Fs Cleaning Validation Krk08

Cleaning validation of clean-
rooms and preparation

equipments
Dr Farshid SADEGHIPOUR
Head of production
Central Pharmacy, Geneva University Hospitals
EAHP Foundation Seminar:

“Patient Safety; More About Compounding"
23-25 May, 2008
Krakow, Poland
Useful Definitions
Cleaning validation of clean-rooms and preparation equipments
Cleaning :
Removal of soil particles /product residues
from surfaces by the use of chemical
“Patient Safety; More About Compounding”
agents and manual or mechanical action

23-25 May 2008, Krakow, Poland
EAHP Foundation Seminar,
Sanitization (Disinfection) :
Destruction of vegetative state organisms
1
3
Cleaning validation of clean-rooms and preparation equipments Legal Basis

“Particular attention should be accorded to
the validation of … cleaning procedures”
(WHO)
“Cleaning validation should be performed in

order to confirm the effectiveness of a
cleaning procedure” (PIC/S, EU GMP)

“The data should support a conclusion that
residues have been reduced to an
‘acceptable’ level” (FDA)
New in Hospital Pharmacy

Development of the sterile drugs prepared

by aseptic techniques
Centralization of the preparation of

cytotoxic drugs in hospital pharmacies

2
5
Cleaning validation of clean-rooms and preparation equipments Problems
Cross-contamination of the preparations

Microbiological problems due to poor
cleaning
Chemical contamination of the operators

Cross-contamination of the
6
preparations
Hospital Pharmacy Production units :

a Multi-product facility
an effort of validating the cleaning of each
piece of equipment which has been exposed

to a product
if not, considering seriously the possibility

and the cost of permanently dedicating this
equipment to a single product
3
Cross-contamination of the
7

preparations
Hospital Pharmacy Production units :
a Multi-product facility
For each Equipment :
cleaning validation is performed during process

development
Test-until-clean not considered acceptable

The validation methodology :

Products which simulate the physicochemical
properties of the substance to be removed may
be considered for use instead of the substances
themselves, when such substances are either
toxic or hazardous
Microbiological aspects
There should be some documented evidence that

routine cleaning and storage of equipment do not
allow microbial proliferation : equipment should
be dried before storage
The control of the bioburden through adequate

cleaning and storage of equipment is important to

ensure that subsequent sterilization or sanitization

procedures achieve the necessary assurance of
sterility
4
9

Operators Chemical contamination
Preparation of cytotoxic drugs and

other hazardous drugs
Contamination due to aerosol formation

and drugs sublimation/evaporation

Spill management
After production cleaning procedures
and the risk assessment
10
Operators Chemical contamination
The risk associated with occupational low-

level exposure has not been determined
Without evidence to the contrary, risk is
assumed to be present and proportional to

exposure in a dose-dependent fashion

A GMP compliant Cleaning validation
covers also operators risks
5
11

Defining the problem
Product (patient) oriented
Cross contamination
Residues
Microbiology
Operator oriented
Contamination risk
Accumulation problem due to poor cleaning
12
Ideal cleaning solution

Non-toxic to operators
Non-flammable
Fast-drying but not reasonably so
Not harmful to clean room surfaces

Not likely to leave particles or residue that

could be harmful to the product

Effective in removing undesirable
contamination
Reasonably priced
6
13

Possible contaminants
Product residues
Cleaning agent residues and breakdown
Airborne matter
Lubricants, ancillary material

Decomposition residues
Bacteria, mould and pyrogens
14
Strategy on cleaning validation

Product contact surfaces

After product changeover
Bracketing products for cleaning

validation
Periodic re-evaluation and revalidation
Training Modules on Good Manufacturing Practices, WHO, EDM , 01.2002
7
15
Cleaning validation of clean-rooms and preparation equipments Cleaning Validation Protocol I

Objective of the validation
Responsibility for performing and
approving validation study
Description of equipment to be used

