Supplementary Training Workshop on Good
Manufacturing Practices (GMP)
CLEANING
VALIDATION
János Pogány, pharmacist, PhD,
consultant to WHO
Pretoria, South Africa, 28 June 2005
E-mail: pogany@t-online.hu
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WHO GMP
 4.11 It is of critical importance that particular
attention is paid to the validation of ... cleaning
procedures.
 16.11 Contamination of ... a product by another
material or product must be avoided. This risk of
accidental cross contamination arises from ...
products in process, from residues on equipment.
Among the most hazardous contaminants are
highly sensitizing materials ... and highly active
materials.
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WHO GMP
 16.15 Before any processing operation is started,
steps should be taken to ensure that the work area
and equipment are clean.
 16.18 Time limits for storage of equipment after
cleaning and before use should be stated and
based on data.
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Why do we validate cleaning processes?
 The cleaning process is an integral part of the
pharmaceutical manufacturing process.
 Industry should view cleaning of equipment as
the first manufacturing step. (It will have effect on
the safety, efficacy and quality of the batch to be
manufactured.)
 A cleaning process must be chosen based on
products (e.g., ARVs, solid dosage forms), objectives,
resources,
and
limitations
within
each
manufacturing company.
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Pharmaceutical Process Validation: Second
Edition, Revised and Expanded, edited by Ira
R. Berry and Robert A. Nash, Marcel Dekker,
Inc., New York – Basel – Hong Kong (1993).
GENERAL
CONSIDERATIONS
Potential Contaminants
 Chemical contamination



Product residues
Decomposition residues
Cleaning or disinfecting agent residues
 Microbiological contamination

Bacteria, moulds, pyrogens
 Unintended materials


Airborne (particulate) matter
Lubricants, ancillary material (e.g. pieces of brushes)
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Manual Cleaning Procedures
 Equipment disassembly (if required)
 Prewash and inspection (most visible material removed)
 Wash (cleaning agent, temperature, multiple steps until
visually clean)
 Initial rinses (rinse water, temperature)
 Final rinse (minimum dissolved solids, microorganisms)
 Reassembly (if required)
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Automated Cleaning Procedures
 Clean-in-place (CIP) systems (dishwasher-type
equipment)
 portable (tank and pump assemblies on wheels)
 stationery, cabinet-type
 Control system qualification (IQ, OQ and PQ:
reproducibility, water, temperature control)
 Sampling (sampling port, pause capability)
 Material supply (hard-plumbed supply lines, volume and
dispensing controls, potential impact of long storage periods)
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Documentation and Traceability





Equipment identification
Equipment use, maintenance and cleaning records
Labeling
Cleaning equipment maintenance and calibration
Utilities (water for injection (WFI), purified water, steam
and compressed air systems) qualified and validated.
 Standard Operating Procedure(s) [SOP(s)]
 Personnel training
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Cleaning Materials and Tools
 Solvents (source and quality controlled)
 Cleaning agents (acids, bases, surfactants, etc., qualified
type and brand QC controlled)
 Ancillary utilities (steam and compressed air qualified)
 Scrubbing agents (compression of placebo tablets to
clean punches and dies)
 Cleaning tools (standard sets of brushes, rags, sponges)
 Equipment (thermometers, CIP systems consisting of
tanks, metering pumps, heat exchangers, etc. maintaned and
kept in calibrated status)
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Frequency of Cleaning
 Cleaning between batches of the same product
(abbreviated procedures)
 Cleaning between batches of different products
 Cleaning after maintenance
 Cleaning after accidental contamination
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Cleaning Validation Guidelines,
Health Products and Food Branch Inspectorate,
Canada
http://www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/clean_val_gui_entire_e.html
PRESENTATION IS LIMITED TO
SOLID PHARMACEUTICAL
DOSAGE FORMS
Validation of cleaning processes
 Equipment cleaning validation may be performed
concurrently with actual production steps during process
development and clinical manufacturing. Validation programs
should be continued through full-scale commercial
production.
 All pertinent parameters should be checked to ensure the
process, as it will ultimately be run is validated. Therefore, if
critical temperatures are needed to effect cleaning, then these
should be verified. Any chemical agents added should be
verified for type as well as quantity. Volumes of wash and
rinse fluids, and velocity measurements for cleaning fluids
should be measured as appropriate.
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Validation of cleaning processes
 Validation of cleaning processes should be based
on a worst-case scenario including:


