Pharma Times - Vol 42 - No.

07 - July 2010 21
* E-mail:slaxmanvel@gmail.com
Introduction
Cleaning validation is a documented
process that proves the effectiveness and
consistency in cleaning a pharmaceutical
producti on equi pment
1
. Val i dati ons of
equipment cleaning procedures are mainly
used in pharmaceutical industries to prevent
cross contamination and adulteration of drug
products hence is critically important
2
. The
prime purpose of validating a cleaning
process is to ensure compliance with federal
and other standard regulations. The most
important benefit of conducting such a
validation work is the identification and
correction of potential problems previously
unsuspected, which could compromise the
safety, efficacy or quality of subsequent
batches of drug product produced within the
equipment. This paper provides a review of
the current trends in cleaning validation and
its related importance.
Objective
The objectives of equipment cleaning
and cl eani ng val i dati on i n an Acti ve
Pharmaceutical Ingredient (API) area are
same as those in pharmaceutical production
area. In both these areas efforts are
necessary to prevent contamination of a
future batch with the previous batch material.
The cleaning of 'difficult to reach' surface is
one of the most important consideration in
equipment cleaning validation. Equipment
cleaning validation in an API facility is
extremely important as cross contamination
in one of the pharmaceutical dosage forms,
will multiply the problem. Therefore, it is
Cleaning Validation and its importance in
Pharmaceutical Industry
S. Lakshmana Prabu
1
*, T.N.K. Suriyaprakash
2
1
Dept. of Pharm. Technology, Anna University-Tiruchirappalli, Tiruchirappalli - 620 024.
2
Dept. of Pharmaceutics, Periyar College of Pharmaceutical Sciences for Girls, Tiruchirappalli-620 021.
important to do a step-by-step evaluation of
API process to determine the most practical
and efficient way to monitor the effectiveness
of the cleaning process.
It is necessary to validate cleaning
procedures for the following reasons
3
1. It is a prime customer requirement since
it ensures the purity and safety of the
product.
2. It is a regulatory requirement in Active
Pharmaceutical Ingredient product
manufacture.
3. It also assures the quality of the process
through an i nternal control and
compliance.
Types of contaminations
1. Cross contamination with active
ingredients
Contamination of one batch of product
with significant levels of residual active
ingredients from a previous batch cannot be
tolerated. In addition to the obvious
problems posed by subjecting consumers or
pati ents to uni ntended contami nants,
potential clinically significant synergistic
interactions between pharmacologically
active chemicals are a real concern.
2. Contamination with unintended
materials or compounds
While inert ingredients used in drug
products are generally recognised as safe
or have been shown to be safe for human
consumption, the routine use, maintenance
and cleaning of equipments provide the
potential contamination with such items as
equipment parts, lubricants, chemical
cleaning agents and pieces of cleaning tools
such as brushes and rags.
3. Microbiological contamination
Maintenance, cleaning and storage
conditions may provide adventitious micro
organisms with the opportunity to proliferate
within the processing equipment.
FDA requirements
4
1. FDA expects firms to have written
standard operating procedures (SOP)
detailing the cleaning process used for
various pieces of equipment.
2. If firms have a specific cleaning process
for cleaning between different batches
of the same product and use a different
process for cleaning between product
changes, FDA expects the written
procedures to address these different
scenarios.
3. If firms have one process for removing
water-soluble residues and another
process for non-water soluble residues,
the written procedure should address
both scenarios and make it clear when
a given procedure is followed.
4. It is required by the FDA, in the general
validation procedure, that the personnel
responsi bl e for performi ng and
approving the study should comply with
the acceptance cri teri a and the
revalidation data.
