PDA Letter Article

Key Takeaways from the 2022 PDA Annex 1 Workshop in Dublin

by Eilish Kelly and Patrick Nieuwenhuizen, PharmaLex

Following publication of the approved revision of the European Union (EU) Annex 1: Manufacture of Sterile Medicinal Products in August 2022, the timing of the “2022 PDA Dublin Annex 1 Workshop” held 11 November was very opportune. Industry leaders, experts, regulators and pharmaceutical company representatives gathered to review the challenges and possible solutions for the compliance implementation of the new revision to Annex 1. The workshop sessions were very successful based on the length of discussions and information shared among peers.

The issues included:

  • Contamination control strategies not being fit for purpose
  • Lack of clarity on container–closure integrity testing requirements, and finding the balance as to when risk assessments are required
  • Tools to use when conducting these assessments
  • Establishing when airflow-visualization studies or smoke studies are required

Contamination Control Strategy

Following the revision of Annex 1, we understand that a contamination control strategy (CCS) and quality risk management (QRM) go hand in hand and are synonymous. Therefore, a good practical understanding of QRM is key to creating a successful CCS. Similarly, knowledge management is a very important factor within a company to ensure that the rationale and justification are captured for the design, control and operation of the process and facility in all its elements. Hence, the use of knowledge and data are of paramount importance as these provide the scientific evidence required to support your CCS.

The CCS summarizes all elements that are in place regarding the underlying documents. The monitoring process is the listening system and shows that all elements are still operating as designed.

CCS governance is another key factor; however, who is responsible for maintaining the strategy? Each organization should establish this to ensure the CCS’s successful implementation and ongoing maintenance. It is imperative that the entire team takes ownership of the implementation of the strategy, as it is of paramount importance that the CCS is maintained as a live document and is not left sitting on a shelf to tick a regulatory compliance box. Furthermore, The CCS must drive continuous improvement and, therefore, must be periodically reevaluated and adjusted where necessary, particularly when the underpinning risk assessment has been revised based on the change management and deviation processes.

Sterilization of Indirect Contact Parts

Another topical subject discussed at the event was the sterilization of indirect contact parts. Although vaporized hydrogen peroxide (VHP) is a robust process, EU regulators do not view VHP as a sterilization process. It is not a silver bullet, and many things can still go wrong. Additionally, as VHP is nonpenetrative, occluded surfaces pose a risk for effective decontamination. Therefore, materials are expected to be cleaned and sterilized before the decontamination of VHP in an isolator.

Another question was asked about what can be done with indirect product parts that cannot be disassembled and put through the sterilization process. It may be the case that a redesign of the unit is required to allow an engineering solution for the removal and reassembly of indirect product contact parts such as stopper bowls and tracks. Companies now need to consider how to bring their technology up to the required standards to meet the expectations of Annex 1.

To prevent unwanted contamination from disassembling and reassembling parts, the packaging, storing, transporting and reinstalling of parts must be considered while applying the principles of QRM. We must be present to assess how the process is executed and not rely solely on procedural checks to ensure the correct handling of such materials. It is important to engineer out as much as possible and to ensure Grade A continuity.

Cleanroom Practices

Cleanroom practices and the importance of a strong quality culture concerning good cleanroom behavior are key elements in implementing the revised Annex 1 guidelines. As industry leaders, we need to ensure personnel working in cleanroom environments understand what they do, how it impacts product quality and, ultimately, how it affects patient safety. For example, are personnel aware of the risks associated with the manufacturing steps they are involved with? Educating people empowers them to embrace this responsibility, and selecting personnel with the right attitude engages teams and promotes good behavior. Therefore, it is essential we embed a healthy quality culture in this environment rather than the more traditional approach of relying on monitoring alone, which is problematic with limited effect.

From a regulatory perspective, when engaging with an inspector, personnel must display a deep understanding of process knowledge and the impact of their role and its importance.

Airflow-Visualization (Smoke) Studies

Airflow visualization or smoke studies and their requirements are described in the revised Annex 1. The expectation for Grade A areas is that these studies are mandatory, demonstrating unidirectional airflows, and that first-air airflows are not obstructed due to equipment design or operator interventions.

Grade B studies are required at potential ingress points (i.e., mouseholes) to demonstrate that there is no ingress into the Grade A area or from lower-grade cleanrooms into the Grade B areas. Smoke studies are not required for Grade C and D cleanrooms. However, the data can be useful to identify locations of increased risk for accumulation of contamination due to inadequate airflows or obstructions caused by equipment.

