From 2008 to 2022: What YOU Need to Change Per the New Premise Section of Annex 1

As the pharmaceutical industry navigates beyond the August 2023 deadline for implementing most of the revised 2022 Annex 1: Manufacture of Sterile Products, with an extended August 2024 deadline for lyophilization procedures, the pharmaceutical industry now stands at a crucial juncture. These updates introduce significant changes, especially in the premise section, affecting the management of cleanrooms and associated controlled environments. For many, the gap between current practices and the new requirements could pose substantial compliance challenges. In this article, let's delve into a comprehensive gap analysis essential for navigating these changes effectively. This analysis not only highlights what’s new but also offers strategic insights to ensure your facilities are not just compliant, but also positioned for enhanced operational efficiency and safety. Stay ahead of the curve — understanding and implementing these updates now could save significant time, costs, and compliance headaches down the line. The following sections show the revisions and updates made in the 2022 release of Annex 1 in comparison to its 2008 version with respect to facility design and construction.

1. RABS and Isolators

The 2022 version of Annex 1 emphasizes the utilization of RABS and isolators to minimize direct operator interaction with the critical work environment, acknowledging that human intervention poses one of the most significant sources of microbial contamination.

RABS and isolators facilitate unidirectional airflow patterns designed to sweep particles and potential contaminants away from the critical zone, while also maintaining air pressure differentials (DP) to prevent the ingress of air from the surrounding environment. Additionally, they ensure adequate air changes per hour (ACH) through the use of HVAC systems with High-Efficiency Particulate Air (HEPA) filtration, thereby ensuring a constantly clean environment.

Furthermore, RABS and isolators are compatible with automation and can complement the use of robotic systems and automated equipment. The integration of automated and robotic systems within RABS and isolators create a fully enclosed and controlled environment for critical processes which further reduces the potential for contamination from external sources.

Impact of using RABS and isolators on Facility Design and Construction:

• Implementation of RABS and isolators in new facilities is mandatory, unless a verified scientific justification is provided in the Contamination Control Strategy (CCS)
• Allows Grade B as the background environment for RABS, and Grade C or D for isolators
• Facilitates design in meeting airflow pattern requirements (unidirectional flow, DP, ACH, HEPA integrity testing, etc.)
• Modular design provides greater flexibility in layout and space utilization
• Provides long-term cost reduction (although high initial investment) due to lower contamination during manufacturing operations?

2. Cleanrooms and Clean Air Equipment

Specification on Airlocks and Personnel Movement

Annex 1 now requires separate airlocks for personnel and materials moving between different cleanroom grades. It also recommends separate entry (Grade C to Grade B) and exit (Grade A to Grade B) airlocks where feasible. If separate airlocks are not possible, procedural time-based separation is suggested. It also specifies that airlocks must adhere to the cleanliness standards of the cleanroom they access, including total particle concentration and microbial contamination levels. Additionally, the presence of handwashing facilities directly in airlocks accessing Grade B areas is prohibited, emphasizing movement from lower to higher cleanliness grades (D to C to B).

Specification on Materials, Equipment, and Component Transfer

The 2022 update of Annex 1 outlines stringent protocols for transferring materials, equipment, and components between cleanrooms, focusing on minimizing contamination risks. Transfers into Grade A and B cleanrooms must follow a unidirectional process, incorporating cleaning, disinfection, or sterilization like double-door autoclaves. If direct sterilization isn't feasible, validated alternative procedures ensuring contamination prevention must be implemented. Furthermore, only pre-approved items can be transferred into these high-grade areas, with unapproved items requiring prior validation and approval.

Specification on Pipes, Ducts, and Other Utilities

To prevent contamination and maintain airflow integrity, the new Annex 1 guidelines strictly limit the presence of pipes, ducts, and other utilities within cleanrooms. Recognizing the difficulties posed by this rule, it allows for the installation of utilities that can be cleaned and disinfected on their surfaces. However, the potential risks of contamination from leaks or maintenance activities persist.

Specification on Material to Be Used in Cleanrooms

Materials used in cleanroom construction and operations must now be specifically selected to minimize particle generation and withstand frequent cleaning and disinfection. Suitable materials include steel, metal alloys, glass, plastic, and rubber, which are less likely to shed particles compared to gypsum and exposed concrete.

Addition of Observation Facilities and Equipment for Grade A and B Areas

The updated Annex 1 encourages the installation of observation technologies in Grade A and B areas to enhance real-time monitoring and reduce contamination risks. This includes the use of camera systems for continuous surveillance, documenting conditions and activities to meet regulatory expectations for quality and safety. Existing facilities are encouraged to adopt these technologies based on a risk-based assessment, and new facilities should incorporate them into initial designs for compliance and operational efficiency.

Impact of the changes in Cleanroom and Clean Air Equipment on Facility Design and Construction:

