A REVIEW ON SCOPE AND APPLICATIONS OF CLEANING VALIDATION IN

THE PHARMACEUTICAL INDUSTRY

I.Ponnilavarasan *, S.Vignesh, M.Velmurugan, D.Gowtham, M.Prakash
Department of pharmaceutical sciences, KMCH College of Pharmacy, Kovai Estate,
kalapatti road, Coimbatore – 641048, Tamilnadu, India.

ABSTRACT
In the pharmaceutical industry, there is some potential for contamination and cross-
contamination because of improper cleaning of equipment, apparatus, processing area, or
the starting material, this can lead to harmful hazards, therefore in the pharmaceutical
industry we can't afford any contamination as well as cross-contamination. This can be
reduced by proper cleaning of equipment, apparatus as well as the processing area. The
Industry wants to achieve these main goals with the help of GMP. Pharmaceutical
Manufacturers should validate their cleaning process to assure complies with cGMP
guidelines. Reducing equipment downtime can maybe affect the productivity and
financial aspects of pharmaceutical production. The important role of cleaning validation
is to prove the effectiveness and consistency of cleaning in a piece of given
pharmaceutical production equipment to avoid the cross-contamination and adulteration
of medication products. So it's necessary to validate the cleaning procedures to assure
safety, efficacy, quality of the subsequent batches of the drug product and regulatory
requirements in Active Pharmaceutical Ingredients (API) product manufacture. This
review article briefly discusses the scope and application of cleaning validation in the
pharmaceutical industry.

Keywords: Cleaning validation, cleaning procedure, sampling technique.

1. INTRODUCTION
Pharmaceutical Validation is the documented act of establishing that any procedure,
process, equipment, material, activity, or system has been followed that leads to the
expected result.
Pharmaceutical Validation also can be defined as documented evidence that gives a high
degree of assurance that a specific process will consistently produce a product that will
meet its predetermined specifications and quality characteristics.
Cleaning means making any object, piece of equipment, and are free of dirt, marks, or
any unwanted matter. There is a great need for cleaning equipment and processing areas
in the pharmaceutical industry. Inappropriate cleaning can lead to contamination and
cross-contamination. Pharmaceutical products can be contaminated with various
materials such as residues of previously used active pharmaceutical ingredients, raw
materials, cleaning agents, and dust mites.
The main objective of GMP is to prevent contamination and cross-contamination of
materials. Hence a correct cleaning method is required to avoid the possibilities of
contamination and cross-contamination, it requires a validated program, this program is
known as cleanliness verification.
"Pharmaceutical cleaning validation is documentary evidence assuring that the cleaning
of kit, piece of kit or system will achieve pre-determined and acceptable limits".
Pharmaceutical cleanliness verification helps in the analytical investigation of the
cleaning process. The purpose of pharmaceutical cleaning validation is to verify the
efficacy of cleaning methods to remove residues from the previous product,
preservatives, or cleaning agents and microbial contaminants.1, 2

2. OBJECTIVE
The objectives of kit cleaning and cleaning validation in a lively Pharmaceutical
Ingredient (API) area are the same as those in the pharmaceutical production area. In both
these areas, efforts are necessary to stop contamination of a future batch with the
previous batch material 3.
The cleaning of the 'difficult to reach' surface is one of the foremost important
considerations in equipment cleaning validation. Cleaning validation is an API facility is
extremely important as cross-contamination is one of the pharmaceutical dosage forms,
which will multiply the matter. Therefore, it is important to try to do a step-by-step
evaluation of the API process to work out the foremost practical and efficient thanks to
monitoring the effectiveness of the cleaning process 4.
It is necessary to validate pharmaceutical cleaning procedures for the subsequent reasons
1. it's a major customer requirement since it ensures the purity and safety of the
merchandise.
2. it's a regulatory requirement in Active Pharmaceutical Ingredient product manufacture.
3. It also assures the standard of the method through indoor control and compliance5.

What is Cleaning Validation?

