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Not only has the length of Annex 1 been increased from 16 to 50 pages, but the whole approach has changed, which will have repercussions on the technologies and the procedures used in pharmaceutical manufacturing.
It anticipates that all pharmaceutical manufacturing activities will be governed holistically by the QRM principles and documented in the contamination control strategy (CCS). The CCS will become a living document, based on a data-driven scientific approach, which should be continuously updated and improved in order to control potential risks to quality.
The new draft is calling for a proactive approach: simply reacting to and correcting detected contamination will no longer be enough. Manufacturers will be expected to fully understand their processes and procedures, so that they can identify the potential risks to quality, put in place all the technical and procedural means to control these risks and aim for continuous improvements.
Since cleanroom garment systems are a critical part of sterile and aseptic manufacturing, they need to be managed under QRM (Quality Risk Management) principles too.
Quality risk management starts with an analysis and understanding of all the risks to quality associated with cleanroom operators wearing cleanroom garments. A complete data-based analysis will allow for design certification, qualification, validation and monitoring procedures which have quality built into them, thus being part of a holistic contamination control strategy.
A risk analysis is needed to understand the contamination risks coming from operators wearing cleanroom garments. Operators represent the biggest source of contamination inside cleanrooms, responsible for 75% of all contaminants. This contamination is coming both from the operators themselves and from their cleanroom garments.
The EU guidance advises on a validation approach that consists of five steps
Operator contamination is due both to our human nature (an average person sheds 40 000 particles per minute and 10% of them carry microorganisms) and human behaviour. While it is possible to mitigate the latter aspect through careful operator selection, training, slow movements or impeccable hygiene, the fact is that operators will always be shedding particles, as multiple studies have proven.
There is just one way to prevent particles generated by operators from contaminating the cleanroom: use cleanroom garments. They are the only barrier between the operator and the production environment.
The 2020 draft of Annex 1 clearly points this out: “(the cleanroom garments should) retain particulates shed by the body”.
Cleanroom garments themselves may be a source of contamination and this risk needs to be assessed too.
For example, the material used for making the garments (non-woven for single-use garments or woven for reusables) can shed more or fewer particles depending on the nature of the fibres or filaments used, their resistance to abrasion or their construction. The trims (zipper, buttons, elastic or sewing threads) may also be a source of contamination.
The design of the garment plays a role too and should be evaluated. One detail which is often neglected is the packaging in which the cleanroom garments come, which could be an additional source of contamination (i.e. paper-back bag vs. plastic bags).
Once the risks have been evaluated, they should be removed or replaced by technical or organisational means as far as possible, and the residual risks mitigated as much as possible using a validated cleanroom garment system.
The EU general guidance on validation (GMP Annex 1519) provides the general framework which can be applied to the qualification of cleanroom garment systems as well. This validation approach consists of five steps: the definition of User Requirements Specification (URS), the Design Qualification (DQ), the Installation Qualification (IQ), the Operational Qualification (OQ) and the Performance Qualification (PQ).
While the DQ and IQ have the highest impact on the quality achieved, the other stages should not be neglected, and it is important to proceed step by step.
While they are not formally part of the validation process, it is important to define upfront the requirements on the cleanroom garments system from the users and the environment they work in.
The URS will define the critical requirements against which the garment system needs to be assessed so that they will be in line with the risk assessment.
For example, a trained operator may have to be able to work at least 3 hours in the same set of cleanroom garments without causing unacceptable (cGMP) levels of contamination of the garments and the aseptic working environment. The garment’s packaging system may have to be suitable for the layout of the cleanroom and its material pass-through systems, or may have to be suitable for manual spray disinfection.
Sometimes, the operator may also need chemical or biological protection against the substances they are handling inside.
The compliance of the cleanroom garment system with cGMP must be demonstrated and documented during the DQ, which aims to confirm that the selected cleanroom garment is qualified for the intended use.
As the new Annex 1 will require a data-driven scientific approach, the DQ should include tests to simulate the intended use and the performances of the garments. As recommended by ISO 11607-1, the DQ should be split into four key areas: Material qualification, Performance testing, Stability testing and Usability evaluation. For reusable garments this needs to be extended to the garment maker’s subcontractors, suppliers and service providers.
