Summary
- CAPA, Deviations, Quality Events
- CAPA and Deviations
- New QMS? Pay attention to these key success factors!
- Validation of the Imaging Technology for a novel microbiological colony counter
- Barrier Technologies & Revision of Annex 1: requirements & operational responses for manufacturers
- GMP Annex 1 and Lyophilization
Barrier Technologies & Revision of Annex 1: requirements & operational responses for manufacturers
The final official version of Annex 1 (Manufacture of Sterile Medicinal Products – Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use), dated 22 August 2022, was published on 25 August 2022. This final version was keenly awaited by manufacturers and follows a long revision process initiated in 2015 by a working group made up of GMP/GDP inspectors and PIC/S representatives (Inspection Working Group – IWG) and a consultation process led by different associations such as A3P, PDA, PHSS, ISPE, EFPIA …
The final official version of Annex 1 (Manufacture of Sterile Medicinal Products – Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use), dated 22 August 2022, was published on 25 August 2022. This final version was keenly awaited by manufacturers and follows a long revision process initiated in 2015 by a working group made up of GMP/GDP inspectors and PIC/S representatives (Inspection Working Group – IWG) and a consultation process led by different associations such as A3P, PDA, PHSS, ISPE, EFPIA …
La Vague 76 A3p Barrier Technologies Revision of Annex 1 Requirements Operational Responses For Industry 1
The final version of Annex 1 is therefore the result of the updating of the last draft version proposed by the IWG (draft of Annex 1-version 12 published on 19 February 2020) on the basis of comments made by pharmaceutical industry associations.
Within the inter-associations group, A3P has contributed significantly to the consultation process through the Annex 1 CIG composed of industrial experts and suppliers by communicating their comments and proposals to the EMA in response to the Concept Paper published in 2015, to the draft version of December 2017 and finally to version 12 of February 2020.
Of the various changes observed in the successive drafts and in the final version of Annex 1, the section on Barrier Technologies (BT) in Chapters 4.18 to 4.22, has been significantly modified and strengthened relative to the last official version of 2008. In addition to the expansion of BT isolator technology with the introduction of RABS, these chapters introduce updates relative to industry practices, as well as new requirements some of which may have a significant impact on manufacturers.
This article aims to point out and comment on the changes in the final version of Annex 1 relative to draft version 12 (used for a long time as a working basis to anticipate the changes and new regulatory requirements) for Barrier Technologies and to take stock of the operational responses possible that meet the new specific requirements of BT, notably through proposals made by the A3P Annex 1 CIG.
1. Promotion of Barrier Technologies for aseptic processes
Chapter 4.3 of the final version of the new Annex 1 clearly recommends the use of BT in aseptic processes. This chapter has remained identical to the text of version 12.
4.3 Restricted Access Barrier Systems (RABS) or isolators are beneficial in assuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.
The A3P Annex 1 CIG had however proposed an alternative text to take account of the situation on many sites that use conventional A/B zones:
When designing new processes/manufacturing lines or revamping existing ones, Restricted Access Barrier Systems (RABS) and isolators should be preferred in order to minimize the microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Alternative approaches to the use of RABS or isolators should be justified.
In the 2022 version of Annex 1, there is no clear explanation of how manufacturers can justify the maintenance of conventional A/B zones, but it may be thought that any new project / new line or major modification of existing lines without evolving in the direction of BT or any other system offering the same level of Sterility Assurance (closed system, robotization, etc.) could be called into question during inspections or change requests / notification of health authorities.
In view of future GMP inspections which will be based on the new version of Annex 1 (binding date of implementation: 25 August 2023 except for the requirements of Chapter 8.123), it thus seems risky for manufacturers not to prepare short/medium-term investment plans to demonstrate the commitment of Management to the reinforcement of staff/product segregation for existing conventional lines and to investment to move towards BT for aseptic processes.
