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 Article

Cleaning Validation and its importance in

Pharmaceutical Industry
S. Lakshmana Prabu1*, T.N.K. Suriyaprakash2
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.

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.

important to do a step-by-step evaluation of

Introduction API process to determine the most practical
equipment parts, lubricants, chemical
cleaning agents and pieces of cleaning tools
Cleaning validation is a documented and efficient way to monitor the effectiveness such as brushes and rags.
process that proves the effectiveness and of the cleaning process.
consistency in cleaning a pharmaceutical 3. Microbiological contamination
It is necessary to validate cleaning
production equipment 1 . Validations of procedures for the following reasons3 Maintenance, cleaning and storage
equipment cleaning procedures are mainly conditions may provide adventitious micro
used in pharmaceutical industries to prevent 1. It is a prime customer requirement since
organisms with the opportunity to proliferate
cross contamination and adulteration of drug it ensures the purity and safety of the
within the processing equipment.
products hence is critically important2. The product.
prime purpose of validating a cleaning 2. It is a regulatory requirement in Active FDA requirements4
process is to ensure compliance with federal Pharmaceutical Ingredient product
and other standard regulations. The most manufacture. 1. FDA expects firms to have written
important benefit of conducting such a 3. It also assures the quality of the process standard operating procedures (SOP)
validation work is the identification and through an internal control and detailing the cleaning process used for
correction of potential problems previously compliance. various pieces of equipment.
unsuspected, which could compromise the 2. If firms have a specific cleaning process
safety, efficacy or quality of subsequent
Types of contaminations for cleaning between different batches
batches of drug product produced within the of the same product and use a different
1. Cross contamination with active
equipment. This paper provides a review of process for cleaning between product
ingredients
the current trends in cleaning validation and changes, FDA expects the written
its related importance. Contamination of one batch of product procedures to address these different
with significant levels of residual active scenarios.
Objective ingredients from a previous batch cannot be 3. If firms have one process for removing
tolerated. In addition to the obvious water-soluble residues and another
The objectives of equipment cleaning problems posed by subjecting consumers or process for non-water soluble residues,
and cleaning validation in an Active patients to unintended contaminants, the written procedure should address
Pharmaceutical Ingredient (API) area are potential clinically significant synergistic both scenarios and make it clear when
same as those in pharmaceutical production interactions between pharmacologically a given procedure is followed.
area. In both these areas efforts are active chemicals are a real concern. 4. It is required by the FDA, in the general
necessary to prevent contamination of a validation procedure, that the personnel
future batch with the previous batch material. 2. Contamination with unintended responsible for performing and
The cleaning of 'difficult to reach' surface is materials or compounds approving the study should comply with
one of the most important consideration in While inert ingredients used in drug the acceptance criteria and the
equipment cleaning validation. Equipment products are generally recognised as safe revalidation data.
cleaning validation in an API facility is or have been shown to be safe for human 5. FDA expects firms to prepare specific
extremely important as cross contamination consumption, the routine use, maintenance written validation protocols in advance
in one of the pharmaceutical dosage forms, and cleaning of equipments provide the for the studies to be performed on each
will multiply the problem. Therefore, it is potential contamination with such items as manufacturing system or piece of