Pharmaceutical Cleaning validation is a procedure of establishing evidence that cleaning
processes for manufacturing equipment and it's preventing product contamination.
Cleaning validation should be properly documented to demonstrate Current Good
Manufacturing Practice (CGMP) for finished pharmaceuticals6.
Why Is It Needed?
Pharmaceutical Cleaning validation is required because Active Pharmaceutical
Ingredients (APIs) cross-contaminated with chemical residues and microorganisms can
cooperate with patient safety. Ineffective cleaning processes not only cause more
downtime and batch failures, but they also end in FDA rejection and dear fines thanks to
drug adulteration.
Importance and purpose of cleaning validation 7
Cleaning validation is
1. not only required to suits regulations, but also it's necessary to satisfy customers'
requirements.
2. It ensures the safety, identity, purity, and strength of the product which are the basic
prerequisites of cGMP (Current Good Manufacturing Practice).
3. It provides the manufacturer with enough confidence that internal control is well
established.

3. CLEANING VALIDATION GUIDELINES

3.1. FDA Guidelines6
While the U.S. Food and Drug Administration (FDA) has yet to release pharmaceutical
cleaning validation guidelines for pharmaceutical firms, they supply reference material
for the inspections frequently administered by investigators and other FDA personnel. In
the document, FDA commonly expects:
• To Written the standard operating procedures (SOPs) for equipment cleaning processes
that address different scenarios (e.g. one process for various batches, different processes
between product changes, etc.)
• To Written the pharmaceutical cleaning validation procedures, including who is liable
for performing and approving the validation study, the acceptance criteria, and when re-
validation is receiving to be necessary
•To Written the pharmaceutical cleaning validation protocols for the inspection of every
piece of equipment that addresses common issues (e.g. sampling procedures, analytical
methods, etc.), conducting the validation consistent with the protocols and documenting
its results
FDA REQUIREMENTS8
1. FDA expects firms to possess written standard operating procedures (SOP) detailing
the cleaning process used for various pieces of instruments.
2. If a firm contains a particular cleaning process for cleaning between different batches
of the identical product process for cleaning between product changes, FDA expects the
written procedures to handle these different scenarios.
3. If firms have one procedure for removing water-soluble residues and another
procedure for non-water soluble residues, the written procedure should address both
scenarios and make it clear when a procedure is followed.
4. it's required by the FDA, within the validation procedure, that the personnel in charge
of performing and approving the study should fit the acceptance criteria and also the
revalidation data.
5. FDA expects firms to rearrange particularly written validation protocols ahead for the
studies to be working on each manufacturing system or piece of kit which should address
such issues as analytical methods, and sampling procedures to be used including the
sensitivity of these methods.
6. it's expected that firms perform the validation studies under the protocols and
document the effect of studies.
7. Final validation report is to be permitted by the regulatory board which states whether
the cleaning procedure is valid.

