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www.wjpr.net Vol 3, Issue 3, 2014.
3819
S.Venugopal World Journal of Pharmaceutical Research
DESIGNING OF CLEANING VALIDATION PROGRAM FOR ACTIVE
PHARMACEUTICAL INGREDIENTS
*S.Venugopal
Vindhya Pharma (India) Pvt. Ltd, Plot No. F-11A&B, Phase-1, IDA Jeedimetla,
Hyderabad-500055, Andhra Pradesh, India.
ABSTRACT
Cleaning validation is an important activity in the manufacturing of
active pharmaceutical ingredients and its intermediates. Cleaning
validation gives the assurance that the previous products residues are
completely removed from the equipment, facility, system and area
prior to the next product manufacturing. Regulatory agencies like
USFDA, MHRA, EDQM etc., are more interested in reviewing the
organization policies and procedures on cleaning during their
inspections to ensure that no carryover, contamination or cross
contamination from previous products and any other means, is
adulterated the subjected drug under inspection. So it is important to
any organization to have a cleaning validation program that is
scientifically sound and it should give the assurance that the cleaning is
performed using a validated procedure and previous product residues are reduced to an
acceptable level. This review includes the fundamental and most important aspects involved
in the design of a cleaning validation. The job of Cleaning Validation is to prove that the
cleaning Procedure consistently removes the previous product down to acceptable levels and
the cleaning does not contribute to unacceptable result levels.
Key words: Cleaning validation, Active pharmaceutical ingredients, Bulk drug, Validation.
1. INTRODUCTION
Current good manufacturing practices (CGMP) guidelines are clearly indicating that cleaning
procedures should be in place for every activity involved in the manufacturing, storage,
handling and distribution of the active pharmaceutical ingredients. Cleaning procedures
should be validated in order to ensure that no carry over, contamination or cross
World Journal of Pharmaceutical ReseaRch
Volume 3, Issue 3, 3819-3844. Review Article ISSN 2277 – 7105
Article Received on 09 February 2014, Revised on 01 March 2014, Accepted on 19 March 2014
*Correspondence for
Author
Sriram Venugopal
Vindhya Pharma (India) Pvt.
Ltd, Plot No. F-11A&B, Phase-
1, IDA Jeedimetla,
Hyderabad, Andhra Pradesh,
India.
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contamination poses the high risk to API quality. Cleaning validation is the process of
assuring that cleaning procedures effectively removes the residue from manufacturing
equipment / facilities below a predetermined level. This is necessary to assure the quality of
future products using the same equipments to prevent cross contamination –Cleaning
validation provides such assurance.
For example , in the U.S., section 211.67 of part 21 of the Code of Federal Regulations(CFR)
states that “Equipment and utensils shall be cleaned, maintained and sanitized at appropriate
intervals to prevent contamination that would alter the safety, identity, strength, quality or
purity of the drug product beyond the official or other established requirement.” Section
21.182 of part 21 of the CFR identifies that cleaning procedures must be documented
appropriately, and that a cleaning and use log should be established. Historically speaking,
FDA was more concerned about the contamination of non penicillin drug products with
penicillins or the cross-contamination of drug products with potent steroids or hormones. A
number of products have been recalled over the past decade due to actual or potential
penicillin cross-contamination.
Definition: It is defined as providing a high degree of assurance that a specific cleaning
procedure when performed appropriately will consistently clean a particular piece of
equipment to a predetermined level of cleanliness.
Purpose: Purpose of the cleaning is remove residues of the just manufactured product, so
that residues are not transferred to subsequent product.
Some important definitions to know
Cleaning Validation: Documented verification that the cleaning process, can perform
effectively and reproducibly, based on the approved cleaning method and cleaning
acceptance criteria.
Cleaning Verification: A confirmation by examination and provision of objective evidence
that specified cleaning requirements have been fulfilled. Verification studies must be planned
and document in the same manner as validation studies.
Cleaning Monitoring: Documented routing examination performed as a process control
based on approved cleaning acceptance criteria. Monitoring studies are usually planned in
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standard operating procedures and documented as part of batch production and control
record.
2.0 Designing Cleaning Validation Program:
Usually there are three types of cleanings needs to employed during the manufacturing of
API.
Those are..
