Validation of Pharmaceutical Process

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

Documented evidence that an approved cleaning procedure

will provide equipment, which is suitable for processing
medicinal products EU GMP Guide
Cleaning Validation is documented evidence that an
approved cleaning procedure will provide equipment which
is suitable for processing of pharmaceutical products or
active pharmaceutical ingredients (APIs)
PICS Guide 006-2
 Cleaning Validation is a Confirmation Exercise:

There must be an effective, consistent and safe cleaning

procedure in place prior to the commencement of the
validation work
All development or optimisation work around cleaning
equipment and processes must be completed prior to entering
cleaning validation activities.
 Cleaning Validation

Sufficient consecutive executions and verifications of the

cleaning process must be completed to demonstrate
consistency (generally 3 times)
As with any validation exercise, all activities must be
performed in accordance with pre-approved protocols
EU Guide - Annex 15: Paragraphs 36 - 42 are dedicated
to cleaning validation
 Regulations / Guidelines

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

The level of cleaning validation required will be based

on a number of factors:
-the level of dedication of equipment and product contact parts
-the complexity of the equipment and cleaning operation
-the types of products involved and the risk to the patient
-other product components and cleaning materials (e.g. detergents)
that may pose a risk to patients when carried over to subsequent
products
-economic factors
 Dedicated Vs Non-dedicated

Level of Operational &

Validation Compromise Equipment Cost
Required

Non-dedicated Cost cGMP Dedicated

Drivers Drivers
 Documentation: Plans and Reports

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)

Process / product Cleaning agents /

development methods identified

Cleaning method developed

Scale-up /
+ sampling techniques /
industrialisation
methods of detection

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

Facility and equipment

IQ and OQ including Evaluation of cleaning
cleaning equipment SOPs Cleaning Validation
PQ Report
Report

Validation Summary Report

 Cleaning Validation Process (Retrospective)

Existing Production Existing Cleaning Process

Operation (no validation)

Generate Cleaning Validation

Establish / review / revise Plan (may cover cleaning
acceptable levels equipment IQ / OQ)
of carryover

No
Develop new rationale Generate Protocols
Are levels OK?
for limits
Yes

Review existing cleaning Execute Protocols

process / equipment /
methods of detection

Generate Reports
No
Are methods of
Develop and validate
detection / sampling OK
new methods
and validated?
Generate Final Reports
Yes

Are cleaning No Develop / evaluate new and

procedures validated procedures
/ equipment OK? and / or equipment

Yes
 Pre-requisites for Cleaning Validation
There must be an effective, consistent and safe cleaning procedure in
place with a documented development history

The challenge to the cleaning procedure must be consistent

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

All sampling and analytical procedures must be validated and levels of

recovery established and incorporated into the acceptance criteria
 Pre-requisites for Cleaning Validation

An assessment of areas of greatest challenge in terms of difficulty to

clean and levels of residue must have been performed and documented
in terms of difficulty to clean and residual levels of material

All equipment / control systems used in the cleaning process, for

example Clean In Place (CIP) systems, washers, dryers, etc., must be
adequately qualified in terms of correct installation and operational
performance

Acceptance criteria must be set prior to performance of the Cleaning

Qualification
 Specific Validation Considerations

Equipment hold times (both clean and dirty / used):

-Maximum hold times (maximum amount of time equipment can be left dirty
prior to a clean and maximum amount of time equipment can be left clean
prior to use), must be determined on a scientific basis and meet user
requirements

Clean until clean is not acceptable for non-dedicated process

equipment. The cleaning procedure must be developed such that it is
effective and consistent and then qualified

Normally only cleaning procedures for product contact surfaces of

the equipment need to be validated
 Specific Validation Considerations

Validation of cleaning procedures should reflect actual equipment

usage patterns (Annex 18 - APIs - EU Guide):
-applicable to both APIs and non-dedicated pharmaceutical
product manufacturing equipment
-equipment usage will effect the rationale for selection /
derivation of acceptable levels of carryover
 Validation Matrix

