What are the major drivers for the new Annex 1? Join us to know more about implications for Filters & Single Use. In this webinar, you will learn: • Closed Processing and Single Use Technology implementation • Points to consider using Single Use Technology • Sterile Filtration The Annex 1 “Manufacture of sterile medicinal products” of the EU GMP Guide is currently being revised. A first draft of the revised version was published in 2017 and released for public comment. The second draft as of February 2020 was open for targeted consultation via stakeholder from selected industry organisations. The current Annex 1 draft emphasises Contamination Control Strategy (CCS) multiple times and as a key consideration.

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
EU GMP Annex 1 Draft
Implication on Sterilizing
Filtration & Single-Use Systems
Somasundaram (Som)
Senior Technical Consultant
Asia Pacific
Dr. Simone Biel
Senior Regulatory Consultant

2. Agenda
1
2
3
Regulatory Framework
PUPSIT (Pre-use
Post-sterilization Integrity
Testing)
5
Draft Annex 1 - Impact of
Proposed Additional Sections
& Key Differences - Single-use
Systems
4
Conclusions
Draft Annex 1 - Impact of
Proposed Additional Sections &
Key Differences - Filtration

3. Regulatory
Framework

4. Boost Covid-19 vaccine production would not be possible without SUT
Fast Growing Biopharmaceutical Market Challenges
4
Business driver to implement SUT
 Speed to Market
 High flexibility
 Quick changeover of equipment
Ensure patient safety
 Identity
 Efficacy
 Purity

5. Sterile Medicinal Product
 subject to regulatory guidelines
 compliant filter qualification
EU GMP Annex 1 – guidance on sterile medicinal product manufacturing
Contamination Risks Throughout the Process
Sterile media filtration
 Not subject to regulatory guidelines
 BUT should require aspects of sterilizing filter
qualification

6. Sterilizing-grade designation is a functional definition
6
Sterilizing Grade Filter – Definition
EU GMP, Annex 1 draft, Feb 2020
“Sterilizing grade filter – A filter that, when appropriately
validated, will remove a defined microbial challenge from a fluid or
gas producing a sterile effluent. Usually, such filters have a pore size
equal or less than 0.22 μm”
PDA TR 26, revised 2008
A filter that reproducibly removes test microorganisms from the
process stream, producing a sterile filtrate.
FDA cGMP, Guidance for Industry, 2004
“A sterilizing grade filter should be validated to reproducibly
remove viable microorganisms from the process stream,
producing a sterile effluent. Currently, such filters usually have a
rated pore size of 0.2 μm or smaller.”
 Demonstrate removal of a
standard test organism
Brevundimonas diminuta
 At minimum concentrations
of 107 cfu/cm2
 ASTM F 838-05 is a
“Standard Test Method
for Determining Bacterial
Retention of Membrane
Filters Utilized for Liquid
Filtration”

7. Critical steps are transferred from end-user to supplier
Drug Product Manufacturing
7

8.  Risk assessment (starting point)
− Sterility/integrity
− Particles
− Process fluid interaction with SUS
 SUS supplier’s data as basic information
 Additional validation studies if required
 Supplier management
− Audit, audit reports and follow up
 Incoming control
 Transport, storage, material flow at end-user’s site
 Operator training
 Usage of SUS
 Documentation
 …
8
“Do you know what your supplier does?”
The GMP Inspector

9. Patient safety: identity, efficacy, purity
Key regulatory concerns for medicinal products
9
Market
authorization
Manufacturing
authorization

10. Ongoing consultation of new draft – global approach
10
EU GMP, Annex 1: Manufacture of Sterile Products
 1971 → ensure sterility of medicinal
products
− Since then several updates
 2017 → full review of Annex 1
− 140 companies provided more than
6200 comments
 2020 → targeted stakeholder
consultation
− 16 organisations
− WHO and PIC/S to maintain
global alignment
PIC/S, The Pharmaceutical Inspection Co-
operation Scheme
 non-binding, informal co-operative
arrangement between Regulatory
Authorities in the field of Good
Manufacturing Practice (GMP) of medicinal
products
 54 participating authorities from Europe,
Africa, America, Asia and Australia
 Mission:
lead the international development,
implementation and maintenance of
harmonised GMP standards and quality
systems of inspectorates in the field of
medicinal products.