1. Batch to batch cleaning: Required after the every batch of the same product
2. Periodical cleaning: Required after predetermined number of batches for the same product
3. Product changeover cleaning: Required for different products
Batch to batch cleaning does not require validation and physical verification of the cleaning
activity needs to be done. All though batch to batch cleaning is performed it is required to
clean the equipment thoroughly periodically to avoid the contamination of degradation
products as batch to batch cleaning does not involve effective cleaning techniques like
refluxing with cleaning agent instead of rinsing. Periodicity of this cleaning needs to be
established by a validation study. Periodical cleaning is also imparted where in few cases the
batch to batch cleaning is not possible. In such case the number of cycles after which the
equipment is to be cleaned shall be established by a cleaning validation program. But this
type of cleaning program is not advisable and involves risk to the quality of the API. Product
change over cleaning is the most important type of cleaning and the current review is focused
on the product change over cleaning only.
While designing a product change over cleaning validation program a step by step approach
needs to be followed as depicted below.
Selection of cleaning agent
Selection of cleaning procedure
Selection of sampling technique & calculating the limits based on sampling techniques.
Establishing the allowable limits.
Preparation of validation protocol
Preparation of validation report and final conclusion.
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2.1 Selection of cleaning agent
While selecting the cleaning agent for a particular product the selection should be done based
on the solubility matrix of the product.
Solubility matrix of the product
Solubility Cleaning agent 1
Cleaning agent 2
Cleaning agent 3
Cleaning agent 4
Cleaning agent 5
Cleaning agent 6
Very Soluble (Less than 1 part)
Freely Soluble (1 to 10 parts)
Soluble (10 to 30 parts)
Sparingly Soluble (30 to 100 parts)
Slightly Soluble (100 to 1000 parts)
Very slightly soluble (From 1000 to 10,000
parts)
Practically insoluble (More than 10,000 parts)
“*” indicates complies and “X” not complies
In the above table use * where the solubility complies and use X for solubility is not complies
in appropriate columns. The minimum criterion for the selection of the cleaning agent is, the
product should be at least soluble in the selected cleaning agent. Test the solubility of the
compound in water, dilute acid, dilute base, detergent solution and common solvents in which
it is soluble (this should based on the product development data). Once the preparation of the
table is done, based on the below mentioned properties the cleaning agent is to be selected.
Cleaning agent should not be an ICH class 1 solvent.
Cleaning agent should be volatile.
Cleaning agent should not react with the equipment surface or with the residues
present inside the equipment. It should be compatible with equipment and process
residues.
Cleaning agent should not be corrosive or harmful to the human or environment.
Cleaning agent should be easy to handle.
Cleaning agent should not cause any contamination in subsequent product.
Cleaning agent should be easily available and inexpensive.
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Based on the above properties the cleaning agent is selected with scientific justification. The
above activity can be performed as part of validation program or an individual study can be
performed and later it can be presented in the cleaning validation protocol.
2.2 Selection of cleaning procedure
Cleaning of any equipment shall be carried out in four phases.
Phase-1: Removal of gross accumulation of the previous product on the equipment surface
and all accessories. This may include the dismantling and cleaning of the removable
accessories if required.
Phase-2: Washing or cleaning of the equipment product contact surface by means of flushing
or refluxing with the cleaning agent whichever is suitable.
Phase-3: Rinsing of the equipment with the cleaning agent of fixed quantity, dry the
equipment and check for the visual cleanliness.
Phase-4: Upon satisfactory completion of the visual cleanliness, further rinsing with the
fixed volume of the cleaning agent is done and the rinsed samples shall be sent for the
previous products content as per the predetermined protocol. The rinsing will be done till the
acceptable limits are achieved. Swab sampling is also performed to determine the previous
product content. The selection procedure of the sampling technique is discussed in section
2.3.
2.3 Selection of sampling technique and calculating the limits based on sampling
techniques
Sampling technique for the cleaning validation study is done in two methods. One is direct
method (swabbing) and second is indirect method (rinsing). Direct method is most advisable
and accurate. However sampling technique is to be selected based on the nature, size and
design of the equipment. Regulatory agencies insisting to use the combination of the both
sampling techniques. In case of large vessels rinsing is suitable. Rinsing volume should be
fixed for each equipment based on its size. A recovery study should be done on specimen
material which is equivalent to equipment surface with same material of construction in order
to establish the recovery capacity of the cleaning agent from the equipment surface. The
recovery should not be less than 80% and if it is less than 80% a scientific justification is
required, appropriate correction factor needs to be used during the calculation. With the use
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of rinse sampling technique, sampling from wide area is possible and sampling is possible
from a position not accessible by hand. With the use of swab technique it is possible to
recover dried residues and insoluble substances.
Advantages of rinse sampling: A larger surface area may be sampled and inaccessible
systems or ones that cannot be routinely disassembled can be sampled and evaluated.
Disadvantages of rinse sampling: Reproducibility is difficult to achieve, contact time is
important and numbering of samplings are required for the calculation of the carryover
amount.
