Cleaning validation

CLEANING VALIDATION
1) Pharmaceutical product and active pharmaceutical ingredients (APIs) can be
contaminated by other pharmaceutical products or APIs, by cleaning agents, by
microorganisms or by other materials e.g. air borne particle, dust, lubricants, raw
materials, intermediates. Mainly cleaning is performed to remove product and non-product
contaminating material.
2) Ineffective cleaning can lead to adulterated product, which may be from previous
product batches, cleaning agent or other extraneous material introduced into generated by
the process. In many cases, the same equipment may be used for processing different
products.
3) To avoid contamination source or facility configuration there is a need to ensure that
cleaning procedure must strictly follow carefully established and validated method of
execution.
Validation is documented evidence which provide a high degree of assurance that a
specific process will consistently produce a product meeting its predetermined
specification and quality attributes.
The process of providing documented evidences, that provides a high degree of assurance
that specific process, method, will consistently produce a result with pre – determine
acceptance criteria.
Concept of validation evolving continuously since its 1st formal appearance in US in
1978. It comes from the word “VALID” which means “can be justified or defended”.
WHY VALIDATION IS NEEDED
• To makes working easier and safer.
• To set the recognized level of Quality.
• To facilities integrability.
• To enhances efficiency.
• Validation Streamlines production, increases productivity.
• Before using in routine work like analysis or production.
VARIOUS TYPE OF VALIDATION
• Analytical Method Validation
• Process Validation

• Software Validation
• Cleaning validation
• Analytical Method Validation : Confirmation by examination and provision of object
evidence that the particular requirements for a specific intended use can be consistently
fulfilled
• Process Validation: Establishing documented evidence which Provides a high degree of
assurance that a specific process will consistently produce a product meeting its
predetermined specifications and quality attributes.
a) Prospective validation: Prospective validation is the most common level of
validation, conducted prior to the commercial release of a product. Usually applied
to the new facilities.
b) Concurrent validation:
To demonstrate the validated state concurrent validation has to be conducted.
There may be instances when it is appropriate to validate a process during production
to ensure that the status is maintaining its validated status.
c) Retospective validation :
Validation of the process using historical data to provide the necessary documentary
evidence that the process is doing what it is believed to do. Source data includes
batch documents, process control charts, maintenance log books, finished product
data and storage stability results.
• Software Validation:-
When software or automated data processing systems are used as a part of the
production or the quality system, the manufacturer shall validate computer software
for its intended use according to an established protocol.
All software changes shall be validated before approval and issuance
Defination :
Cleaning validation is documented evidence with high degree of assurance that one can
consistently clean a system or piece of equipment to predetermined and acceptable limits.
Cleaning Validation in the context of Active Pharmaceutical Ingredient manufacture may be
defined as: The process of providing documented evidence that the cleaning methods employed
within a facility consistently controls potential carryover of product (including intermediates and
impurities), cleaning agents and extraneous material into subsequent product to a level which is
below predetermined levels cleaning process used in pharmaceutical operations have achieved an
increasing emphasis in the past decade both by regulatory agencies and industry itself. Several
developments have caused this emphasis on the cleaning process.

1. New generation of products tends to be more potent.
2. A series of tragic contaminations occurred over the last several years that lid to serious
personal injury.
Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment
in pharmaceutical industry. It is necessary to have effective cleaning programs in place because
of regulatory requirements.
Cleaning validation is the process of assuring that cleaning procedures effectively remove the
residue from Manufacturing equipment / facilities below a predetermined level.
 The Cleaning technique depends on the solubility of the drug and difficulty of cleaning.
 Cleaning Validation is a mandatory requirement by the regulatory agencies and the
industry itself.
Why Cleaning Validation ?
1. Cleaning is like any other critical process that requires validation. However, it is not
generally well understood or studied. The greater the risk of the product, the greater the
drug potency or toxicity, the more effort on the validation of cleaning methods is
required. Once established and validated, the cleaning process must be followed, adhered
to, documented, recorded and maintained.
• Pharmaceutical products can be contaminated by a variety of substances (some of them
potentially dangerous) left over from previous batches by poor cleaning methods. They
can also be contaminated by cleaning agents, micro-organisms and materials such as
airborne particles, dust, lubricants and raw materials. It is essential that adequate
cleaning procedures be established and validated.
To verify the effectiveness of cleaning procedures and to ensure no risks are associated with
cross contamination of active ingredient or detergents/sanitizer.
 A cleaning validation plan & it’s execution should demonstrate that the quality features
built into facilities, equipment, utilities, and cleaning processes operate consistently and
reliably.
 The monitoring and removal of microbiological contamination (including endotoxins)
as well as chemical and other contamination (detergent residues) should also form part of
cleaning validation.
 To Protect product integrity and to avoid cross contamination for internal control and
compliance.