Interval between end of production and

cleaning, and commencement of
cleaning procedure
16
Cleaning Validation Protocol II

Cleaning procedures to be used

Any routine monitoring equipment used
Number of cleaning cycles performed
consecutively
Sampling procedures used and rationale

Sampling locations (clearly defined)
8
17
Cleaning validation of clean-rooms and preparation equipments Record of Cleaning Validation

Analytical methods including Limit of
Detection (LOD) and Limit of
Quantification (LOQ)
Acceptance criteria and rationale

When revalidation will be required

Must have management and QA
involvement
18
Results and reports

Cleaning record signed by operator,

checked by production and reviewed by
QA
Final Validation Reports, including

conclusions
9
19
Cleaning validation of clean-rooms and preparation equipments Personnel
Manual cleaning methods are difficult to

validate
Must have good training

Must have effective supervision

Cannot validate people; can measure

proficiency
20
Microbiological aspects
Include in validation strategy

Analyze risks of contamination
Consider equipment storage time

Equipment should be stored dry

Sterilization and pyrogen contamination
10
21
Cleaning validation of clean-rooms and preparation equipments How to sample

Swab/swatch
Rinse fluid
Placebo
The sample transport and storage

conditions should be defined
22
Swab samples
Direct sampling method

Reproducibility
Extraction efficiency
Document swab locations

Disadvantages

inability to access some areas

assumes uniformity of contamination
surface
must extrapolate sample area to whole
surface
11
23
Cleaning validation of clean-rooms and preparation equipments Rinse samples

Indirect method
Combine with swabs
Useful for cleaning agent residues
pH, conductivity, TOC

Insufficient evidence of cleaning

Sample very large surface areas
Need specific and sensitive analytical
method Training Modules on Good Manufacturing Practices, WHO, EDM , 01.2002
24
Analytical methods I
Validate analytical method

Must be sensitive assay procedure:
HPLC, GC, HPTLC
TOC
pH
conductivity
UV
ELISA Training Modules on Good Manufacturing Practices, WHO, EDM , 01.2002
12
25
Cleaning validation of clean-rooms and preparation equipments Analytical methods II

Check:
Precision, linearity, selectivity
Limit of Detection (LOD)
Limit of Quantification (LOQ)

Recovery, by spiking
Consistency of recovery
26
Setting limits I
Regulatory authorities do not set limits

for specific products
Logically based
Limits must be practical, achievable and

verifiable
Allergenic and potent substances

Limit setting approach needed
13
27
Cleaning validation of clean-rooms and preparation equipments Setting limits II

Uniform distribution of contaminants not
guaranteed
Decomposition products to be checked
Setting limits; cleaning criteria:

visually clean
10ppm in another product
0.1% of therapeutic dose
28
Setting limits: “Visually clean”

Always first criteria

Can be very sensitive but needs
verification
Use between same product batches of

same formulation
Illuminate surface
Spiking studies
14
29
Cleaning validation of clean-rooms and preparation equipments Setting limits: “10 ppm”
Historical
In some poisons regulations
Pharmacopoeias limit test
Assumes residue to be harmful as heavy

metal
Useful for materials for which no

available toxicological data
Not for pharmacologically potent
material Training Modules on Good Manufacturing Practices, WHO, EDM , 01.2002
30
Setting limits: not more than 0.1%
Proportion of MINIMUM daily dose of

current product carried over into
MAXIMUM daily dose of subsequent
product
Need to identify worst case
15
31
Cleaning validation of clean-rooms and preparation equipments Auto-inspection questions

How is equipment cleaned?
Are different cleaning processes required?
How many times is a cleaning process
repeated before acceptable results are
obtained?
What is most appropriate solvent or

detergent?
At what point does system become clean?
What does visually clean mean?
When prefer to use disposable devices?
32
Operator Validation
16
33
Operator Validation
Cleaning validation of clean-rooms and preparation equipments Validation Elements
Validation of each operator evaluating his
capacity to control chemical contaminations
during cytotoxic preparations
Scheduled at the end of the work session
with a second controlling operator

