Understanding the Impact of Annex 1 on Isolator Operation

A revised draft of the European Union (EU) good manufacturing practice (GMP) Annex 1 was published in February 2020 (1), and a final version is expected in 2021. The GMP guidance includes several key points related to isolator design and operation, which are illustrated in Figure 1.

As the author discussed in the first part of this article series, the design of an isolator is the basis for compliance with GMP in aseptic processing and in cleanability (2). Isolator design also affects surface decontamination.

Surface decontamination

Hygienic design and cleaning to remove particulate and microbiological contamination are important attributes for surface decontamination of the inner surfaces of isolators and of their installations (e.g., a vial or syringe filling line, an incubator, or other utilities for manufacturing cell and gene therapies). Consider section 4.24 of the new EU Draft GMP Annex 1, which says (1):

For RABS [restricted access barrier systems] and isolator systems, decontamination methods should be validated and controlled within defined cycle parameters. The cleaning process prior to the disinfection step is essential; any residues that remain may inhibit the effectiveness of the decontamination process:

i. For isolators, the decontamination process should be automated and should include a sporicidal agent in a suitable form (e.g., gaseous, aerosolized, or vaporized form) to ensure thorough microbial decontamination of its interior. Decontamination methods (cleaning and sporicidal disinfection) should render the interior surfaces and critical zone of the isolator free of viable microorganisms. (1)

This section has two messages in terms of isolators: decontamination methods should be validated and controlled within defined cycle parameters and the process should be automated and should use a sporicidal agent.

In most isolators, surface decontamination is carried out with vaporized or sprayed hydrogen peroxide (H₂O₂) as the sporicidal agent. Direct spraying of micro-nebulized H₂O₂ into the isolator system produces a quick distribution with a smaller amount compared to vaporizing H₂O₂. 

The decontamination cycle, using the selected agent, must be validated in accordance with GMP to generate a reliably aseptic atmosphere inside the isolator. The phrase “controlled with defined cycle parameters” does not mean solely the amount and time of the H₂O₂ in the isolator system; the following questions should be considered:

• How homogeneous and quick is the distribution of the sprayed or evaporated H₂O₂, including at difficult-to-reach positions (worst case observation)?
• If an uneven enrichment of the sprayed or evaporated H₂O₂ takes place, what consequences does this have for the decontamination cycle to be validated? Are surfaces exposed for a shorter or longer duration with a lesser or greater amount of H₂O₂, and what influence does this have?

• How is the concentration distribution of the H₂O₂ in the overall isolator system? Is a uniform H₂O₂ film created on all surfaces without undesirable droplets forming on surfaces?
• What materials are used in the isolator system and what is their influence on the surface decontamination? Stainless steel has a different decontamination factor (D-value) than glass or polymers, for example. These parameters need to be taken into account as well in the cycle to be validated.
• Are moveable parts located in the isolator system? How are transfers into and out of the isolator accomplished and what influence do these transfers have on the decontamination cycle?
• Are surfaces exposed during the production process and during work in the isolator system that are not sufficiently exposed during the decontamination cycle?

The phrase “defined cycle parameter” also contains quality-by-design (QbD) attributes in regards to the variable parameters in the isolator system. Consider questions such as the following when developing a validated decontamination cycle:

• In which defined acceptance criteria (e.g., temperature range, relative humidity range, quantitiy and concentration of H₂O₂, air velocity and speed range if used) does the decontamination cycle function?
• Additionally what influence do the criteria have on the decontamination cycle? For example, what is the effect if the temperature is 15°C instead of 20°C or if the relative humidity is 30% instead of 40%?