 To reuse the equipments and make the process more cost effective.
 To combat the regulatory authorities (FDA, USFDA, cGMP).
 To increase Equipment Utilization.
 For multiproduct Equipments.
 To assure maximum cleaning without affecting the safety or efficacy of the next product
to be manufactured in the cleaned equipment.
When Cleaning Validation:
1. Initial qualification of process/ equipment.
2. Critical change in a cleaning procedure.
3. Critical change in formulation.
4. Significant change in formulation.
5. Change in a cleaning process.
6. Change in a cleaning agent.
Advantages of Cleaning Validation
1. Safety: Validation can also result in increased operator safety. Properly calibrated, validated
instruments and gauge used to reduce accident and results in safety.
2. Better Custome r quality: Through proper validation, market recall is avoided which results
in better customer care and quality of the product.
Contamination & Cross Contamination: Generally cross contamination and contamination by
a foreign material are two types of contamination.
Cross contamination is usually through an active ingredient from one product carrying over into
subsequent manufactured product. However, carryover of other product component such as
excipients can also be problematic and may degrade and final quality of product.
Contamination of one batch of product with significant level of residual active ingredient from a
previous batch may pose obvious problem to consumer or patients from unintended
contaminants. Potential clinically significant synergistic interaction between pharmacologically
active chemical is a real concern. Inert ingredients used in drug product are generally recognized
as safe for human consumption and for routine use also. Maintenance and cleaning of equipment
provide the potential for contamination with items such as equipment parts and lubricant.
Chemical cleaning agent and piece of cleaning tools can cause problems ranging from poor
pharmaceutical elegance to exceeding acceptable levels of particulate matter in parenteral
products to inadvertent inclusion of toxic compounds in the product.

In addition, some activities are adversely affected by trace contaminants and may exhibit change
in stability or bioavailability if exposed to such contamination.
The second type of contamination is by foreign material these may be bacterial in nature or could
represent part of the equipment. Maintenance, cleaning, and storage condition may provide
adventitious microorganisms with the opportunity to proliferate with in processing equipment.
This could pose obvious problems for sterile products manufacture (generation of high level of
pyrogens, decreasing the assurance of sterile achieved by equipment sterilization procedures etc.)
It also possess serious problem for the manufacture on non-sterile dosage form particularly
unpreserved products which support microbial growth.
Mechanism of Contamination:
1. Cross contamination with active ingredient: One of the real dangers in cross
contamination of active ingredients is that by being contaminated results in a multiple
ingredient product instead of single active ingredient. Depending on medical effects, the
contamination may enhance the action or negate the action or contaminant may have an
entirely different medical effects.
2. Microbiological contamination: This form of contamination is particularly insidious
because the contamination may develop at any time even after cleaning. A major
contributing factor is the storage of equipment in a wet condition. This provides a natural
medium in which bacteria can grow.
3. Contamination by cleaning or sanitizing agents: Some pharmaceutical operations may
find it necessary to use fairly toxic materials for cleaning purpose for stubborn residues.
This is particularly true in the manufacture of active pharmaceutical ingredients (APIs).
As such, these materials represent a potential threat as contaminants. It seems obvious that
one effective way of dealing with this potential problem is to use cleaning a gents with the
lowest toxicity that will still be effective in removing the residue in the given cleaning
situation. The same factors also apply to sanitizing agents used to wipe down cleaned
equipment.
4. Contamination by miscellaneous other materials: In addition to the usual expected or
anticipated list of potential contamination in a pharmaceutical operation, many other less
likely materials can also contaminate products. A partial list includes equipment parts such
as excipients, bristles from brushes used in packaging filling equipment, paper filters,
micron filters, fibers and rubber particles from gloves, cleaning aids such as brush bristles,
cloth, and cotton fibers from rags and wiping materials, lubricants.
Equipment characterization: Cleaning validation involves not only the removal of residues but
also gives assurance that each and every piece of equipment associated with the process has been

