Biopharmaceutical manufacturing capacities have expanded dramatically which has resulted in an increased demand for single-use systems (SUS) as they have their own advantages. Although SUS are well established in the biopharmaceutical industry there is limited guidance on regulatory expectations. Please attend the webinar to learn more!
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EU GMP Annex 1 Draft - Closed System Design Consideration with Single-Use Systems
1. The life science business of Merck operates
as MilliporeSigma in the U.S. and Canada.
Closed System Design Consideration with Single-Use
Systems
Somasundaram (Som), Senior Technical Consultant, Asia Pacific
Dr. Simone Biel, Senior Regulatory Consultant
EU GMP
Annex 1 Draft
4. “Closed system. Where a drug substance or product is not exposed to
the immediate room environment during manufacture.” (1)
“Live organisms and spores are prevented from entering non-related areas or
equipment by addressing all potential routes of cross-contamination and
utilizing single use components and engineering measures such as
closed systems.” (1)
“Closed or contained equipment should be used whenever
appropriate.” (2)
“Concurrent production of two different ATMPs/batches in the same area is not
acceptable. However, closed and contained systems may be used to
separate activities…” (3)
The use of closed systems [i.e. single use systems] can reduce the risk of
extraneous contamination such as microbial, particulate and chemical from
the adjacent environment (4)
(1) EudraLex Vol 4, Annex 2: Manufacture of Biological active substances and Medicinal Products for Human Use
(2) EudraLex Vol 4, Part II: Basic Requirements for Active Substances used as Starting Materials
(3) EudraLex Vol 4, Part IV: GMP Guiedelines specific to Advanced Therapy Medicinal Products
(4) EudraLex Vol 4, Annex 1 draft (2020): Manufacture of Sterile Products
Single-Use Systems to Reduce Cross-Contamination
Closed System – Some Quotes
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
5. Contamination Risks Throughout the Process
Manufacturing process can affect patient outcomes
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
6. Closed Systems – Benefits of Single-Use Technology
Compared to stainless-steel manufacturing
Benefits of single-use technologies
Speed to
market
Ease of use
Increased
productivity
• Plug and play
• Sterile connections
• Reduced room
classification stringency
• Decreased risk of
product cross-
contamination
• Elimination of SIP/CIP
and decontamination
process steps
• Reduced capital
investment in facility
and equipment
• Reduced time to get
facility up and running
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
7. Who is doing what?
Regulatory and Industry Expectations
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
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
8. Ongoing consultation of new draft – global approach
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.
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
9. Prevent any contamination in the final product
EU GMP Annex 1 draft – Scope
Scope
“…to provide guidance for the manufacture of sterile
products. However, some of the principles and guidance,
such as contamination control strategy, design of
premises, cleanroom classification, qualification,
monitoring and personnel gowning, may be used to
support the manufacture of other products that are not
intended to be sterile such as certain liquids, creams,
ointments and low bioburden biological intermediates but
where the control and reduction of microbial, particulate and
pyrogen contamination is considered important.”
Annex 1 draft, 2020
https://ec.europa.eu/health/sites/health/files/files/gmp/2020_annex1ps_sterile_medicinal_products_en.pdf
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
11. • Why & What is Contamination Control Strategy
• Understand the impact of bioburden excursions
• Recognize the sources of bioburden
• Develop strategies to mitigate risk
Contamination control strategy (CCS)
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
12. CCS – Definition & Regulatory Drivers
“A planned set of controls for microorganisms, pyrogens and particulates, derived from current product and process
understanding that assures process performance and product quality”.
The controls can include parameters and attributes related to active substance, excipient and drug product materials and
components, facility and equipment operating conditions, in-process controls, finished product specifications, and the
associated methods and frequency of monitoring and control.
EU GMP Annex 1 Draft 2020:
‘A contamination control strategy should be implemented across the facility in order to assess the effectiveness of all the
control and monitoring measures employed’
CCS is mentioned 44 times in the update
PIC/S GMP Part I, 2021:
‘Cross-contamination should be prevented for all products by appropriate design and operation of manufacturing facilities.
The measures to prevent cross contamination should be commensurate with the risks. Quality Risk Management
principles should be used to assess and control the risks’
‘5.10 At every stage of processing, materials and products should be protected from
microbial and other contamination’
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
13. Contamination Control Strategy: Holistic program
that encompasses concepts within the context of the
entire manufacturing facility and process
Facility Design: Designed according to GMP Regulations
/ Guidelines, Best practice and process requirements
Personnel: Gowning regime with personnel monitoring
program, suitable limits and action plan, training and
culture
Cleaning and Disinfection/Sterilisation: Consistent
removal of soiling and microbial load deactivation
Environmental Monitoring: Monitor viable and non-
viable, suitable limits and action plan
Process Simulation: End to end testing including
intervention assessment and worse case stressing
Process Design: Process controls including GMP and
GEP to ensure product is microbial/pyrogen, chemical,
non-viable and cross-contamination free.
