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Cross contamination risk assessment in multi-product facilities: case

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Gedeon Richter Plc
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I. Ziegler, A. Boda-Szcsi, G. Szab, B. Lugosi-Czangr, . Bnszegi, Cs. Blint

Cross contamination risk assessment in multi-product facilities:

case studies on steroid hormones and cytotoxic products

SMis 1st Highly Potent Active Pharmaceutical Ingredients Conference

London, United Kingdom, 22nd and 23rd May, 2017.
About Gedeon Richter

The company was established in

1901 by Mr. Gedeon Richter, a
talented young pharmacist.
Success was founded on the
professionalism and Richters
relentless dedication to research
and innovation. He started to
manufacture drugs on industrial
bases in 1907. The company
became a joint stock company in
1924.
Now, Richter is the biggest
Hungarian pharmaceutical
manufacturer.
1872-1944
About Gedeon Richter
then
About Gedeon Richter

now
About Gedeon Richter
Now the Richter Group has 7 subsidiaries and 29 repr. offices.
About Gedeon Richter
Disclaimer

Any views or opinions

expressed or presented
are solely those of the
author and do not
necessarily represent
those of any authority
or Gedeon Richter.
Objectives

EU GMP: Cross contamination guideline,

Chapters 3 & 5 and the importance of
toxicological concerns
Complexity of cross contamination risk - role
of premises and production in failure modes
Case studies:
1. Steroid hormonal API production
2. Manufacturing parenteral cytotoxic products
 EU guide on cross contamination

Revision of EU GMP
Chapters 3 (Premises
and equipments)
and 5 (Production)
simultaneously
How to handle
risk of cross
contamination?
technical guide
Risk-MAPP classification

Mix-ups
Retention cleaning validation
Mechanical transfer
Air transfer

Relevance of EU GMP
Chapters 3. and 5.
Operational control measures

Partial dedication of premises/equipment

Dust containment system
Closed system processing
Gowning control
Controls for campaign manufacture, etc.
Program aimed to comply with cross
contamination requirements

Projects consists of the following parts:

Protocol in line with our risk assessment system
(ID code, register and archive, etc).
R part 1.: cleaning and CV, cleaning of equipments,
cleaning of premises establishment of new
cleaning limits based on PDE values!
R part 2.: review of HVAC and other supply
systems
R part 3.: review of the personal and material flow
Program aimed to comply with cross
contamination requirements

Projects consists of the following parts, cont.:

R part 4.: Risk identification of products and production
cleanability? solubility? open/closed operations? static
charge? viscous component? number of batches? Etc.
R part 5.: Failure mode and effects analysis based on
the actual technology(ies) focusing on cross
contamination
Summary report
Program: Report part 5 - FMEA

Risk Identification :
E.g. brain storming
Risk ranking:
E.g. FMEA engineering aspects
Scoring by Probability, Severity, Detectability
(being hidden!)
 Program: Report part 5 - FMEA

Risk ranking:
Probability

Probability
Score
Event in connection with batches Event in general
10 One or more in a batch One or more daily
7 One or more in 50 batches One or more monthly
5 One or more in 600 batches One or more annually
3 Once in more then 600 batches Once per 1-5 years
Once during more then five
1 -
years time
 Program: Report part 5 - FMEA

Risk ranking cont.:

Severity

Severility
Score
PDE (g/nap) Event in general
Critical serious injury, death, irreversible
10 <10
effects
7 10 -100 Major side effects, birth defects
5 1 00 1 000 reversible effects
3 1 000 10 000 Minor irritation, mild reversible effects
1 10 000 100 000 There is no appreciable effect
 Program: Report part 5 - FMEA

Risk ranking cont.:

Detectability

Score Imperceptibility

10 Current methods can not detect it.

7 Uncontrolled, but it can be identified during the production
5 Statistical sampling or documented manual control
3 Automatic control or manual control documented amply
1 Obvious or automatically monitored and alarmed
Program: Report part 5 - FMEA

Risk filtering:
Classification - criticality

Risk level Acceptability or criticality

Unacceptable. The shutdown of production
K3 > 490
should be considered
further risk reduction measurements before
350 - 490
resuming production
K2
Consider additional or more detailed
100 - 349
investigation
Acceptable, but the prospect of continuous
30 - 99
K1 improvement has to be considered
< 30 Generally accepted
Program aimed to comply with cross
contamination requirements

But what about the toxicological concerns?