cleaned to acceptable levels. It is typically referred as train based approach. The equipment train
is series of equipment through which the product or products move as they progress through the
manufacturing process. In order to asses that the equipment is cleanable or not it should be
characterized in such a way that its design features are well known. Equipment characterization
can assist cleaning validation initiatives in many ways:
1. Promote more effective cleaning procedure by identifying cleaning challenges and ensuring
that they are addressed in the cleaning methods employed.
2. Identifying hard to clean locations and high risk locations in equipment for the purpose of
sampling site selection.
3. Target materials of construction that will be included in sampling recovery studies and those
that will not be included.
4. Isolate materials that will be disposed of at the end of a production process and/or will be
dedicated to a single product.
5. Verify that all materials of construction are compatible with the selected cleaning agents and
temperature that will be used with the cleaning process.
6. Collect product contact and sample site surface areas for the purpose of calculating limits and
results.
7. Confirm similar geometries, capacities, and use of process equipment for the purpose of
grouping that equipment
Note: When performing correctly, equipment characterization is the process whereby it
catalogues the features and attributes of equipment, thereby ensuring that equipment can be
cleaned reliably and reproducibly.
Product Grouping and Equipment Grouping: Grouping, sometimes also called as a family
approach. It is a method by which products or equipment is considered to be similar or
equivalent for the purpose of cleaning validation. When considering similar, a worst case
member of the family is selected for demonstrating cleaning validation. When considering
equivalent, any member of the family may be selected as representative of any other member.
Grouping may also be used to simply prioritize cleaning validation studies or may be used to
eliminate some of the numerous possible combinations of product and equipment studies that
might otherwise need to perform. When grouping products, all products must be:
1. Manufacture on the same equipment group.
2. Cleaned with the same cleaning agent.
3. Cleaned with the same cleaning procedure.

Grouping considerations for products include:
1. Similar patient risk levels (e.g. therapeutic indication, patient population route of
administration, potency, toxicity for drugs/devices/nutraceuticals/ cosmetics or in case of in-vitro
diagnostics used, such as so called health and safety products)
2. Similar formulations.
3. Similar manufacturing process.
Cleaning validation must always be carried out to meet lowest limit of the entire product group.
When grouping equipment, all equipment must be:
1. Used to produce products from the same product group.
2. Cleaned with the same cleaning agent.
3. Cleaned with the same cleaning method.
Grouping considerations for equipment include:
1. Equivalent in terms of position or role in the manufacturing process.
2. Similar functionality.
3. Similar design.
Cleaning Agent selection: Cleaning chemistries fall into several broad categories;
1. Water
2. Solvents
3. Commodity chemicals
4. Formulated cleaning agents
1. Water: It is the universal solvent. If water alone will effectively clean the product without
undue time or physical effort to remove the residues, by all means employ water alone. For
many, however the water alone requires an unacceptable increase in time to get the cleaning
accomplished. For these individuals, one of the other approaches must be sought.
2. Solvent: These are typically applied in processes where solvent usage is already called for by
the manufacturing process. For example, mother liquors are typically used as the solvents for
cleaning of APIs. As the mother liquors is already known to dissolve the primary residue, there is
little risk in employing if for cleaning.
3. Commodity chemicals: In this, chemicals such as NaOH can be used for cleaning as well.
Like their solvent counterparts, there may be hazard issues, effluent issues associated with these