5. FDA expects firms to prepare specific
written validation protocols in advance
for the studies to be performed on each
manufacturing system or piece of
Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Minimizing
equipment downtime has the potential to impact the efficiency and economics of pharmaceutical production. The main purpose of
cleaning validation is to prove the effectiveness and consistency of cleaning in a given pharmaceutical production equipment to
prevent cross contamination and adulteration of drug products with other active ingredients like unintended compounds or
microbiological contamination, leads to prevent several serious problems and also useful in related studies like packaging component
cleaning validation. So it is necessary to validate the cleaning procedures to ensure safety, efficacy, quality of the subsequent
batches of drug product and regulatory requirements in Active Pharmaceutical Ingredients (API) product manufacture. The benefits
due to cleaning validation are compliance with federal regulations, identification and correction of potential problems, previously
unsuspected which could compromise the safety and efficacy of drug products. In this article cleaning, validation and importance
are discussed in brief.
Article
Pharma Times - Vol 42 - No. 07 - July 2010 22
equipment which should address such
issues as sampling procedures, and
analytical methods to be used including
the sensitivity of those methods.
6. It is expected that firms conduct the
validation studies in accordance with
the protocols and document the result
of studies.
7. Final validation report is to be approved
by the regulatory board which states
whether or not the cleaning process is
valid.
Current approaches in
determining the
acceptance limits for
cleaning validation
6-8
Acceptance limits for pharmaceutical
manufacturing operation
1. Approach 1 (Dose criterion)
Not more than 0.001 of minimum
daily dose of any product will appear in the
maximum daily dose of another product.
Milligrams of active ingredient = I x K x M
in product A permitted per J x L
4 inch
2
swab area
I = 0.001 of the smal l est strength of
product A manufactured per day
expressed as mg/day and based on
the number of milligrams of active
ingredient.
J= Maximum number of dosage units of
product B per day
K = Number of dosage units per batch of
final mixture of product B
L = Equipment surface in common between
product A & B expressed as square
inches.
M= 4 inch
2
/swab.
2. Approach 2 (10 ppm criterion)
Any active ingredient can be present in
a subsequently manufactured product at a
maximum level of 10 ppm.
Milligrams of active ingredient = R x S x U
in product A permitted per T
4 inch
2
swab area
R = 10mg active ingredient of product A in
one kg of product B
S = Number of kilograms per batch of final
mixture of product B
T = Equipment surface in common between
product A & B expressed as square
inches.
U = 4 inch
2
/swab.
3. Approach 3 (Visually clean criterion)
No quantity of residue should be visible
on the equipment after cleaning procedures
are performed.
Cleaning Procedures
Standard cleaning procedures for each
piece of equipment and process should be
prepared. It is vital that the equipment design
is evaluated in detail in conjunction with the
product residues which are to be removed,
the available cleaning agents and cleaning
techniques, when determining the optimum
cleaning procedure for the equipment.
Cl eani ng procedures shoul d be
sufficiently detailed to remove the possibility
of any inconsistencies during the cleaning
process. Following parameters are to be
considered during cleaning procedures.
A. Equipment Parameters to be evaluated
1. Identification of the equipment to be
cleaned
2. 'Difficult to clean' areas
3. Property of materials
4. Ease of disassembly
5. Mobility
B. Residues to be cleaned
1. Cleaning limits
2. Solubility of the residues
3. Length of campaigns
C. Cl eani ng agent parameters to be
evaluated
1. Preferabl e materi al s that are
normally used in the process
2. Detergents available (as a general
guide, minimal use of detergents
recommended unless absolutely
required)
3. Solubility properties
4. Environmental considerations
5. Health and safety considerations
D. Cleaning techniques to be evaluated
1. Manual cleaning
2. CIP (Clean-in-place)
3. COP (Clean-out-of-place)
4. Semi automatic procedures
5. Automatic procedures
6. Time considerations
7. Number of cleaning cycles
Sampling Technique
9-15
General l y there are two types of
sampling that are accepted. The most
desirable is the direct method of sampling
the surface of the equipment, another
method being the use of rinse sampling.
1. Direct surface sampling
It involves the determination of the type
of sampling material used and its impact on
the test data to check the interference of the
sampling material with the test. Therefore,
early in the validation programme, it is crucial
to assure the sampling medium and solvent
if they are satisfactory and be readily used.
Advantages of direct sampling are that,
areas hardest to clean and which are
reasonably accessible can be evaluated,
l eadi ng to establ i shi ng a l evel of
contamination or residue per given surface
area. Additionally, residues that are "dried
out" or are insoluble can be sampled by
physical removal.
