Cleaning validation

CLEANING VALIDATION
By:
P. ALEKYA
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Validation:
❖ Validation is defined as ‘The collection and evaluation of data, beginning at the
process development stage and continuing through the production phase.
The outcome of validation studies are:
❖ To prove that equipment, system and process is consistently doing what it is
supposed to do.
❖ To determine the process variables and acceptable limits for these variables and
to set up appropriate process control.
INTRODUCTION

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CLEANING VALIDATION
Cleaning validation is providing documented evidence that an approved cleaning
procedure will provide equipment which is suitable for processing medicinal
products.
Background:
❖ Through its regulatory activities, FDA became aware in the early 1960's of
the potential health hazards of product residues
❖ FDA inspections revealed manufacturing practices leading to contamination
of certain drug preparations with penicillin
❖ Amendments to drug regulations for current good manufacturing practices
(GMPs) were published January 29, 1965 for the control of cross
contamination by penicillin.
❖ In 1963 The FDA published a Guide to Inspections ”Validation of Cleaning
Processes”, intended to cover equipment cleaning for chemical residues only.

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IMPORTANCE
❖ Heart of pharmaceutical activity.
❖ Related to safety and purity of the products.
❖ Level of cleanliness is achieved by clean procedure which depends on its
validation
❖ Cleaning method if performed confidently, method produced reproducible results.

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cGMP REQUIREMENTS
21 CFR 21.1.67
❖ Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate
intervals to prevent malfunctions or contamination that would alter the safety,
identity, strength, quality, or purity of the drug product beyond the official or other
established requirements.
❖ Written procedures shall be established and followed for cleaning and
maintenance.
WHO, Annex 4, 4.11
❖ It is of critical importance that particular attention is paid to the validation of
analytical test methods, automated systems and cleaning procedures.

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PRINCIPLE:
❖ Prevention of possible contamination and cross- contamination of
pharmaceutical starting materials and products.
❖ The objective of cleaning validation is to prove that the equipment is
consistently cleaned of product, detergent and microbial residues to an
acceptable level, to prevent possible contamination and cross- contamination.

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GENERAL REQUIREMENTS
❖ There should be written SOPs detailing the cleaning process for equipment
and apparatus.
❖ The cleaning procedures should be validated.
❖ The manufacturer should have a cleaning policy and an appropriate procedure
for cleaning validation.

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MICROBIAL CONSIDERATIONS
❖ Measures to prevent microbial growth and remove contamination .
❖ Documented evidence to indicate that routine cleaning and storage of equipment
does not allow microbial proliferation.
❖ The period and conditions for storage of unclean equipment before cleaning,
and the time between cleaning and equipment reuse, should form part of the
validation of cleaning procedures.
❖ Equipment should be stored in a dry condition after cleaning.

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CLEANING VALIDATION PROTOCOLS AND REPORTS

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CLEANING PROCEDURE
❖ Standard cleaning procedure for each piece of equipment and process should
be prepared.
❖ Following parameters are to be considered during cleaning procedures.
Equipment:
❖ Surfaces that come into contact with the product
❖ “non-contact” parts
❖ Critical areas
❖ The design of equipment
❖ Process for cleaning a piece of equipment
❖ Ease of disassembly
❖ Fixed or not

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❖ Composition of the detergent
❖ Acceptable limits for detergent residues
❖ Solubility properties
❖ Environmental considerations
❖ Health and safety considerations
❖ It should not degrade the product Cleaning
agents aqueous organic water chelates oxidants
surfactants solvents Acids/bases
DETERGENT

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Method involved in cleaning of residue are:
❖ Dissolution
❖ Saponification
❖ Wetting agents
❖ Emulsifying agents
Steps involved:
❖ First Step (Removing gross accumulations).
❖ Second Step (Washing of the Equipment).
❖ Third Step (Initial rinses or swab)
❖ Fourth Step (Second rinse or swab)