materials. Their typically high alkalinity or low acidity, however, often makes them helpful in
inactivation processes. However these chemicals lack the detergency of a formulated cleaning
agent and they may be difficult to rinse, taking larger volumes of water to rinse free from
systems than would a formulated cleaning agent.
4. Formulated cleaning agent is the largest class of cleaners. This category includes solvent
based formulations and aqueous formulations. Typically formulated cleaning agents can include
one or more alkalinity or acidity sources, surfactants builders, sequestrants, chelants and either a
solvent or water. For industrial applications, unlike consumer-use products, these materials are
formulated to be low foaming and therefore are more readily rinsable and are appropriate for
high impingement or high turbulence cleaning.
Sampling Techniques:
Sampling sites was selected based on the difficult clean geometries of the equipment and these
locations are inaccessible i.e. their inaccessibility makes them difficult to clean therefore, before
choosing for sampling sites one must be conscious in selecting the desired sampling locations.
Equipment is characterized into hot spots and critical sites. Hot spot is the location that is likely
to become dirty during the manufacturing process and it is difficult to clean. Critical sites are
those locations if remain dirty will certainly show disproportionate level of contamination to the
next exhibit batch.
In developing the sampling plan for a validation study, it makes scientific sense to incorporate an
understanding of the acceptance criteria and the limitations of the sampling method relative to
the surface to be sampled.
Example.,
An example of hot spot is bottom of an agitator or instrument port inside a vessel that become
soiled during the manufacturing process and proves to be difficult to clean during the cleaning
process. Before selecting sample sites one must evaluate a variety of locations i.e. hot spots and
critical sites. The number of sample locations selected for individual equipment was based on the
same consideration that was mentioned in sampling location selection i.e. difficult to clean
geometries, representative location were disproportionately contaminate the portion of the next
batch. Besides sampling sites and sample locations selected was influenced by:
1. Material of construction
2. Over all scale of the piece of equipment.
E.g. in a fluid bed granulator which is of nearly two stories tall may find difficulties to coverage
side to side and top and bottom. To ensure adequate cleaning sample locations are preferred on
the side wall of this equipment despite the fact that the sidewall is made up of the same material
of construction and may not find difficult to clean.

The common sampling method employed in cleaning validation is rinse sampling and swab
sampling.
1. Swab Sampling: It usually requires materials which are absorptive & to physically wipe the
surface and recover the analyte. Because the need to physically wipe the surface was the
preferred method that is readily accessible to human hand or arm.
· Swab sampling does not cover the entire equipment surface area therefore sites must be chosen
with care. It is important that, as a minimum, the swab sites represent worst case locations on the
equipment and that the result is then extrapolated to account for the total product contact surface
area. This calculation makes it possible to make a worst case determination of potential
carryover into subsequent product.
· Due to the nature of this method which employs physical forces as well as chemical forces it
may be necessary to perform sampling technique evaluation.
· Swabbing efficiency (% recovery) for the swabbing method must be determined.
· It is necessary to ensure that extractables of the swab do not interfere with the sampling
method.
· Using this technique it is possible to sample insoluble residues due to the physical action
associated it.
Advantages of Swab Sampling:
1. Dissolve and physically remove sample.
2. Adaptability to wide variety of surfaces.
3. Economically and widely available.
4. May allow sampling of a defined area.
5. Applicable to active, microbial, and cleaning agent residues.
Limitation:
1. An Invasive technique that may introduce fibers.
2. Results may be technique dependent.
3. Swab material and design may inhibit recovery and specificity of the method.
4. Evaluation of large, complex and hard to reach areas difficult
2. Rinse Sampling: Rinse sampling does not employ mechanical action on the surface and the
sample is collected as a final rinse or rinse applied specifically for collecting a validation sample.
· The solvent rinse occurs after cleaning has been completed