3.2. European Medicines Agency (EMA) 9

EMA has been a leader concerning setting up hazard-based cleaning approval rules for
anticipation of cross-defilement in shared creation offices. In direction, compelling June
01, 2015, EMA made it required to set up Health-Based Exposure Limits for all the
medication items dependent on Permitted Daily Exposure Values as portrayed in
Appendix 3 of ICH Q3C (R4).
The rule was before long followed up by a Q&A on the execution of the above rule. The
full Q&A is an absolute necessity read anyway a couple of key things are recorded here.
HBELs ought to be set up for all restorative products. The toxicological or
pharmacological information, on which the HBEL estimation depends, requires
periodical reassessment all through an item's lifecycle.
Step-by-step instructions to Use HBELs: Establishing HBELs is only the beginning.
These qualities fill in as a premise to decide the extra controls that might be set up
through a Quality Risk Management measure.
Acknowledgment versus Alert Limits: While HBELs fill in as Residue Acceptance
Limits the producers need to draw ready lines dependent on the generally utilized
Cleaning Limits (like dependent on measurements) while guaranteeing that the Cleaning
Processes are proficient. This implies that if your chronicled dose-based cutoff is the
most noticeably awful yet that outcomes in CpK < 1.33, should be set dependent on the
measurable assessment and not founded on as far as possible.
Logical Testing at Product Changeover: This is presently required except if the danger is
measured low. Hazard evaluation is completed hooked into the Severity (Toxicity Scale),
Probability (Cleaning Process Capability), and Detectability (Visual Threshold).
Utilizing LD50: For drug items, presently LD50 cannot be utilized as a sufficient take-off
point to decide HBELs.
3.3. World Health Organization (WHO) 9
WHO Cleaning Validation Guideline is the same as that of FDA. WHO Good
manufacturing rehearses for dynamic drug fixings (Annex 2) spreads out the necessities
all through the archive yet explicitly under Sections 5.2 and 12.7. The following are a few
things to remember:
Worst Case Approach: WHO acknowledges the most noticeably awful item way to deal
with select agent APIs to approve Cleaning Procedures. It further adds that the choice
ought to be founded on the dissolvability and trouble of cleaning and the computation of
buildup limits dependent on intensity, harmfulness, and steadiness. It is extremely
indistinct however how to fuse solidness into buildup limits.
Continuous Process Verification: WHO suggests constant checking utilizing techniques
like logical testing and visual assessment. It gives a clue to the danger-based strategy yet
the absence of any further subtleties passes on a ton to be wanted.
In May 2020, WHO delivered a functioning draft for remarks Points to consider on the
various methodologies – including HBEL – to set up remainder limits in cleaning
approval for ID of tainting hazards when producing in shared offices. This direction is
surely roused by the HBEL upheaval that has gotten force across every significant
controller. It likewise incorporates a characteristic danger scale to quantify peril
dependent on PDE esteems which is defective as it shows hazard as a discrete amount
and not as an"art-13">Contamination: "The undesired presentation of the synthetics or a
microbial nature, or unfamiliar matter into or on to a beginning material or transitional,
during creation, examining, bundling or repackaging, stockpiling, and transport."

4. CONTAMINANTS:
Contaminants are any contamination, Product, or substance other than item fabricating.
Unfamiliar items, Particulate matter, Microorganisms, Endotoxin (debase
microorganisms), Cross-defilement is instances of contamination.10

4.1Types of contaminations
1. Cross-contamination with active ingredients
Contamination of one group of the item with critical degrees of leftover dynamic fixings
from a past clump can't go on without serious consequences. Notwithstanding the
conspicuous issues presented by exposing customers or patients to accidental toxins,
expected clinically huge synergistic connections between pharmacologically dynamic
synthetic compounds are a genuine concern11.
One of the genui ne risks in cross-contamination of dynamic fixings is that after