11. Prevent any contamination in the final product
11
QRM through entire document
Key Changes
 Introduction of new sections
 Introduction of Quality Risk Management (QRM)
Principles
 Restructured to give more logical flow
 Added detail to a number of the previous sections to
provide further clarity
Annex 1 draft, 2020
https://ec.europa.eu/health/sites/health/files/files/gmp/
2020_annex1ps_sterile_medicinal_products_en.pdf

12. Established ICH Quality Guidelines
Manufacturing and Control Strategy
 ICH Q8 (R2), Pharmaceutical Development
− “Quality by Design” – understand the process and
its control early in development, based on sound
science and quality risk management
 ICH Q9, Quality Risk Management
− Systematic process for assessment, control,
communication, and review of risks to protect the
patient
− Higher risk require higher level of qualification
 ICH Q10, Pharmaceutical Quality System
− Knowledge management – systematic approach to
acquiring, analysing, storing, and disseminating
information
Quality Guidelines of the International Council for Harmonisation (ICH) Overview of a typical quality risk management process
(ICH Q9)
12

13. Keep it close and sterile
13
CCS = Contamination Control Strategy
General considerations
 “aseptic process should be clearly defined”
 “identify risks”
 “control”
 “describe”
 “document residual risks”
 “minimize contamination”
Specific guidance
 Sterile filtration and PUPSIT
 Closed processing
 Single-Use Systems

14. EU GMP Annex 1 draft (Feb 2020)
 “specific risks associated with SUS” → contamination control strategy
− Interaction with DP and SUS surface
− Integrity (“fragile”, “risk of holes and leakage”, “complexity”
− Risk of particulate contamination
 What to do?
− Supplier qualification, including sterilization verification
− Evaluation of adsorption and reactivity of product
− Verification of integrity throughout the process
− Establish acceptance criteria and incoming control procedure
− Operator training
14
Finally, regulatory expectations are formalized!
SUS in Aseptic Processing

15. Who is doing what?
Regulatory and Industry Expectations
Biosafety Seminar | 22 October 2020
Law
 Country specific drug law
Regulatory Agencies
 Provide regulations and recommendations
 Market authorization
 Surveillance
Compendia - Reference for quality control of
medicines
 Ph. Eur is legally binding
 USP standards are legally recognized
Harmonization effort
 Through consensus organizations
Industry expectations
 Interpretation and elaboration on regulatory
expectations
15

16. Guidelines on primary packaging materials and container
16
Supporting documents – Drag and Drop
Ph. Eur. 3.1.x, Materials used for the manufacture of containers
USP <661>, Plastic Packaging Systems and Their Materials of
Construction (obsolete in 2025)
<661.1>, Plastic Materials of Construction
<661.2>, Plastic Packaging Systems for Pharmaceutical Use
USP <87>, Biological Reactivity Test, In Vitro
USP <88>, Biological Reactivity Test, In Vivo
ISO 10993-xx, Biological evaluation of medical devices
USP <85>, Ph. Eur. 2.6.14 and JP 4.01 , Bacterial endotoxin
testing
USP <788>, Ph. Eur. 2.9.19, JP 6.07 sub-visible particulate
testing
<665>
Plastic components used in
manufacturing, draft 2020
First and only standard approach
on SUS component qualification