Chapter 8.9 (Aseptic Processing section) strengthens the requirements for the use of BT to reduce the need for critical interventions in grade A zones and to minimize the risk of contamination. Robotics and process automation may also be considered to eliminate direct human critical interventions (for example, dry heat tunnel, automated lyophilizer loading, sterilization in place).
2. Changes to chapters on Barrier Technologies (Chapters 4.18 to 4.22)
The final version of Annex 1 covers the GMP requirements for BT in 5 chapters (4.18 to 4.22), while version 12 covered them over 7 chapters (4.18 to 4.24). Although the requirements remain globally the same, there is now a clear distinction between RABS and isolators (recommendation formulated by the A3P Annex 1 CIG and therefore taken into account by the IWG).
2.1 Introduction on BT and risks associated with incoming/outgoing transfers of components and equipment
Discussion
The final version of Annex 1 emphasizes the contamination risks associated with incoming/outgoing transfers of equipment from the surrounding area to the grade A critical zone.
Multiple transfer systems adapted to RABS and especially to isolators are available according to need (RTP® systems, transfer isolators, decontamination airlocks, VH2O2 tunnel, E-Beam, NTT, Component Processing System …..). These systems must:
- be subject to a risk analysis with respect to their design and their adaptation to processes and needs and to a robust qualification consistent with the results of the risk analysis,
- be controlled via use and maintenance procedures that allow for control of the risks associated with their use (for example control of the “Ring of Concern” by prior decontamination of the Alpha/Beta part seals of DPTE® systems before they are connected),
- be the the subject of staff training /qualification in all of these risks.
2.2 Design of RABS and isolators
Discussion
RABS and isolator technologies are clearly differentiated in the 2022 version, reducing the risks of confusing these two technologies. For closed isolators, a unidirectional flow is required when critical operations are taking place (for example aseptic filling).
2.3 Classification of the surrounding area and Risk Analysis
Discussion
The final version of Annex 1 differentiates clearly between isolators and RABS with regard to classification of the surrounding area (a single, better structured chapter) and adds specific requirements with regard to prevention of contamination of the critical zone of isolators.
- Siting open isolators in grade D zones is no longer permitted, only grade C (as a minimum) is now authorized, which is also now the standard normally applied in the industry for production isolators (particularly for aseptic filling).
- The classification of the surrounding area must be justified by a risk analysis taking account of the contamination risks (microbiological and particulate) posed by equipment that enters isolators via transfer systems and by considering all sources/ potential entry routes of contaminants into “open” isolators. The transition to a grade C minimum instead of grade D as previously authorized allows better control of environmental conditions and of particulate/microbiological contamination around isolator entry/exit points through the following elements:
- Monitoring of environmental conditions by a more intensive monitoring plan (min twice a week for a grade C instead of once a month for grade D),
- Better controlled entry conditions for staff and equipment (design of staff and equipment airlocks and staff clothing that provides greater coverage),
- Increased frequency of cleaning and decontamination of the surrounding area.
- The new version of Annex 1 lists more precisely the points to be considered for risk analyses for the purposes of the Contamination Control Strategy (CCS) for the use of isolators, in particular the potential risks associated with the loss of integrity of glove/sleeve assemblies and the consequences for the critical zone environment and products. In terms of operational response, manufacturers should have an effective overall management program for glove/sleeve assemblies covering:
- the definition of materials (type and thickness),
- the justification of their positioning on the isolator to guarantee access to all equipment without constraint,
- the methods and frequency of cleaning/decontamination, microbiological tests and integrity tests,
- staff training to raise awareness to the risks of using gloves and the performance of visual inspections to detect holes in gloves,
- a decision flow chart in case of loss of integrity taking account of the time of detection (before, during or after a production campaign).
- The risks associated with maintenance or set-up operations between campaigns are also mentioned: in terms of operational response, risks must be controlled by clear organizational rules, a minimum opening time for isolator doors, specific more protective clothing if operating inside the isolator to minimize the input of particles and dirt that could affect the efficacy of the bio-decontamination cycle, maintenance of ventilation to sweep the critical zone during machine assembly (if the system allows it).
