ISPE Works with Associations on Annex 1

Implementation Timelines
ispe.org/pharmaceutical-engineering/ispeak/ispe-works-associations-annex-1-implementation-timelines

iSpeak Blog

27 May 2021

Jean-Francois Duliere

Christopher John Potter, Ph.D.

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.

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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),

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 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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View Regulatory Comments

About the Authors

Jean-Francois Duliere

Pharmaceutical Senior Expert, Consultant, Chair ISPE France Affiliate

Jean Francois Duliere is a Pharmacist by education. Jean Francois

started his professional life 20 years in pharmaceutical industry Quality
Control, Production in various positions...
More
Christopher John Potter, Ph.D.

CMC Pharmaceutical Consultant

Chris Potter graduated from the University of Exeter with a degree in

chemistry and completed a PhD at Imperial College London University
in organic chemistry...
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Thomas Zimmer, PhD

VP, European Operations

ISPE

Thomas Zimmer, PhD, is ISPE Vice President, European Operations. He

previously was Senior Vice President of the Corporate Division, Safety, Quality &
Environmental Protection at...
More
Regulatory

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