As expected, the regulator’s perspective focuses on the areas of the highest risk. If an area is found to have poor environmental monitoring data, however, there may be a request to demonstrate that ventilation is adequate, and smoke studies may be appropriate to demonstrate compliance in this case.

For standard Grade C rooms, where normal activities occur and there is relatively low risk, there is no point in conducting smoke studies as no sterile product is in the area.

Implementation of Annex 1 by Contract Manufacturing Organizations

A highly discussed point at the PDA event was the implementation of Annex 1 by contract manufacturing organizations (CMO). How can one manage compliance and maintain oversight? A huge challenge encountered by the industry is how to obtain the information required to ensure the CMO implemented the revised Annex 1 requirements. Risk assessments are often confidential due to other clients’ involvement, and those provided with redacted information are often almost useless. In cases where a company has only one or two manufacturing slots with a CMO yearly, it can be very hard to influence the CMO to share this information. In addition, these companies often do not have the power other larger clients may have to implement the required changes.

As we know, the qualified person (QP) must have sufficient oversight of drug substance, drug product and packaging activities, even when multiple sites are involved. Moreover, per EU Annex 16: Certification by a Qualified Person and Batch Release, it is the QP’s responsibility to ensure there is evidence that Annex 1 requirements are in place and that there is knowledge of all activities performed at the CMO.

It is important to ensure that discussions between the contract-giving firms and CMOs remain fully transparent and maintain an open relationship so that issues are communicated promptly. A QP does not have to be on site all the time; however, they should evaluate the quality culture at the CMO and assess if it meets the expectations of the company the QP is representing.

In relation to aging facilities, such as technologies and utilities at CMOs, it can be challenging to implement Annex 1 requirements. Many CMOs in Europe have not implemented pre-use/post-sterilization integrity testing (PUPSIT), which is the norm in Ireland and the United Kingdom. It is now described as a requirement in the revised Annex 1. Educating the CMO about updated regulations and pointing out the risks of noncompliance with these regulations are keys to success.

Container–Closure Integrity

Most companies still use a lifecycle approach to demonstrate container–closure integrity (CCI) for units other than closed by fusion. The lifecycle approach uses data from the initial validation, transportation, equipment (capper) set-up and stability testing. Some companies are moving to in-line/off-line periodic CCI testing of vials or syringes at set intervals. Other organizations use periodic torque-testing or residual seal-force as additional information to ensure CCI.

It is still unclear if regulatory bodies expect CCI testing for units other than those closed by fusion as part of batch-release testing. Ireland’s Health Products Regulatory Authority indicated that regulators are currently not looking specifically for batch-by-batch testing and still accept the lifecycle approach. For marketing authorization holders, it is important to know what is registered in the marketing authorization and to adhere to it. USP General Chapter <1207> Package Integrity Evaluation—Sterile Products and PDA Technical Report No. 26 (Revised 2008): Sterilizing Filtration of Liquids provide overviews of methods available and guidance for the selection of CCI. Potential methods to consider are headspace analysis and high-voltage testing. It is the responsibility of the company to assess what the most suitable option is based on product knowledge and primary packaging configuration. There is an expectation that companies will move to more detrimental methods as more technologies become available.


Although companies have many questions about implementing the requirements of the revised Annex 1 and are still experiencing challenges at their sites, many are progressing through the gap-analysis process and planning remediation activities for identified gaps. In addition, most companies indicated a medium level of compliance with the updates and are ironing out the logistics to reach the highest possible level of compliance. It will be interesting to see how compliance to Annex 1 is assessed by regulators in 2023.

About the Authors

Eilish KellyEilish Kelly is a Manager Consultant at PharmaLex; she has been in the pharmaceutical industry for over 20 years. Kelly has worked for several licensed global pharmaceutical and biopharmaceutical companies across a variety of platforms, including biologics, solid oral dosage and API manufacture. Also, she has extensive experience in quality management systems, quality control systems, GMP manufacturing, equipment and utilities validation, manufacturing support, QP batch release and data-integrity controls.

Patrick NieuwenhuizenPatrick Nieuwenhuizen is a Consultant Director at PharmaLex with a microbiology and sterile-manufacturing background; he has more than 25 years of experience in the pharmaceutical industry. Nieuwenhuizen has worked for several global pharmaceutical and biotechnology companies across various platforms, including biologics, sterile fill finish and solid oral dose.