In case of direct sampling method is selected, select the swab sampling location, where there
is a probability of the more product residue and use fixed quantity of the disorbent. The
disorbent should the same cleaning agent which is used for the final rinsing of the equipment.
Typically a swab area is considered as 10 x 10 cm (10 cm2) if 10 cm2 is not possible to sample
then select the required area and calculate the allowable limits accordingly. Swab a portion of
sampling area vertically in top to bottom and dip into the disorbent. Squeeze the swab to
press out disorbent. Repeat the same operation to cover the sampling area selected. Collect
the sample in horizontal direction from right to left as mentioned above in the same area.
Swab all the critical sampling points and collect the sample in a cleaned sample bottle and
send for analysis. The direct sampling is done in selected equipment surface in predetermined
area as presented in the below figure with a suitable swab bud.
While selecting the swab sampler the following point needs to be considered.
Swab sampler should be compatible with the cleaning solvent and product.
Swab sample should not cause the degradation of the product.
Swab sampler should not release fiber during sampling.
Swab sampler should allow the extraction of the compound during sampling.
Advantages from swab sampling
Areas hardest to clean and which are reasonably accessible can be evaluated, leading to
establishing a level of contamination or residue per given surface area.
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Additionally, residues that are "dried out" or are insoluble can be sampled by physical
removal.
Disadvantages from swab sampling:
Swab must release the analyte.
Interference from Swab.
Swabbing is manual procedure.
The below mentioned calculations are used in for the calculating the limits for direct
and indirect methods.
Direct method (Swab sampling)
Limit in ppm = MACO (mg) X Swabbed area (m2) x Rf x 1000
Total surface area of all equipments (m2) x100x Disorbent volume (ml)
Where
MACO is the maximum allowable carryover calculated as mentioned in the section 2.4.
Rf is the recovery factor and 1000 is for conversion into ppm.
Indirect method (Rinse sampling)
MACO for equipment (mg) = MACO (mg) x Surface are of each equipment (m2)
Total surface are of all equipments (m2)
Limit in ppm = MACO for equipment (mg) x 1000
Volume of rinse for each equipment (ml)
Where
MACO is the maximum allowable carryover calculated as mentioned in the section 2.4. and
1000 is for conversion into ppm.
2.4 Establishing the allowable limits.
The maximum allowable carryover during product change over shall be determined in three
types.
1. Based on the therapeutic daily dose
2. Based on 0.1% limit
3. Based on safety factor (10ppm for API’s)
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Based on the therapeutic daily dose
Use the following equation to calculate the maximum allowable carryover.
Dmin (Previous) x BS
MACO = ----------------------------------
Dmax (Next product) x SF
Where
MACO: Maximum Allowable Carryover of previous product in subsequent product.
Dmin : Minimum daily dose of previous product manufactured in mg
BS : Batch Size of subsequent product in mg.
SF : Safety Factor for subsequent product.
Dmax : Maximum Daily Dose of Subsequent product in mg.
Based on routes of administration the following safety factors can be used for MACO
Topical products : 100
Oral products : 1000
Parental : 10000
Calculation based on 0.1% limit
MACO = [0.1 x Batch size of next product (in mg)] / 100
MACO as 10ppm limit
Considering 10 ppm limit for the product dosage information is not available. 10 ppm is also
considered where the values from the above 2 methods are more than the 10ppm. 10 ppm is
considered based on the safety factor for oral products 1/1000 = 0.001% = 10ppm. Some
limits that have been mentioned by industry representatives in the literature or in
presentations include analytical detection levels such as 10 ppm, biological activity levels
such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible
residue.
Upon calculation of the allowable limits from the three methods the value whichever is lower
that shall be fixed as acceptable limit. When more than two products are manufactured in the
same facility, calculate MACO for different changeovers. Select the combination which has
the lowest MACO and clean the equipment to reach the lowest MACO limit using the
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cleaning procedure. Based on this validation report establish the validated cleaning procedure
for different products changeovers.
If more than two products are manufactured in the same equipments the products that are
having lowest value limits shall be considered as limits for cleaning validation so that there is
no need to validate the cleaning process for every product.
Example for Calculation of limits for rinse and swab sample in multi product situation
(same facility/equipment):
Consider products A, B, C and D are produced in same equipment and changeover of product
from A to B/C/D. Calculate the MAC, allowable limit in rinse and swab sample for Product
A to B, C and D.
Change over from Change over to Allowable limit in swab sample (ppm)
A B 20 ppm C 40 ppm D 13 ppm
If we achieve the lowest value by cleaning the equipment, no need to validate the cleaning
process at other values. In the above table, if we achieve 13 ppm (product A to product D),
there is no need to validate the product change over for other values 20ppm (product A to
product B) and 40ppm (product A to product C).