M. Pavičić and T. Wagner have listed properties which should be assessed in table 1 below.
In this article, only a couple of these properties will be highlighted to show their importance and the scientific test methods which may be used to assess the performance of cleanroom garment systems.
1. Material qualification: In order to ascertain whether the garments are truly sterile, it is important to check if the manufacturer is following a validated sterilisation process and can guarantee a sterility assurance level of 10-6 as per ANSI/AAMI/ISO 11137-1 and document this in a certificate of sterility. A simple certificate of irradiation or a document attesting an internal autoclaving process are not enough.
Since the cleanroom garments need to be a barrier against the human contamination generated by the operators, it is important to assess the filtration efficiencies of the materials (non-woven or reusable polyester fabrics) used for making the garments. The particle filtration efficiency (PFE) against dry particles can be assessed with the test method EN 143 (TSI 8130), which measures the filtration efficiency using salt particles having a diameter of 0.3µm. While the bacterial filtration efficiency (BFE) can be assessed with the test method ASTM F2101.
2. Performance testing: The Helmke Drum test method as per IEST-RP – C003.4 is a good way to assess the particle shedding of cleanroom garments, especially for garments that are washed multiple times.
The Body box test (IEST-RP-CC003.4) is the only test method available to assess particle shedding when a garment is being worn by an operator. It allows evaluation of both the particle shedding of the garment and its PFE & BFE of the particles shed by the operator.
3. Stability testing: It is important to check how the garment characteristics and properties will change over time (due to ageing, wear, and wash-dry-sterilisation cycles). Therefore the performances listed above should be validated under worst-case conditions, i.e. for single-use garments, assessing garments from different batches and at the end of their shelf-life, and for reusable garments after 10, 20, 30, 40 and 50 wash-dry-sterilisation cycles to assess the end-of-life of the garments (studies by Romano F., Ljungqvist B. and B. Reinmüller have demonstrated that repeated washing deteriorates garment performance).
It is important to go through the user scenarios and to assess the packaging of the garments to ensure that the cleanroom garments can be used with acceptable remaining contamination and safety risks. While this is typically done by the end-user, suppliers can also evaluate and supply data to users.
Even though the IQ is a formal check to verify if all required elements of the cleanroom gowning system are present, it is important to check the following in order to eliminate unforeseen risks: Are the gowning and de-gowning facilities in order? Did the supplier provide the required certificates of conformance and/or analysis, supplier instructions, etc? Have the SOPs for gowning and de-gowning been written or adapted? Have the logistical processes for garments and accessories been validated? Has the operators’ training and qualification plans been established?
The OQ aims to qualify the gowning and de-gowning concept, including logistics & material pass-throughs, and the aseptic presentation of the garments (i.e. folding, packaging).
The PQ is typically done under worst-case conditions, which must be determined based on a risk assessment to validate the performance of the cleanroom garment system when it is used. The requirements specified in the URS must be complied with fully. They include the aseptic gowning qualification and the validation of the microbiological quality of the gowned personnel with the garments and other accessories during the actual work.
PQ is typically done under worst-case conditions
Of course, it does not end there: periodic revalidation of the garment system, constant monitoring and critical review of changes to the garments or the system are important to demonstrate the state of control.
Cleanroom garment systems are a critical part of the contamination control strategy and process validation. A Risk and Science-based Quality-by-Design approach and verification is the correct strategy to control contamination risks related to people and offer designed-in risk reductions. This approach is an adequate response to the latest regulatory requirements.
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Annex 1 is a legally binding part of EU GMP (European Union Good Manufacturing Practice) that provides guidelines and information relating to the manufacture of sterile medicinal products.
The new version of EU GMP Annex 1 was published on 25th August 2022 and will be implemented one year later on 25th August 2024.
The EU GMP Annex 1 provides comprehensive guidance on the design, construction, and maintenance of facilities and equipment used in the manufacture of medicinal products. It also includes guidelines on the production process, quality control, and documentation.
Annex 1 applies to all sterile medicinal products manufactured in the European Union and the UK, as well as those manufactured elsewhere and exported into the European Union and the UK. It applies to:
Sources of contamination within a cleanroom include raw materials, packaging, equipment, fluids, tools, processes and the most significant source of contamination, people. Microorganisms are shed from hair, skin, eyes and mucus membranes1.
When people move around in controlled and sterile environment, they shed 10 times more particles than when they are sitting or at rest, hence the reason for clear guidelines on the correct controlled behaviour of personnel.