What Residues to Test For?
❖ Actives ingredients:
If several active ingredients are processed in a single piece of equipment, a marker
active, an indicator active can be selected based on its solubility in the cleaning
agent, potency, previous production experience, and R&D studies.
❖ Excipients:
The removal of excipients can either be confirmed through analytical testing but is
normally by visual inspection. The approach followed should be stated along with
training requirements for individuals performing visual inspection.
❖ Cleaning Agents:
An indicator compound can be selected for analysis based on the recommendation
of the cleaning agent manufacturer.
❖ Microbial Residues:
Determined based on science and risk.
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Approaches to cleaning validation:
❖ By adopting Bracketing procedure the substances are grouped.
❖ A worst case scenario rating is used to select the worst case in each group
Bracketing:
❖ The total manufacturing processes are grouped such as early step, critical step
and API.
❖ Each group of processes is further grouped as per equipment usage similarities.
Then worst case rating is done.
Worst case rating :
❖ It is that member(s) who shows the highest challenge in the cleaning program.

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RECOVERY STUDIES
❖ Recovery studies are the evaluation of the performance of the sampling method
to determine the recovery (or loss) of the analyte at the surface.
Procedure :
❖ Spike coupon with known amount
❖ Allow to dry
❖ Remove in swab or simulated rinse procedure
❖ Analyze sample
❖ Compare to expected 100% value Recovery should be greater than 50% for
rinse and 70%-80% for swab.

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Levels of cleaning
Depends on the following;
❖ The equipment usage (dedicated use or not)
❖ The stage of manufacture (early , intermediate or final)
❖ The nature of potential contaminants (toxicity , solubility etc)

