Understanding the Impact of Annex 1 on Isolator Design

The first draft of the European Union (EU) good manufacturing practice (GMP) Annex 1, “Manufacture of Sterile Medicinal Products” was published for comment on the December 20, 2017 (1) and generated great interest internationally, as it was the first adaptation to the full EU GMP document on the manufacture of sterile medicinal products since November 20, 2008 (2). And, as during the creation of the document, the Pharmaceutical Inspection Cooperation Scheme (PIC/S) and the World Health Organization (WHO) were also involved. The previous applicable document of Annex 1 was completely revised and contained many changes, adaptations, and new contents, which resulted in a large number of comments (6400 in total) to the European Commission. The second published draft of the EU GMP Annex 1 appeared just two and a half years later, on February 20, 2020 (3). For the new draft version, stakeholders such as the International Society for Pharmaceutical Engineering (ISPE), Parenteral Drug Association (PDA), and others were contacted for comments. The comments on the second publication of the draft document concluded in July 2020, and the final version is expected to be published in the beginning of 2021.

Barrier systems in Annex 1: RABS and isolators

The expressions “Contamination Control Strategy (CCS)” and “Quality Risk Management (QRM)” are mentioned frequently in the document, along with barrier systems, such as isolators or restricted access barrier systems (RABS). This article describes the impact on isolator design for aseptic processing and how contamination control strategies are observed in relation to isolators.

Compared to RABS, isolators have a closed barrier between the surroundings and the interior of the isolator in which the sterile product is processed. During production, access to the interior of the isolator is only possible through validated transfer systems, such as decontamination airlocks (e.g., using hydrogen peroxide [vH₂O₂]), or e-beam, dry heat tunnels (i.e., depyrogenation tunnel), rapid transfer ports (RTPs), or through interventions via the gloves attached to the isolator.

The most important points in the draft EU GMP Annex 1 with regard to isolators are illustrated in Figure 1. The starting point for every CCS is the risk observation of the design of the isolator system, including the installation of equipment in an isolator, such as a fill/finish machine for vials, syringes, etc. Most of the design failures could occur during the risk observation of the isolator System. The design forms the basis for cleaning in order to prevent a possible particulate or microbiological contamination of the sterile products, or to avoid cross-contamination in the case of a multi-product system. The entire design is also important for the subsequent surface decontamination with vH₂O₂. A high degree of automation reduces the manual interventions in the aseptic area through the gloves attached to the isolator. If highly active/toxic substances are to be manufactured in the isolator (or substances with an increased bio-safety factor), the protection of employees is a further important factor.

Consider section 4.3 of the draft Annex 1, which says (3):

The document expressly indicates that RABS or isolators should be used, which means that RABS or isolators are the favored technologies of the future for handling sterile products.

The following differences between RABS and isolators should be mentioned:

• RABS are installed in a grade B room, while isolators are installed in a grade D room. The installation of an isolator in a grade D cleanroom means more comfort for the operator when wearing the required cleanroom clothing. Training employees for a grade D cleanroom is also less intensive than training them for a grade B cleanroom.
• RABS systems are classified into the following systems: passive RABS, active RABS, or closed RABS. Apart from the closed RABS, the operator always has access to critical areas within the RABS. With the isolator, access is only possible using gloves at the isolator, just like with the closed RABS.
• In most cases, RABS are decontaminated via the room. With isolators, there is an integrated and validated decontamination system, for example, with vH₂O₂.
• With the isolator, the aseptic critical zone is self-contained, while with most RABS, the aseptic critical zone is opened to the surrounding room during interventions.
• Isolators are suitable for handling highly active, toxic substances or for substances that require a higher biosafety level, and they can also handle substances with an extremely low acceptable daily exposure (ADE) or permitted daily exposure (PDE) when further technical measures are implemented.

The use of isolators in sterile manufacturing, in particular, has rapidly increased over the past 10 years. The main reasons are the increased safety of the product in the isolator, as well as the large number of highly active substances that have entered the market in recent years or are expected to do so in the coming years.

Isolator design

Figure 1 shows that manufacturing control starts with the aseptic engineering design. The design of an isolator system, including its installations, is the basis on which all further requirements, such as cleaning or surface decontamination, are built. The design plays an important role in a variety of ways.

Consider section 4.4 of the draft GMP Annex 1 (3); the following description applies to the interior of an isolator:

Grade A zone: The critical zone for high risk operations for making aseptic connections by ensuring protection by first air (e.g., aseptic processing line, filling zone, stopper bowls, open ampoules, and vials). Normally, such conditions are provided by a localized airflow protection, such as unidirectional airflow work stations, RABS, or isolators.