In Annex 1 Part 7.18, activities in clean areas that are not critical to the production processes should be kept to a minimum, especially when aseptic operations are in progress.
Movement of personnel should be slow, controlled and methodical to avoid excessive shedding of particles and organisms due to over-vigorous activity. Operators performing aseptic operations should adhere to aseptic technique at all times to prevent changes in air currents that may introduce air of lower quality into the critical zone. Movement adjacent to the critical zone should be restricted and the obstruction of the path of the unidirectional (first air) airflow should be avoided.
A review of airflow visualisation studies should be considered as part of the training programme.
Sitting:
We shed approx 100,000 particles per minute
Walking:
We shed approx. 1,000,000 particles per minute
Running
We shed approx. 10,000,000 particles per minute
Part 7 of Annex 1 outlines the requirements needed regarding personnel numbers, behaviors, skills and protective clothing. A precise contamination control strategy needs to ensure that the personal protective equipment (PPE) they’re wearing is suitably assessed and monitored.
Outlined in the IEST-RP-CC003.4 standard - Garment system consideration for cleanrooms and other controlled environments, lists six types of non-woven fabrics for use in cleanrooms and other controlled and sterile environments, and describes each fabric as follows:
When selecting garments for cleanroom use, depending on the specific application, the IEST standard recommends evaluating the fabric properties including testing for (selecting those relevant to the fabric type);
Figure 1 - Bound Joining Seam ConstructionConstruction of cleanroom garments is another important consideration, and the IEST standard outlines recommendations for thread and seam structure. Seams for cleanroom garments should be joining seams to avoid free-air / particulate passage from the inside of the garment to the outside environment.
The IEST standard recommends for the construction of cleanroom garments that they are constructed using a bound joining seam, as shown in figure 1.
As well as consideration for how the cleanroom garments are constructed and the type of material used, Annex 1 Parts 7.11 & 7.12 outline what garments to wear in each cleanliness grade and how they should be worn and donned has been outlined in Part 7.13 & 7.14. Utilizing cleanroom garments that are in compliance with industry standards offers better protection.
Annex 1 Part 7.11 states that protective clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. When the type of clothing chosen needs to provide the operator protection from the product, it should not compromise the protection of the product from contamination.
Cleanroom garments should be visually checked for cleanliness and integrity immediately prior to and after gowning. Gown integrity should also be checked upon exit. For sterilised garments and eye coverings, particular attention should be taken to ensure they have been subject to the sterilisation process, are within their specified hold time and that the packaging is visually inspected to ensure it is integral before use.
Reusable garments (including eye coverings) should be replaced if damage is identified, or at a set frequency that is determined during qualification studies. The qualification of garments should consider any necessary garment testing requirements, including damage to garments that may not be identified by visual inspection alone.
Annex 1 Part 7.12 states that protective clothing should be chosen to limit shedding due to operators’ movement. This is important to minimize the risk of contamination from fibres or particles shed from the clothing.
A description of typical clothing required for each cleanliness grade is given below:
Cleanroom gowning should be performed in change rooms of an appropriate cleanliness grade to ensure gown cleanliness is maintained. Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas.
Single or two-piece facility trouser suits, covering the full length of the arms and the legs, and facility socks covering the feet, should be worn before entry to change rooms for grades B and C. Facility suits and socks should not present a risk of contamination to the gowning area or processes.
Our extensive portfolio of controlled environment protection includes sterile cleanroom coveralls, gloves, goggles and facemasks to ensure you meet all the guidelines set out in Annex 1 Part 7.
Ansell's full range of head-to-toe sterile PPE & product protection solutionsGLOVES: Our sterile 300mm/12” gloves are available in Latex (NRL), Neoprene, Nitrile and PI (Polyisoprene) and can be disinfected using alcohol disinfectants* and double-donned to comply with aseptic gowning and SOPs. Our longer length 400mm/16” & 600mm/24” gloves provide extra coverage of the arm to make sure no risk of gaps between garment and gloves.