17. Interpretation of regulatory guidance and filling the gap
17
Industry Associations
BioPhorum
 Extractables & Leachables
 User requirement specification (BPSA)
 Change notification (BPSA)
 Sterile filtration (PDA), 2020
 Supply partner program
BPSA
 Particles
 Integrity
 Cell & Gene Therapy
ISPE
 Good Practice Guide: Single-Use Technology
(2019)
PDA
 TR 26, Sterilizing Filtration of Liquids
(revised 2008)
 TR 66, Application of Single-Use Systems in
Pharmaceutical Manufacturing (2014)
ASTM - Standard test methods
 Bacterial retention
 Filter integrity
 Single-use systems integrity

18. PUPSIT (Pre-use
Post-sterilization Integrity
Testing)
Applies to BOTH single and redundant sterilizing
filtration systems

19. Annex 1 to Volume 4 of EU GMP
“The integrity of the sterilised filter should be verified before use
and should be confirmed immediately after use by an appropriate
method such as a bubble point, diffusive flow or pressure hold” test.
2017 PIC/S guidelines
“The integrity of the sterilised filter should be verified before use
and should be confirmed immediately after use by an appropriate method
such as a bubble point, diffusive flow or pressure hold test.”
Draft Annex 1 (Feb 2020)
8.88 The integrity of the sterilised filter assembly should be verified by testing
before use, in case of damage and loss of integrity caused by processing, and
should be verified by on line testing immediately after use by an appropriate
method such as a bubble point, diffusive flow,
water intrusion or pressure hold test.
Regulatory PUPSIT References

20. 20
Since 1998, the EU Guidelines to Good Manufacturing Practice: Medicinal Products for Human
and Veterinary Use, Annex 1 (Manufacture of Sterile Medicinal Products) or “Annex 1” has
contained the requirement for verifying the integrity of a sterilizing grade filter before
use and after its sterilization.
The requirement remained in the 2008 revision and in the 2017 and 2020 draft revisions
to Annex 1. Concerns by European and other Health Authorities over the risk of filtration
failure resulted in an increase in enforcement of this requirement. This enforcement started
a discussion within the industry of the of the challenges, benefit, and aseptic process
related risk of PUPSIT.
The resulting debate has exposed a need for scientific evidence to support and effective
risk-based approach to PUPSIT use. To help meet that need, BioPhorum and the PDA
formed the Sterile Filtration Quality Risk Management (SFQRM) Consortium, which has been
working to provide objective, unbiased, scientific data to help guide informed decisions about
sterile filtration control measures.
PDA/BioPhorum conducted Series of Webinars in from
September 2020
PDA & BioPhorum Task Force

21. EMA response was to keep PUPSIT
• The EU’s rationale for keeping PUPSIT was offered by Andrew Hopkins, rapporteur for the
revision’s drafting group and an expert GMDP inspector with the UK’s Medicines and
Healthcare products Regulatory Agency. He said, “PUPSIT is necessary.”
• “sterilization is an aggressive process, even the irradiation mode; that filter
manufacturing is not always consistent and damaged filters can go undetected
through the manufacturing process.”
• “the argument against is that manufacturers don’t like it, that it is difficult to do such
testing.” It “has been a reality since 2007” to comply with Annex 1 and that “it is not
sufficient to say that such testing is unnecessary; rather these arguments need to be
supported by scientific rationale.”
Rationale is a scientifically and fact based risk assessment document
October 2017 PDA Meeting – Proposal to Remove PUPSIT

22. Draft Annex 1 - Impact of
Proposed Additional
Sections & Key Differences
- Filtration

23. “8.15-16 Aseptic manipulations (including non-intrinsic aseptic connections) should
be minimized using engineering solutions such as the use of preassembled
and sterilized equipment. Whenever feasible, product contact piping and
equipment should be pre-assembled, then cleaned and sterilized in place.”
8.82 “Due to the potential additional risks of a sterile filtration process, as compared
with other sterilization processes, a second filtration through a sterile sterilizing
grade filter, immediately prior to filling, should be considered as part of an overall
CCS.”
− Added explanation avoids the question of “How close is close”
- result should be focus on connections and risk of loss of sterility
− Places major focus on aseptic risk reduction (CCS) including SUS systems
Example of Additional Specific Recommendations in Draft Annex 1
Revision – 2nd SGF as close as possible