challenge of the cleaning process to show that the
challenge soil can be recovered in sufficient quantity or
demonstrate log removal to ensure that the cleaning
process is indeed removing the soil to the required
level, and
the use of stress cleaning parameters such as
overloading of contaminants, overdrying of equipment
surfaces, minimal concentration of cleaning agents
and/or minimum contact time of detergents.
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Validation of cleaning processes
 At least three (3) consecutive applications of the
cleaning procedure should be performed and
shown to be successful in order to prove that the
method is validated.
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Approach for setting limits
1. Product specific cleaning validation for all products;
2. Grouping into product families and choosing a worst
case product;
3. Grouping into risk categories (e.g., very soluble
products, similar potency, highly toxic products or
difficult to detect);
4. Setting limits on not allowing more than a certain
fraction of carryover;
5. Different safety factors for different dosage forms.
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Carry-over of product residues
 NMT 0.1% of the normal therapeutic dose of any
product to appear in the maximum daily dose of the
following product (may not be acceptable for parenterals).
 NMT 10 ppm of any product to appear in another
product (may not be acceptable for parenterals).
 No quantity of residue to be visible on the equipment
after cleaning procedures are performed. (Spiking studies
should determine the concentration at which most active
ingredients are visible.)
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Carry-over of product residues
 Residues levels that do not interfere with subsequent
manufacturing processes.
 For certain allergenic ingredients, penicillins,
cephalosporins or potent steroids and cytotoxics, the
limits should be below the limit of detection by best
available analytical methods. In practice this may
mean that dedicated plants are used for these products.
 Acceptable limits should be defined for detergent
residues after cleaning (there is no normal therapeutic dose,
thus e.g. the limit of detection of the most toxic component).
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Analytical methods
 The analytical methods used to detect residuals
or contaminants should be specific and be
validated before the cleaning validation study is
carried out.
 The specificity and sensitivity of the analytical
methods should be determined.
 The analytical method and the percent recovery
of contaminants should be challenged in
combination with the sampling method(s).
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Sampling and related issues
 Direct surface sampling (swab method)
 Indirect sampling (use of rinse solutions)
 Indirect testing such as monitoring conductivity
may be of some value
 In terms of cross-contamination, the main concern
is residue left on the internal product-contact
surfaces of the manufacturing equipment.
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An Illustrative Approach to
Cleaning Validation
ANTIRETROVIRAL
FPP(s)
Cleaning validation (master) plan
 Validation plan is based on risk analysis.
 Cleaning of individual pieces of the manufacturing
and packaging equipment is validated with products
selected as the worst case.
 The three regulatory consecutive batches can be
extended to include potentially the last batches of
one or more campaign productions
 Water solubility, toxicity and risk analysis data of
all ARV APIs.
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Risk Analysis
WATER SOLUBILITY
RISK FACTORS
T
O
X
I
C
I
T
Y
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LOW
MODERATE
HIGH
HIGH
High
High
Moderate
MODERATE
High
Moderate
Moderate
Moderate
Moderate
Low
LOW
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Illustrative Indicators for Toxicity
LD50 (rat or /mouse/)
Category
< 200 mg/kg
High
200 – 2000 mg/kg
Moderate
> 2000 mg/kg
Low
Composite toxicity indicators may take into account
high activity, hypersensitizing indicators, etc.
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Illustrative Categories for Solubility
Descriptive Term for Solubility (Ph.Eur.)
Very soluble (< 1 ml/g)
Freely soluble (1 – 10 ml/g)
Soluble (10 – 30 ml/g)
Category
High solubility (<30 ml/g)
LD
50 (rat or /mouse/)
Moderately
soluble Category
< 200 mg/kg
High
Sparingly
soluble
(30
– 100 ml/g)
200 – 2000 mg/kg
Moderate
soluble (100Low
– 1000 ml/g)
>Slightly
2000 mg/kg
Very slightly soluble (1000 – 10000 ml/g)
Practically insoluble (> 1000 ml/g)
Relatively insoluble
Insoluble
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Moderate solubility
(30 – 1000 ml/g)
Low solubility
(> 1000 ml/g)
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Illustrative Risk Analysis of ARV APIs
API
TOXICITY
INDICATOR
SOLUBILITY IN WATER
Abacavir
Moderate
High
Efavirenz
Low
Low
Indinavir sulfate
Low
High
Lamivudine
Low
High
Nevirapine
Low
Low
Ritonavir
Low
Low
Saquinavir
Low
Low
Stavudine
Low
High
Zidovudine
Low
High
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77 mg/mL at 25oC
100 mg/ml
90 μg/ml at 25°C
20 mg/mL at 25oC
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Pharmaceutical Technology Europe,
1 February 2004
Griet Van Vaerenbergh
Cleaning Validation Practices:
Using a One-Pot Processor
Summary
This article describes the use of a one-pot processor for the
cleaning and cleaning validation of two drug compounds:
water-soluble theophylline and water-insoluble mebendazole.
Both substances were produced using wet granulation and
microwave drying, after which the processor was cleaned
using its clean-in-place (CIP) system. Swab samples were
taken from areas considered critical during processing and
analysed for remains of active ingredient. It was concluded
from the results that the processor's CIP system is capable of
removing both APIs to a level well within accepted
regulations.
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One-pot processor
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Acceptance criteria
 10-ppm criterion
 absolute mass criterion: NMT 1 µg/cm2
 for residual detergent traces: the conductivity of
the final rinsing water should be lower than the
conductivity of a 1:1000 dilution of the detergent
solution.
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Acceptable quantity of an API per swab
Initial trials on the swab
determined that the
theophylline recovery was
between 95–100%.
Nevertheless, the Factor 2
for swab yield was
maintained in the formula for
calculating the acceptance
criteria, to account for any
operator influence.
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Theophylline sample analysis
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Mebendazole sample analysis
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Study conclusions
This study has shown that the CIP system of this
one-pot processor is capable of removing both
water-insoluble mebendazole and water-soluble
theophylline from the system to a level significantly
less than acceptable maxima. Although certain areas
show a larger variation in results than others, the
reproducibility of the cleaning cycle can be
considered good, as the results for all areas were
always consistent.
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Main Points Again
 Validation of equipment cleaning processes is
critical to safety, efficacy and quality of FPPs.
 There is no generally accepted approach to cleaning
validation.
 One possible approach is risk analysis and selection
of worst case for each item of equipment.
 CIP equipment must be qualified and the cleaning
processes must be validated.
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