2.5 Preparation of validation protocol
Cleaning validation protocol should contain below mentioned contents.
a. Objective, Scope and responsibility matrix
These should contain purpose of the validation, its applicability and personnel details
responsible for execution of the validation and team member’s details.
b. Selection of batches and equipments
Three consecutive batches should be selected for the validation.
The first batch is for information (to gather the information on process).
The second validation batch is for confirmation (conforming the repetition).
The third validation batch is for evidence (Evidence of the consistency upon repetitive
results).
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Responsibility matrix
Activity Responsible function Validation Team member name
Preparation of the protocol Manufacturing and Engineering
Review of the protocol Quality Unit Approval of the protocol Quality Assurance
Training on validation protocol Manufacturing/Quality Unit
Verification of the pre-requisites Quality Unit
Execution of the protocol Manufacturing and Validation team
To ensure the proper cleaning of equipments Manufacturing
Visual Inspection of the cleaned equipment Quality Unit
Sampling Quality Control Analysis of samples Quality Control
Compilation of the validation data/report Manufacturing
Verification of the validation data/report Quality Unit
Summary and Conclusion Quality Unit Approval of the validation report Quality Unit Implementation of the validation
results Quality Assurance
Change Control Manufacturing & Quality Assurance
This is basis for why three batches needs to be considered (minimum) for a validation study,
is as the validation is a never ending process and all the time we have to give the assurance
for consistency by applying statistical control and trend data. So that it can give the assurance
that the validated process is giving the consistent results which are similar to validation
results and the process is in the state of art. One can take more than three batches also, but its
time taking and other production related aspects also needs to be addressed. See the below
sentence from the ICH Q7 guideline for better understanding.
12.50. The number of process runs for validation should depend on the complexity of the
process or the magnitude of the process change being considered. For prospective and
concurrent validation, three consecutive successful production batches should be used as a
guide, but there may be situations where additional process runs are warranted to prove
consistency of the process (e.g., complex API processes or API processes with prolonged
completion times).
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According to the mathematics minimum three points are required to understand a graph (for
consistency) rather than two. This is also can be considered as a reason why three batches are
required.
The quantity to used for each equipment should be clearly defined and fixed based on the size
and design of the equipment, such details should be clearly mentioned along with each
equipment size, capacity, material of construction, equipment surface area, parts to be
dismantled and sampling locations.
S.No. Name of the equipment
Equipment No. Capacity Material of
construction Surface
area (m2) Cleaning SOP No.
Total equipment surface area c. Cleaning procedure
A cleaning procedure should be formalized based on the experience and laboratory
development data. While preparing the procedure, the points discussed in the section 2.2 to
be considered. Care should be taken to avoid the complexity and the procedure should be
practically usable and scientifically justifiable.
d. Sampling technique
Type of sampling technique to be followed should be clearly mentioned along with the
sample quantities, rinse quantities. Swab area, No. of points to be sampled, sampling intervals
should clearly mentioned and indicated with pictures if required. The sampling technique is
selected based on the equipment size and design. If required both the sampling techniques
(rinse and swab) to be executed for better comparison which intern give the information
during the conclusion of the validation.
S.No. Name of the equipment
Equipment No.
Rinse Volume (L)
Swab area and Disorbent
volume
Sampling technique to be
used
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e. Analytical methods
Based on the product nature and type analytical tools like, UV, HPLC, GC, TOC, TLC, etc to
be used. Among all these techniques HPLC and UV are widely used in the industry. All these
analytical method should be validated for its selectivity, sensitivity, accuracy, linearity,
ruggedness and robustness as per the ICH guidelines. Based on the application of the method
the validation parameter shall be selected. The comparison of the analytical techniques used
is mentioned in below table.
Method Advantages Disadvantages
HPLC 1.Highly specific
2.Moderate to high sensitivity 3.Quantitative
1.Long analysis time 2.Expensive
GC 1.Highly specific
2.Moderate to high sensitivity 3.Quantitative
1. Not applicable for non volatile sample. 2. Expensive
3. Compounds may degrade during analysis. 4. Carryover problems
UV 1.Moderate to high specificity
2.High sensitivity 3.Use as screening method
1.Not quantitative
TOC
1.Broad-spectrum 2.Low level detection 3.On-line capability
4.Rapid sample turn around 5.Minimal sample preparation
6.Fast & easy measurement
1. Non-specific 2. Aqueous soluble samples only
TLC 1.Moderate specificity 2.Moderate sensitivity
3.Quntitative
1. Compounds should be UV active. 2. Not high specific.
3. Exact quantity cannot be determined. f. Acceptance criteria
Acceptance criteria/maximum allowable carryover shall be calculated (as mentioned in
section 2.4) with the three methods and whichever value is lower that shall be considered as
the limit.