A total validation time of 60 minutes

Worst conditions Concept

Negative pressure isolator
A total cleaning of the isolator after the
validation
R. Ing & al., GSASA Congress Zurich, 2005,
34
Operator Validation
Validation Materials
A non-toxic tracer : 0,1 M Quinine HCl

solution
KCL 1 M 50 mL vials
NaCl 0.9% solution infusion bags

Sterile : Cytosafes, syringes, needles,

stoppers, Transfer-set, tubing, connectors,

gloves, working pad, waste bag, …
17
35
Operator Validation
Cleaning validation of clean-rooms and preparation equipments Validation Procedure
Sterile gloves over the isolator gloves

Dissolve the quinine vial with the
solvent to have a final 0.1 M solution
(drug reconstitution simulation)

Preparation of 4 different drug

simulation
36
Operator Validation
Validation Procedure
20
x =
18
Dr Farshid SADEGHIPOUR Dr Farshid SADEGHIPOUR
EAHP Foundation Seminar, EAHP Foundation Seminar,
“Patient Safety; More About Compounding” “Patient Safety; More About Compounding”
23-25 May 2008, Krakow, Poland 23-25 May 2008, Krakow, Poland
Cleaning validation of clean-rooms and preparation equipments Cleaning validation of clean-rooms and preparation equipments
Quinine quantity [µmol] / Number of spots
(CAMAG)
UV light
Results
Working pad
Operator Validation
Operator Validation
(Perkin Elmer LS 40)
Operator
Fluorimetric detection
Detection equipment
Quinine quantity
Number of spots
C. Ziewitz, Pharmacy HUG, 2008

38
37
19
39
Operator Validation
Cleaning validation of clean-rooms and preparation equipments Discussion
Detected quantities:
0.116 – 0.441 µmol of Quinine
(= 1.16 – 4.41 µl of the Quinine 0.1M solution)
« Acceptable level » according to FDA:

0.1% of the daily dose of the active ingredient
5-FU 50 mg/ml, Daily dose 1000 mg

« acceptable level » → 100 µg

Detected quantity equivalence : min → 6 µg
max → 22 µg
Vincristine 1 mg/ml, Daily dose 2 mg
« acceptable level » → 2.0 µg
Detected quantity equivalence : min → 1.6 µg
max → 4.6 µg
C. Ziewitz, Pharmacy HUG, 2008
40
General Conclusions
Need for a cleaning validation strategy

Assess each situation on its merits
Scientific rationale must be developed
equipment selection
contamination distribution
significance of the contaminant
“Visually clean” may be all that is required

Disposable devices each time it is possible
Developing non-toxic evaluation methods
20
41
Cleaning validation of clean-rooms and preparation equipments References

Supplementary Training Modules on
Good Manufacturing Practices, WHO, EDM ,
01.2002
FDA. "Guide to Inspectors of Validation of
Cleaning Procedures," 1993

Health Canada, Health Products and Food Branch

Inspectorate, "Good Manufacturing Practices -

Cleaning Validation Guidelines, 2000
21

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Cleaning validation of clean-

rooms and preparation

EAHP Foundation Seminar:

agents and manual or mechanical action

Cleaning validation of clean-rooms and preparation equipments Legal Basis

 “Cleaning validation should be performed in

cleaning procedure” (PIC/S, EU GMP)

New in Hospital Pharmacy

 Development of the sterile drugs prepared

 Centralization of the preparation of

cytotoxic drugs in hospital pharmacies

Cleaning validation of clean-rooms and preparation equipments Problems

 Cross-contamination of the preparations

 Chemical contamination of the operators

 Hospital Pharmacy Production units :

piece of equipment which has been exposed

 if not, considering seriously the possibility

Cleaning validation of clean-rooms and preparation equipments

 cleaning validation is performed during process

 Test-until-clean not considered acceptable

 The validation methodology :