2. Swab sampling
After cleaning the equipment, product
contact surfaces could be swabbed to
evaluate surface cleanliness. Swabs used
shoul d be compati bl e wi th the acti ve
ingredients and should not interfere with the
assay. They shoul d not cause any
degradation of the compound. The solvent
used for swabbing should provide good
solubility for the compound and should not
encourage degradation.
3. Rinse sampling
Sampling and testing of rinse samples
for residual active ingredient is a commonly
adopted method to evaluate cleaniness. This
is a fairly convenient method in many cases
and requires control over the solvent used
for rinsing, the contact time and the mixing
involved. The solvent used should be
selected based on the solubility of the active
ingredient and should either simulate a
subsequent batch of product or at least
provide adequate solubility.
A disadvantage of rinse samples is that
the residue or contaminant may not be
soluble or may be physically occluded in the
equipment. An analogy that can be used is
the "dirty pot." In the evaluation of cleaning
of a dirty pot, particularly with dried out
residue, one does not look at the rinse water
to see that it is clean; one looks at the pot.
Testing methods
The basic requirements of the analytical
methods should have the following criteria.
1. Testing method should have the ability
to detect target substances at levels
consistent with the acceptance criteria.
2. Testing method should have the ability
to detect target substances in the
presence of other materials that may
also be present in the sample.
3. The testing analytical method should
include a calculation to convert the
amount of residue detected in the
sample to 100% if the recovery data
generated indicates a recovery outside
the allowed range.
Analysing cleaning
validation samples
There are many analytical techniques
available that can be used in cleaning
validation
24
. But choosing the appropriate
analytical tool depends on a variety of
factors
15-17
. The most important factor is to
determine the specifications or parameters
to be measured
18
. The limit should always
be established prior to the selection of the
analytical tool
19-20
.
Specific and non-specific
methods
A specific method detects unique
compounds in the presence of potential
contaminants. Ex: HPLC. Non-specific
methods are those methods that detect any
compound that produces a certain response
Ex: Total Organic Carbon (TOC), pH and
conductivity.
Pharma Times - Vol 42 - No. 07 - July 2010 23
High performance liquid
chromatography
Al most every pharmaceuti cal
company has an HPLC instrument, utilising
a variety of detectors. These include UV,
fluorescence, electrochemical, refractive
index, conductivity, Evaporate light scattering
detector (ELSD) and many others. The vast
majority of techniques described in the
l i terature are for the determi nati on of
surfactants in concentrated products
21-22
.
Therefore, the limits of quantitation and the
limit of detection are rather high. Analysis of
anionic and cationic surfactants is done by
HPLC and Capillary electrophoresis (CE),
where as amphoteri c surfactants are
analysed by HPLC, CD and ELSD
23-25
.
Capillary electrophoresis
Capillary electrophoresis can be used
for many different types of analysis, viz;
separation, detection and determination of
sodium lauryl sulphate in cationic, anionic
and non-ionic surfactants
26-28
. Another
technique known as Micellar electro kinetic
capillary chromatography is used for the
separation of non-ionic alkyl phenol polyoxy
ethylene type surfactants
29
.
Total organic carbon (TOC)
Presently total organic carbon is used
widely in the pharmaceutical industries for
various purposes
30-32
. TOC is determined
by the oxidation of an organic compound into
carbon dioxide. The oxidation can occur
through a number of mechanisms depending
on the instrument being used. TOC is used
for the analysis of detergents, endotoxins,
biological media and poly ethylene glycol
33
.
Ion chromatography
Ion chromatography can be used for the
analysis of inorganic, organic and surfactants
present in the cleaners
34-39
. Most cleaners
contain sodium and/or potassium. The ion
chromatography detection technique of
suppressed conductivity is more sensitive to
potassium ions than to sodium ions. Very
low levels of cleaning agents can be detected
by using this technique.
Others
40-44
1. Thin layer chromatography (TLC): TLC
i s wi del y used for the qual i tati ve
determination of surfactants.