What is a Contamination Control Strategy
Process
Design
Process
Simulation
Environmental
Monitoring
Cleaning &
Disinfection/Sterlisation
Personnel
Facility Design
Contamination
Control Strategy
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
15. 30
Percent
1- 6
Months
1-14
Million Euro
Percent of process deviations
caused by contamination*
Length of time to complete
an investigation
Operations cost
*Sources Langer 2013, Wiebe 2014
Biologics in-process contamination
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
16. 30
Percent
1- 6
Months
1-14
Million Euro
*Sources Langer 2013, Wiebe 2014
Biologics in-process contamination
Impact
Productivity losses
Material replacement costs
Batch loss
Interruption of product supply
Delay in clinical development
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
18. Facility & Environment
Equipment
Processes
Materials
Utilities
Personnel
Each source
contributes
to the
process
bioburden
profile
Sources of bioburden
Staphylococcus
Bacillus
Non-fermenting
Gram Negative
rods
Aspergillus
Source: Public domain CDC/
Robert Simmons
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
19. • Many routes for microbial ingress
• Bioburden excursions are often the result of
− Improper cleaning, storage, or sanitization
− Suboptimal system design
− Aseptic connections
− Sampling
− Lapses in aseptic technique
Intensive risk assessments can prevent many of these contaminations or excursions
Key Points
Sources of bioburden
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
20. Downstream
Risk profile & control strategies differ throughout the process
Secondary
Clarification
Chromatography
Protein A
Final Filling
Final Sterile
Filtration
Concentration
& Formulation
Bulk Storage
and Transport
Viral
Inactivation
Chromatography
CEX
Virus Filtration
Clearance
Ultrafiltration /
Diafiltration
Bioreactor
Primary
Clarification
MCB WCB Seed Train
Raw Materials
Filtration Bioburden
Reduction
Bioburden
Reduction
Chromatography
AEX
Bioburden
Reduction
Bioburden
Reduction
Final Fill
Risk Areas
Upstream
Downstream
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
21. The risk profile varies from upstream to final fill
Risk Hammock
Upstream Downstream Finish and Fill
Operations
Risk
High
Low
Aseptic Aseptic
Bioburden Controlled
“The level of effort, formality and
documentation of the quality risk
management process should align
with the level of risk”
(ICH Q9A)
Shifting “the QRM focus from
reactive to proactive will enable
continual improvement to become a
key aspect of the PQS. Revision of
ICH Q9 is of strategic importance.
ICH Q(R1) Concept Paper, 2020
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
23. Assess Risks
Key Points
▪ Characterize the microbial profile of the process
▪ Utilize a combination of assessment tools
▪ A cross-functional team is crucial to the process
▪ Your Bioburden risk mitigation strategy should
address
▪ Patient safety
▪ Drug supply
▪ Business risk
0
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
24. Prevent Contamination by Containment (Risk Mitigation)
Implement Single Use Systems and Closed Sampling
Eliminate
bioburden
contribution
Prevent
microbial
ingress
Minimize
process
validation
Mitigate
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
25. Downstream Monitoring
What do I test for? Where? Why?