Automation

Automation, including robotics, can make manufacturing of sterile products more efficient, quicker, and safer. Robotic systems are mentioned specifically in section 2.1 of the new EU Draft GMP Annex 1, which says (1):

The manufacture of sterile products is subject to special requirements in order to minimize risk of microbial, particulate and pyrogen contamination. The following key areas should be considered:

i. Facility, equipment and process design should be optimized, qualified, and validated according to the relevant sections of the Good Manufacturing Practices (GMP) guide. The use of appropriate technologies (e.g., Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid microbial testing and monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and product. (1)

Robotic work processes are widely used in pharmaceutical packaging, and their use has been expanding; they are now employed for handling sterile products, free of any manual interventions. The International Society for Pharmaceutical Engineering (ISPE) DACH [Germany/Austria/Switzerland] Future Robotics special interest group (SIG) was founded by the author in 2019. The SIG concerns itself with possible new work processes for robotic systems, the facility of the future using robotics, and the regulatory requirements from the EU GMP Annex 1 Draft for using robotics.

For example, a new work process for robotic systems is to place molded parts in transport containers and transport them to the washing machine and, after washing, back to the isolator. This process needs to take into account transfers between individual cleanroom grades.

Another work process is aseptic filling and automated handling of sterile finished products by means of robotic systems in isolators, as well as implementing their technical and regulatory compliance with current good manufacturing practice (CGMP). It is necessary, for example, to adapt viable monitoring to fully automated robotic solutions in aseptic manufacture. In the Draft Annex 1, the application of rapid microbial monitoring is mentioned, but the technical and organizational measures needed to replace the current monitoring methods using settle plates with rapid microbial testing methods need to be redefined. This topic will be addresed by the ISPE Future Robotics SIG in 2021.

Containment requirements

The production of highly active and hazardous substances in the biopharmaceutical industry has increased rapidly in recent years, requiring consideration of environment, health, and safety protection. Viral vectors, for example, require high protection for the employee as well as prevention of cross-contamination with other substances.

Consider section 4.14 of the new EU Draft GMP Annex 1, which says, regarding the topic of containment of highly active and dangerous substances (1):

… Particular attention should be paid to the protection of the critical zone. The recommendations regarding air supplies and pressures may need to be modified where it is necessary to contain certain materials (e.g., pathogenic, highly toxic or radioactive products or live viral or bacterial materials)…(1)

In addition to the pressure concept, the following aspects need to be taken into consideration for fill/finish of parenteral pharmaceuticals in an isolator system:

• Is there an Accepted Daily Exposure (ADE) or Permitted Daily Exposure (PDE) that sets a limit value for exposure, such as that found in the European Medicines Agency’s guideline on setting health based exposure limits (3)? This limit value is important for calculating cleaning limit values as well as for determining how to protect employees during manufacturing.
• Which biological safety level (BSL) is required, and which technical and organizational measures are necessary to achieve this BSL?
• Is this a monoproduction or a multi-purpose system? On a multi-purpose system, the necessary cross-contamination requirements have to be observed. For products with an ADE/PDE, these requirements are determined by toxicologists. For viral vectors, there currently are no defined limit values, so a no-tolerance level from the previous to the subsequent product is assumed.
• A quality risk management (QRM) process is needed that covers the requirements of GMP for product protection as well as protection of employees and the environment. A contamination control strategy CCS is derived from the QRM. Furthermore, prevention of cross-contamination and containment strategies must be developed.

References

1. EC, Draft Revision to “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2020).
2. R. Denk, Pharm. Tech. 44 (11) 34-37 (2020).
3. EMA, Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities, EMA/CHMP/CVMP/ SWP/169430/2012 (London, 2014).

About the author

Richard Denk is senior consultant for Aseptic Processing and Containment at SKAN in Switzerland and is a member of the ISPE Commenting Team of the new draft of EU GMP Annex 1.

Article details

Pharmaceutical Technology
Vol. 45, No. 4
April 2021
Pages: 30–33

Citation

When referring to this article, please cite it as R. Denk, “Understanding the Impact of Annex 1 on Isolator Operation,” Pharmaceutical Technology 45 (4) 2021.