COVERALLS (SUITS), HOODS & OVERBOOTS: Our BioClean-D™ sterile disposable cleanroom coverall and accessories range includes sterile single piece disposable suit with hood S-BDCHT, and S-BDSH drop-down garment a coverall designed to be donned over the head for true aseptic donning or a disposable coverall without hood S-BDCCT, they all feature full length coverage of the arms and legs with elasticated wrists and ankles to ensure a secure fit. BioClean™ headgear comprising of 3-piece constructed hood S-BDHD-L, which features an extra-long cape to be tucked into the neck of the coverall to ensure no gaps for contamination risk. A range of BioClean™ standard and longer length sterile Overboots S-BDOB & S-BDOB-L completes the offering.
COVERALL KITS: Our convenient coverall kits S-BDKM & S-BDHB include all the body protection a person needs in one package, coverall with collar (or hood), Overboots, hood (with or without facemask), to reduce packaging waste and enable efficient donning with everything in one easy open package.
CHEMO PROTECTION RANGE: The BioClean-C™ range of aprons S-BCDA & S-BCAS and sleeve covers S-BCSC provide an extra layer of protection when handling chemotherapy drugs and have been tested against ASTM F739-12.
GOGGLES: Our range of BioClean™ goggles include a sterile single-use version BCGS1 and BVGS, autoclavable versions BCAG and BCAH, and another autoclavable version with a wraparound lens to provide panoramic vision BCAP, all BioClean™ goggles have anti-fog technology to ensure a clear view every time. The also feature indirect ventilation systems for wearer comfort but avoiding droplets and particles from entering the controlled environment.
FACEMASKS: The BioClean™ range of sterile product protection looped, tie-on, flat or duck-bill facemasks – MEA210-1, MTA210-1, BDBS, BDBS-G have high bacterial, particle and viral filtration efficiency ensuring your critical products stay protected from droplets and particles shed from operators.
ACCESSORIES: Also available is a range of BioClean™ bouffant caps BBC and beard snoods BBS to ensure all hair is covered.
Annex 1 places considerable emphasis on barrier technology to separate the operator from the product to maintain Grade A conditions. This can be accomplished using RABS and Isolators gloves:
Annex 1 Part 4.18 - RABS or Isolators gloves, which are different technologies, and the associated processes, should be designed to provide protection through separation of the grade A environment from the environment of the surrounding room. The hazards introduced from entry or removal of items during processing should be minimized and supported by high capability transfer technologies or validated systems that robustly prevent contamination and are appropriate for the respective technology.
Annex 1 Part 4.21 - The materials used for glove systems (for both RABS and Isolators gloves), should be demonstrated to have appropriate mechanical and chemical resistance. The frequency of glove replacement should be defined within the CCS.
Our clean & sterile Nitrile RABS and Isolator glove range comprises of gloves, mittens, sleeves and sleeve/glove systems. Gloves and mittens are 100% water leak tested for glove integrity and resistant to VHP, IPA and disinfectants for in situ sanitizing.
Superior Barrier Technology with Isolator & RABS GlovesOther RABS and Isolator glove materials available are CSM, NRL, Neoprene, EPDM & EPDM+. The most suitable material will be dependent on the applications and can be decontaminated by autoclaving, VHP or IPA*.
PE packaging and sterilisation play a crucial role in maintaining a cleanroom environment during production. Inadequate packaging and sterilisation can lead to contamination of the cleanroom, thereby compromising the quality and integrity of the final product. It is therefore essential to choose appropriate packaging and sterilisation methods that meet the standards set for cleanroom environments.
All Ansell sterile PPE is double or triple-bagged in durable plastic packaging to reduce contamination and includes sterilisation indicators to show the PPE has been sterilised to a sterility Assurance Level (SAL) 10-6.
Certificates of Irradiation (Gamma) or Certificates of Processing (EtO) per product lot number can be downloaded via our easy-to-use certificate tool on www.ansell.com/life-sciences/certificates to prove the PPE has been subjected to the full sterilisation process. All packaging clearly states expiry and manufacturing dates.
In conclusion, understanding and adhering to the EU GMP Annex 1 PPE guidelines is crucial for maintaining a sterile environment.
By following these best practices, you'll ensure the safety and quality of your products. Don't hesitate to invest in proper protective clothing for your team. If you're ready to elevate your facility's safety standards, contact our experts today to find the right PPE solutions tailored to your needs.
1. Brandes, R. Aseptic Processing: Qualification of Personnel, Mass & Peither AG-GMP Publishing, April 12, 2012
*Please check the product validation pack for full test results.
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