Chromatography
Protein A
Bulk Storage
and Transport
Viral
Inactivation
Chromatography
CEX
Virus Filtration
Clearance
Ultrafiltration /
Diafiltration
Bioburden
Reduction
Bioburden
Reduction
Chromatography
AEX
Bioburden
Reduction
Bioburden
Reduction
Bioburden
Virus
Mycoplasma
Endotoxin
V
M
B
E
B
E
B
E
B
E
V
E
V
E
B
E
B
E
M
Monitor
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
27. Case Study
Bioburden/Endotoxin excursions in the Protein A Pool
Chrom
Protein A
Bulk
Storage and
Transport
Viral
Inactivation
Chrom
CEX
Virus
Filtration
Clearance
Ultrafiltration
Diafiltration
Bioburden
Reduction
Bioburden
Reduction
Chrom
AEX
Bioburden
Reduction
Bioburden
Reduction
Situation
• Spore-forming bioburden alert-level excursions in the
Protein A pool over several campaigns
Root Cause
• Failure to recognize a trend in the pattern of excursions
• Sanitization solution was not sporicidal
• Sub-optimal sanitization process
Corrective and Preventative Actions
• Scale down studies with a new sanitizer and
optimization of sanitization conditions
• Process scale verification
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
28. Case Study
Bioburden action-level excursions of in the UF/DF step
Chrom
Protein A
Bulk
Storage and
Transport
Viral
Inactivation
Chrom
CEX
Virus
Filtration
Clearance
Ultrafiltration
Diafiltration
Bioburden
Reduction
Bioburden
Reduction
Chrom
AEX
Bioburden
Reduction
Bioburden
Reduction
Situation
• Bioburden and endotoxin exceeded action levels in
multiple batches
• Intensive investigation of the process and support areas
Root Cause
• Bioburden formation in the TFF cassettes due to inadequate
cleaning and storage processes
Corrective and Preventative Actions
• Improve cleaning and storage processes
• Sterilization or sanitization of buffer tanks
• Assessment of the water for injection (WFI) system and
transfer lines
• Introduction of bioburden reducing filters
• Validation of hold times and storage conditions
• Revision of bioburden limits based on process capability
Buffer, Sanitizer, and
Storage Solutions
Operations
WFI
Operation
Suvarna K. et. al. “Case Studies of Microbial Contamination in Biologic Product”,
American Pharmaceutical Review 14(1) January/February 2011.
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
29. Case Study
Sporadic bioburden action-level excursions
Chrom
Protein A
Bulk
Storage and
Transport
Viral
Inactivation
Chrom
CEX
Virus
Filtration
Clearance
Ultrafiltration
Diafiltration
Bioburden
Reduction
Bioburden
Reduction
Chrom
AEX
Bioburden
Reduction
Bioburden
Reduction
Situation
• Sporadic mixed bioburden excursions at multiple
points in the downstream process
Root Cause
• Aseptic connections of equipment and sampling devices
Corrective and Preventative Actions
• Short term:
• Retrained operators in aseptic techniques
• Long term:
• Reduced the number of aseptic connections
• Implemented sterile to sterile connectors and steam
to sterile connectors.
• Introduced a facility-wide sterile sampling system
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
30. Case study
Bulk solution contamination with Bacillus species
Chrom
Protein A
Bulk
Storage and
Transport
Viral
Inactivation
Chrom
CEX
Virus
Filtration
Clearance
Ultrafiltration
Diafiltration
Bioburden
Reduction
Bioburden
Reduction
Chrom
AEX
Bioburden
Reduction
Bioburden
Reduction
Situation
• Prefiltration bioburden load was 20 x the
specification
• Bacillus species suggested a steam-in-place issue
Root Cause
• Equipment design: improper pipe slope resulted in cold
spots that were insufficiently sterilized
Corrective and Preventative Actions
• Discard (scrap) the batch
• Redesign piping
• Requalify SIP (steam-in-place) cycle
• New processes will use single-use storage systems
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
32. Formulation Filtration Filling
Connect Connect
Closed processing (maintaining sterility)
Entire process can be designed with single-use assemblies
Focus: Sterile Production
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
33. Lots of components, connections, assemblies
Your Single-Use System Process
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
34. Critical steps are transferred from end-user to supplier
SUT in Manufacturing – Considerations
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
Some guidance
− 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
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
35. A Collaboration between Supplier and End User
Integrity Assurance
Components
Bag and
assembly
manufacture
Packaging
and shipping
Receipt and
unpacking
Pre-use
stage
Post-use
stage
Tear resistant
and superior
bond strength
bag film
Sterile connector
integrity test
Quality by
design
Automated bag
bonding
Visual inspection
Integrity/leak
test
Define packaging
instructions
Shelf life
validation
Shipping
validation
Best handling
practices
Visual inspection
to confirm the
design
Best practices
for installation
Point of use
integrity/leak
test
Visual
verification
Supplier
End-user
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
36. Do you know what your supplier does?
Manufacturing and Control
Bag manufacturing
Automation
Validated process
In-process leak test
Assembly
Standard operating
procedures
Operator training
In-process controls
Release testing
Visual inspection
Final product leak testing
Fluid path water extract
testing (particles, endotoxin)
Leak/integrity testing
Various methods depending
on application and sensitivity
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
37. Leak Test Integrity Test Helium Integrity Test
Leak Test vs Integrity Test
Release Test
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
Detects defects of a known size that have a correlation to a known
parameter using a specific test methodology such as aerosolized or
liquid bacterial ingress.