Once the MACO value is obtained rinse and swab sample limits shall be calculated as
mentioned in the section 2.3.
It is important that all the equipments should be visually clean and it should be verified by
trained quality unit person and details of the activity should be documented and furnished in
the validation report.
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S. No. Name of the equipment
Equipment No.
Surface area (m2)
MACO for Equipment
(mg)
Rinse limit (ppm)
Swab limit (ppm)
Total g. Recording
The activities to be recorded and data to be compiled shall be described in this section.
h. Revalidation criteria
Whenever a new product is required to be manufactured in the same manufacturing
equipments, then cleaning validation shall be carried out for that new product, the MACO
shall be recalculated.
Based on the MACO, the swab and rinse limits shall be recalculated.
If the results obtained during previous validation are less than the recalculated limit (new
limit), revalidation is not required.
If the results obtained during previous validation are more than the new limit, revalidation
shall be carried out.
In case of new equipment is added or any deviation is observed during the execution of
the cleaning procedure, then revalidation is required.
In case of any introduction of new cleaning method or cleaning agent revalidation shall be
considered.
2.6 Preparation of validation report and final conclusion.
Upon completion of the validation program as per the predefined protocol compile the
data in a tabular form as mentioned in the below.
Equipment ID No.
Cleaning agent Qty.
used for rinse
Dismantled parts
Cleaning areas
Residue removal
/ flushing
Sampling technique
used (Put mark)
Accessories cleaned
(Lines and additional
parts)
Remarks
Rinse Swab
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Visual verification details of the equipment
S.No. Equipment ID No.
Visual cleanliness verified (Person name) Observation Remarks
Val
idat
ion
Run
-1
Val
idat
ion
Run
-2
Val
idat
ion
Run
-3
Val
idat
ion
Run
-1
Val
idat
ion
Run
-2
Val
idat
ion
Run
-3
Validation batches results summary
Equipment ID No.
Rinse Sample
limit
Rinse Sample Result
Result Status
(Pass/Fail)
Swab Sample result
Result Status
(Pass/Fail) Remarks
Val
idat
ion
Run
-1
Val
idat
ion
Run
-2
Val
idat
ion
Run
-3
Val
idat
ion
Run
-1
Val
idat
ion
Run
-2
Val
idat
ion
Run
-3
Manufacturing and Handling area cleaning verification details
S.No. Name of the Area Cleaning activity verified by
Observation (Visually Clean /Not clean)
Remarks
Upon completion of the validation report, conclude the observations made and regularize
cleaning procedure that is validated. If any abnormalities/ deviations observed during the
validation study, justify and make appropriate corrective and preventive action. The revision
of the cleaning procedure needs to be done in line with the validation report, through an
established change control program. The final conclusion should be made by quality unit.
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Cleaning validation flow diagram.
3.0 Validation of analytical procedure selected for cleaning samples.
The test method used for the cleaning verification equipments for the selected product should
be validated for the below mentioned parameters.
Specificity
Limit of detection (LOD)
Limit of quantitation (LOQ)
Precision
Linearity
Accuracy
Recovery study
Robustness
Ruggedness
Solution stability
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Analytical method should be validated as per the ICH-Q2 guideline “Validation of analytical
procedure”. The organization should select the validation parameters based on the analytical
technique and its applicability.
4.0 Regulatory requirements
US FDA Requirements: FDA guide to inspections validation of cleaning process.
FDA expects firms to have written standard operating procedures detailing the cleaning
process step wise and the procedure should logical and scientifically sound.
FDA expects the firm to have the cleaning validation policy on how the cleaning
procedure is validated for its intended use.
The cleaning validation process should cover the responsibility matrix, preparation,
review and approval of the validation program. Establishing the acceptance limits,
sampling techniques to be used and criteria for revalidation.
FDA also insists to follow direct sampling wherever possible; in case of the sampling
location is not accessible use rinse sampling.
FDA expects the firms to conduct the validation studies in accordance with the written
protocols and document the results of the validation program.
FDA also expects the firm to consider microbiology aspects along with the chemical
cleanliness. This is consisting of preventive measure for microbiological contamination.
Determine the specificity and sensitivity of the analytical method used to detect the
residuals or contaminants.
The firm should validate the analytical method used during the cleaning validation in
combination with the sampling techniques selected.
FDA also expect the firm to conduct the recovery study on specimen instead of
considering the 100% recovery.
FDA expects a final validation report which is approved by management and which
states whether or not the cleaning process is valid. The data should support a conclusion
that residues have been reduced to an "acceptable level."
