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ISPE Works with Associations on Annex 1 Implementation Timelines

Jean Francois Duliere
Christopher John Potter, PhD
Thomas Zimmer, PhD

ISPE continues to work with a group of industry associations to assist the European Union (EU) and the European Medicines Agency (EMA) with implementation of revision of Annex 1, Manufacture of Sterile Products. Annex 1 is a key document in "The rules governing medicinal products in the European Union", which contain guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use. The current Annex 1 is being reviewed to facilitate implementation of the principles of relevant ICH guidelines, to extend the underlying concepts to include new areas of technology and processing not previously covered and also to clarify areas that have been highlighted as ambiguous due to the age of the document.

In order to maintain the global alignment of standards, achieving at the same time assurance for the highest quality, the Annex 1 Working Group (WG) is made of experts from the European Commission, the World Health Organization (WHO) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S).

ISPE provided detailed, justified comments in July 2020 directly to the Working Group as an identified stakeholder in a targeted stakeholder consultation. In parallel, ISPE worked with a joint group of industry associations to provide some important common points and these were provided to the EU and EMA also in July 2020. The joint industry association group, which was originally formed in 2013 to address drug shortages, consists of 12 associations: A3P Association, AnimalhealthEurope, Association of the European Self-Medication Industry (AESGP), ECA Foundation, European Federation of Pharmaceutical Industries and Associations (EFPIA), European Industrial Pharmacists Group (EIPG), European QP Association (EQPA), ISPE, Medicines for Europe, Parenteral Drug Association (PDA), Pharmaceutical and Healthcare Sciences Society (PHSS) and Vaccines Europe, with PDA acting as current rapporteur. The associations work in the spirit of cooperation to assist EMA, PIC/S and WHO with gathering, analysis and communication of input from the sterile healthcare community and offer to work with EMA to further the development of the guidance.

The joint industry associations had a meeting in January 2021 with the representatives of EMA GMP/GDP inspectors working group and among the topics of interest was information on progress of finalization and implementation of Annex 1. Discussion indicated that the Annex 1 working group had received about 2000 comments on which they were working in cooperation with other regulatory partners such TGA, Australia and Health Canada. EMA was considering a normal implementation period of 6 months after issue of Annex 1 revision, however, representatives from the joint industry associations voiced concerns that some of the new requirements in Annex 1 may require longer implementation times due to the need to update and change facilities, or in some cases, to develop or adapt existing technology to ensure compliance. EMA requested that the joint industry associations produced justified examples of implementation challenges with more detailed rationale to explain why implementation times could be greater than 6 months.

Examples of particular implementation challenges in the latest version of the draft Annex revision are:

  • Annex 1 Section: 8.21 Performing 100% integrity testing of containers closed by fusion, e.g. Blow-fill-seal (BFS), Form-Fill-Seal (FFS), Small and Large Volume Parenteral (SVP & LVP) bags, glass or plastic ampoules
  • Annex 1 Section: 4.23 For both remote access barrier systems (RABS) and isolators, performing using a methodology demonstrated to be suitable for the task and criticality, leak testing at defined periods, at a minimum at the beginning and end of each batch.
  • Annex 1 Section: 8.88 The requirement for non-destructive pre-use and post-use integrity testing (PUPSIT) of sterilization filters
  • Annex 1 Section: 6.22 Detecting any leaks from in lyophilizers for equipment that currently does not have leak detection built in.
  • Annex 1 section 8.112; “Lyophilizers that are manually loaded or unloaded should normally be sterilized before each load’, however, many companies currently are operating without sterilization between each batch based on their validation work.

Some of these requirements are new or have clarified interpretations and it is anticipated that they will present challenges in their implementation, to both individual companies and the suppliers/contractors that support them. In these cases, longer timelines will be needed for completion to allow for the required activities such as:

  • identification of the potential solutions,
  • technical evaluations,
  • execution of studies to support the planned change,
  • re-engineering of existing manufacturing processes/facilities,
  • actual modification of facility/equipment,
  • purchase/receipt/installation of equipment,
  • qualification/validation of changes,
  • procedure changes (creation/revision),
  • development and delivery of training to ensure procedural control measures are followed, and
  • potentially submission for regulatory approvals.

In addition, for some of the requirements the technology is not yet available or reliable and new technology will need to be developed (e.g., 100% integrity testing of filled flexible bag containers in an automated line). In these cases, it will be dependent on when the new technology becomes available which may require significant time to develop.

Compounding these factors is the COVID-19 crisis that is currently impacting the Pharma industry as a whole, not just vaccine and treatment manufacturers.

Based on these considerations, the industry association coordination group has requested in a formal response to the Annex 1 revision working group that a phased approach is taken to the implementation of the revised Annex 1. An approach that includes a 12-month rather that 6-month general implementation period for items that require minor to moderate changes and an understanding that specific changes may require longer periods of time to implement, for example changes:

  • that require specialized equipment,
  • that require significant engineering or facility redesign work,
  • to the manufacturing process,
  • that require extensive studies to support, or
  • with a significant impact on the manufacturing capacity that could lead to supply disruptions
  • that require regulatory approval

A clear expectation would be needed that the justification for individual items requiring longer implementation times, including any risk mitigation steps required, be documented and supported through the contamination control strategy (CCS) document with product quality and patient (human and animal) safety and supply the top priorities.

The joint industry association provided a formal response to EMA in mid-March 2021 summarizing the implementation challenges and separately indicated that it was continuing its work to provide more detailed examples of implementation challenges and associated timelines for a few specific examples. These additional examples should be provided to EMA in May 2021

There is consensus among the associations that this Annex revision represents a great opportunity to meet a key objective of the Annex 1 revision concept paper, which is to “embrace the use of new technologies to prevent detrimental impact on product and to encourage the introduction of new technologies that are not currently covered

In conclusion, ISPE has been very active in the joint association group to encourage a justified flexible approach to implementation of Annex 1 revision justified by some realistic practical examples of implementation challenges.

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