DESIGNING OF CLEANING VALIDATION PROGRAM FOR ACTIVE

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.


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


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


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


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 /


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


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


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



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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


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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Documents

DESIGNING OF CLEANING VALIDATION PROGRAM FOR ACTIVE