• Facilities need to be designed with separate airlocks for personnel and material moving between cleanrooms of different grades. If not possible, time based separation of movement of personnel and material by procedure should be considered.
• Airlocks must be designed such that they meet the standard for the total particle concentration and microbial contamination level of the cleanroom to which it leads to.
• For Grade B cleanrooms, separate airlocks for entering and leaving is highly recommended to be considered in the design. If this is not possible, then a time-based separation of movement, into and out of the cleanrooms, by procedure should be considered.?
• In areas deemed as high risk by the CCS, separate airlocks for ingress and egress should be employed.
• There should be no hand washing facilities in airlocks directly accessing Grade B cleanrooms.
• Premises should be designed to require personnel to move from areas of increasing cleanliness, i.e., from Grade D to Grade C, then to Grade B.
• For airlocks accessing Grade A and B cleanrooms, an interlocking system is strictly required, while for those leading to Grade C and D cleanrooms, a visual and/or audible warning, at the minimum, is compulsory.
• Double-ended sterilizers sealed into the wall such as a double-door autoclave or depyrogenation oven or tunnel should be provided for items to be transferred into Grade A and B cleanrooms. If not possible, procedures that prevent contamination such as the use of an effective transfer disinfection process, rapid transfer systems for isolators, or a bacteria retentive filter for gaseous or liquid materials should be validated to ensure compliance and be implemented.
• Premises should be designed such that material transfer into Grade A and B cleanrooms would only occur in a unidirectional process. Facilities should also encourage a separate but unidirectional process for materials leaving Grade A and B cleanrooms. If separation is not possible, then a time-based separation of movement, into and out of the cleanrooms, by procedure should be considered.
• Pipes, ducts, and other utilities are prohibited inside the cleanroom and should be carefully assessed in the design.
• Materials inside the cleanroom, those that are used for the construction of the cleanroom and those that are used within the cleanroom, must be chosen specifically to reduce the generation of particles and to allow the repeated application of disinfectant, cleaning solutions, and sporicidal agents.
• Facilities should be designed with observation facilities and equipment for Grade A and B areas. These may include but are not limited to provision of cameras that show the production area and process or just a simple window.

3. Total Particle Concentration, Microbial Contamination, and Operational States

The latest update of Annex 1 made some significant changes in cleanroom classification and qualification, which taps on the limits of the total particle concentration (TPC) used for classification, level of microbial contamination used for qualification, and operational states. The changes to the TPC include the removal of the limit for particles with sizes ≥ 5 μm for the “at rest” state of Grade A and B cleanrooms as well as that of the “in operation” state of Grade A cleanrooms. This was done because particle counters have difficulty in detecting low concentrations such as 29 μm/m3, which was the one of the limits used before. Moreover, the limits for the “at rest” state of Grade C and D were added with 30 μm/m3 and 300 μm/m3, respectively. The limits for the “in operation” state of Grade B and C were also added with 30 μm/m3 and 300 μm/m3, respectively.? This was done so that Annex 1 is harmonized with other international standards such as the International Organization for Standardization (ISO), which uses the same limits. Table 1 highlights the changes in the maximum permitted TPC in Annex 1.

Table 1. Maximum Permitted Total Particle Concentration for Classification

The level of microbial contamination level, on the other hand, was updated such that the requirement now is no growth for Grade A cleanrooms for all categories instead of just less than 1 colony-forming unit (CFU), which means that there should be no recovery of microorganisms in Grade A cleanrooms. Though in the industry, it is understood that less than 1 CFU automatically means no growth, this update nevertheless provides clearer expectations for manufacturers and regulators in qualifying cleanrooms, thus reducing ambiguity. It essentially eliminates the instances that allow the interpretation of “less than 1 CFU” to “minimal” contamination when, in fact, the goal is to have none. Another update in Annex 1 is that the glove print contamination was eliminated and implied to be just the same as the contact plate contamination, which, in a sense, also provides clarity to the readers.??

Lastly, the definitions of the operational states in Annex 1 were also updated and clarified. While the idea of the “at rest” state remains the same, the definition of “in operation” changed in that it now requires the maximum number of personnel performing and simulating the usual operation and not just a specified number of personnel working. This was done to better replicate the worst possible case scenario and induce the maximum TPC and microbial contamination inside the cleanroom. Lastly, the “clean up” period requirement is simplified to just “less than 20 minutes” instead of “15-20 minutes” so that the validation process becomes more efficient.

Impact of the changes in Total Particle Concentration, Microbial Contamination, and Operational States on Facility Design and Construction:

• Facilities may now need to install advanced air handling systems with enhanced filtration capabilities, such as HEPA filters, to meet the new requirements.
• Facility layouts should be designed to optimize the flow of personnel and materials to ensure that the TPC and microbial contamination meets the standards.
• Environmental monitoring systems to be installed need not be capable of measuring the maximum for particulates with sizes greater than 5 μm/m3 for both “at rest” and “in operation” state for Grade A cleanrooms and for “at rest” state for Grade B cleanrooms.

4. Disinfection, Decontamination, and Sterilization

The 2022 version of Annex 1 requires cleaning before disinfection of cleanrooms and clean air systems, especially in critical areas. This directive was aimed to enhance the efficacy of disinfection by eliminating residues that could shield microorganisms from disinfectants. Additionally, the update introduced requirements for employing advanced disinfection methods, such as fumigation with vapor-phase hydrogen peroxide.?

Furthermore, Annex 1 emphasized the addition of sporicidal agents in the Comprehensive Microbial Control to address the challenge of microbial spores, which are resistant to standard disinfectants. This update ensures a more comprehensive microbial control by targeting both active microorganisms and their dormant forms.?

Lastly, extending the use of sterile disinfectants to Grade C and D areas (previously required only for Grade A and B) enhances the overall sterility assurance across all cleanroom environments.

Impact of the updates for disinfection, decontamination, and sterilization on Facility Design and Construction:

• Facilities should be designed with surfaces and materials that are easy to clean and compatible with sporicidal agents and advanced disinfection methods. This includes selecting non-porous materials such as steel or metal alloys, glass, plastic, and rubber
• Facility layouts should be designed to minimize contamination risks and facilitate thorough cleaning and disinfection.
• New or renovated facilities should assess the incorporation of built-in systems for advanced disinfection methods, such as integrated vapor-phase hydrogen peroxide systems, in areas where high levels of sterility are required.

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Contributors: Edel Alcairo, Aries Fernan Garcia, John Mark Guiquing, Sean Kenneth Sala, and Kyle Anthony Vinson