1.Selection of cleaning Level
2.Selection of cleaning method
3.Selection of sampling method
4.Selection of Scientific basis for the contamination limit (acceptance criteria)
5.Selection of Worst case related to the equipment
6.Selection of Worst case related to the product
7.Establishing the storage period after cleaning (hold time study)
8.Selection of analytical method
9.Documentation
CLEANING VALIDATION PROGRAM
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A. SELECTION OF CLEANING LEVEL
❖ TYPE A: MINOR
This type of cleaning take place between two batches of same product or between
different strengths of the same product. For minor cleaning, cleaning validation is not
required, since cross contamination is not an issue.
❖ TYPE B: MAJOR
This type of cleaning take place between two products.
B. SELECTION OF CLEANING METHOD
❖ Manual cleaning
❖ Semi automatic procedures
❖ Automatic procedures
❖ CIP (Clean-in-place)
❖ COP (Clean-out-of-place)
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Clean-In-Place (CIP) Method
❖ Cleaning of the equipment is performed in place without disassembling
❖ Cleaning process may be controlled manually or by an automated program.
❖ Very consistent and reproducible cleaning method.
❖ Can be validated readily.
❖ Being a closed system visual inspection of all components is difficult.
Clean-Out-Of-Place (COP) Method
❖ Cleaning of disassembled equipment is performed in a central washing machine.
❖ The washing machine also requires validation such as the temperature, ultrasonic
activity, cycle time, cleaning operation sequence, detergent quantity dispensed etc.
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Manual Cleaning Method
❖ Difficult to validate
❖ Most extensive and elaborate cleaning procedures are required.
❖ A high quality and extensive training program is required.
The risk involved in manual cleaning processes is taken care of with
following:
❖ Proper washroom design with drying, protection and storage requirement.
❖ Detailed cleaning SOP
❖ Training / Qualification of cleaning operators
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C. SELECTION OF SAMPLING METHOD
Generally there are two types of sampling that are accepted. The most desirable is the
direct method of sampling the surface of the equipment, another method being the use
of rinse sampling.
I. 1. Rinse samples (indirect method)
This method is based on the analytical determination of a sample of the last rinsing
solvent (generally water) used in the cleaning procedure. The volume of solvent
used for the last rinse must be known to allow for the quantitative determination of
the contamination.
Advantages
❖ Ease of sampling.
❖ Evaluation of entire product contact surface.
❖ Accessibility of all equipment parts to the rinsing solvent.
❖ Best fitted to sealed or large scale equipment and equipment which is not easily or
routinely disassembled.
Disadvantages
❖ No physical removal of the contaminant.
❖ The rinsing solvent may not reach inaccessible or occluded part of equipment.
❖ Use of organic solvents for water insoluble materials.
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2. Swab sampling
It is also know as direct surface sampling method. This method is based on the physical
removal of residue left over on a piece of equipment after it has been cleaned and dried.
A swab wetted with a solvent is rubbed over a previously determined sample surface
area to remove any potential residue, and thereafter extracted into a known volume of
solvent in which the contaminant active ingredient residue is soluble. The amount of
contaminant per swab is then determined by an analytical method of adequate
sensitivity.
Advantages
❖ Direct evaluation of surface contamination.
❖ Insoluble or poorly soluble substances may be physically removed from the
equipment surfaces.
❖ Hard-to-clean but accessible areas are easily incorporated into the final evaluation.
Disadvantages
❖ Difficult to implement in large-scale manufacturing equipment.
❖ Extrapolation of results obtained for a small sample surface area to the whole
product contact surface area.
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❖ Sampling Method Selected
❖ Looking at the advantages and disadvantages of both the sampling methods swab
sampling method was selected. The cleaning procedure uses water as a solvent and we
have dosage forms having active ingredient which is insoluble in water.
❖ Sampling Location and Number of Samples
❖ The sample locations are dictated by worst-case conditions. The equipment’s hard to
clean locations are identified based on cleaning experience and the design of equipment.
The number of samples should take into consideration the equipment surface area,
design, shape, operating principle and construction material.
❖ Sample Surface Area
Sample surface areas usually vary from 25 sq.cm to 100 sq.cm.
❖ Swab Recovery Study
A swab recovery study is performed to determine the ability of the swab to quantitatively
remove the contaminant from the surface sampled.
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❖ Once the acceptance limit of cleaning validation is determined swab recovery
study should be carried out. Product solutions of 50%, 100% and 150% of the
acceptable limit of area are prepared and spiked on the model surface
equivalent to the swab surface area. Surface is dried under gentle
airflow. Surface is sampled as per the standard swabbing technique, which will
be used for sampling. The swab is tested as per the Validated Analytical
procedure.
❖ Test result reported
❖ % Recovered by the swab=------------------------------X 100
❖ Known amount of product spiked
❖ There should be evidence that samples are accurately recovered.
❖ For example, a recovery of > 80% is considered good, > 50% reasonable and <
50% questionable.
❖ Recovery factor shall be taken into consideration while calculating the Acceptable
limit for residue.
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D. SELECTION OF SCIENTIFIC BASIS FOR THE CONTAMINATION LIMIT
(ACCEPTANCE CRITERIA)
i. Approach 1 (Dose criterion)