Detects gross leaks in a system
Decreasing Defect Detection Size Limit
Increasing Level of Risk-Reduction
System Volume
Approximate
Detection Limit
Tubing Assemblies 50 µm
1 – 9 L 150 µm
10 – 999 L 1000 µm
>1,000 L 2000 µm
System Volume
Validated
Detection Limit
Tubing Assemblies 20 µm
Up to 50 L 20 µm
System Volume
Validated
Detection Limit
Tubing Assemblies 2 µm
Up to 50L 2 µm
38. Aerosol Challenge Test
Bags with known defect sizes (filled with TSB)
Microbial aerosol concentration 106 cfu/ml
60 mins
Correlation between leak size and bacterial ingress
Single-Use System Integrity Test
Incubation
30-35 °C
14 days
Result
Growth present in bags with
defects 12.65 µm or greater
BPSA Technical Guide, Design, Control, and Monitoring of Single-use Systems for Integrity Assurance, 2017
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
39. ISO 11137, Sterilization of Health Care Products — Radiation
Sterilization Validation
Irradiation Process
− Development, validation, and routine control of
sterilization process (VDmax)
− Establishing sterilization dose with SAL <10-6
− Guidance on dosimetric measurement of
radiation
Quarterly dose audits to substantiate the
sterilization dose on an on-going basis.
− Demonstrate clean environment by testing
bioburden of reference assemblies pre-gamma
− Sterility test after low irradiation dose
Review of historical data over the last decade
− verifies robustness of sterility validation
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
40. Ensure integrity during shipment
Packaging Design
Protect rigid components
Qualified packaging
material (shelf life, low
particle load, outgassing)
Ensure that easy unpacking
is possible
Vacuum in packaging bags
to avoid movement of
components
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
41. Ensure Integrity during shipment
Transport Validation
Manufacturing
Visual inspection
Leak test (assembly)
assembly packaged
and boxed per
packaging SOP
Gamma irradiation
(25-40kGy)
ISTA 2A treatment
1st Vibration Test
Impact Test (drop
Test)
2nd Vibration Test
Bubble Emission
testing of vacuum
sealed packaging
bags
Visual inspection
Leak test (assembly)
ISTA 2A
Reference
Assembly
Irradiation Testing
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
42. Proper installation of SUS is key to keep integrity
New Handling Procedures for End-User
Outside
Isolator
Inside
Isolator
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
43. Combined filtration and filling set
Dosing pump inside isolator
Dosing pump
outside isolator
Sterile connection
device required
There is no common or standard approach
Final Filling Single-Use Set - Examples
Grade C Grade A
Bulk
Product
Peristaltic
Pump
Sterile
Filter
Header
Bag
Peristaltic
Pump
Filling
Needle
Grade C Grade A
Bulk
Product
Peristaltic
Pump
Sterile
Filter
Header
Bag
Peristaltic
Pump
Filling
Needle
Sterile filtration
inside isolator
Transfer of entire
SUS via Getinge
DPTE® Beta Bag
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
44. 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).
8.119 Appropriate measures should be in place to ensure the integrity
of components used in aseptic connections. The means by which this is
achieved should be determined and captured in the CCS. Appropriate
system integrity tests should be considered when there is a risk of
compromising product sterility. Supplier assessment should include the
collation of data in relation to potential failure modes that may lead to a loss
of system sterility.
8.120 The background in which closed systems are located should be based on
their design and the processes undertaken. For aseptic processing and where
there are any risks that system integrity may be compromised, the system
should be located in a Grade A zone. If the system can be shown to
remain integral at every usage (e.g. via pressure testing and/or
monitoring) then a lower classified area may be used.
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
“Determined and captured in the Cross-Contamination Strategy”
Annex 1 Draft and Closed Systems
45. Reduce complexity and keep flexibility of the SUS
Sterile Connection Device
Handling
Quick and easy
Avoid operator mistakes
Design
Robust and consistent
performance
100% air-integrity tested in
manufacturing
Validation
Aerosolized microbial challenge test
Media fill
Brevundimonas diminuta aerosol
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
46. SUS enable your process closed!
Microbial & Particulate contamination present
a real & underappreciated risk
Testing is just one aspect of integrity
assurance
Include your SUS supplier in your
cross-contamination/contamination
control strategy
EU GMP Annex 1 Draft - Closed System Design Consideration with Single-use Systems
Reduce complexity with the right SUS design
to enable easy operator handling
Impact of Microbial contamination/excursions
can be highly significant