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Validation of sterile Medical
Devices manufacturing processes - A Notified Body’s view
Dr. Jan Havel
TÜV SÜD Product Service GmbH Slide 1 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
MHS – Gate to worldwide markets
Brazil Product certification via
agreements with UCIEE
or CERTUSP
Full support world wide conformity assessment & testing
Japan Recognized Certification Body
(RCB), Medical Test Lab,
certification (PAL, RCB)
China SFDA Registration, CCC
(China Compulsory
Certification)
Europe Conformity assessment
procedures
according to AIMDD, MDD, IVDD
(notified body number 0123)
Russia Certification via
GOST
Australia Certification as CAB under
MRA (Conformity Assessment
Body)
Canada CMDCAS (ISO 13485),
CAN/CSA C22.2
NR.601.1 as NRTL
USA FDA 510(k) NRTL,
FDA QSReg
inspection
in compliance with
MRA
Taiwan
Technical
Cooperation
Program
New:
• Biocomp Lab
• Saudi Arabia CAB
• Consulting Japan
• Korea CAB
TÜV SÜD Product Service GmbH Slide 2 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Regulatory Requirements
Responsibilities Documentation
Regulatory Requirements
Validation
Connection to Risk Management
Consequences for validation
TÜV SÜD Product Service GmbH Slide 3 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Why process validation?
Also, medical devices must be packed and sterilzed safely! Where does that
requirement come from?
EC-Directive 93/42/EEC
for Medical Devices
Medical Device 93/42 EEC
TÜV SÜD Product Service GmbH Slide 4 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
• 93/42 EEC Article 3: • Medical devices, must meet the essential requirements
(MDD Annex I).
•
• 93/42 EEC Article 11:
• Compliance to Essential Requiremnts (MDD Annex I) must be
demonstrated by a Conformity Assessment Procedure (e.G. Annex II.3).
Medical device 93/42 EEC Annex II.3
Why Conformity?
TÜV SÜD Product Service GmbH Slide 5 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Regulatory Requirements of the MDD
Directive 93/42/EEC (MDD) Essential Requirements:
• Devices delivered in a sterile state must be designed, manufactured and
packed in a non-reusable pack and/or according to appropriate procedures
to ensure that they are sterile when placed on the market and remain
sterile, under the storage and transport conditions laid down, until the
protective packaging is damaged or opened. The risk posed by
contaminants and residues to the persons involved in the transport, storage
and use of the devices and to the patients must be minimized (7.2, 8.3).
• Devices delivered in a sterile state must have been manufactured and
sterilized by an appropriate, validated method (8.4)
• The design must allow easy handling and, where necessary, minimize
contamination of the device by the patient or vice versa during use (8.1)
TÜV SÜD Product Service GmbH Slide 6 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Manufacturer Responsibilities: Technical Documentation
• Objective: Demonstration of Compliance
of products with the requirements of the
Directive
=> Especially:
Conformity with the essential
Requirements
Content:
• Product description
• Risk Analysis
• Applied standards
• Essential requirements
• Manufacturing Process
• Sterilization Method
• Design tests including
Test results and clinical Data
• Labeling and IFU
TÜV SÜD Product Service GmbH Slide 7 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Regulatory Requirements
Responsibilities Documentation
Regulatory Requirements
Validation
Connection to Risk Management
Consequences for validation
TÜV SÜD Product Service GmbH Slide 8 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Validation of manufacturing processes
Requirements according to 7.5.2 of EN ISO 13485:2012
• The organization shall validate any processes for production and service
provision where the output cannot be verified by subsequent monitoring or
measurement.
• http://www.ghtf.org/documents/sg3/sg3_fd_n99-10_edition2.pdf
TÜV SÜD Product Service GmbH Slide 9 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Accreditors view: Requirements by ZLG: Validation
7.5.2.1 General requirements
... Validation shall demonstrate the ability of these processes to achieve the
planned results. The organization must define regulations for these processes
including the following, as applicable:
a) Define requirements for the assessment and approval of the processes,
b) approval of the equipment and qualification of the operators,
c) Application of defined methods and procedures
d) requirements for documentation and
e) revalidation
TÜV SÜD Product Service GmbH Slide 10 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Accreditors view: EK-MED decision 3.9 B18
Stages of validation to be implemented by the manufacturer
Installation Qualification
Operational Qualification (machine capability, Short-term
capability, effectiveness of the process control tolerances)
Performance Qualification (Long-time capability to produce a
product corresponding to its specification)
For each stage a corresponding protocol has to be established prior to
the Qualification, in which the criteria for the acceptance are defined
and where the results for the particular stage will be entered.
GHTF/SG3/N99-10 : 2004
TÜV SÜD Product Service GmbH Slide 11 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
How often do I need to calibrate/ validate?