No more than 0.1% of the normal therapeutic dose of one product will appear in
the maximum daily dose of a subsequent product.
ii. Approach 2 (10 ppm criterion)
No more than 10 ppm of one product will appear in another product
iii. Approach 3 (Visually clean criterion)
(No residue should be visible on equipment after cleaning.)
Spiking studies should determine the concentration at which most active
ingredients are visible. This criterion may not be suitable for high potency, low-
dosage drug.
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❖ The acceptance limit calculation for chemical residue shall be based on Dose Criteria
and 10 ppm Criteria. Minimum value obtained among these two criterions shall be
selected as L1. The calculation for Dose and 10 ppm criteria is given as below.
❖ As per dose criteria
There have been a number of examples of industry guidance documents
implementing some form of the toxicology based approach proposed by Dr. Hall.
❖ NOEL(No observed effect level) is amount of drug in mg that does not have any
effect on human health.
❖ NOEL= LD50 X 70 KG/2000
❖ where
LD50 = Lethal Dose for 50% of animal population in study
NOEL = No observed effect level
70Kg = Average adult dose
2000 =Constant
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❖ Now NOEL used to calculate Maximum Allowable Carry Over (MACO).
❖ MACO (L1) =NOEL(A) X MBS/SF X TDD(B)
❖ where
NOEL = No observed effect level
MBS = Maximum batch size
TDD = Total daily dose
SF =Safety factor
(A) = Previous product
( B) = Incoming Product
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❖ As per 10 ppm criteria
❖ Minimum therapeutic dose of product A X safety Factory
MACO (L1) =---------------------------------------------------------------
Maximum daily dose of product B
❖ L1= 10 mg of product A per Kg of product B
❖ MACO limit of product A into total batch size of the Product B (L2) shall be
calculated as per below formulae;
❖ L2= L1 X minimum batch size of product B
❖ MACO limit of product A per sq cm surface area (L3) shall be calculated by using
following formulae;
❖ L2
L3= ---------------------------------------------------------------
Cumulative product contact surface area of the equipments
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❖ MACO limit of product A per swab area (L4) shall be calculated as per following
formulae;
❖ L4= L3X swab area (cm2)
❖ MACO limit of product A per rinse (L4) shall be calculated as per following
formulae;
❖ (L3) X (area rinsed)
L4(Rinse) = ----------------------------------------
(Amount of rinsing solvent)
E. SELECTION OF WORST CASE RELATED TO THE EQUIPMENT.
Bracketing by equipment should be done only when it is similar equipment, or the
same equipment in different sizes (e.g. 300-L, 500-L and 1000-L tanks). An
alternative approach may be to validate the smallest and the largest sizes separately.
The worst case for a group of equipment is represented by the equipment with the
larger product contact surface and the hardest-to-clean locations.
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F.SELECTION OF WORST CASE RELATED TO THE PRODUCT
Only one product out of a group of product processed in a piece of equipment is
selected for the cleaning validation study, based on the lowest solubility of the active
ingredient and its therapeutic dose.
G.ESTABLISHING THE STORAGE PERIOD AFTER CLEANING
The objective for establishing time limit between equipment cleaning and reuse is to
ensure that the equipment remains clean till the next use. This needs demonstration that
there is no microbial proliferation in cleaned equipment during storage.
❖ For establishing the time limit, the equipment should be dried. Initial swab samples
for surface should be taken. Thereafter, the equipment should be protected as
prescribed in the SOP and stored in its designated area. Periodic samples of product
contact surface for microbiological contamination should be taken. (1st day, 2nd day,
3rd day etc.)
❖ Based on the data generated establish the acceptable time limit.
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H. SELECTION OF ANALYTICAL METHOD
There are many analytical techniques available that can be used in cleaning validation
Basic Requirements for the Analytical Method.
❖ The sensitivity of the method shall be appropriate to the calculated contamination
limit.
❖ The method shall be practical and rapid, and, as much as possible use
instrumentation existing in the company.
❖ The method shall be validated in accordance with ICH, USP and EP requirements.
❖ The analytical development shall include a recovery study to challenge the
sampling and testing method
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SPECIFIC METHODS
❖ Chromatographic methods such as GC, HPLC etc.
❖ Thin layer chromatography
❖ Specific ion meter
❖ Of the above methods, chromatography methods are the methods of choice, as they
separate analytes, are highly specific, highly sensitive, and quantitative. But the
methods are costly and time consuming.
NON-SPECIFIC METHODS.
❖ Spectrophotometric methods in the visible, infrared, or UV ranges
❖ Total organic carbon (TOC)
❖ Other Methods
❖ For monitoring cleaning procedure TOC method is used. It offers at a moderate cost
and in addition to its rapidity, a detection capability down to the ppb range
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DOCUMENTATION
❖ Detailed cleaning procedure(s) are to be documented in SOPs.
❖ A Cleaning Validation Protocol is required to define how the cleaning process will
be validated.
❖ It should include the following:
❖ The objective of the validation process.
❖ Responsibilities for performing and approving the validation study.
❖ Description of the equipment to be used.
❖ The interval between the end of production and the beginning of the cleaning
procedure.
❖ The number of lots of the same product, which could be manufactured during a
campaign before a full cleaning is done.
❖ Detailed cleaning procedures to be used for each product, each manufacturing
system or each piece of equipment.
❖ The number of cleaning cycles to be performed consecutively. 40

