EU GMP Annex 1 Aseptic Process Simulation (APS).

October 2023

La Vague n°79

Special A3P Congress 2023 : Annex 1, Environmental and process monitoring

✻

EU GMP Annex 1 (2022): Aseptic Process Simulation (APS). New challenges for the pharmaceutical industry?
How to evaluate pyrogenic risk in an injectable pharmaceutical process? Decision-making tool
Introduction to the dual chamber systems (DCS) filling process
Implementation of decontamination processes in the pharmaceutical industryentation of decontamination processes in the pharmaceutical industry
Container Closure Requirements in the New EU GMP Annex 1 - Enabling Compliance with a Holistic Science-Based Approach
Improving the efficiency & reliability of AVI qualification: Determining the optimal number of runs with the KNAPP method
Case Study: Effective Sterile Powder Transfer for Parenteral Drug Products

EU GMP Annex 1 (2022): Aseptic Process Simulation (APS). New challenges for the pharmaceutical industry?

It is almost 12 months since Annex 1 “Manufacture of Sterile Medical Products” was published. The date of application of this text (August 25, 2023) officially heralds the start of a new era to help authorities in applying the European regulation (and very probably even beyond its scope).

This new text without any doubt provides additional and more accurate information. It takes account of technological changes relative to the previous text (2007 version of Annex 1). Through its structure and its organization in separate chapters, the clarity of the text has been considerably improved.

Nevertheless, questions remain on several issues regarding its application. For this article, we wish to provide a specific reflection on Chapter 9 and more specifically on the Aseptic Process Simulation (APS) part also known under the name Media Fill Test (MFT).

1. A change in the text that has been well received

The content of Annex 1 has changed significantly quantitatively and qualitatively. While the previous version covered expectations regarding APS/MFT in 7 sections (7. & 66. A 70.), the latest 2022 version contains around 5 pages for 18 sections (9.32 to 9.49). Other requirements are also visible in other chapters such as 7.4 Personnel “for unsupervised access”, 8.16 for “the list of interventions evaluated via risk analysis and APS” or 8.139 relating to Single Use Systems for which critical operations such as assembly or connections must be verified during APS. These developments of the text provide clarification, a directive and principles whose added value is undeniable. APS is and will very certainly remain a Sterility Assurance system that will be scrutinized attentively during future inspections. The purpose of this article is to examine the changes made and to assess whether certain specific points could present new challenges for manufacturers of sterile products which have an aseptic process, when they are implemented. The text provides the essential principles for the preparation and performance of APS. However, the APS remains a challenge as it is a complex process, whose principles must be specifically adapted to the reality of a manufacturing process. This adaptation must in particular consider the barrier technology used, the organization of production (campaign, in several shifts), the components used in the process and the other specific elements that contribute to the routine sterility assurance of processes. This is why the quality of the documentation developed for the APS must be clear, robust and well supported to ensure a scenario and execution that meets the many expectations of the regulations.

2. Careful documentation of the APS is essential

Although the documentation associated with the APS is at the discretion of each manufacturer, it is recommended that a comparison be made between the commercial process and the APS/MFT comprising of a risk analysis including the justification of all parameters selected for the final validation exercise scenario. Thus, quality documentation should be composed of: the site procedure for the principles for preparing and executing an APS, a justified risk analysis of the production process (routine versus APS), a protocol for conducting the APS, an appropriate and specific batch record, site validation documentation in the form of a “Master Plan” and a report documenting and ensuring that APS acceptance criteria for validity and compliance are achieved.

3. New challenges for aseptic process simulation ?

APS is one of the key processes which demonstrate the performance of a production process with regard to sterility assurance. Preparing and implementing the APS involves many departments on a production site, and the principles defined for its execution are the fruit of collective and multidisciplinary reflection. It consists in finding the right compromise between regulatory compliance, the level of quality assurance expected for the APS and the level of industrial performance that complies with the expectations of the company. For this article, we selected three sections of Annex 1 taken from the APS part. Their principles, depending on interpretation, could have consequences for the interpretation of regulations versus the choices made by manufacturers.

The three sections selected from Annex 1 are: section 9.36xii and xiii (APS campaign including duration); section 9.38 (Consideration given to performing an APS after the last batch prior to shut down); section 9.39 (APS for Manual Aseptic Operation).

9.36 xii & xiii : APS campaign

xii. “…the process simulation so that it simulates the risks associated with both the beginning and the end of the campaign and demonstrating that the campaign duration does not pose any risk.”

xiii. “The performance of “end of production or campaign APS” may be used as additional assurance or investigative purposes; however, their use should be justified in the CCS and should not replace routine APS. If used, it should be demonstrated that any residual of product does not negatively impact the recovery of any potential microbial contamination”

This section 9.36 as a whole provides real added value when developing an APS protocol. Points xii and xiii, the last two in this section, potentially impact the APS structure, particularly when these are conducted using barrier technologies (mainly isolators) whose organization in campaign-mode is a widespread principle. Considering the requirements of these two points from Chapter 9 including the requirement which consists in covering interventions and associated risks at the beginning of the campaign, and up to the end of the campaign: what would be an appropriate strategy for initial validation and periodic revalidation for the maximum duration of the campaign?

A commercial manufacturing campaign corresponds to a series of batches of the same product in an established and validated period of time.

