Guenther Gapp, Head QA/QC Microbiology

Sandoz GmbH, Austria

Sterile Operations Quality Risk Assessment
IVT, Dublin, November15th, 2012
a Novartis company

Sterile Operations Quality Risk Assessment

We want to prevent : a non sterile result and ....

Sterile Operations Quality Risk Assessment

Created 2006 at Sandoz GmbH/ Austria and rolled out within
Sandoz globally from 2007 on
Risk Analysis of Sterile Plants API & FDF presented at the PDA
Conference on Pharmaceutical Microbiology, Berlin Feber 2010

Publication in the PDA Journal Risk Analysis of Sterile Production

Plants: A new and Simple, Workable Approach, 2011 65 217- 226;
2011 : Roll out within all Novartis sterile sites (approx. 30)

Initial concept has been improved/ is in improvement, an Update

about the current Risk Assessments and outlook to the version
2013 will be provided.

Sterile Operations Quality Risk Assessment

The initial concept from 2006 :
No FMEA analysis like PDA Technical Report 44
Several very detailed questions, from the practical experience and
regulatory requirements, are asked to the different production units
Answers: 1 (= good and fulfilling) to (2-4) to 5 (= poor or missing)

Unit Average Risk Factor (UARF), e.g. = 1,33 (average of answers)

The lower .. The better !

Sterile Operations Quality Risk Assessment

Example of API Sterile Plant: 5 units with different impacts
Unit Risk Emphasis Factor (REF): Impact Factor on Total Quality Risk

The highest Risk and Impact for microbial contamination are the
pressure differentials exposed process units, because vacuum
may pull in nonsterile air or liquids into the sterile product !

Sterile Operations Quality Risk Assessment

The initial concept from 2006 :

Unit Risk Factor(URF) = Unit Average Risk Factor x Unit Risk Emphasis Factor
1,33 = 1,33 (average of all questions) x 1 (Non sterile material / REF )

Sterile Operations Quality Risk Assessment

Sum of Unit Risk Factors (URF) = TRF (Total Risk Factor)
Example of Sterile API Plant: TRF is the final result

Lowest TRF : average of answers 1 (= Unit Average Risk Factor)

1(UARF)x1(REF)+1x3+1x5+1x3+1x5 =17
Highest TRF: average of answers 5 (= Unit Average Risk Factor)
5(UARF)x1(REF)+5x3+5x5+5x3+5x5 = 85
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Sterile Operations Quality Risk Assessment

TRF (Total Risk Factor) provides information
Non- compliance regarding microbial & endotoxins
contamination of a sterile product
Non- compliance regarding Regulatory Non- compliance of the
process/ product

The Lower (More Green) the Better and Lower Risk !

Sterile Operations Quality Risk Assessment

Sterile Operations Quality Risk Assessment

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Sterile Operations Quality Risk Assessment

Example to High Risk Plant :

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Sterile Operations Quality Risk Assessment

Example to High Risk Plant :

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Sterile Operations Quality Risk Assessment

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Sterile Operations Quality Risk Assessment

An important weak point of initial Risk Assessment: too less impact of

individual questions , e.g. examples below as RED ARROWS

Examples from the MEDIUM RISK Sterile API plant (Production Part)

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Sterile Operations Quality Risk Assessment

BUT: The Medium Risk Plant is actually a High Risk Plant !

Action:

1st Change in 2012 : several Knock- Out Questions have been included
with Ratings of 100 instead of 5 as Show Stoppers , e.g.

e.g. : Does transfer of unwrapped equipment with product contact surfaces

take place from grade A through grade B to grade A : no transfer (1) or
transfer or exposure to class B (100)
....
> 20 KO questions included

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Sterile Operations Quality Risk Assessment

Examples about Knock Out Questions (for Aseptic Filling) :
Have Clean Room operators in class A/B no exposed skin (e.g. total faecial coverage with
gogges) (1) or skin is exposed, e.g. wearing face shields or no goggles (100)
During QA oversight deviations are never observed from the written procedure (1) or
individual mistakes are observed (e.g. rapid movements of clean room operators, missing
disinfection before transfer from grade B to A (5) multiple (100)
Is your Microbiological Environmental Monitoring System well designed with an adequate
number of samples with defined worst case sampling requirements (1) or not (100)
Are the Media Fills designed with worst case parameters according cGMP and summarized
in a Risk Assessment (1) or not (100)
Is the initial qualification for the grade A/B clean room operators and maintenance
personnel/mechanics (e.g. interventions into grade A) performed by media fill (1) or not
(100)
Are follow up actions defined for critical and non critical interventions in a procedure ( e.g.
line clearance, finger sampling, disinfection , ...) (1) or not (100)
Is there no contact of gloved hands or even gowning with product contact surfaces (1) or
not (100)
.........
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Sterile Operations Quality Risk Assessment

2nd Change 2012:
Process unit Aseptic Operations has initally a fixed Unit Risk
Emphasis Factor with 3 : set a new variable REF relating on the
aseptic processing technology and push industry into advanced aseptic
technologies

A lower TRF will be achieved with an isolator filling and RABS than
conventional filling:

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Sterile Operations Quality Risk Assessment