Program: Report part 4 Cross
contamination risk

Review of cleaning limits and cross contamination

risks at a production area
Oral/ parenteral/ transdermal PDE values were
obtained from our toxicologist
Scoring by Production characteristics formed the
base for the quantification of cross contamination
risk product risk, vulnerability, total risk
Case study 1.: Steroid Plant
Steroid hormonal API production

Products at production area NORII:

12 APIs: 4 crude and 8 crystalline
All the cleaning processes are validated.
Premises:
Unclassified 16 (with equipments)
Class D: 2
Program aimed to comply with cross
contamination requirements

What is taken into account?

Solubility
Toxicity (PDE/ADE), MD dose
Statistics: No. batches, No. Campaigns
Open operations
Manufacturing time
Experience on cleaning
Experience on production
Viscous / static component?
History, etc.
 Case study 1.: Steroid Plant
Steroid hormonal API production
Some examples.

M factor

Batches
C factor
E factor

time (h)

BS (kg)

in 2016

Vulner.
Prod.
Proc.
MDD PDE

Risk
No.
API P
mg/day mg/day

LEL CY 0.75 2.5.10-5 1 4 43 7 12 34 22 10560000 0.2671

LAC CU 0.85 0.001 1 4 53 8 13 39 24 312000 0.2833

LAC CY 0.85 0.001 1 4 34 5 10 35 16 160000 0.2429

MAT CU 0.25 0.003 1 1 39 7 9 35.5 24 72000 0.0634

MAT CY 0.25 0.003 1 1 29 5 7 30 24 56000 0.0583
MIN CU 6.0 0.006 1 2 65 6 9 27.3 13 1950 1.9636
MIN CY 6.0 0.006 1 2 55 7 10 24 14 2333.3 2.5
Case study 1.: Steroid Plant
Steroid hormonal API production
Case study 1.: Steroid Plant
Steroid hormonal API production
Case study 1.: Steroid Plant
Steroid hormonal API production
Case study 1.: Steroid Plant
Steroid hormonal API production
Case study 1.: Steroid Plant
Steroid hormonal API production
Case study 1.: Steroid Plant
Steroid hormonal API production
Case study 2.: Injection Plant
Manufacturing parenteral cytotoxic products

Products at production area CITO:

5 different products, 3 APIs
Monitoring: cleaning + environmental aspects!
Premises:
Class D: 11
Class C: 4
Class A/B: 5
Un-classified, monitored: 3
Not classified: 2
Case study 2.: Injection Plant
Manufacturing parenteral cytotoxic products
Case study 2.: Injection Plant
Manufacturing parenteral cytotoxic products
Case study 2.: Injection Plant
Manufacturing parenteral cytotoxic products

In the absence of data usually needed for the application of one of

the established risk assessment methods, i.e. data from
carcinogenicity long-term studies or data providing evidence for a
threshold mechanism of genotoxicity, implementation of a generally
applicable approach as defined by the Threshold of Toxicological
Concern (TTC) is proposed. A TTC value of 1.5 g/day intake of a
genotoxic impurity is considered to be associated with an
acceptable risk.
Case study 2.: Injection Plant
Manufacturing parenteral cytotoxic products
Case study 2.: Injection Plant
Manufacturing parenteral cytotoxic products
Summary
Evaluation of cross contamination risk is a
structured review of an existing
manufacturing area, its equipments,
processes and systems according to a new
point of view.
At GMP-compliant manufacturing areas, critical or dramatic
observations are not expected, but it is good chance to
further improve quality,
review the processes and procedures,
notice if certain practical steps/ details are not regulated
sufficiently,
notice if processes of similar manufacturing areas differ from
each other, so they can be standardized (within site or within
company).
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