The hygienic design plays an important role in ensuring this first air within the isolator system. No installations should be located, and no handling carried out, above critical operations that could lead to possible contamination of the sterile product. When observing critical operations, consider all transfers, interventions, movement sequences in the isolator, and so on. The investigation of every individual process steps on a GMP Annex 1 compliant aseptic hygiene design plays an important role here.

Other important points when it comes to aseptic engineering design are cleaning and surface decontamination. With regard to surface decontamination by means of vH₂O₂, all surfaces should be structured and designed so that the vH₂O₂ reaches them quickly and completely. Dead spaces, areas with difficult accessibility, feed-throughs from the room into the isolator, screw connections, and so on, should be avoided. Figure 2 illustrates a hygienic design of a filling line. The walking beam is designed with easy to clean surfaces and with couplings to allow a fast removal of all components. Dead legs or areas not easy to access are eliminated.

Cleaning

The aseptic engineering design also plays an important role in cleaning with regard to avoiding contamination and cross-contamination. Consider section 5.4 of the new EU Draft GMP Annex 1, which says (3):

The cleaning process should be validated to:

i. Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.

ii. Minimize chemical, microbial, and particulate contamination of the product during the process and prior to disinfection.

In this paragraph special attention should be paid to the wording: “The cleaning process should be validated”. Many of the process systems within an isolator are cleaned manually. To be able to perform this manual cleaning in a validated way, a process and system design are required that permit validation. In addition, highly qualified employees are required to carry out this validated cleaning process. In the future, the author expects that complex and unwieldy manufacturing/filling processes will be simplified and a suitable hygienic design used. A hygienic risk assessment is certainly a beneficial tool for simplifying the system design.

An optimal process and isolator hygienic design also enables the handling of highly active toxic pharmaceutical products or pharmaceutical products that require an increased biosafety level. For several years the quantity of these substances has been increasing steadily. The prognosis for the next few years shows that many new substances currently in the preclinical or clinical phase are being classified as highly active, toxic, or with an increased biosafety level. As well as the process and isolator hygienic design, further important aspects play a role in the cleaning of these pharmaceutical products. It is important to consider the following questions:

• Which PDE or ADE limit value is required?
• Can the materials that are used in the isolator and their surface qualities be cleaned to the required PDE or ADE, and which surface limit values should be considered?

Up until a few years ago, there were still no cleaning recommendations for surfaces that did not come into contact with the product, but there were already requirements from an EU GMP directive. Section 5.21 of Part 1 of these GMP guidelines (4) mentions:

Depending on the contamination risk, verification of cleaning of non-product contact surfaces and monitoring of air within the manufacturing area … in order to demonstrate effectiveness of control measures against airborne contamination or contamination by mechanical transfer.

Especially in isolators with the associated process systems for aseptic filling in vials, syringes, etc., most surfaces are considered non-product contacting. A PDA expert group, led by the author of this article, was established in 2015 to look into this topic; the group published “Isolator Surfaces and Contamination Risk to Personnel and Patient” (5) and “Preventing Cross-Contamination during Lyophilization: GMP and Occupational Cleaning Requirements for Nonproduct and Indirect Product Contacts Parts” (6) that provide recommended limit values for cleaning surfaces that do not make contact with the pharmaceutical product. Table I summarizes some of these recommendations.

Conclusion

This article reviewed considerations for aseptic design and cleaning. A second article to be published will consider surface decontamination, automation, and considerations for environmental health and safety when operating isolators.

References

1. EC, Draft Revision to “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2017).
2. EC, EudraLex Volume 4: Good manufacturing practice Guidelines, “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2008).
3. EC, Draft Revision to “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2020). 
4. EC, EudraLex Volume 4: Good manufacturing practice Guidelines, “Part 1, Chapter 5: Production,” (Brussels, 2014).
5. R. Denk et al., “Isolator Surfaces and Contamination Risk to Personnel and Patient,” PDA Letter, (Nov. 6, 2017).
6. R. Denk et al., PDA J. Pharm. Sci. Tech., 73 (5) 487–496 (2019).

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

Article details

Pharmaceutical Technology
Vol. 44, No. 11
November 2020
Pages: 34–37

Citation

When referring to this article, please cite it as R. Denk, “Understanding the Impact of Annex 1 on Isolator Design,” Pharmaceutical Technology 44 (11) 2020.