contamination the result is a various dynamic fixing item rather than a single dynamic
fixing item. Contingent upon clinical impacts, the contamination might upgrade the
activity or invalidate the activity or impurity might have unique clinical and wellbeing
effects12.
2. Contamination with accidental materials or mixtures
While latent fixings utilized in drug items are by and large perceived as protected or have
been demonstrated to be ok for human utilization, the normal use, support, and cleaning
of supplies give the potential contamination such things as gear parts, ointments,
compound cleaning specialists and bits of cleaning instruments like brushes and clothes.
3. Microbiological contamination
Upkeep, cleaning, and capacity conditions might give extrinsic miniature creatures the
chance to multiply inside the preparing equipment11.
This type of contamination is especially guileful because the contamination might create
whenever, even after cleaning. A huge contributing variable is the capacity of hardware
in a wet or soggy condition. This gives a characteristic medium wherein microscopic
organisms can develop easily12.
From where does cross-contamination create?
1. It might be because of the helpless plan and worked air dealing with frameworks and
residue extraction framework.
2. Inadequate strategy for staff and hardware
3. Not legitimate cleaning of the instrument.
How to limit cross-contamination?
• Use of shut creation frameworks
• By applying an approved cleaning methodology
• By keeping a degree of item produce
• Adequate premises
• By introducing of right gaseous tension course
Step-by-step instructions to control dust in pharmaceuticals: Dust control is exceptionally
important to control contamination and cross-contamination in drugs. at whatever point
conceivable the residue or fume tainting ought to be eliminated at the source. dust
extraction pipe ought to be planned with adequate exchange speed to guarantee dust is
out of hand. Wind current bearing ought to be painstakingly picked that the administrator
doesn't contaminate the item. Utilization of very much approved HEPA channels in
series, to give extra insurance. A modern PC-based information checking framework
might be installed10.
5. Equipment characterization
Cleaning approval includes the evacuation of buildups as well as gives confirmation and
certainty that every single piece of hardware related to the cycle has been cleaned to
alluring or satisfactory levels. It normally alludes to train-based methodology. The
equipment train is series of hardware by which the item or items move as they progress
through the assembling system. To make sure that the equipment is cleanable or not it
ought to be described so that its plan highlights are well known13
6. Cleaning procedures
Standard cleaning systems for each piece of hardware and interaction ought to be ready.
Significantly, the hardware configuration is sorted out exhaustively in blend with the item
deposits which are to be eliminated, the accessible cleaning specialists, and cleaning
methods, while deciding the most useful cleaning methodology for the gear. Cleaning
techniques ought to be adequately and appropriately definite to keep away from the
chance of any irregularities during the cleaning system. Following boundaries are being
considered during cleaning procedures14
A. Hardware Parameters to be evaluated14
1. Recognizable proof of the gear to be cleaned
2. 'Hard to clean' regions
3. Property of materials
4. Simplicity of dismantling
5. Versatility
B. Deposits to be cleaned
1. Cleaning limits
2. Solvency of the deposits
3. Length of missions
C. Cleaning specialist boundaries to be assessed
a) Preferable materials that are generally utilized simultaneously
b) Detergents accessible (as an overall aide, negligible utilization of cleansers suggested
except if required)
c) Solubility properties
d) Environmental contemplations
e) Health and security contemplations
D. Cleaning procedures to be assessed
1. Manual cleaning
2. CIP (Clean set up)
3. COP (Clean-awkward)
4. Self-loader strategies
5. Programmed strategies
6. Time contemplations
7. Number of cleaning cycles
Cleaning Agent selection15
Cleaning specialists fall into a few general classifications;
1. Water
2. Solvents
3. Ware synthetic substances
4. Figured cleaning specialists