2. Atomic absorption spectroscopy (AAS):
AAS is used for the determination of
inorganic contaminants.
3. Bi ol umi nescence: It i s useful for
biologicals. This type of analysis usually
uses ATP-bioluminescence.
4. Optically simulated electron
emission (OSEE)
In some cases the limits of residue are
very less that they can't be detected by
conventional methods. OSEE is a very
sensitive method that can be used for both
qualitative and quantitative manner in this
regard.
5. Portable mass spectrometer
Portable mass spectrometer can be
used to detect ultra sensitive measurements
and identification of the residue.
Additional techniques
Apart from the above menti oned
techniques the biopharmaceutical industry
utilises a wide variety of techniques
45
. These
include Enzyme-Linked Immuno Sorbent
Assay (ELISA)
46
and Limulus amaebocyte
lysate (LAL) technique.
Method validation
It is very important to scientifically
establish the residue limit prior to choosing
the method of analysis. This includes the
limit in the analytical sample and the limit in
the next product. This will ensure the ability
of the chosen method to detect and
quantitate the limit present. Once the
technique for analysis has been chosen, it
is very important to validate the method
used
47-50
. The validation of a method is very
different from validation of recovery. A
validated method is one that is rugged and
robust enough to measure the residue limit
established. Whereas, the validation of a
recovery helps to determine the amount that
can be recovered from a surface.
Data analysis for
estimating possible
contamination
51-52
To support the cleaning validation study,
an appropriate analytical method must be
developed to produce a sensitivity level, at
least equal to that of the acceptable residual
level. For each analytical method, values
defined as 'minimum quantifiable quantity'
(MQQ) and ' non-detectabl e' (ND) are
applied. A test result greater than or equal
to the MQQ is considered reliable, whereas
i f i t l i es between ND and MQQ i t i s
considered unreliable. Therefore values
reported as ND or between ND and MQQ
can be manipulated to apply for the possible
contamination.
Validation report
A validation report is necessary to
present the results and conclusions and
secure approval of the study. The report
should include the following information:
1. References to al l the procedures
followed to clean the samples and tests.
2. Physical and analytical test results or
references for the same, as well as any
pertinent observations.
3. Conclusions regarding the acceptability
of the results, and the status of the
procedures being validated.
4. Any recommendations based on the
results or relevant information obtained
during the study including revalidation
practices if applicable.
5. Review of any deviations from the
protocol.
6. When it is unlikely that further batches
of the product will be manufactured for
a period of time, it is advisable to
generate reports on a batch by batch
basis until such time.
7. The report shoul d concl ude an
appropri ate l evel of veri fi cati on
subsequent to validation.
An effective cleaning
validation maintenance
programme
5, 53
When a minimum of three cleaning
validation runs get completed and if the
results meet the acceptance criteria, then the
cleaning procedures would be demonstrated
sufficiently and consistently to remove
chemical and detergent residues from
equipment surfaces during the study in order
to meet the pre-establ i shed cri teri a.
However, overtime and certain other factors
can decrease the efficiency and consistency
of the cleaning program. They are,
1. Operator variability
2. Equipment aging and repair
3. Potential non representative results and
monitoring programmes
4. Changes to the product, equipment and
process.
Operator variability
Additional questions to be asked when
evaluating the cleaning process:
1. Does the equi pment have to be
scrubbed by hand?
2. What i s accompl i shed by hand
scrubbing as opposed to just a solvent
wash?
3. How variable are manual cleaning
process from batch to batch and
product to product?
These questions are all related to
manual cleaning. The last question focuses
on sources of variation associated with a
manual cleaning process that is operator
variability. Many companies rellay on
intensive training programme to reduce
operator variability. These programmes train
operators on equi pment di sassembl y
procedure, detergent preparation, step-by-
step cl eani ng procedures and dryi ng
processes. It is difficult to train an operator
to perform certain elements, the same each
time, such as strength applied, adherence
to detailed instructions on the correct
scrubbing procedure (up and down or side
to side) and scrubbing time. It is even more
difficult to train different operators to perform
these functions the same. Hence, the
problems of within operator variability and
operator-to-operator variability are to be
rectified by sufficient training programmes.