24. 8.81 If the product cannot be sterilized in the final container, solutions or liquids should be
sterilized by filtration through a sterile sterilizing grade filter (with a nominal pore size of 0.22
μm (or less) that has been appropriately validated to obtain a sterile filtrate) and
subsequently aseptically filled into a previously sterilized container. The selection of the filter
used should ensure that it is compatible with the product and as described in the marketing
authorization (refer to paragraph 8.125).
Shows what should be considered during sterilizing filter qualification but no
definition of “compatible”
8.82 “Due to the potential additional risks of a sterile filtration process, as compared with
other sterilization processes, a second filtration through a sterile sterilizing grade filter,
immediately prior to filling, should be considered as part of an overall CCS.”
Replaces term “microorganism retentive” in old annex – now MORE SPECIFIC
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Choice of Product Sterilization

25. Traditional Style Sterile Filtration System with Bioburden
Reduction Filter and EMA/PIC/S Draft Annex 1 Compliant
8.82 “Due to the potential additional risks of a sterile filtration process, as compared
with other sterilization processes, a second filtration through a sterile sterilizing grade
filter, immediately prior to filling, should be considered as part of an overall CCS.”
Aseptic Filler
Sterile Hold
Tank
Vent
Filter
Vent
Filter
Sterilizing
Filter
Bioburden
Reduction
Filter
Sterilizing
Filter
Prefiltered
Formulation
NOT Redundant Filtration

26. 8.83 The selection of components for the filtration system and their
interconnection and arrangement within the filtration system, including
pre-filters, should be based on the critical quality attributes of the
product, justified and documented. The filtration system should minimize
the generation of fibres and particulates, not cause or contribute to
unacceptable levels of impurities, or possess characteristics that otherwise
alter the quality and efficacy of the product. Similarly, the filter
characteristics should be compatible with the fluid and not be adversely
affected by the product to be filtered. Adsorption of product components
and extraction/leaching of filter components should be evaluated (refer to
paragraph 8.125).
Component selection is Drug Manufacturer’s responsibility
Prefilter needs to be part of the validated system (8 elements)
Greater focus on target quality product profile / QbD
Reference point is the final sterile medicinal drug product safety
and patient protection
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Filtration & prefilters

27. 8.84 The filtration system should be designed to:
i. Allow operation within validated process parameters.
ii. Maintain the sterility of the filtrate.
iii. Minimize the number of aseptic connections required between the
sterilizing filter and the final filling of the product.
iv. Allow cleaning procedures to be conducted as necessary.
v. Allow sterilization procedures, including sterilization in place, to be
conducted as necessary.
vi. Permit in-place integrity testing, of the 0.22 μm sterilizing filter, preferably
as a closed system, prior to filtration as necessary. In-place integrity
testing methods should be selected to avoid any adverse impact on
the quality of the product.
Open for interpretation – “in-place”
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Filtration System Design

28. 8.85 Sterile filtration of liquids should be validated in accordance with European (or other
relevant) Pharmacopeia requirements. Validation can be grouped by different strengths or
variations of a product but should be done under worst case conditions. The rationale for
grouping should be justified and documented.
The filter vendor can and should provide this – but the user must understand this
8.86 During filter validation, wherever possible, the product to be filtered should be used
for bacterial retention testing of the sterilizing filter. Where the product to be filtered is not
suitable for use in bacterial retention testing, a suitable surrogate product should be
justified for use in the test. The challenge organism used in the bacterial retention test
should be justified.
Environmental monitoring and bioburden studies are vital
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Sterilizing Filter Validation