- Annex 1 specifies the necessity to check air flows at the interfaces of isolators “open” to the surrounding area to demonstrate the absence of retrograde contamination. In terms of operational response it is appropriate to perform these tests at the low differential pressure limits between the isolator and the surrounding area to correlate the pressure alarms with the protection of the critical zone particularly in dynamic mode (potential impact when taking out product units).
- Annex 1 does not distinguish between isolators used for sterility tests and production isolators. Consequently these laboratory isolators with an essentially “closed” design could be sited in a minimum grade D environment. Currently, other regulations (PICs, USP) do not impose a strict classification of the surrounding area for these isolators but nevertheless recommend limiting access to only persons carrying out control operations, having a sufficiently spacious area to authorize transport and movement of connected equipment, controlling temperature and humidity particularly during isolator decontamination phases. Environmental monitoring of the area is also not a requirement.
- Clarification by the EMA or the PICs of the classification of the surrounding area for sterility test isolators is considered necessary.
2.4 Characteristics – Integrity of glove/sleeve assemblies and barrier systems
Discussion
As for previous chapters, the final version of Annex 1 differentiates between the requirements for glove integrity tests for isolators and RABS and clearly distinguishes glove/sleeve assembly tests, periodic integrity checks and isolator leak rate. This revision corresponds to the recommendations formulated by the A3P Annex 1 CIG in response to version 12.
- It was effectively necessary to not require integrity tests by physical testers at the start and end of each batch, specifically in campaign mode (several batches) given the design of some equipment. In fact, positive pressure integrity testers (most used by manufacturers) require inflation and complete extension of the glove and the sleeve (if applicable) to obtain a reliable test result. In this case, these tests can only be performed when the isolator doors are open. On the other hand, the use of such a system during production could entail a risk of contamination of the grade A zone if a glove is not intact. The use of negative pressure systems allows an integrity test to be run during the campaign, as the gloves and sleeves are tested by being directed (extended) towards the outside of the isolator. These systems nevertheless offer lower sensitivity than positive pressure systems.
- In order to provide a high level of confidence in the integrity of glove/sleeve assemblies for the whole duration of the production campaign, these physical tests should be combined with regular visual inspection (on each use) by staff who have received awareness-raising and training in the detection of holes in gloves and sleeves. The duration and intensity of the inspection are to be adapted to the production context:
- Complete, meticulous inspection (in the order of several minutes) during the preparation of the isolator before decontamination, localized inspection (fingers of glove/palm) (in the order of several seconds) after each use,
- Specific inspection after operations that could affect glove integrity.
- It was aIso necessary to differentiate glove integrity tests from the periodic check of the integrity and the acceptable leak rate of the barrier system. Open isolators at positive pressure are leaky by design, maintained in overpressure monitored continuously. The risk of contamination of the grade A environment is better controlled, but a periodic check (annual /six-monthly maintenance) of the leak rate is nevertheless required to check that no deviations are present and is necessary in the event of an operation on the equipment and at filling machine/isolator interfaces.
- Annex 1 specifies the requirements for glove integrity checks for RABS and seems to prefer visual inspection on each use. Integrity test requirements are more open to interpretation and allow manufacturers greater freedom of implementation with respect to the test location (online/offline with the risk and constraints of introducing a tester into grade B).
- Annex 1 repeats the requirements for sterilization/decontamination of RABS gloves described in version 12 and adds a requirement for decontamination of these gloves when they are exposed to a surrounding grade B area.
2.5 Cleaning and bio-decontamination
Discussion
The different requirements for the decontamination processes of isolators and RABS remove the ambiguity of version 12 regarding automation of the process and its possible control for isolators, while for RABS this process remains largely manual.