Pharma Times - Vol 42 - No. 07 - July 2010 24
Equipment aging and
repair
Through normal use, the smoothness
and structural integrity of the equipment
surfaces can change over time. As the
surface becomes rougher, it is more difficult
to clean because it has a greater contact area
that can adsorb and coul d trap more
chemical residues. Repairing a piece of
equipment or installing new parts could
create new stress centres, leading to difficulty
in cleaning the surfaces. To make an
equipment maintenance programme, the
following points could be considered
1. Enforcement of standard operating
procedures (SOPs).
2. A routine functionality check.
3. Mechanical maintenance.
4. A cleanability evaluation programme for
equipment repair.
Potential non-respective
results and monitoring
programme
However, cl eani ng val i dati on
resulting from three runs does not provide a
high degree of confidence, especially for
manual cleaning procedures. Operators may
introduce a bias in their cleaning during
cleaning validation process. To confirm the
validity of extrapolating validation results to
future operations, a monitoring programme
can be implemented to ensure a consistent
cl eani ng capabi l i ty after the cl eani ng
validation has been completed.
Monitoring programme can be done in
either of the following two ways.
1. Difficulty in cleaning the equipment
2. Difficulty in cleaning the product and
equipment.
Difficulty in cleaning the
equipment
The most 'difficult to clean' pieces of
equi pment requi re the most i ntensi ve
monitoring schedule. 'Easier to clean' pieces
require a moderate monitoring schedule.
'Easiest to clean' pieces of equipment require
only a periodic monitoring schedule.
Di ffi cul ty i n cl eani ng the product and
equipment:
It is divided into three groups based on
the degree of difficulty in cleaning the product
and equipment.
1. Most 'difficult to clean' product and
equipment requires the most intensive
monitoring schedule.
2. 'Easier to clean' product and equipment
that requires a moderate monitoring
schedule.
3. ' Easi est to cl ean' product and
equipment that requires only periodic
monitoring.
The monitoring programme provides a
mechanism to verify the capability of the
cleaning procedures, the efficiency of the
training programme and the effectiveness of
the equipment maintenance programme.
Changes to the products, equipment &
process
When new products and equipments
are added to the cl eani ng val i dati on
programme, revalidation of the acceptance
limits for all of the products and equipments
involved in the original cleaning validation
study may be necessary. The acceptance
limits for a cleaning validation programme
usually take into account parameters viz; the
product, equipment matrix, potency, daily
dose and batch size. A well designed
cleaning validation expansion programme
provides a scientific and systematic process
for managing new product, new equipment
and changes in manufacturing process and
batch sizes after the cleaning validation study
has been completed.
Conclusions/Summary
A cleaning validation programme should
contain the assessment of equipment and
products, assessment of the impact of a
process on routine process, determination
of an appropri ate cl eani ng agent and
method, determination of acceptance criteria
for the residues, determination of a degree
of eval uati on requi red to val i date the
procedure, decisive on the residues to be
tested based on solubility and toxicity,
development of sampling and analytical
methods for recovery and detection of
resi dues. acceptance cri teri a for the
validation, compilation and approval of the
validation protocol, scope for the validation
studies to be performed in accordance with
the protocol, compilation and approvals of
validation reports, documented studies,
concl usi ons, recommendati ons and
revalidation policy.
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Appeal for Appeal for Appeal for Appeal for Appeal for
IPA Building
Fund
Proposed IPA Building
The President of Indian Pharmaceutical Association (IPA)
appeals to all members of IPA to contribute
minimum of Rs. 1000/-
towards the proposed IPA building at Mumbai.
Kindly send your contribution through D/D or
local cheque in favour of
IPA Building Fund
on the following address.
Executive Secretary,
Indian Pharmaceutical Association
C/o. Bombay College of Pharmacy, Kalina,
Santacruz (E), Mumbai 400098.
All donations towards this fund will get tax
exemption u/s 80G of Income Tax Act.