate the impact on microbial growth, and trend analysis must be conducted at intervals to evaluate the effectiveness.
- Fixtures, fittings, and furniture must be constructed from cleanroom-suitable materials and be resistant to the cleaning agents you plan to use.
Are you aware of updates to regulatory requirements, and which guidance and regulations apply to you and your cleanroom? Consider asking your cleanroom construction company, who must stay up to date with all the latest changes, this question to ensure that they are building a complaint facility for you.
With the soon-to-be-implemented Annex 1 (issued Aug-2022, implementation date of 25-Aug-2023), plus relatively recent alterations to several ISO-14644 parts, including Test methods - Part 3 (2019), and Design, construction and start up - Part 4 (2022), you and your cleanroom constructor need to ensure you are keeping up to date with these changes. You must regularly review the changes against your cleanroom to stay compliant.
When regulations change, does your facility meet the new requirements? A gap analysis audit is a useful tool to determine whether the changes to regulations have impacted your facility. A mix of internal and external audits will provide an understanding of how your facility is used and the interaction with your processes, along with a fresh perspective and potential broader knowledge of regulatory requirements.
For newly built cleanrooms or an upgrade to an existing facility, you should expect a regulatory inspection before moving into production. You need to ask yourself whether you are inspection ready, and if not, what do you need to prepare? If this is a new facility, how do you know what you need to be “inspection ready”?
A mock inspection will help you prepare, and you should expect the inspector to scrutinise the full cleanroom validation package, so make sure you have it ready, and it is suitable to share.
Cleanroom construction companies may be able to provide support on the day of the inspection – with support on documentation and any potential technical queries that you may not be able to answer about the design of your facility.
In summary, you must consider compliance before starting the cleanroom project through the design, installation, operation, servicing, and requalification stages and during continued cleanroom use to ensure the room functions as required. Without compliance as an integral part of your cleanroom project, you run the risk of your facility not meeting the requirements, both regulatory and for your process.