7. level of Cleaning 16, 17

Level 1 Cleaning
This is utilized by assembling different clumps of a similar item. Model – In an
assembling Campaign for Product X, there are 3 Batches to be fabricated as displayed
beneath. Cluster A, Batch B, Batch C for a given hardware and/or gear train, if bunch An
in the mission is to be trailed by Batch B in the mission, then, at that point, a level 1
cleaning is required.
Level 2 Cleaning
This level is utilized between assembling of various Batches of various Products and/or
toward the finish of assembling activity regardless of whether the same item is made
arrangements for the following activity. The over two degrees or level of cleaning shifts
from one another as far as the level of hazard related with it, acknowledgment breaking
point, and level of cleaning and strategy for confirming the cleaning system as displayed
in Table 1. Moreover, the CEFIC-APIC (European Chemical Industry Council-Active
Pharmaceutical Ingredients Committee) manual for cleaning approval suggests three
degrees of cleaning that might be executed.
8. TYPES OF SAMPLING METHODS 18
Right now, neither the FDA nor the government guideline for hardware cleaning and
upkeep (Section 211.67) notices particular kinds of cleaning validation. Notwithstanding,
it is by and large acknowledged in the drug business that there are two sorts of testing
techniques for cleaning validation: immediate and backhanded.
• Direct testing for cleaning validation is otherwise called the swab strategy, where a
clean material is deliberately scoured across a surface to be dissected for the presence of
buildup.
• Indirect examining for cleaning validation is frequently alluded to as wash inspecting,
where a dissolvable like water is flushed in a particular space of clean surface and tried
for hints of contaminants
9. TYPES OF CLEANING METHODS 19
• Clean-in-place Method – typically utilizing fixed or pivoting shower gadgets with a
wash tank, distribution siphon, and related channeling
• Clean-out-of-place Method– frequently utilized for mechanized parts washing through
the bureau or passage washers with cleaning, flushing, and drying cycles
• Immersion Method – either unsettled, where a cleaning specialist in a cycle vessel is
precisely invigorated to accomplish a cleaning impact, or static, where the interaction
vessel is simply splashed with the cleaning specialist.
• Ultrasonic Washing – ordinarily turns out better for unpredictable parts, for example,
filling needles as it includes a tank furnished with ultrasonic transducers to induce
cavitation
• High-pressure Spraying – serves to dislodge any deposits on a superficial level through
high-pressure, constant, and coordinated water or cleaning arrangement
• Manual Cleaning – generally the most troublesome cleaning strategy to validate;
incorporates three most normal procedures: cleaning, sink brushing, and equipment
brushing
10. Acceptance Criteria
Precisely drawing the acceptance criteria for the line in cleaning validation is significant
to decide the consequences of the review. To more readily assess whether cleaning
strategies are powerful, cleaning validation Acceptance Criteria can be by and large
ordered into three different testing boundaries:
• Physical Criterion: a visual inspection of the equipment should reveal that there are no
particulate matters or deposits
• Chemical Criterion: close to 10 ppm (parts per million)
of a product should be detected in another product as well as close to 0.1% of the normal
therapeutic dose of a product should appear in the maximum daily dose of another
product.
• Microbial Criterion: close to 20 CFU (state shaping units) for bacterial counts, close to
2 CFU for molds, and additionally close to 25 CFU/25cm2 of contaminants in an
example
11. VALIDATION PROTOCOLS 20, 21
A Validation Protocol is important to characterize the particular things and exercises that
will establish a cleaning approval study. Organizations should have drawn up a Master
Validation plan demonstrating the general Cleaning Validation technique for the item
range/hardware type/whole site. The convention should be ready preceding the inception
of the review and should either incorporate or reference the documentation needed to
give the accompanying data:
• Background
• Purpose of the validation study
• Scope of the validation study
• Responsibilities for playing out the validation study
• Sampling methodology to be utilized
• Testing technique to be utilized
• Acceptance criteria
• Change control
• Approval of convention before the review
• Deviations
12. VALIDATION REPORTS 21
A validation report is important to introduce the outcomes and ends and secure
endorsement of the review. The report ought to incorporate the accompanying:
• Summary of or reference to the systems used to clean, example, and test
• Physical and analytical test outcomes or references for same, just as any appropriate
perceptions
• Conclusions in regards to the worthiness of the outcomes, and the situation with the
procedure(s) being approved
• Any proposals dependent on the outcomes or important data got during the review
including revalidation rehearses if pertinent.
• Approval of ends
• Review any deviations for the convention that happened.
• In situations where it is impossible that further groups of the item will be fabricated for
a while, it is fitting to create an interval that gives an account of a clump by cluster
premise until the cleaning approval study has been finished.
• The report should conclude a suitable degree of confirmation ensuing to approval.
13. REVALIDATION
A change control system is in place to ensure that all progressions that may affect the
cleaning system are surveyed and archived. Huge changes should follow palatable audit
and approval of the reported change proposition through the change control procedure.
Minor changes or changes straightforwardly affecting last or in-measure item quality
ought to be dealt with through the documentation framework. The review should
incorporate the thought of re-validation of the cleaning system. Changes that should
require assessment and reasonable re-validation incorporate yet are not restricted to:
• Changes in the cleaning technique;
• Changes in the raw material sources;
• Changes in the plan and additionally interaction of items;
• New products;
• Changes in the formulation of cleaning agent;
• New detergents;
• Modifications of instruments.
The cleaning system should be rethought at characterized spans, and revalidated
approved as important. Manual methods should be rethought at more successive intervals
than clean-in-place (CIP) systems.
14. Sources of Contamination in the Pharmaceutical Industry 22
Impurities can gain entry into a production process stream from several sources such as
Personnel, Poor facility design, Incoming ventilation air, Machinery and other equipment
for production, Raw materials, finished products, Utilities, Different media used in the
production process as well as for cleaning and Cleanroom clothing.
1) Personnel
Personnel who are overseeing or performing drug assembling or control can be a likely
potential source of microbiological contaminant and a vector for different impurities.
The primary purposes behind contamination from the personnel include:
• Lack of training
• Direct contact between the administrator's hands and starting materials, primary
packaging materials, and intermediate or bulk product
• Inadequate personnel tidiness
• Access of unapproved staff into creation, stockpiling, and item control regions
• Inadequate gowning and staff defensive hardware, and
• Malpractices like eating food, drinking refreshments, or utilizing tobacco in the capacity
and processing areas.
Buildings and Facility
The structures and manufacturing facilities
may likewise add to the tainting.
The primary reasons for contamination because of facility issues include:
Insufficient size and lacking association of the space prompting choice mistakes like
misunderstandings or cross-contamination between consumables, starting materials, in-
process materials, and completed items
Inadequate foulness and bug controls
Rough floors, ceilings, and walls.
Lack of air filtration
Improper lighting and ventilation
Poorly found vents, edges, and depletes, and
Inadequate washing, cleaning, toilet, and storage offices to consider sterile activity,
cleaning of offices, gear, and utensils; and personal cleanliness.
2) Equipment
The Equipment utilized in handling, holding, moving, and bundling are the common
source of pharmaceutical contamination.
The principle behind contamination from the equipment includes:
• Inappropriate configuration, size, material prompting consumption and aggregation of
static material or potentially defilement with greases, coolants, soil, and cleaning
specialists
• Improper cleaning and disinfection
• Design preventing appropriate cleaning and maintenance.
• Improper calibration.
• Deliberate utilization of flawed gear
3) Materials
The crude materials utilized for creation can be a possible source of contamination.
The fundamental purposes behind contamination from the crude materials include:
• Storage and taking care of mix-ups causing mistakes or determination errors.
• Contamination with microorganisms or different synthetic substances
• Degradation from exposure to inordinate natural conditions like warmth, cold, daylight,
dampness, etc,
• Improper labeling
• Improper sampling and testing, and
• Use of materials that fail to meet acceptance criteria.
4) Manufacturing Process
There are different opportunities for contamination of crude material, intermediates, or
bundling materials all through the Manufacturing system.
The reasons for contamination during the manufacturing process include:
• Lack of committed offices to make a solitary item
• Inappropriate cleaning in the middle of batches to limit the measure of product
changeovers
• Inappropriate drafting
• Absence of a spaceline leeway as per endorsed methodology following each cleaning
cycle and between each bunch, and
• Lack of cleaning status marking on all gear and materials utilized inside the assembling
office To limit the dangers of assembling defilement
• Manufacture items in a mission, with the fittingly qualified cleaning cycles and checks,
acted in the middle of bunches to limit the measure of item changeovers
• Utilize a shut assembling framework. This is the place where the item isn't presented to
the quick room climate (as well as the other way around)
• Perform a region line leeway as per supported systems following each cleaning cycle
and between each group/crusade
• Zone the office and
• Use Cleaning Status marking on all gear and materials utilized inside the assembling
office
5) Air conditioning System
A poor HVAC framework can be an expected wellspring of an organism's development
and a transportation mode for scattering foreign substances all through the assembling
office.
The primary reasons of contaminants because of HVAC issues include:
• Accumulations of natural material in or close to HVAC air admissions
• Ineffective filtration of the stock air
• Insufficient extent of strain differentials causing a stream of inversion
• Erroneous proportion of natural air to recycled air
• Inability to get to ventilation dampers and channels from outside the assembling
regions, and
• Non-directional wind current inside creation or primary package regions

CONCLUSION:
It is practically impossible to prove that pharmaceutical equipment is 100% clean.
However, it's possible to prove that the traces of active product remaining spread through
the equipment parts are within a suitable limit which we are capable of detecting and
quantifying these traces levels. Pharmaceutical Cleaning validation provides a way of
proving that the contamination levels are acceptance limit or not.
The pharmaceutical industry should be free of any contamination or cross-contamination,
it might be safe for the consumer. With the help of cleaning validation, any department of
the pharmaceutical industry can achieve a high degree of assurance regarding the
cleaning, with we can minimize any kind of contamination or cross-contamination which
is maybe any residue of the previous product, the substance of machine, or any microbial
contamination.

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