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

Validated cleaning methods / processes should be monitored

at defined intervals to confirm their effectiveness
Aspects which can effect cleaning validation:
-changes to materials used.
-changes to usage regimes.
-lengths of campaigns.
-changes to company / regulatory standards.
-changes to equipment.
-personnel changes / training
-changes to supporting systems
 Equipment Design

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

Generally the safest rule to apply

is
No more than 1/1000th of a
minimum recommended daily
dose of a contaminant must
appear in the maximum daily
dose of the following product.
 Limits - Levels of Carryover

The worst case carryover limit will be affected by three

main factors:

Maximum daily dose of following product:

As this increases, the allowable concentration of contaminant decreases
The total quantity of active in the following product batch:
As this decreases, the total allowable level of active material carryover
decreases
The minimum recommended (therapeutic) dose of contaminant:
As this decreases, the amount of allowable contamination in the maximum
daily dose of the following product decreases
 Limits - Levels of Carryover: detergents

The composition of detergents should be known to the

manufacturer. If such information is not available, alternative
detergents should be selected whose composition can be defined
EU Annex 15
It is expected that no (or for ultra sensitive analytical test methods
- very low) detergent levels remain after cleaning. Detergents are
not part of the manufacturing process and are only added to
facilitate cleaning during the cleaning process. Thus, they should
be easily removable. Otherwise, a different detergent should be
selected - FDA Guide
 Levels of Carryover General Considerations

When establishing limits for specific materials the

following should be considered:
-potential disproportional build up of impurities during campaign
processing
-potential degradation of residues during campaigns (e.g.
polymerisation)
-formation of undesirable material from residues in subsequent
processing or additional cleaning steps:
--heat sanitisation / sterilisation following cleaning
--residues may react further in subsequent processing
-use of non-specific determinations (e.g. TOC) to back up specific
determinations (detect presence of other organic material missed
by specific determinations
 Methods of Detection / Evaluation

Two quantitative methods are generally used to measure and

document the effectiveness of the cleaning processes. They are all
based on determination of, either directly or indirectly, residual
levels of material remaining on product contact surfaces after
cleaning:
-direct surface swabbing: Quantitative determination of residues of a specific
material on a specified surface area
-rinse solution analysis (indirect): Analysis of rinse solution concentration to
estimate the total quantity of material remaining on surfaces prior to rinsing
(based on total rinse weight / volume).
Validation sampling should only be carried out when the cleaning
process has been completed and the equipment is left in the normal
state for use (e.g. clean and dry)
 Methods of Evaluation: Direct Surface Swabbing

Generally, the most common method of sampling area contamination. Key

considerations are:
-swab area must be known and fixed (100cm2, use of template)
-recoveries and consistency of recovery should be known
-method validated using trained operatives
-same method should be used for swabbing as used for recovery studies
-method should be sufficiently detailed to ensure consistency
-detection methods validated ; precision / accuracy / sensitivity
-ensure no components of the swab can interfere with determinations e.g.adhesive
-recovery from a sample surface in the laboratory may not be the same as the actual
equipment surface
-ensure there is some level of back-up for the swab data ; visual inspection and
rinses ; especially where not all surfaces are accessible
-contamination may not be uniform ; reflected in sampling frequency and targeted
locations
 Methods of Evaluation: Rinse Sampling

Key considerations for rinsing as a means for measuring cleaning

effectiveness:
-rinsing must take place after the end of the defined cleaning process (will
probably include drying)
-the rinse solution needs to contact all product contact surfaces under evaluation
-the volume of rinse solution may have to be adjusted for detection purposes
-the rinse has to be capable of recovering residues; the level of recovery should be
established and built into acceptance criteria; may not be 100% !
-rinse determinations must be linked to swabbing and essentially reconcilable
-serial dilution should be demonstrated
-if more residual material is recovered from rinsing than determined by swabbing
then its back to the drawing board
 Methods of Detection / Evaluation

Other methods of detection:

Direct Surface Analysis (not widely used but will become more
prevalent in the future as technology progresses and methods are
validated)
-example: Near Infra red
Organoleptic:
-(visual inspection); to determine the absence of visual residues
-(olfactory (smell)); should only be used to reinforce other methods.
It is possible for odours to be detected below the level of analytical
determinations
 Methods of Detection / Evaluation

Product in product testing should not be used as a

primary indication of detection of carried over residues /
product:

-contamination may not be homogeneously distributed.

