Cleaning Validation: Acme Pharmaceuticals
Cleaning Validation: Acme Pharmaceuticals
Cleaning Validation: Acme Pharmaceuticals
Cleaning Validation
Acme Pharmaceuticals
Dhamrai, Dhaka
4th November 2008
Presentation Contents
The importance of effective
cleaning
Definitions and explanations of
cleaning validation
Terminology and regulations
Factors affecting the levels of
cleaning validation required
Documentation involved
(protocols and validation master
plans)
Cleaning validation process
Presentation Contents
Validation considerations /
cleaning processes / equipment
design considerations
Limits Levels of carryover
Methods of detection
Supporting Quality Systems
What are the risks of not
performing validation
Cleaning Validation: Definition
EU Guide - Annex 15
USA - 21 CFR 211.67 - Equipment cleaning and
maintenance
FDA - Guide To Inspections Of Validation Of
Cleaning Processes (July, 1993)
EU Guide - Annex 18 (GMP for APIs) - 12.7
PICS document PI 006 July 2004 Recommendations
on cleaning validation
Levels of Cleaning Validation
Validation Plan:
A VP is a structured, detailed plan of work which
provides information about how all of the validation
work is going to be controlled
A cleaning validation plan is generated to cover the
approach to and requirements for cleaning validation
Validation Report:
An approved document that closes out a
particular qualification activity, giving details
and a review of the results obtained and a
conclusion as to the success of the exercise
Documentation: Rationales and Protocols
Rationales:
Their purpose is to provide an agreed / approved explanation
and justification for an approach to and acceptance criteria for a
cleaning validation exercise
Separate or combined rationale documents may be raised to
cover:
-allowable limits for carryover for process systems.
-rationale for qualification
-cleaning matrix
-sampling regimes
All these areas can be covered in cleaning VPs and protocols:
the choice is yours
Documentation: Rationales and Protocols
Validation Protocol:
An approved document that:
-details the scope and objective of work to be carried out
-describes the system under test
-provides details of the strategy for validation testing
-describes the tests to be carried out, in terms of test objective,
methodology and acceptance criteria
-details the responsibilities of the personnel involved
Supported by detailed test sheets
Cleaning Validation Process (Prospective)
Design of industrial
Formulation of acceptable
Facility VMP equipment including Cleaning VP
levels of carryover
cleaning equipment
Build / implementation
Development of cleaning
of facility / equipment
procedures Cleaning Validation
(to approved protocol)
PQ of Process
No
Develop new rationale Generate Protocols
Are levels OK?
for limits
Yes
Generate Reports
No
Are methods of
Develop and validate
detection / sampling OK
new methods
and validated?
Generate Final Reports
Yes
Yes
Pre-requisites for Cleaning Validation
There must be an effective, consistent and safe cleaning procedure in
place with a documented development history
All operators must be trained in both the cleaning procedure and any
aspects of the cleaning qualification protocol that pertains to their
activities during the qualification
Where there are a large number of products manufactured on the same equipment,
it is acceptable to select a matrix of products that will cover the entire range
Drivers for this approach could be the time / cost / production schedules
The matrix must be truly representative of the range of materials used, i.e., the
potency and toxicity of materials, diversity and similarity of materials, difficulty of
cleaning, cleaning procedure and cleaning materials used
The rationale for the acceptance criteria chosen must be very strong and cover
worst case scenarios and potency / toxicity
All products and dosage forms need to be considered unless deliberately set
outside of the scope of the exercise
Risks relating to matrix approach:
-if one element fails it can all fail
-the exercise is not complete until all elements have been covered
-if rationale for choice of matrix and acceptance criteria is weak, the validation
has no basis
Cleaning Process Considerations
All product contact surfaces must be identified
Equipment should be cleaned according to detailed and written procedures and
stored only in a clean and dry condition (EU GMP guide)
Manual cleaning is inherently variable and should be avoided wherever possible
if unavoidable then:
- procedures must be very clear and detailed
-operator training and competence must be reviewed on an annual basis
-SOP and training should be regularly monitored (every 12 months?)
The cleaning process should not contaminate the equipment
-must demonstrate the removal of any cleaning agent to acceptable levels
(this may be water!!!)
-need to take care that portable CIP units and automated washing machines
do not cross-contaminate
Automated methods of cleaning are preferred as they provide a much greater
level of consistency
Cleaning Process Monitoring
The design of the equipment should be carefully examined. Critical areas (those
hardest to clean) should be identified, particularly in large systems that employ
semi-automatic or fully automatic clean-in-place (CIP) systems
Dedicated equipment should be used for:
-products which are difficult to remove (e.g. tarry or gummy residues in the bulk
manufacturing)
-for equipment which is difficult to clean and or poses greatest risk of cross-
contamination (e.g. filling heads or dosators)
-products with a high safety risk (e.g. biologicals or products of high potency which
may be difficult to detect below an acceptable limit)
Clean in place systems have the advantage of reducing / eliminating the need to
dismantle equipment but increase the effort during validation
The use of automated washers should be considered for washing of ancillary
items, e.g. utensils / spool pieces
Equipment Design
CIP systems should maximise the usage of process equipment and pipe-
work to ensure maximum levels of cleaning
The total area of contact surfaces should be known
Surface finishes should be considered in terms of ease of cleaning
Some CIP systems use PLC controllers (automated) Make sure you
consider computer system validation
Piping and valves should be tagged and easily identifiable by the
operator performing the cleaning function. Sometimes, inadequately
identified valves, both on prints and physically, have led to incorrect
cleaning practices (FDA Guide)
Supporting equipment systems should be deigned to minimise the risk of
contamination and cross-contamination (extraction, HVAC, vacuum,
wasteetc)
Limits - Levels of Carryover
Levels of allowable carryover from one product to another must be
based upon potential patient risk and on worst case scenarios.
Factors to consider:
-similarity / diversity of therapeutic action and toxicity profiles
-batch sizes and amounts of active material involved
-when more than one stage is involved in a process the cumulative
effect of all the stages in the process must be calculated
-calculated acceptance criterion limits which are outside the
capability of current analytical methodology
-the presence of antibiotic sensitising agents and the cytotoxicity
of products
-penicillin and non-penicillin products must not be manufactured
in the same building
Limits - Levels of Carryover
TOTAL 256.00 mg
MACO calculations A-B (Atenolol to Digoxin)
Min therapeutic daily dose A X Total amount of active B in grams in next batch
max daily dose of product B
OR Alternatively
MAC in mg =
Harm to patients !