REFs flexible : 1 3 5

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Sterile Operations Quality Risk Assessment

2007 there were 3 Risk Assessments for following processes:
Sterile API plant : 5 process units , see above
Sterile Finish Dosage Form Filling Process A: 4 process units

Non- sterile Raw material

Sterilisation Step (e.g. Sterile Filtration)
Aseptic Filling (Liquid oder Solid product after Liophilization)
Packaging and Transportation

Sterile Finish Dosage Form Filling Process B: 2 process units

Aseptic Filling of (solid/ liquid) sterile API product
Packaging and Transportation

Examples regarding Impact of REF / Aseptic Filling onto TRF / Process B

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Sterile Operations Quality Risk Assessment

Process B (2 process units)
2 process steps: Aseptic Filling and Packaging for Isolator

table 1
low bio compunding
Sterile Filtration
production blending
Filling
terminal sterilization
Packaging/Transport

Unit Average Unit Risk

Risk Factor Emphasis
Factor
Empty
0
Empty
0
Empty
0
1,4
1
Empty
0
2,0
3

Total Risk Factor

Unit Risk
Factor
0,0
0,0
0,0
1,4
0,0
6,0
7

Average : UARF of Filling e.g. 1.4

Isolator : 1 is REF
Minimum TRF for isolator : 1 +3 = 4
Maximum TRF for isolator: 5 +15 = 20
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Sterile Operations Quality Risk Assessment

Isolator example :

The plant shows a Total Risk Faktor of

Therefore the probability for product insterility is

low

Important: the initial Reference table/ rating left unchanged (no.6)

REF is 3 for Aseptic Filling
1x3 +1x3 (6) vs. 5x3 + 5x3 (30)
Total risk factor
table 3
low
medium
high
very high

process
1

process 2 process 3 process 4 process 5 process 6 process 7 process 8

17-33
34-50
51-67
68-85

6-11
12-18
18-24
25-30

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Sterile Operations Quality Risk Assessment

Sample UARF , but now Open Process (Class A without RABS/ class B background)

The plant shows a Total Risk Faktor of

Open Process : REF is 5

Minimum TRF: 5 +3 = 8
Maximum TRF: 25 +15 = 40

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Therefore the probability for product insterility is

table 1
low bio compunding
Sterile Filtration
production blending
Filling
terminal sterilization
Packaging/Transport

Unit Average Unit Risk

Risk Factor Emphasis
Factor
Empty
0
Empty
0
Empty
0
1,4
5
Empty
0
2,0
3

Total Risk Factor

TRF with an Isolator filling is always lower than Open Process !

medium

Unit Risk
Factor
0,0
0,0
0,0
7,0
0,0
6,0
13

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Sterile Operations Quality Risk Assessment

Same Example one Knock Out Question answered with 100

table 1
low bio compunding
Sterile Filtration
production blending
Filling
terminal sterilization
Packaging/Transport

Unit Average Unit Risk

Risk Factor Emphasis
Factor
Empty
0
Empty
0
Empty
0
5,0
5
Empty
0
2,0
3

Total Risk Factor

The plant shows a Total Risk Faktor of

Unit Risk
Factor
0,0
0,0
0,0
25,0
0,0
6,0
31

31

Therefore the probability for product insterility is

very high

1 KO question answered as 100 : UARF (gets automatically 5 )

Note: a knock out question overrules the TRF (e.g. isolator filling with 1 KO ) !
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Sterile Operations Quality Risk Assessment

Summary of 3 Examples above:

UARF (Filling)
TRF Isolator
TRF Conventional

1,4
7
13

Risk
Low
Medium

Knock Out (at least 1)

UARF
TRF

100
5

Risk
Very High

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Sterile Operations Quality Risk Assessment

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Sterile Operations Quality Risk Assessment

4th Change : CAPA list added - set actions from findings and good
tracking possible !
CAPA list

Date : 01.06.2012

Question
Number

Production Site : xxx

Answer (> 3)

Q403
5
Q407

Justification
SOP and documentation should be more detailed , e.g. like
B 511 Omnitrope
Currently monthly of disinfectants , no detergents used.

Name :

CAPA
required

Measure

YES

SOP update

YES

SOP update

Responsibility Timeline
production

Status

CAPA ref.

1
2

31.03.2013 open

qa micro deptm. 31.12.2012 open

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Sterile Operations Quality Risk Assessment

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Sterile Operations Quality Risk Assessment

Summary and Key Learnings:
8 different tools for 8 sterile product processes have been created
Its a great tool to identify and reduce microbiological contamination
risks and regulatory non- compliance
Goes into the very deep and requires expertise and honesty in
answering
Can be updated based on audit findings and experiences
Is a good and simple tool for senior management to control the GMP
compliance status and Risk of noncomplying products

The SOQRA is an effective tool to attain our Goal to improve and

better control our sterile products quality for
1) assurring safety for our patients and
2) achieving regulatory compliance

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Sterile Operations Quality Risk Assessment

Many Thanks to my colleagues from the Novartis SOQRA Team and
other colleagues:
Ton Bronkhorst, Alexandra Staerk, Peter Holzknecht, et. al.

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