* E-mail:slaxmanvel@gmail.com

Pharma Times - Vol 42 - No. 07 - July 2010 21

 equipment which should address such product residues which are to be removed, should be compatible with the active
issues as sampling procedures, and the available cleaning agents and cleaning ingredients and should not interfere with the
analytical methods to be used including techniques, when determining the optimum assay. They should not cause any
the sensitivity of those methods. cleaning procedure for the equipment. degradation of the compound. The solvent
6. It is expected that firms conduct the used for swabbing should provide good
Cleaning procedures should be solubility for the compound and should not
validation studies in accordance with
sufficiently detailed to remove the possibility encourage degradation.
the protocols and document the result
of any inconsistencies during the cleaning
of studies.
process. Following parameters are to be 3. Rinse sampling
7. Final validation report is to be approved considered during cleaning procedures.
by the regulatory board which states Sampling and testing of rinse samples
whether or not the cleaning process is A. Equipment Parameters to be evaluated for residual active ingredient is a commonly
valid. adopted method to evaluate cleaniness. This
1. Identification of the equipment to be is a fairly convenient method in many cases
Current approaches in cleaned
and requires control over the solvent used
2. 'Difficult to clean' areas
determining the for rinsing, the contact time and the mixing
3. Property of materials involved. The solvent used should be
acceptance limits for 4. Ease of disassembly selected based on the solubility of the active
5. Mobility
cleaning validation6-8 ingredient and should either simulate a
B. Residues to be cleaned subsequent batch of product or at least
Acceptance limits for pharmaceutical 1. Cleaning limits provide adequate solubility.
manufacturing operation 2. Solubility of the residues A disadvantage of rinse samples is that
1. Approach 1 (Dose criterion) 3. Length of campaigns the residue or contaminant may not be
Not more than 0.001 of minimum C. Cleaning agent parameters to be soluble or may be physically occluded in the
daily dose of any product will appear in the evaluated equipment. An analogy that can be used is
maximum daily dose of another product. the "dirty pot." In the evaluation of cleaning
1. Preferable materials that are of a dirty pot, particularly with dried out
Milligrams of active ingredient = I x K x M normally used in the process residue, one does not look at the rinse water
in product A permitted per JxL 2. Detergents available (as a general to see that it is clean; one looks at the pot.
4 inch2 swab area guide, minimal use of detergents
I = 0.001 of the smallest strength of recommended unless absolutely Testing methods
product A manufactured per day required)
expressed as mg/day and based on 3. Solubility properties The basic requirements of the analytical
the number of milligrams of active 4. Environmental considerations methods should have the following criteria.
ingredient. 5. Health and safety considerations
1. Testing method should have the ability
J = Maximum number of dosage units of D. Cleaning techniques to be evaluated to detect target substances at levels
product B per day
1. Manual cleaning consistent with the acceptance criteria.
K = Number of dosage units per batch of 2. CIP (Clean-in-place)
final mixture of product B 2. Testing method should have the ability
3. COP (Clean-out-of-place) to detect target substances in the
L = Equipment surface in common between 4. Semi automatic procedures presence of other materials that may
product A & B expressed as square 5. Automatic procedures also be present in the sample.
inches. 6. Time considerations
M = 4 inch2/swab. 7. Number of cleaning cycles 3. The testing analytical method should
include a calculation to convert the
2. Approach 2 (10 ppm criterion) Sampling Technique9-15 amount of residue detected in the
Any active ingredient can be present in sample to 100% if the recovery data
Generally there are two types of
a subsequently manufactured product at a generated indicates a recovery outside
sampling that are accepted. The most
maximum level of 10 ppm. the allowed range.
desirable is the direct method of sampling
the surface of the equipment, another Analysing cleaning
Milligrams of active ingredient = R x S x U
method being the use of rinse sampling.
in product A permitted per T validation samples
4 inch2 swab area 1. Direct surface sampling
R = 10mg active ingredient of product A in It involves the determination of the type There are many analytical techniques
one kg of product B of sampling material used and its impact on available that can be used in cleaning
the test data to check the interference of the validation24. But choosing the appropriate
S = Number of kilograms per batch of final
sampling material with the test. Therefore, analytical tool depends on a variety of
mixture of product B
early in the validation programme, it is crucial factors15-17. The most important factor is to
T = Equipment surface in common between to assure the sampling medium and solvent determine the specifications or parameters
product A & B expressed as square if they are satisfactory and be readily used. to be measured18. The limit should always
inches. be established prior to the selection of the
Advantages of direct sampling are that,
U = 4 inch2/swab. areas hardest to clean and which are analytical tool19-20.
3. Approach 3 (Visually clean criterion) reasonably accessible can be evaluated,
leading to establishing a level of Specific and non-specific
No quantity of residue should be visible
on the equipment after cleaning procedures
contamination or residue per given surface methods
area. Additionally, residues that are "dried
are performed. out" or are insoluble can be sampled by A specific method detects unique
physical removal. compounds in the presence of potential
Cleaning Procedures contaminants. Ex: HPLC. Non-specific
2. Swab sampling methods are those methods that detect any
Standard cleaning procedures for each
piece of equipment and process should be After cleaning the equipment, product compound that produces a certain response
prepared. It is vital that the equipment design contact surfaces could be swabbed to Ex: Total Organic Carbon (TOC), pH and
is evaluated in detail in conjunction with the evaluate surface cleanliness. Swabs used conductivity.