EU GMP guideline Part II: Basic Requirements for Active Substances used as Starting
Materials requirements on the cleaning validation and ICH Q& Good manufacturing
practices for API.
Cleaning procedures should normally be validated and should be directed to situations
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or process steps where the contamination or carryover of the materials poses greatest risk
to API quality.
Validation of cleaning procedures should reflect actual equipment usage patterns.
Cleaning validation should be based on the solubility and difficulty of cleaning and the
calculation of residue limits based on potency, toxicity, and stability.
The cleaning validation protocol should describe the equipment to be cleaned,
procedures, materials, acceptable cleaning levels, parameters to be monitored and
controlled, and analytical methods. The protocol should also indicate the type of samples
to be obtained and how they are collected and labeled.
Sampling should include swabbing, rinsing, or alternative methods (e.g., direct
extraction), as appropriate, to detect both insoluble and soluble residues. The sampling
methods used should be capable of quantitatively measuring levels of residues remaining
on the equipment surfaces after cleaning.
Validated analytical methods having sensitivity to detect residues or contaminants
should be used.
Residue limits should be practical, achievable, verifiable and based on the most
deleterious residue. Limits can be established based on the minimum known
pharmacological, toxicological, or physiological activity of the API or its most
deleterious component.
Cleaning procedures should be monitored at appropriate intervals after validation to
ensure that these procedures are effective when used during routine production.
Equipment cleanliness can be monitored by analytical testing and visual examination,
where feasible.
5. Microbiology aspects to be considered during cleaning validation.
Microbiology testing is required if the following product needs to have a low microbiological
load, also depending on the cleaning agent used, if there is any risk for microbiological
contamination of the subsequent product (e.g. if water is used for final cleaning. Although
water is used as a cleaning agent a final rinse of solvent is most desirable to avoid the
microbial contamination after which drying of the equipment using nitrogen or heating.
These should be done once the chemical residues are come down to the acceptable limits. It is
also important that the solvent used for the rinse should satisfy the conditions mentioned in
the section “Selection of cleaning agent”. It is very advisable to go for the solvent which is
used in the subsequent product in this particular case.
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Regulatory requirements
US FDA: Validation of Cleaning Processes (7/93)
GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES
Cleaning of processing equipment, microbiological aspects of equipment cleaning should be
considered. This consists largely of preventive measures rather than removal of
contamination once it has occurred. There should be some evidence that routine cleaning and
storage of equipment does not allow microbial proliferation. For example, equipment should
be dried before storage, and under no circumstances should stagnant water be allowed to
remain in equipment subsequent to cleaning operations.
21 CFR 211.67 Equipment cleaning and maintenance
a) Equipment and utensils shall be cleaned, maintained and sanitized at appropriate intervals
to prevent contamination that would alter the safety, identity, strength, quality or purity of the
drug product.
21 CFR 211.113 Control of microbiological contamination
(a) Appropriate written procedures, designed to prevent objectionable microorganisms in
drug products not required to be sterile, shall be established and followed.
21 CFR 211.113
Control of microbiological contamination
(b) Appropriate written procedures, designed to prevent objectionable microorganisms in
drug products required to be sterile, shall be established and followed. Such procedures shall
include validation of any sterilization process.
PhRMA report on microbiological monitoring in nonsterile pharmaceutical manufacturing
areas (March, 1997) recommended that depending on the product, e.g. inhalation
products,oral aqueous liquids, vaginal creams, etc, cleaning validation should include
microbial sampling to ensure microbiological quality.
EU GMP guideline Part II: Basic Requirements for Active Substances used as Starting
Materials requirements on the cleaning validation and ICH Q& Good manufacturing
practices for API.
Equipment cleaning/sanitization studies should address microbiological and endotoxin
contamination for those processes where there is a need to reduce total microbiological count
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or endotoxins in the API, or other processes where such contamination could be of concern
(e.g., non-sterile APIs used to manufacture sterile products).
Microbiological Determination
Appropriate studies shall be performed (e.g. swab sampling, rinse sampling) wherein the
possibility of microbial contamination of subsequent product is reckoned possible and
presents a product quality risk. Organization should have a policy on fixing the limits for
microbiology determination during the validation of a cleaning procedure,
The limits should be practical, achievable and verifiable. These should be established based
on the product development data and should be justified with a scientific justification.
For a non-sterile API the following limits may be used as a guide.
Total aerobic microbial count: Not more than 100 CFU/ml
Total Yeast and mould count: Not more than 10 CFU/ml
USP Indicator organisms: Should be absent (E. coli, S. Aureus and Salmonella)
Most of the organizations are using purified water specification as control limit for microbial
determination during cleaning validation program, which is sufficient for non-sterile active
pharmaceutical ingredients.