-detection sensitivity is usually low
-too late , if contamination detected, lots of expensive material
sitting around awaiting a disposition material
-proves cleaning process is invalid
 Maximum Allowable Carry-over

Based on the equipment used in the manufacture of

the product and the product range
To meet the Acceptance criteria previously discussed
then the MACO on the equipment must be calculated
The MACO is a function of surface area of
equipment and therapeutic dose of the next and
previous product manufactured with the equipment
 Examples of risk from carryover

A manufacturing unit has

a range of solid dosage
from including Atenolol
and Digoxin
Consider the residual
levels of active drug found
on the equipment
following cleaning
 Process Equipment Issues

Product A Atenolol 100mg Batch size 200 Kg 1,000,000 tablets in batch

Dispensing Granulation Milling/ Sieving Blending Compression

4m2 5m2 2m2 10m2 1m2

Product B Digoxin 250g Batch size 50 Kg 1,000,000 tablets in batch

Equipment residues for product A after cleaning

Equipment Residue/m2 Total residue

Dispensing 20.0 mg 80.0 mg
Granulation 10.00 mg 50.00 mg
Mill/Sieving 10.00 mg 20.00 mg
Blending 10.00 mg 100.00 mg
Compression 6.00 mg 6.00 mg

TOTAL 256.00 mg
 MACO calculations A-B (Atenolol to Digoxin)

Total amount of Atenolol on equipment surface= 256.0mg

Batch size of Digoxin = 50Kg
Concentration of Atenolol in Digoxin batch = 256.0mg/ 50Kg = 5.12 ppm
5.12 < 10 ppm criteria therefore passes
Batch Quantity of digoxin tablets = 1 million
Max daily dose for 250g digoxin is 4 tablets i.e. 250,000 days treatment
Amount of Atenolol in the max daily dose of digoxin = 256.0/250 g = 1.024 g
0.1% of the normal dose of 100mg Atenolol = 100g
1.024 g < 100g criteria therefore passes

What if we use the same information, in terms of residues

found, but the Digoxin is carried over into the Atenolol
batch?
 MACO calculations B-A (Digoxin to Atenolol)

Total amount of Digoxin on equipment surface= 256.0mg

Batch size of Atenolol = 200Kg
Concentration of Digoxin in Atenolol batch = 256.0mg/ 200Kg = 1.28 ppm
1.28 < 10 ppm criteria therefore passes
Batch Quantity of Atenolol tablets = 1 million
Max daily dose for 100mg Atenolol is 1 tablets i.e. 1 million days treatment
Amount of digoxin in the max daily dose of Atenolol = 256.0/1000 g =
0.2560 g
0.1% of the normal dose of 250 digoxin = 0.2500g
0.256 g > 0.2500 g criteria therefore FAILS
 Maximum Allowable Carryover related to 0.1 % Limit
of Product A in the max daily dose of product B
MAC in mg =

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 =

Min therapeutic dose of A x Total number of single doses in batch B

1000 X Number of single doses in Max daily dose of B
 Maximum Allowed Carryover

10 ppm criteria < 0.1% criteria

! 1 gram carryover in ! 25000 mg in 1 million
100Kg of next batch tablets where 4 is daily
! 500 mg carryover in 50 dose. This for a 100mg
Kg of next batch tablet is approx 0.1% i.e.
in mg terms 50 times the
ppm limit
A pass on one criteria could be far in excess of the limit of the other
criteria. You must pass both to meet requirements for cleaning validation
 Supporting Quality Systems

As with any validation exercise, cleaning validation will

only remain valid, if the supporting quality systems are
working effectively these include:
-change control
-training
-failure investigation
-calibration / maintenance
-document control
-material control
 Risks of Not Validating Your Cleaning Processes

No assurance of effectiveness of cleaning

Cross-contamination
Recalls (expensive and damages reputation)
Increased operational cost
Loss of business
Regulatory censure

Harm to patients !