 There should be some documented evidence that

 The control of the bioburden through adequate

cleaning and storage of equipment is important to

ensure that subsequent sterilization or sanitization

Cleaning validation of clean-rooms and preparation equipments

 Preparation of cytotoxic drugs and

 Contamination due to aerosol formation

and drugs sublimation/evaporation

Operators Chemical contamination

 The risk associated with occupational low-

assumed to be present and proportional to

exposure in a dose-dependent fashion

Cleaning validation of clean-rooms and preparation equipments

 Accumulation problem due to poor cleaning

Ideal cleaning solution

 Not harmful to clean room surfaces

 Not likely to leave particles or residue that

could be harmful to the product

Cleaning validation of clean-rooms and preparation equipments

 Lubricants, ancillary material

Strategy on cleaning validation

 Product contact surfaces

 Bracketing products for cleaning

 Periodic re-evaluation and revalidation

Training Modules on Good Manufacturing Practices, WHO, EDM , 01.2002

Cleaning validation of clean-rooms and preparation equipments Cleaning Validation Protocol I

 Description of equipment to be used

 Interval between end of production and

Cleaning Validation Protocol II

 Cleaning procedures to be used

 Sampling procedures used and rationale

Training Modules on Good Manufacturing Practices, WHO, EDM , 01.2002

Cleaning validation of clean-rooms and preparation equipments Record of Cleaning Validation

 Acceptance criteria and rationale

 When revalidation will be required

Results and reports

 Cleaning record signed by operator,

 Final Validation Reports, including

Training Modules on Good Manufacturing Practices, WHO, EDM , 01.2002

Cleaning validation of clean-rooms and preparation equipments Personnel

 Manual cleaning methods are difficult to

 Must have good training

 Must have effective supervision

“Cleaning validation should be performed in

Development of the sterile drugs prepared

Centralization of the preparation of

Cross-contamination of the preparations

Chemical contamination of the operators

Hospital Pharmacy Production units :

if not, considering seriously the possibility

cleaning validation is performed during process

Test-until-clean not considered acceptable

The validation methodology :

There should be some documented evidence that

The control of the bioburden through adequate

Preparation of cytotoxic drugs and

Contamination due to aerosol formation

The risk associated with occupational low-

Accumulation problem due to poor cleaning

Not harmful to clean room surfaces

Not likely to leave particles or residue that

Lubricants, ancillary material

Product contact surfaces

Bracketing products for cleaning

Periodic re-evaluation and revalidation

Description of equipment to be used

Interval between end of production and

Cleaning procedures to be used

Sampling procedures used and rationale

Acceptance criteria and rationale

When revalidation will be required

Cleaning record signed by operator,

Final Validation Reports, including

Manual cleaning methods are difficult to

Must have good training

Must have effective supervision

Cannot validate people; can measure

Include in validation strategy

Consider equipment storage time

Equipment should be stored dry

Sterilization and pyrogen contamination

The sample transport and storage

Direct sampling method

Document swab locations

inability to access some areas

pH, conductivity, TOC

Insufficient evidence of cleaning

Validate analytical method

Limit of Quantification (LOQ)

Regulatory authorities do not set limits

Limits must be practical, achievable and

Allergenic and potent substances

Setting limits; cleaning criteria:

Always first criteria

Use between same product batches of

Assumes residue to be harmful as heavy

Useful for materials for which no

Proportion of MINIMUM daily dose of

Need to identify worst case

What is most appropriate solvent or

A total validation time of 60 minutes

Worst conditions Concept

A non-toxic tracer : 0,1 M Quinine HCl

NaCl 0.9% solution infusion bags

Sterile : Cytosafes, syringes, needles,

Sterile gloves over the isolator gloves

Preparation of 4 different drug

« Acceptable level » according to FDA:

5-FU 50 mg/ml, Daily dose 1000 mg

« acceptable level » → 100 µg

Need for a cleaning validation strategy

significance of the contaminant

“Visually clean” may be all that is required

Health Canada, Health Products and Food Branch