These limits should be clearly mentioned in the validation protocol along with the appropriate
sampling procedure. Direct sampling and indirect sampling should be selected based on the
equipment design and product nature.
For microbiology determination advantages and disadvantages of different sampling
techniques are mentioned below.
Sampling technique Advantages Disadvantages
Swab method (Direct sampling)
Most common method used with selective media to isolate directly different microbial populations.
Recovery may not be reproducible & quantitative.
Rinse method (Indirect sampling)
Higher counts obtained than swab method & better overall assessment possible.
Entire surface evaluated, microbial population must be detached & membrane filtration necessary to obtain countable numbers.
Microbial contamination can be prevented by selection of suitable equipment, sound
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cleaning programs, cleaning equipment directly after use and dry storage of equipment.
Example for calculating the limits for chemical residues
S.No. Name of the equipment
Equipment No. Capacity Material of
construction Surface
area (m2) Cleaning SOP No.
1 Reactor EQP-01 5.0 KL Stainless steel 50 CLV-001 2 Reactor EQP-02 4.0 KL Stainless steel 40 CLV-002 3 Reactor EQP-03 3.0 KL Stainless steel 30 CLV-003 4 Centrifuge EQP-04 48 Inch Stainless steel 5 CLV-004 5 Tray drier EQP-05 48 Trays Stainless steel 60 CLV-005
Total equipment surface area 185
S.No. Name of the equipment
Equipment No.
Rinse Volume (L)
Swab area and Disorbent
volume
Sampling technique to be
used 1 Reactor EQP-01 30 25 ml Rinse and Swab 2 Reactor EQP-02 20 25 ml Rinse and Swab 3 Reactor EQP-03 20 25 ml Rinse and Swab 4 Centrifuge EQP-04 10 25 ml Rinse and Swab 5 Tray drier EQP-05 10 25 ml Rinse and Swab
Method-1
MACO = Dmin (Previous) x BS / Dmax (Next product) x SF
MACO: Maximum Allowable Carryover of previous product in subsequent product.
Dmin : Minimum daily dose of previous product manufactured in mg = 150 mg
BS : Batch Size of subsequent product in mg = 55 kg (55000000 mg)
SF : Safety Factor for subsequent product = 1000 (oral product)
Dmax : Maximum Daily Dose of Subsequent product in mg = 100 mg
MACO in mg = 150 x 55000000/ 100 x 1000 = 82500 mg
Direct method (Swab sampling)
Limit in ppm = MACO (mg) X Swabbed area (m2) x Rf x 1000
Total surface area (m2) X 100 x Disorbent volume (ml)
= [82500 x 0.01 x 100 x 1000]/[185 x 100 x 25] = 178 ppm
Indirect method (Rinse sampling)
MACO for = MACO (mg) X Surface are of each equipment (m2)
equipment (mg) Total surface are of all equipments (m2)
For EQP-01 = 82500 x 50 /185 = 22297.2 mg
For EQP-02 = 82500 x 40 /185 = 17837.8 mg
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For EQP-03 = 82500 x 30 /185 = 13378.4 mg
For EQP-04 = 82500 x 5 /185 = 2229.7 mg
For EQP-05 = 82500 x 60 /185 = 26756.7 mg
Limit in ppm = MACO for equipment (mg) x 1000 /
Volume of rinse for each equipment (ml)
For EQP-01 = 22297.2 x 1000/30000= 743.2 ppm
For EQP-02 = 17837.8 x 1000/20000= 891.89 ppm
For EQP-03 = 13378.4 x 1000/20000= 668.9 ppm
For EQP-04 = 2229.7 x 1000/10000= 222.9 ppm
For EQP-05 = 26756.7 x 1000/10000= 2675.6 ppm
S. No. Name of the equipment
Equipment No.
