Title: Supplementary Training Workshop on Good Manufacturing Practices (GMP)
1Supplementary 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_at_t-online.hu
2WHO 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.
3WHO 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.
4Why 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.
5Pharmaceutical 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).
6Potential 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)
7Manual 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)
8Automated 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)
9Documentation 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
10Cleaning 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)
11Frequency of Cleaning
- Cleaning between batches of the same product
(abbreviated procedures) - Cleaning between batches of different products
- Cleaning after maintenance
- Cleaning after accidental contamination
12Cleaning Validation Guidelines,Health Products
and Food Branch Inspectorate, Canada
http//www.hc-sc.gc.ca/hpfb-dgpsa/inspectorate/cl
ean_val_gui_entire_e.html
- PRESENTATION IS LIMITED TO SOLID PHARMACEUTICAL
DOSAGE FORMS
13Validation 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.
14Validation 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.
15Validation 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.
16Approach for setting limits
- Product specific cleaning validation for all
products - Grouping into product families and choosing a
worst case product - Grouping into risk categories (e.g., very soluble
products, similar potency, highly toxic products
or difficult to detect) - Setting limits on not allowing more than a
certain fraction of carryover - Different safety factors for different dosage
forms.
17Carry-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.)
18Carry-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).
19Analytical 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).
20 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.
21An Illustrative Approach to Cleaning Validation
22Cleaning 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.
23Risk Analysis
RISK FACTORS
24Illustrative Indicators for Toxicity
Composite toxicity indicators may take into
account high activity, hypersensitizing
indicators, etc.
25Illustrative Categories for Solubility
26Illustrative Risk Analysis of ARV APIs
27Pharmaceutical Technology Europe, 1 February
2004Griet Van Vaerenbergh
- Cleaning Validation Practices Using a One-Pot
Processor
28Summary
- 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.
29One-pot processor
30Acceptance 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 11000 dilution of the
detergent solution.
31Acceptable quantity of an API per swab
- Initial trials on the swab determined that the
theophylline recovery was between 95100.
Nevertheless, the Factor 2 for swab yield was
maintained in the formula for calculating the
acceptance criteria, to account for any operator
influence.
32Theophylline sample analysis
33Mebendazole sample analysis
34Study 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.
35Main 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.