29. 8.87 Filtration parameters that should be
considered in validation and routine processing
should include but are not limited to:
a) If the system is flushed or integrity tested in-
situ with a fluid other than the product, then
flushing with the product should be part of the
process.
b) The wetting fluid used for filter integrity testing
based on filter manufacturer’s recommendation or
the fluid to be filtered. For the latter, the
appropriate integrity test value specification
should be established.
29
Example of Additional Specific
Recommendations in Draft Annex 1
Revision – Filter Validation (FIT)
Regulators want to see water flushing study information and
product based integrity testing studies and filter integrity test
result trending

30. 30
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Filtration Process Condition
8.87 c) Filtration process conditions including:
i. Fluid prefiltration holding time and effect on bioburden.
ii. Filter conditioning, with fluid if necessary.
iii. Maximum filtration time/total time filter is in contact with fluid.
iv. Flow rate.
v. Filtration volume.
vi. Temperature.
vii. The time taken to filter a known volume of bulk solution and the pressure difference
to be used across the filter.
Note: Results of these checks should be included in the batch record. Any significant
difference in parameters from those validated to those observed during routine
manufacturing should be noted and investigated.
So much of this
is the basis of
QbD and of user
requirement
specifications

31. 31
Examples of Key Differences in Draft Annex 1 Revision –
Filter Integrity Testing
8.88 The integrity of the sterilized filter assembly should be verified by integrity testing before use, to
check for damage and loss of integrity caused by the filter preparation prior to use. A sterilizing grade
filter that is used to sterilize a fluid should be subject to a non-destructive integrity test post-use prior
to removal of the filter from its housing.
“assembly” is stated rather than “system” – may implication for SUS assemblies
“on-line” testing may immediately require risk assessment due to lack of liquid at POU
It is recognized that pre-use post sterilization integrity testing (PUPSIT) may not always be possible
after sterilization due to process constraints (e.g. the filtration of very small volumes of solution). In these
cases, an alternative approach may be taken providing that a thorough risk assessment has been
performed and compliance is achieved by the implementation of appropriate controls to mitigate any
risk of non-sterility. Points to consider in such a risk assessment should include but are not be limited to:
i. In depth knowledge and control of the sterilization process to ensure that the potential for damage to the filter is
minimized.
ii. In depth knowledge and control of the supply chain – sterilization facility, transportation & packaging validation
iii. In depth process knowledge such as – product type, particle content that could mask/plug the filter
First time have mentioned on risk assessment for PUPSIT

32. 32
Example of Additional Specific Recommendations in Draft
Annex 1 Revision – Old vs Revised – Compressed Gas
“7.19 Compressed gases that come in direct contact with the product/container primary
surfaces should be of appropriate chemical, particulate and microbiological purity . . .
Compressed gases must be filtered through a sterilizing filter (with a nominal pore size of a
maximum of 0.22μm) at the point of use. Where used for aseptic manufacturing,
confirmation of the integrity of the final sterilization gas filter should be
considered as part of the batch release process.”
“8.89-91 The integrity of critical sterile gas and air vent filters in the filter assembly
should be verified by testing after use. The integrity of non-critical air or gas vent filters
should be confirmed and recorded at appropriate intervals. For gas filtration, attention
should be paid to avoiding unintended moistening or wetting of the filter or filter equipment.
This can be achieved by the use of hydrophobic filters.”
Post-use testing requirement has not changed HOWEVER 7.19 is specific as to the
more specific requirements for critical gas filtration

33. 8.92 If the sterilizing filtration process has been validated
as a system consisting of multiple filters to achieve the
sterility for a given fluid, the filtration system is considered
to be a single sterilizing unit and all filters within the
system should satisfactorily pass integrity testing after
use.
8.93 In a redundant filtration system (where a second
filter is present as a backup but the sterilizing process is
validated as only requiring one filter), post-use integrity
test of the primary sterilizing filter should be performed
and if demonstrated to be integral, then a post-use
integrity test of the secondary filter is not necessary.
However, in the event of a failure of the post-use integrity
test on the primary filter, a risk assessment should be
carried out to determine the acceptability of performing a
post-use integrity test on the secondary (redundant)
filter.
33
Examples of Key Differences in Draft Annex 1 Revision -
Serial and Redundant Filtration
First time serial and redundant filtration mentioned in EU GMP guidelines
BUT no guidance as to when to use redundant filtration. Potential conflict
with PDA redundant FIT recommendations Bioburden sampling risk