22 Pharma Times - Vol 42 - No. 07 - July 2010

High performance liquid qualitative and quantitative manner in this practices if applicable.
regard. 5. Review of any deviations from the
chromatography protocol.
5. Portable mass spectrometer 6. When it is unlikely that further batches
Almost every pharmaceutical Portable mass spectrometer can be of the product will be manufactured for
company has an HPLC instrument, utilising used to detect ultra sensitive measurements a period of time, it is advisable to
a variety of detectors. These include UV, and identification of the residue. generate reports on a batch by batch
fluorescence, electrochemical, refractive basis until such time.
index, conductivity, Evaporate light scattering Additional techniques 7. The report should conclude an
detector (ELSD) and many others. The vast appropriate level of verification
majority of techniques described in the Apart from the above mentioned
techniques the biopharmaceutical industry subsequent to validation.
literature are for the determination of
surfactants in concentrated products 21-22. utilises a wide variety of techniques45. These
Therefore, the limits of quantitation and the include Enzyme-Linked Immuno Sorbent An effective cleaning
limit of detection are rather high. Analysis of Assay (ELISA)46 and Limulus amaebocyte validation maintenance
anionic and cationic surfactants is done by lysate (LAL) technique.
HPLC and Capillary electrophoresis (CE),
programme5, 53
where as amphoteric surfactants are Method validation When a minimum of three cleaning
analysed by HPLC, CD and ELSD23-25. validation runs get completed and if the
It is very important to scientifically
establish the residue limit prior to choosing results meet the acceptance criteria, then the
Capillary electrophoresis the method of analysis. This includes the cleaning procedures would be demonstrated
limit in the analytical sample and the limit in sufficiently and consistently to remove
Capillary electrophoresis can be used
the next product. This will ensure the ability chemical and detergent residues from
for many different types of analysis, viz;
of the chosen method to detect and equipment surfaces during the study in order
separation, detection and determination of
quantitate the limit present. Once the to meet the pre-established criteria.
sodium lauryl sulphate in cationic, anionic
and non-ionic surfactants 26-28 . Another technique for analysis has been chosen, it However, overtime and certain other factors
technique known as Micellar electro kinetic is very important to validate the method can decrease the efficiency and consistency
capillary chromatography is used for the used47-50. The validation of a method is very of the cleaning program. They are,
separation of non-ionic alkyl phenol polyoxy different from validation of recovery. A
validated method is one that is rugged and 1. Operator variability
ethylene type surfactants29.
robust enough to measure the residue limit 2. Equipment aging and repair
Total organic carbon (TOC) established. Whereas, the validation of a 3. Potential non representative results and
recovery helps to determine the amount that
monitoring programmes
Presently total organic carbon is used can be recovered from a surface.
4. Changes to the product, equipment and
widely in the pharmaceutical industries for
Data analysis for process.
various purposes30-32. TOC is determined
by the oxidation of an organic compound into Operator variability
carbon dioxide. The oxidation can occur
estimating possible
through a number of mechanisms depending contamination51-52 Additional questions to be asked when
on the instrument being used. TOC is used evaluating the cleaning process:
To support the cleaning validation study,
for the analysis of detergents, endotoxins,
an appropriate analytical method must be 1. Does the equipment have to be
biological media and poly ethylene glycol33.
developed to produce a sensitivity level, at scrubbed by hand?
least equal to that of the acceptable residual 2. What is accomplished by hand
Ion chromatography level. For each analytical method, values scrubbing as opposed to just a solvent
Ion chromatography can be used for the defined as 'minimum quantifiable quantity' wash?
analysis of inorganic, organic and surfactants (MQQ) and 'non-detectable' (ND) are 3. How variable are manual cleaning
present in the cleaners34-39. Most cleaners applied. A test result greater than or equal process from batch to batch and
contain sodium and/or potassium. The ion to the MQQ is considered reliable, whereas product to product?
chromatography detection technique of if it lies between ND and MQQ it is
suppressed conductivity is more sensitive to considered unreliable. Therefore values
reported as ND or between ND and MQQ These questions are all related to
potassium ions than to sodium ions. Very manual cleaning. The last question focuses
low levels of cleaning agents can be detected can be manipulated to apply for the possible
contamination. on sources of variation associated with a
by using this technique.
manual cleaning process that is operator
Others 40-44 Validation report variability. Many companies rellay on
intensive training programme to reduce
1. Thin layer chromatography (TLC): TLC A validation report is necessary to operator variability. These programmes train
is widely used for the qualitative present the results and conclusions and operators on equipment disassembly
determination of surfactants. secure approval of the study. The report
procedure, detergent preparation, step-by-
2. Atomic absorption spectroscopy (AAS): should include the following information:
step cleaning procedures and drying
AAS is used for the determination of processes. It is difficult to train an operator
1. References to all the procedures
inorganic contaminants.
followed to clean the samples and tests. to perform certain elements, the same each
3. Bioluminescence: It is useful for
2. Physical and analytical test results or time, such as strength applied, adherence
biologicals. This type of analysis usually
references for the same, as well as any to detailed instructions on the correct
uses ATP-bioluminescence.
pertinent observations. scrubbing procedure (up and down or side
4. Optically simulated electron 3. Conclusions regarding the acceptability to side) and scrubbing time. It is even more
emission (OSEE) of the results, and the status of the difficult to train different operators to perform
In some cases the limits of residue are procedures being validated. these functions the same. Hence, the
very less that they can't be detected by 4. Any recommendations based on the problems of within operator variability and
conventional methods. OSEE is a very results or relevant information obtained operator-to-operator variability are to be
sensitive method that can be used for both during the study including revalidation rectified by sufficient training programmes.