Definition from Annex 1 :

“A manufacture of a series of batches of the same product in a given period of time with strict adherence to established and validated control measures“.

In the context of an APS conducted in an isolator, validation of the aseptic process must provide guarantees for the content of the entire campaign namely:

the associated risks at the start (items sterilized according to the requirements of section 5.5 of Annex 1 and/or decontaminated by VHP) whose risks correspond to the assembly or set-up or the machine settings, before and after the bio-decontamination cycle;
then the performance of interventions (section 9.34 inherent & corrective interventions, in a representative manner and according to their level of risk);
up to the end-of-campaign operations;
while demonstrating that the duration does not pose a specific risk to the aseptic process.

One of the questions that we ask is that of the possible interpretation of the need to conduct each APS for the maximum campaign duration for a barrier technology of the isolator type?

Isolators are designed to present the maximum level of Sterility Assurance during operations and as they are intended to operate in campaign mode, it would be a pity to lose a competitive advantage because of the use of a barrier technology that is more effective than others with regard to Sterility Assurance. The repetitions of APS that would be performed in accordance with maximum campaign duration could have significant consequences for the immobilization of filling machines in order to perform these APS (over campaign durations of several weeks for example) and therefore for production volumes of sterile medicines, going as far as impacting their availability to patients. It is all a question of correctly assessing the industrial issues against the quality level required.

4. How best to respond to this challenge?

The number of possible options or opinions on the subject are assuredly multiple. The use of Quality Risk Management (QRM), a major principle present since the introduction of Annex 1, is a valuable tool that we recommend using in our case. Firstly, the objective and the context in which the APS is performed could be taken into account: initial validation or periodic revalidation?

In the case of an initial validation (new line for example): because of the absence of historic data on the aseptic process, on principle three APS performed over the maximum campaign duration defined as routine (= maximum number of teams/shifts) would be necessary.
For a periodic revalidation (every 6 months): the nature of the barrier technology and its historic performance demonstrated with regard to Sterility Assurance are factors which could be taken into account to ensure on the one hand a robust APS design, while not significantly penalizing industrial performance by systematically performing an APS of maximum campaign duration every 6 months, on the other hand. It is without doubt possible, for example, to prepare an APS scenario for isolators which covers the associated risks at batch start-up, with the number of interventions at campaign scale and therefore to provide a worst case for revalidation with a sufficiently long filling time without however using the maximum campaign duration for each performance. Revalidation with a maximum campaign duration would be subject to periodic requalification. This frequency would be defined and documented in the CCS then would be based on objective historic data expressing the performance of the aseptic process in terms of Sterility Assurance. Finally, a minimum periodic revalidation frequency of maximum campaign duration would be defined and obligatory, regardless of the historic performance of the process in question.

Without any doubt, this subject merits in-depth study and recommendations agreed by manufacturers and health authorities to clarify validation practices on this point.

9.38 “Consideration should be given to performing an APS after the last batch prior to shut down, before long period of inactivity or before and decommissioning or relocation of a line.”

Annex 1-9-38 advances a logical principle; the word “consideration” is appropriate in this section 9.38. However, its interpretation introduces a risk associated with the different situations described in the same phrase

“Before decommissioning or relocation of a line“, in these situations the performance of an APS seems unavoidable and to be a systematic requirement.
“Prior to shut-down, before long periods of inactivity” are situations for which the term “consideration” takes its full meaning, and which require according to circumstances a justified and documented decision following a risk analysis regarding the specific situation in question. It is therefore important that this section of Annex 1 is applied according to the context using QRM principles.
For this section, the production context and the associated risk may lead to different requirements for the performance of an APS. For this section the use of QRM takes on its full meaning.

9.39 “Where manual (e.g; aseptic compounding or filling) occurs, each type of container, container closure and equipment train should be initially validated with each operator participating in 3 consecutive successful APS and revalidated with one APS approximatively every 6 months …”

In its basic principle, this section seems to make good sense for risk control and management! Nevertheless, adapting this revalidation/operator qualification frequency according to the aseptic process type remains a regulatory novelty.

In this case, is the technology type (for example, barrier technology) taken into account in establishing this frequency? Does this requirement apply in the same way to a manual aseptic process performed without a physical barrier or performed in an isolator or using a closed system? How are the robustness of process design (for example using an isolator or a closed system,…), its design and its validation / qualification strategy taken into consideration versus the potential direct impact that an operator may have on critical operations?

For a manual process which may be a formulation or a bulk process, should we not take the process design into account and particularly the type of barrier technology used (for example an isolator or a closed system) to define, according to a risk analysis, the frequency of operator requalification? Would not the opposite case be counterproductive in relation to the principles supported by Annex 1? Namely choosing the best possible design, appropriate risk management, execution supported by robust procedures, qualified staff and a monitoring process which demonstrates continuous performance at the expected level?

Conclusion

As often in the matter of sterility assurance, nuances of interpretation sometimes cause a major impact. The APS is, on several points, an example of this, which was addressed in this article. A new version of the regulation has arrived. It unambiguously provides great clarity and added value, and its interpretation is underway. There is still time to ask questions, to reflect and above all to provide information, in order to apply this new regulation pragmatically on the basis of the understanding of processes. And in this way to guarantee our patients high-quality sterile medicines derived from competitive industrial production.