34. Aseptic Filler
Sterile Hold
Tank
Vent
Filter
Vent
Filter
Bioburden
Reduction
Filter
Sterilizing
Filter
Sterilizing
Filter
Formulation
Aseptic Filler
Sterile Hold
Tank
Vent
Filter
Vent
Filter
Bioburden
Reduction
Filter
Sterilizing
Filter
Sterilizing
Filter
Vent
Filter
Sterilizing
Filter
Formulation
Sampling point
Potential Sampling Influence on Sterility in Current and in
Redundant Filtration Systems
8.94 Bioburden samples should
be taken from the bulk product
and immediately prior to the
final sterile filtration. Systems
for taking samples should be
designed so as not to introduce
contamination.

35. Draft Annex 1 - Impact of
Proposed Additional
Sections & Key Differences
Single-use Systems

36. “A Process that ensures that biological material does not come into
contact with external environment. Closed processing enables grey
space or Controlled Not Classified (CNC) processing and is
sometimes referred to as being conducted in a “ballroom”.”
According to ISPE:
“A Process condition when the product, materials, critical
components or container/closure surfaces are contained and
separated from the immediate process equipment within
closed/sealed process equipment. A process step (or system) in
which the product and product contact surfaces are not exposed to
the immediate room environment.”
BioPhorum: “The key factor for industry acceptance was the
Pharmaceutical Inspection Cooperation Scheme (PIC/S)
determination that clean room requirements for Biomanufacturing
can be relaxed/eliminated if your process is closed”
ISPE Baseline Guide: “The strategy of using uncontrolled
or unclassified spaces for closed piping system has
always been accepted by the regulatory agencies as
an acceptable risk.”
36
What is Closed Processing about?
Isolating a product
from the
environment and
vice versa

37. 8.116 Closed systems can be single use systems (i.e. disposable
systems) and fixed systems (such as vessels with fixed pipework).
Guidance in this section is equally applicable to both systems.
8.117 The use of closed systems can reduce the risk of extraneous
contamination such as microbial, particulate and chemical from the
adjacent environment. Closed systems should always be designed to
reduce the need for, and complexity of manual interventions.
8.118 It is critical to ensure the sterility of all product contact
surfaces of closed systems used for aseptic processing. The design and
selection of any closed system used for aseptic processing should ensure
maintenance of sterility. Connection of sterile equipment (e.g. tubing /
pipework) to the sterilized product pathway after the final sterilizing filter
should be designed to be connected aseptically (e.g. by intrinsic
aseptic connectors or fusion systems).
37
Key References to Single-use Systems in Draft Annex 1
Revision – Closed Systems
1) Aseptic connections qualified on regular basis as part of routine
sterility assurance policy
2) Supplier assessment should include the collation of data in
relation to potential failure modes that may lead to a loss of
system sterility.

38. 8.121 SUS are those technologies used in manufacture of
sterile products which are used as an alternative to
reusable equipment. SUS can be individual components
or made up of multiple components such as bags,
filters, tubing, connectors, valves, storage bottles
and sensors.
8.123 Sterilization processes for SUS should be validated
and shown to have no adverse impact on system
performance.
8.124 Assessment of suppliers of disposable systems
including sterilization is critical to the selection and use of
these systems. For sterile SUS, verification of sterility
should be performed as part of the supplier
qualification and on receipt and use of each unit.
38
Key References to Single-use Systems in Draft Annex 1
Revision – SUS Relevance