· This method is not as direct as swabbing but will cover the entire surface area (and parts
inaccessible to swabs)
· It is important to ensure chosen solvent has appropriate recovery for residues being quantified
· This method allows much greater ease of sampling than swabbing
· A reduced no of samples are required to generate a carryover figure.
Limitation:
1. Limited information about actual surface cleanliness in some cases.
2. May lower test sensitivity.
3. Residues may not be homogenously distributed.
4. Inability to detect location of residues.
5. Rinse volume is critical to ensure accurate interpretation of results.
6. May be difficult to accurately define and control the areas sampled, therefore usually used for
rinsing an entire piece of equipment, such as vessel.
3. Placebo Sampling: Placebo is recognized as both potential cleaning techniques and potential
sampling techniques. Placebo material comprises of all typical excipients but not the active
ingredient. And the placebo batches were passed through a same line so that it will have
possibility to scrub of the clean system. The principle involved in placebo is that it is passed
through the same pathway as the product therefore; it will have the possibility to scrub off
residual product along those pathways. And it usually employed for measuring system
cleanliness. It majorly depends on;
1. Excipients solubility in placebo.
2. Appropriate contact time of the placebo for collecting representative sample.
3. Coverage of the placebo in-process pathways ensures removal of the placebo from all
equipment location.
4. Quantity of the placebo and residue being matched should be detectable range and the
distribution of residue uniformly in the placebo ensures the detection of sample at any portion of
the placebo.
4. Direct Sampling: It is done by using FTIR or photoelectron emission techniques. By
employing these techniques, specific spectra obtained from residue remaining on the surface will
directly measure the quality of the surface. The advantage of using these techniques is that
sampling and analysis will be taking place in one step and there will be no real loss of sampling

system. Where as in swab sampling direct analysis of the surface is limited to the area that are
accessible for inspection.
5.Coupon sampling(test pieces) involves the use of a coupons(as) an actual removable piece of
pipe that is dropped into high purity water to extract residues for analysis.
(Other sampling methods- testing subsequent batches for residues, etc. )
LEVELS OF CLEANING
Level
Thorough of Cleaning
Cleaning validation
2 Carryover of the previous
product is critical. Cleaning
required until predetermined
stringent carryover limits are
met.
Essential
1 Carryover of the previous
product is less critical.
Cleaning should reduce the
potential carryover to a less
stringent limit as required for
level 2.
Increase from not required to
necessary (Lower acceptable
carryover limits)
0 Only gross cleaning if
carryover of the previous
product is not critical
Not required
The manufacturing process of an active pharmaceutical ingredient (API) typically consists of
various chemical reaction and purification steps followed by physical changes. In general early
steps undergo further process and purification and so potential carryover of the previous product
would be removed.
It is required in order to ensure that the API is free from unacceptable levels of contamination by
previous substances. And it varies depending on the step being cleaned and next substance being
manufactured in the same piece of equipment train. API’s and related intermediate are often
produced in multipurpose equipment with frequent product changes which results in a high
amount of cleaning. The degree or level of cleaning and validation required for process in API
manufacturing depends largely on

1. The equipment usage (i.e. dedicated equipment or not)
2. The stage of manufacture (early, intermediate or final step)
3. The nature of the potential contaminants (toxicity, solubility etc)
Documentation:
A. Cleaning Validation protocol should include the following:
1. The objective of the validation process.
2. Responsibilities for performing and approving the validation study.
3. Description of the equipment to be used.
4. The interval between the end of production and the beginning of the cleaning procedures.
5. Cleaning procedures to be used for each product, each manufacturing system or each piece of
equipment.
6. The number of cleaning cycle to be performed consecutively.
7. Any routine monitoring equipment.
8. Sampling procedures, including the rationale for why a certain sampling method is used.
9. Clearly defined sampling locations.
10. Data on recovery studies where appropriate.
11. Analytical methods including the limit of detection and the limit of quantitation.
12. The acceptance criteria, including the rationale for setting the specific limits.
The cleaning validation protocol should be formally approved by the plant Management, to
ensure that aspects relating to the work defined in the protocol, for example personnel resources,
are known and accepted by the management. Quality assurance should involve in the approval of
protocol and reports.
A final Validation report should be prepared. The conclusions of this report should state
that the cleaning process has been validated successfully and when revalidation will be required.
Limitations that apply to the use of the validated method should be defined. The report should be
approved by the plant management.
Records of cleaning activity should include:

a. The area or piece of equipment cleaned;
b. The person who carried out the cleaning;
c. When the cleaning was carried out;
d. The SOP defining the cleaning process; and
e. The product, which was previously processed on the equipment being cleaned.
operator who performed the cleaning activity
Cleaning Validation procedure:
1.Cleaning validation studies are carried out to provide a documented evidence and actual
experimental data that the procedure being followed for cleaning of equipment and
accessories is effective and removes all residues of previous upto a predetermined
acceptance level, thereby avoiding the risk of cross contamination.
2. Cleaning validation studies conducted shall be carried to determine the leftover residue of
active ingredient for traces of cleaning agent and microbiology status of cleaned
equipments.
Strategy on Cleaning Validation Studies: Basic elements of cleaning validation study includes
1. Evaluating of new product/equipment
2. Determination of limit and reporting.
3. Cleaning procedures.
4. Analytical method and its Validation
1. Evaluating of new product/equipment
For new product: In case there are more than one API for the new product, each API shall be
evaluated for the below detailed parameters and based on the evaluation one API shall be
selected as worst case product
a. Batch size of the product: The product which has minimum batch size should be considered
as worst case product, which makes the acceptance criteria more stringent.
b. Based on Label Claim of API: The Product with highest strength can be considered as worst
case product.
c. Dose for the product: The product having maximum daily dose can be considered as worst
case product.

d. Solubility of the API: Product having least solubility in water and higher strength can be
considered as worst case product on basis of solubility.
e. Based on Therapeutic Potency: The most Potent product can be considered as the worst case
product on the basis of therapeutic potency.
f. For new equipment: When new product is identified as worst case, the total surface area for
the equipment shall be arrived by identifying the equipment used for manufacturing.
Group
Included descriptive terms
Appropriate quantities of
Determination of Limit and Result reporting:
1. Calculation of MAC for Product is given by the formula:
a. By dose criteria: NMT 1/1000th dose of any product shall appear in the maximum daily dose
of another product manufactured subsequently.
MAC= STD × SBS × SF/ LDD
MAC = Maximum allowable carryover in mg; STD = Single Therapeutic dose of previous;
SBS = Smallest batch size of next product to be manufactured in mg; SF = Safety factor; LDD =
Largest daily dose of next product in mg
Or
Solvent by volume for 1 part
of solute by weight
1 Very soluble
Freely soluble
Less than 1 Part
From 1 to 10 Parts
2 Soluble
Sparingly soluble
From 10 to 30 parts
From 30 to 100 Parts
3 Slightly soluble
Very slightly soluble
Practically insoluble
From 100 to 1000 parts
From 1000 to 10000 parts
More than 10000 Parts

b. 10 ppm crite ria: 10 ppm of any product residue shall appear in another product manufactured
subsequently.
MAC (mg) = 10 ppm × SBS
SBS = Smallest batch size of next product to be manufactured in mg.
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. Cleaning procedure should 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 include
a. Identification of the equipment to be cleaned
b. Difficult to clean areas.
c. Property of materials.
d. Ease of disassembly.
e. Mobility.
B. Residues to be cleaned
a. Cleaning limits
b. Solubility of the residues.
c. Length of campaigns
C. Cleaning agent parameters to be evaluated
a. Preferable materials that are normally used in the process.
b. Detergents available (as a general guide, minimal use of detergents recommended unless
absolutely required).
c. Solubility properties.
d. Environmental considerations
e. Health and safety considerations.

D. Cleaning techniques to be evaluated
a. Manual cleaning.
b. CIP (Clean-in- Place)
c. COP (Clean out of place)
d. Semi-automatic procedures
e. Automatic procedures
f. Time considerations.
g. Number of cleaning cycles.
Testing Methods:
The basic requirements of the analytical methods should have the following criteria.
a. Testing method should have the ability to detect target substances at levels consistent with the
acceptance criteria.
b. Testing method should have the ability to detect target substances in the presence of other
materials that may also be present in the sample.
c. 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.
Analyzing cleaning Validation samples: There are many analytical techniques available in
cleaning validation. But choosing the appropriate analytical tool depends on a variety of factors.
The most important factor is to determine the specifications or parameters to be measured. The
limit should always be established prior to the selection of the analytical tool.
Specific and non-specific methods: A specific method detects unique compounds in the
presence of potential contaminants e.g. HPLC. Nonspecific methods are those methods that
detect any compounds that products a certain response
e.g. Total organic carbon, pH and conductivity.
A. High Performance Liquid Chromato-graphy: Almost every pharmaceutical company has
an HPLC instrument, utilizing a variety of detector. These include UV, Fluorescence,
Electrochemical, Refractive Index, Conductivity, Evaporate Light Scattering Detector and many
others.

