Validation of sterile Medical Devices manufacturing processes By J. Havel - Havel tuv sud (Qserve...

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


Regulatory Requirements

Responsibilities Documentation


Validation

Connection to Risk Management

Consequences for validation


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


• 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?


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)


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





Validation




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


http://www.ghtf.org/




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


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


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





Validation




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


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


Example of validation depth

FMEA in production


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


Cause


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


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


Process Step

/ component


Cause


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


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


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





Validation




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


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


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?


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


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:


LTL

UT

L

LTL

UT

L

LTL

UT

L

LTL

UT

L

LTL

UT

L

LTL

UT

L


• 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


• 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?


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!


Validation of sterile Medical Devices manufacturing processes By J. Havel - Havel tuv sud (Qserve...

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Transcript of Validation of sterile Medical Devices manufacturing processes By J. Havel - Havel tuv sud (Qserve...