Surface area (m2)
MACO for Equipment
(mg)
Rinse limit (ppm)
Swab limit (ppm)
1 Reactor EQP-01 50 22297.2 743.2 178 2 Reactor EQP-02 40 17837.8 891.89 178 3 Reactor EQP-03 30 13378.4 668.9 178 4 Centrifuge EQP-04 5 2229.7 222.9 178 5 Tray drier EQP-05 60 26756.7 2675.6 178
Total 185
Method-2
MACO = [0.1 x Batch size of next product (in mg)] / 100
= 0.1 x 55000000/100 = 55000 mg
Swab limit in ppm = [55000 x 0.01 x 100 x 1000]/[185 x 100 x 25] = 118.9 ppm
Indirect method (Rinse sampling)
MACO for = MACO (mg) X Surface are of each equipment (m2)
equipment (mg) Total surface are of all equipments (m2)
For EQP-01 = 55000 x 50 /185 = 14864.86 mg
For EQP-02 = 55000 x 40 /185 = 11891.89 mg
For EQP-03 = 55000 x 30 /185 = 8918.91 mg
For EQP-04 = 55000 x 5 /185 = 1486.48 mg
For EQP-05 = 55000 x 60 /185 = 17837.84 mg
Limit in ppm = MACO for equipment (mg) x 1000
Volume of rinse for each equipment (ml)
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For EQP-01 = 14864.86 x 1000/30000= 495.5 ppm
For EQP-02 = 11891.89 x 1000/20000= 594.59 ppm
For EQP-03 = 8918.91 x 1000/20000= 445.94 ppm
For EQP-04 = 1486.48 x 1000/10000= 148.64 ppm
For EQP-05 = 17837.84 x 1000/10000= 1783.78 ppm
S. No. Name of the equipment
Equipment No.
Surface area (m2)
MACO for Equipment
(mg)
Rinse limit (ppm)
Swab limit (ppm)
1 Reactor EQP-01 50 14864.86 495.5 118.9 2 Reactor EQP-02 40 11891.89 594.59 118.9 3 Reactor EQP-03 30 8918.91 445.94 118.9 4 Centrifuge EQP-04 5 1486.48 148.64 118.9 5 Tray drier EQP-05 60 17837.84 1783.78 118.9
Total 185 Final conclusion: Since the method-1 and method-2 calculated limits are above 10 ppm,
the limit of 10 ppm should be considered as acceptance criteria.
6. Some important points to consider
Upon calculation of the allowable limits from the three methods the lowest value shall be
fixed as acceptable limit.
If the manufacturing process involved multiple reaction in-situe then consider the
particular material content during cleaning process, but should not consider the final
isolated product for cleaning process evaluation.
Example: A complex reaction goes in-situe as mentioned below
Part-1:A + B C, Part-2: C + D E & Part-3:E + F P (Isolated product)
Reaction Equipment used Cleaning to be evaluated Remarks Part-1:A + B C Equipment-1 During cleaning content of
“C” should be checked. Limit should be calculated as mentioned section 2.3
Part-2: C + D E Equipment-2 Equipment-3
During cleaning content of “E” should be checked.
Limit should be calculated as mentioned section 2.3
Part-3:E + F P Equipment-4 Equipment-5 Equipment-6
During cleaning content of “P” should be checked.
Limit should be calculated as mentioned section 2.3
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Swab sampling method is most desirable although rinse sampling method may be
satisfactory.
Visual cleanliness is to be verified prior to the sampling by quality unit.
Use only validated analytical method that are high sensitive and selective during cleaning
validation.
Monitor the effectiveness of the validated method periodically.
Consider the microbiological aspects of the equipment though the product is non-sterile.
(Drug product may be sterile) It works as preventive measures.
When water is used as a cleaning agent always dry the equipment with suitable method
and avoid storage of the water inside equipment. Use only suitable grade water.
Residue limits should be practical, achievable, verifiable and based on the most
deleterious residue.
When detergents are used check the contents and final rinse sample. The cleaning agent’s
content should not be more than 30 ppm otherwise justified.
Ensure only trained personnel are involved in the validation study and training is
imported on validation protocol.
Include the cleaning validation program as a part of validation master plan.
Although equipment is dedicated it needs to be cleaned periodically as per validated
method to avoid the contamination and degradation of the accumulated product (cross
contamination).
When the product changeover is planned manufacturing areas also should include as part
of cleaning program.
7.0 Summary and conclusion
Clean means free from dirt, pollution and contamination. We cannot expect anything perfect
in this imperfect world. 100% cleaning is not possible, cleaning is possible up to certain
extent which our analytical technique can detect and quantify. Cleaning validation is a tool to
demonstrate that the previous products residues are completely removed from the equipment,
facility, system and area prior to the manufacture of subsequent product. In other words the
job of Cleaning Validation is to prove that the cleaning procedure consistently removes the
previous product down to acceptable levels and the cleaning does not contribute to
unacceptable result levels. The design of a cleaning validation program should contain
selection of the cleaning agent, sampling techniques, calculating the limits using scientific
data, calculating the limits for different sampling techniques, conducting recovery studies,
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selection of analytical method and its validation. Cleaning validation should be done
carefully in order to maintain its scientific integrity and after validation the valid status of the
results obtained should be periodically monitored. The data should be collected carefully and
evaluated scientifically as per pre-defined protocol with the trained personnel. Quality
Assurance should approve the protocol and report and regularize the validation results. It is
also necessary to have revalidation program to ensure that the cleaning process is in the state
of art.
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