7.1 Planning of product realization in EN ISO 13485:
• “..... The organization shall establish documented requirements for risk
management throughout product realization...“
To minimize risks in relation to
• intended use (Education / training / skills of the users!)
• Design
• Production
• Storage and transport
TÜV SÜD Product Service GmbH Slide 12 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Regulatory Requirements
Responsibilities Documentation
Regulatory Requirements
Validation
Connection to Risk Management
Consequences for validation
TÜV SÜD Product Service GmbH Slide 13 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Riskmanagement on the example of sterile packaging processes
The following features shall be evaluated:
a) microbial barrier
b) Biocompatibility
(Sterilization effects on biocompatibility should be evaluated)
c) physical/chemical properties
d) compatibility to forming and sealing processes;
e) compatibility to the intended sterilization process(es)
f) shelf-life limitations for pre-sterilization/post-sterilization storage.
ISO 11607-1:2009 5.1.6 ISO 11607-2.:2006 6.1,6.3
TÜV SÜD Product Service GmbH Slide 14 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Validation of processes in risk management: typical errors
FMEA in Production
Process Step
/ component
# Failure Hazard Root
Cause
O S D RPN Risk Control O S D RPN
Packaging 1 channel
creation
in the
seal
Infectio
n
through
in-
sterile
Product
Insuf-
ficient Seal
temp-
erature
6 1
0
8 480 packaging-
validation
(Integrity
testing)
5 1
0
1 50
O: Occurrence; S: Severity; D: Detect ability; RPN: Risk Priority Number
further informationen in e.g. VDA 4.2, DIN 25448, IEC 60812
Packaging 1 channel
creation
in the
seal
Infection
through
in-sterile
Product
Insuf-
ficient
Seal temp-
erature
6 1
0
8 480 packaging-
validation
(Integrity
testing)
1 1
0
8 80
TÜV SÜD Product Service GmbH Slide 15 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Example of validation depth
FMEA in production
O: Occurrence; S: Severity; D: Detect ability; RPN: Risk Priority Number
Occurrence probability (event/year):
10=10-1 5=10-6
9=10-2 4=10-7
8=10-3 3=10-8
7=10-4 2=10-9
6=10-5 1=10-10
Process Step
/ component
# Failure Hazard Root
Cause
O S D RPN Risk Control O S D RPN
Packaging 1 channel
creation
in the
seal
Infection
through
in-sterile
Product
Insuf-
ficient
Seal
temp-
erature
6 1
0
8 480 packaging-
validation
(Integrity
testing)
1 1
0
8 80
TÜV SÜD Product Service GmbH Slide 16 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Example of validation depth
Validation of an increase in 10-5 of the
risk control or final risk control to 10-10
FMEA in production
O: Occurrence; S: Severity; D: Detect ability; RPN: Risk Priority Number
Process Step
/ component
# Failure Hazard Root
Cause
O S D RPN Risk Control O S D RPN
Packaging 1 channel
creation
in the
seal
Infection
through
in-sterile
Product
Insuf-
ficient
Seal
temp-
erature
6 1
0
8 480 packaging-
validation
(Integrity
testing)
1 1
0
8 80
TÜV SÜD Product Service GmbH Slide 17 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Implementation of risk control measure(s)
EN ISO 14971 6.3 Implementation of risk control measure(s)
The manufacturer shall implement the risk control measure(s) selected.
Verify:
• Implementation of each risk control measure
• Effectiveness of the risk control measure(s)
The verification shall be recorded in the risk management file.
risk management
file
specification
documents
verification
documents
TÜV SÜD Product Service GmbH Slide 18 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Risk management output
Designresults
• Information related to the Procurement of
components, Production-, installation- and
Maintenance processes
Examples of risk control
• Requirements for Quality agreements
• consideration of critical outsourced
processes
• Maintenance requirements of
Production Facilities
• Storage and Transportation Conditions
• Installation instructions
• Maintenance instructions
• Training of service personnel
• consideration of external Service
Organizations
TÜV SÜD Product Service GmbH Slide 19 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Regulatory Requirements
Responsibilities Documentation
Regulatory Requirements
Validation
Connection to Risk Management
Consequences for validation
TÜV SÜD Product Service GmbH Slide 20 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Validation-plan
• The validation plan should reflect the rationale for applied test: – Is the order for the test sequences logical?
– For which product characteristics is what standard (state of the art) used?
– Are the acceptance criteria logical for the corresponding type of Product/Feature?
(E.g. permeability of a sterile packaging) Material
Sterilization method
fixation in the packaging system
– The sampling plans used for selection and testing of packaging systems shall be
…. be based upon statistically valid rationale. (e.g. ISO 2859-1, ISO 186 or are
following state of the art standards for sterilization e.g in EN ISO 11135-1, EN
ISO 11137-2)
– Are all the critical parameters are verified based on a risk assessment
TÜV SÜD Product Service GmbH Slide 21 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
EN ISO 11607-1:2009 4.3; 4.4.2/3 EN ISO 11607-2 4.2
So what parameters are to be considered in general?