39. 8.122 There are some specific risks associated with SUS
which should be assessed as part of the CCS.
These risks include but are not limited to:
i) The interaction between the product and product
contact surface (such as adsorption, or the formation of
leachables and extractables).
ii) The fragile nature of the system compared to fixed
reusable systems.
iii) The increase in the number and complexity of manual operations
(including inspection and handling of the system) and connections made.
iv) The complexity of the assembly.
v) The performance of the pre-use integrity test for sterilizing grade filters
(refer to paragraph 8.88).
vi) The risk of holes and leakage.
vii) The potential for compromising the system at the point of opening the outer packaging.
viii. The risk of particulate contamination.
39
Key References to Single-use Systems in
Draft Annex 1 Revision – SUS Relevance

40. 8.125 The adsorption and reactivity of the product with product contact surfaces should
be evaluated under process conditions.
8.126 The extractable and leachable profile of the SUS and any impact on the quality of
the product especially where the system is made from polymer-based materials should be
evaluated. An assessment should be carried out for each component to evaluate the
applicability of the extractable profile data. For components considered to be at high risk
from leachables, including those that may absorb processed materials or those with
extended material contact times, an assessment of leachable profile studies, including
safety concerns, should be taken into consideration. If applying simulated processing
conditions, these should accurately reflect the actual processing conditions and be based on
a scientific rationale.
Consider USP 665 draft guidance & BioPhorum E&L protocol.
Vendors should be able to provide critical help
Key References to Single-use Systems in Draft Annex 1
Revision – SUS Interaction with Product

41. Prerequisite to Patient Safety Evaluation
Extractables & Leachables Evaluation
41

42. 42
8.127 SUS should be designed to maintain
integrity throughout processing under the
intended operational conditions. Attention to the
structural integrity of the single use components
is necessary where these may be exposed to
more extreme conditions (e.g. freezing and
thawing processes) either during routine
processing or transportation. This should include
certification that intrinsic aseptic connections
(both heat sealed and mechanically sealed)
remain integral under these conditions.
8.129 Critical manual handling operations of SUS
such as assembly and connections should be
subject to appropriate controls and verified
during the APS.
Key References to Single-
use Systems in Draft Annex
1 Revision – SUS Relevance
Transport studies should be
included in the OQ studies
Media fills are still required
following same rules as used for
fixed SS equipment

43. 43
8.128 Acceptance criteria should be established and
implemented for SUS corresponding to the risks or
criticality of the products and its processes. On
receipt, each piece of SUS should be checked to
ensure that they have been manufactured, supplied
and delivered in accordance with the approved
specification.
A visual inspection of the outer packaging (e.g.
appearance of exterior carton, product pouches),
label printing, and review of attached documents
(e.g. certificate of conformance and proof of
sterilization) should be carried out and documented
prior to use.
Key References to Single-use
Systems in Draft Annex 1 Revision
– SUS Acceptance Criteria
1) Vendor’s sterilisation validation should be included in audit requirements
and on-going performance and consistency should be confirmed regularly (e.g.
quarterly dose audit reports
2) Vendor’s change notification process should be included in vendor quality
agreements
3) Training is vital across all departments and should be conducted by SMEs

44.  Regulatory framework – understand the risk and
manage it
 Industry associations facilitate implementation
of regulatory guidelines
 Contamination Control Strategy (CCS) is key
 PUPSIT is still emphasized – exceptions through
risk assessment
 For the first time, redundant sterilizing filtration
has been mentioned in EU guideline
 Single-use systems enable closed processing
44
Conclusion

45. © 2021 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
The vibrant M, Millipak, Durapore and Emprove are trademarks of Merck KGaA, Darmstadt,
Germany or its affiliates.
All other trademarks are the property of their respective owners. Detailed information on
trademarks is available via publicly accessible resources.
Dr. Simone Biel
Senior Regulatory Consultant
simone.biel@emdgroup.com
Somasundaram (Som)
Senior Consultant, APAC
somasundaram.g@emdgroup.com
Thank you for the kind attention