- Annex 1 confirms the necessity for effective and validated cleaning prior to any bio-decontamination of surfaces with hydrogen peroxide to eliminate all residues that may produce an inhibitory effect. The “weaknesses” and limits of hydrogen peroxide have been widely commented on by the authorities (VHP (Vapour Hydrogen Peroxide) Fragility – MHRA Inspectorate – April 2018) and appropriate operational responses have been provided by different associations (PHSS Clarity of GMP Guidance notes / Assurance of sterility in Aseptic manufacturing of surfaces that contact product contact parts e.g. Stopper contact surfaces. Relates to MHRA Blog on fragility of VHP (2018), PDA Points to consider for the aseptic processing of sterile pharmaceutical products in isolators (2020)).
- A specific requirement has been added for the extension of gloves and separation of the fingers of gloves in order to ensure complete contact with the sporicidal agent during surface bio- decontamination in isolators. In terms of operational response, manufacturers should supplement this requirement by defining a minimum load in the isolator during bio-decontamination in order to eliminate hidden surfaces that might be discovered during the campaign. Steam sterilization is required for parts in indirect and direct contact with the product (excluding Single Use Systems) and for all compatible equipment that may be transferred in a secure manner into the working isolator after bio-decontamination.
- Hidden surfaces (surfaces not exposed to the decontaminating agent) that may potentially be discovered during production campaigns should be identified, be subject to a risk analysis and prior decontamination (manual) with a sporicidal agent before launching the decontamination cycle. A continuous improvement plan should also allow these hidden surfaces in critical environments to be eliminated.
3. Chapter 5.5 on the sterilization of critical parts in direct and indirect contact
Much as the steam sterilization (essentially) of the equipment parts in direct contact with the solution/product (pumps, needles, filling pipes…) appears obvious to manufacturers, the sterilization of parts in indirect contact (bowl, conveyor, feed hopper, components in contact with stoppers / piston seal / etc.) may represent a technical or organizational constraint for old isolator installations. These often imposing equipment parts (stopper bowl) may be particularly difficult to disassemble, wrap, handle while complying with the EHS rules specific to the company, and difficult to reassemble while avoiding any recontamination. These activities may also necessitate additional adjustments during production with the gloves and therefore potentially generate integrity breaches. Nor are equipment flows and autoclave capacity necessarily anticipated to manage this new requirement. In terms of operational response, manufacturers must initiate a risk analysis to reinforce and validate their cleaning practices in particular, prior to robust surface bio-decontamination. If possible equipment modification should be initiated to move towards the disassembly of parts in indirect contact, cleaning and steam sterilization offline, then reassembly in a controlled environment (bioburden and particles) before decontamination of the isolator.
By design, the new installations must incorporate technical and organizational adaptations that meet this requirement. Different operational options are suggested in the PDA document “Points to consider for the aseptic processing of sterile pharmaceutical products in isolators (2020)”.
Conclusion
Annex 1 version of August 2022 clarifies the requirements set out in draft version 12 for Barrier Technologies, distinguishing between RABS and isolators. WhiIe most of the requirements are already well understood and applied by manufacturers, Annex 1 nevertheless reinforces several points that may impact some installations:
- classification of the surrounding area as grade C minimum for open isolators,
- sterilization of surfaces in indirect contact with products,
- the necessity of reinforcing and validating the cleaning of all surfaces before decontamination with the sporicidal agent.
Finally, we may regret that Annex 1 does not make a distinction for the BT of conventional zones as regards requirements for environmental controls or the simulation of aseptic filling. The exclusion of staff from the critical zone in isolators considerably limits the risk of contamination and it would have been desirable for Annex 1 to offer the possibility of adapting the environmental controls program (frequency) via a risk analysis.
Acknowledgements
The author thanks the members of the A3P Barrier Technology CIG for their active contribution to the validation of this article.
Glossary
EMA European Medicines Agency
CIG Common Interest Group
GMP Good Manufacturing Practices
MHRA Medicines & Healthcare products Regulatory Agency
NTT No Touch Transfer
PIC/S Pharmaceutical Inspection Co-operation Scheme
PUPSIT Pre-Use Post Sterilization Integrity Testing
RABS Restricted Access Barrier System
BT Barrier Technology