TÜV SÜD Product Service GmbH Slide 22
• Process input parameters Output Parameters (Product features)
13-10-22
Aimed Mean
value
e.g. packaging
Seal temperature:120 ± 10°C
Seal pressure: 5 ± 1 bar
Time: 0,5 ± 0,2 sec
e.g. sterile packaging
Seal strength in N/15mm
LTL
UT
L
3σ > Aim <3σ
Relation input parameter – output parameter
TÜV SÜD Product Service GmbH Slide 23 13-10-22
UTL Parameter
LTL Parameter
High Alarm Limit
Low Alarm Limit
Set Parameter
Failure/Defect
Failure/Defect
Identified/verified at Process
development (or during OQ)
Identified/verified at Process
development (or during OQ)
Aim
ed
Me
an
valu
e
LTL
UTL
3σ
> A
im<
3σ
Input: Machine Output: Product
Adequate Sampling
• The sampling plans used for selection and testing of e.g. sterile packaging systems shall be …. be based upon statistically valid rationale. (e.g. ISO 2859-1, ISO 186)
• So what is the basic input into the statistics? What sample pool are we talking about?
– EN ISO 14971:2012 Risk acceptance criteria shall be appropriate for the whole
life-cycle of the device: Life-cycle: Starts at initial conception and ends with final decommissioning and
disposal of a device = direct link to the amount manufactured products during the defined life cycle.
Risk shall be controlled and to a level as safe as possible according to the state of the art
– EN 556-1 – “Sterile” = SAL 10-6 (terminally sterilized)
EN ISO 11607-1:2009 4.3; 4.4.2/3 EN ISO 14971:2012 2.7 Annex Z
TÜV SÜD Product Service GmbH Slide 24 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Justification of sample size
• Based on the risk assessment in risk management
– In case of a risk reduction of 10X for In-sterility due to a specific production
problem.
What process safety is
necessary to verify the
Risk control measure?
TÜV SÜD Product Service GmbH Slide 25 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Sample size
• sample sizes in ISO 2859-1 (AQL) do only apply to certain Test methods.
• cpk is heavily dependent on the chosen range used, but applicable (e.g. >1) – Presumption: Test on normal distribution was successful.
• Stick to harmonized standards if sampling amounts are defined: E.g. Sterilization verification at irradiation sterilization or sensor distributions at each sterilization method.
Test System
with final product
constellation
Test System
for specific features
depending
on the production process
Ok, for what now?
Only Limited
suitable
TÜV SÜD Product Service GmbH Slide 26 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Test on normality – What to be considered?
• What is representative as a sample from a population of data: – Samples distributed over the whole range of a typical production run
– Normality is typically shown per run to make the samples representative
– Sample amount shall be sufficient to assure to be representative at a high confidence:
TÜV SÜD Product Service GmbH Slide 27 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
LTL
UT
L
LTL
UT
L
LTL
UT
L
LTL
UT
L
LTL
UT
L
LTL
UT
L
Test on normality – What to be considered?
• What is representative as a sample from a population of data: – Sample amount shall be sufficient to assure to be representative at a high confidence:
TÜV SÜD Product Service GmbH Slide 28 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Aimed Mean
value
LTL
UT
L
3σ > Aim <3σ
We chose 90%/95% and therefore we take 15 Samples. And
our software tells us this works! Our p-value is >0,05!
Important question:
So how many failures may
remain undetected under our
approach?
X Samples that would have
been detected at >15 samples
Will your argumentation sustain
a trial at court with a p-value
determined from a small
sample?
X
X
X
X
Test on normality – What to be considered?
• What is representative as a sample from a population of data:
Could I have done more Conflict to EN ISO 14971 and MDD (safe
as possible acc. to the state of the art)
Do not trust simply on software!
Is the chosen solution appropriate in relation to risk of a
human life/condition of health?
TÜV SÜD Product Service GmbH Slide 29 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC
Summary
TÜV SÜD Product Service GmbH Slide 30
• Risk Management is an integral part of the technical file used to show conformity
to a medical device to the MDD
• Evidence for each final risk estimation in a released risk analysis has to be
provided in documentation for the life-cycle of the device for manufacturing
process
• Sterile product manufacturing process validation shall provide evidence for the
risk management that the process is safe and reproducible
• The amount of samples shall assure: – To be representative for routine manufacturing including tolerances
– State of the art safety of the device: Considering the amount not detected critical failures
Considering base amount on the decision of a normal distribution
Considerung the right Cpk /AQL level necessary for the life-cycle
13-10-22
Thank you for your
attention!
TÜV SÜD Product Service GmbH Slide 31 13-10-22 Dr. Jan Havel Non Active Medical Devices PS-MHS2-MUC