The vast majority of techniques described in the literature are for the determination of surfactants
in concentrated products.
B. 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 whereas
amphoteric surfactants are analyzed by HPLC.
C. Capillary Electrophoresis: Capillary electro-phoresis 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. Another technique known as Micellar electro kinetic capillary
chromatography is used for the separation of non- ionic alkyl phenol polyoxy ethylene type
surfactants.
D. Total organic carbon(TOC) : It is used widely in the pharmaceutical industries for various
purposes. 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.
E. Ion Chromatography: Ion chromatography can be used for the analysis of inorganic, organic
and surfactants present in the cleaners. 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.
F. Others
1. Thin layer chromatography: TLC is widely used for the qualitative determination of
surfactants.
2. Atomic absorption spectroscopy: AAS is used for the determination of inorganic
contaminants.
3. Bio luminescence: It is useful for biologicals. This type of analysis usually use s ATP-bioluminescence.
G. Optically simulated electron emission: 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.
H. Portable mass spectrometer: Portabe mass spectrometer can be used to detect ultra-sensitive
measurements and identification of the residue.

I. Additional techniques: Apart from the above mentioned techniques, Biopharmaceutical
industry utilizes a wide variety of techniques include ELISA and 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 quantitated the limit present. Once the
technique for analysis has been chosen, it is very important to validate the method used. 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 residual 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: To support the cleaning validation study,
an appropriate analytical method must be developed to product at 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-detectable (ND) are applied. A test result
greater than or equal to the MQQ is considered reliable, whereas if it lies between ND and MQQ
it is considered unreliable. Therefore values reported as ND or between ND and MQQ can be
manipulated to apply for the possible contamination.
Difficulty in cleaning the equipment: The most difficult to clean pieces of equipment require
the most intensive monitoring schedule. Easier to clean pieces require a moderate monitoring
schedule.
Difficulty in cleaning the product and equipment: It is divided into three groups based on the
degree of difficulty in cleaning the product and equipment.
a. Most difficult to clean product and equipments requires the most intensive monitoring
schedule.
b. Easier to clean product and equipment that requires a moderate monitoring schedule.
c. Easier to clean product and equipment that requires only periodic monitoring.
The monitoring program provides a mechanism to verify the capability of the cleaning
procedures, the efficiency of the training program and the effectiveness of the equipment
maintenance program.
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:
a. Reference to all the procedures followed to clean the samples and tests.

b. Physically and analytical test results or reference for the same, as well as any pertinent
observations.
c. Conclusion regarding the acceptability of the results, and the status of the procedures being
validated.
d. Any recommendation based on the results or relevant information obtained during the study
including revalidation practices if applicable.
e. Review of any deviations from the protocol.
f. 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.
g. The report should conclude an appropriate level of verification subsequent to validation.
CONCLUSION:
This review based article concludes that cleaning validation is a documented process that proves
the effectiveness and consistency in cleaning of pharmaceutical equipment. It is necessary to
have effective cleaning program in place because of the regulatory requirement. However, more
fundamental reason that to produce products that as pure and free from contamination. And the
main purpose of cleaning validation is to establish documented evidence with a high degree of
assurance that one can consistently clean a system or a piece of equipment to predetermined and
acceptable limits. And this article primarily covers all aspects related to cleaning validation like
mechanism of cross contamination, different levels of cleaning, cleaning procedure, sampling
procedure, product grouping and equipment characterization, cleaning agent selection, elements
of cleaning validation.
REFERENCES:
1. Robert A Nash. Alfred H W: A Text Book of Pharmaceutical Process Validation. Marcel
Dekker, 3rd Edition,Vol-129 2003: 465-506.
2. Kumar S: A review on concept of cleaning validation in pharmaceutical Industry.
International Research Journal of Pharmaceutical Sciences 2012; 3(7): 17-19.
3. Lakshmana P: Cleaning validation and its importance in pharmaceutical Industry. Pharma
Times 2010; 42(7): 21--25.
4. Chitra and Murthy, IJPSR, 2013; Vol. 4(9): 3317-3327.

Cleaning validation

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