❖ Any routine monitoring requirement.
❖ Sampling procedures, including the rationale for why a certain sampling method is
used.
❖ Clearly defined sampling locations.
❖ Data on recovery studies where appropriate.
❖ Validated analytical methods including the limit of detection and the limit of
quantitation of those methods.
❖ The acceptance criteria, including the rationale for setting the specific limits;
❖ Other products, processes, and equipment for which the planned validation is valid
according to a “bracketing” concept.
❖ Change Control/ Re-validation.
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❖ Depending upon the complexity of the system and cleaning processes, the amount
of documentation necessary for executing various cleaning steps or procedures may
vary.
❖ When more complex cleaning procedures are required, it is important to document
the critical cleaning steps. In this regard, specific documentation on the equipment
itself which includes information about who cleaned it, when the cleaning was
carried out, the product which was previously processed on the equipment being
cleaned should be available. However, for relatively simple cleaning operations, the
mere documentation that the overall cleaning process was performed might be
sufficient.
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❖ Other factors such as history of cleaning, residue levels found after cleaning, and
variability of test results may also dictate the amount of documentation required.
For example, when variable residue levels are detected following cleaning,
particularly for a process that is believed to be acceptable, one must establish the
effectiveness of the process and of the operator performance. Appropriate
evaluations must be made, and when operator performance is deemed a problem,
more extensive documentation (guidance) and training may be required.
❖ A Final Validation Report should be prepared. The conclusions of this report should
state if the cleaning process has been validated successfully. Limitations that apply
to the use of the validated method should be defined (for example, the analytical
limit at which
❖ cleanliness can be determined). The report should be approved by management.
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REVALIDATION CRITERIA
❖ A change control system is in place to ensure that all changes that might impact the
cleaning process are assessed and documented. Significant changes should follow
satisfactory review and authorization of the documented change proposal through the
change control procedure. Minor changes or changes having no direct impact on final or
in-process product quality should be handled through the documentation system.
❖ Revalidation shall be carried out in case of following;
❖ If the solubility of the new product being added is less than the previously considered
worst-case product.
❖ If the potency of the new drug is lower than the previous worst case product.
❖ Change or any major modification to the equipment, which has significant effect on the
contact surface area.
❖ Change in cleaning agent or its concentration wherever applicable.
❖ Change in cleaning procedure (SOP).
❖ Failure during routine monitoring.
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A validation report is necessary to present the results and conclusions and secure
approval of the study.
❖ The report should include the following:
❖ Summary of or reference to the procedures used to clean, sample and test.
❖ Physical and analytical test results or references for same, as well as any pertinent
observations.
❖ Conclusions regarding the acceptability of the results, and the status of the
procedure(s) being validated.
❖ Any recommendations based on the results or relevant information obtained during
the study including revalidation practices if applicable.
❖ Approval of conclusions.
❖ Review any deviations for the protocol that occurred.
VALIDATION REPORTS
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FDA REQUIREMENTS
❖ FDA expects firms to have written standard operating procedures (SOP) detailing
the cleaning process used for various pieces of equipment.
❖ If firms have a specific cleaning process for cleaning between different batches of
the same product and use a different process for cleaning between product changes,
FDA expects the written procedures to address these different scenarios.
❖ If firms have one process for removing water-soluble residues and another process
for non-water soluble residues, the written procedure should address both scenarios
and make it clear when a given procedure is followed.
❖ It is required by the FDA, in the general validation procedure, that the personnel
responsible for performing and approving the study should comply with the
acceptance criteria and the revalidation data.
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❖ FDA expects firms to prepare specific written validation protocols in advance for
the studies to be performed on each manufacturing system or piece of equipment
which should address such issues as sampling procedures, and analytical methods
to be used including the sensitivity of those methods.
❖ It is expected that firms conduct the validation studies in accordance with the
protocols and document the result of studies.
❖ Final validation report is to be approved by the regulatory board which states
whether or not the cleaning process is valid.
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CONCLUSION
There is practically impossible to prove that production equipment is “clean” at the
level of 100%. However, it is possible to prove that the traces of active product
remaining spread through the equipment parts are within an acceptable limit and that
we are capable of detecting and quantifying these trace levels. A cleaning validation
program should contain the assessment of equipment and products, assessment of the
impact of a process on routine process, determination of an appropriate cleaning agent
and method, determination of acceptance criteria for the residues, determination of a
degree of evaluation required to validate the procedure, This article contain a defined
cleaning validation program.
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