Pharma Times - Vol 42 - No. 07 - July 2010 23

 Equipment aging and The monitoring programme provides a Validation. 2nd ed. New York: Marcel
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24 Pharma Times - Vol 42 - No. 07 - July 2010

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17(12): 2691-2704. Appeal for
IPA Building
35. Pan N, Pietrzyck DJ. Separation of Anionic Surfactants on Anion
Exchangers. J Chrom. 1995; 706: 327-337.

Fund
36. Takeda T, Yoshida S, Ii T. Analysis of Sulfonate- and Sulfate-
Type Anionic Surfactants by Ion Chromatography. Chem Exp.
Proposed IPA Building
1992; 7(6): 441-444.
37. Nair LM, Saari-Nordhaus R. Recent Developments in Surfactant
Analysis by Ion Chromatography. J Chrom. 1998; 804: 233- The President of Indian Pharmaceutical Association (IPA)
239. appeals to all members of IPA to contribute
38. Weston A. Ion Chromatography in the Pharmaceutical Industry. minimum of Rs. 1000/-
American Biotech Lab. 1998; 16(3): 32-33. towards the proposed IPA building at Mumbai.
39. Murawski D. Ion Chromatography for the Analysis of Household Kindly send your contribution through D/D or
Consumer Products. J Chrom. 1991; 546: 351-367. local cheque in favour of
“IPA Building Fund”
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Agents with Thin-Layer Chromatography. Fourth World on the following address.
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High Performance Thin-Layer Chromatography. 3rd ed. Kaiser Santacruz (E), Mumbai 400098.
R. editor. Institute of Chromatography. Federal Republic of
Germany. 1985. 157-171. All donations towards this fund will get tax
42. Henrich LH. Separation and Identification of Surfactants in
exemption u/s 80G of Income Tax Act.
Commercial Cleaners. J Planar Chrom. 1992; 5(2): 103-117.

Pharma Times - Vol 42 - No. 07 - July 2010 25

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