Indian Research Journal of Pharmacy and Science; P. Tomar et.al.

June’17

REVIEW

A REVIEW ON CLEANING VALIDATION FOR PHARMACEUTICAL INDUSTRY

Prashant Tomar*, Preeti Khothiyal

Division of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology and Science, Patel Nagar,
Dehradun-248001, Uttarakhand, India.

Submitted on: 18.05.17; Revised on: 27 .05.17; Accepted on: 31.05.17

ABSTRACT:

The objective of this review is establishment of importance of cleaning validation in pharmaceutical industry. It
provides background on cleaning validation in order to prevent the potential problems which may have effect on
safety, efficacy and quality of pharmaceutical product being manufactured. Regulatory agencies like US FDA have
recommended having an effective cleaning validation program. It briefly provides an overview on cleaning
mechanisms, cleaning agents, methods of cleaning, sampling techniques, methods to determine acceptance criteria
and analytical techniques to identify and quantify drug residues.

KEYWORDS: Cleaning validation, Acceptance Criteria, Maximum Allowable Carryover (MAC), Acceptable
Daily Exposure (ADE), Analytical methods.

Corresponding Author: Prashant Tomar, Indian Research Journal of Pharmacy and Science; 13(2017) 950-962
E-mail address: [email protected] Journal Home Page: https://www.irjps.in
DOI: 10.21276/irjps.2017.4.2.2

Ind Res J Pharm & Sci|2017: June.:4(2) 950

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

1. INTRODUCTION 1.1. Need of Cleaning Validation:

Validation: The prime goal of any pharmaceutical 1. To maintain product integrity: To

industry is to manufacture or produce products of maintain product integrity basically includes
required attribute and quality consistently, at the preventing cross-contamination as there
lowest possible cost. Validation studies have been might be the possibility that earlier product
conducted in the pharmaceutical industry of long era manufactured in the equipment may get into
still there is an ever-increasing interest in validation the product which is going to be
because of industry’s greater emphasis in recent years manufactured in the same equipment.
on quality assurance program and is fundamental to Contamination may also occur due to
an efficient production operation.1 equipment residues, drug excipients and
cleaning agents.6 Another contamination
Validation is a concept that evolved in united states
may be due to microbial and/or endotoxins
in 1978.The concept of validation has extended
which may lead to safety issues in
through the years to adopt a range of activities from
pharmaceutical dosage forms and may also
analytical methods used for the quality control and
affect the stability of the product.7
quality assurance of drug substances and drug
products for development, production, clinical trials,
2. For equipment reuse: Almost all of
or process control, Validation is best viewed as a
manufacturing equipment used in
vital and integral part of cGMP.2
pharmaceutical manufacturing is made of
According to US-FDA Validation is defined as stainless steel which is expensive thus,
“Process validation is establishing documented cannot be disposed of after use and should
evidence which provides a high degree of assurance be reused. Therefore, validated cleaning
that a specified process will consistently produce a program should be performed.8
product meeting its pre-determined specifications and
quality characteristics.” 3 3. Due to Regulatory requirements: All the
Regulatory agencies recommends for an
Thus, Cleaning Validation can be defined as “A effective cleaning validation program which
documented evidence with high degree of assurance includes the FDA, GMPs etc.9 The U.S.
that one can consistently clean a system or piece of Food FDA has strict regulations for the
equipment to predetermined and acceptable limits.” cleaning validation which necessarily
includes written procedures, equipment
Cleaning validation is primarily applicable to the design, analytical methods, acceptance
cleaning of process manufacturing equipment in criteria etc.10
pharmaceutical industry. It is necessary to have
effective cleaning programs in place because of 4. Other requirements for cleaning validation
regulatory requirements.4 may include: Initial qualification of process/
equipment, Critical change in a cleaning
The focus of cleaning validation is those cleaned
procedure, Critical change in formulation,
surfaces that, if inadequately cleaned, could
Change in a cleaning process or Change in a
potentially contaminate the product later
cleaning agent.11
manufactured in that same equipment. This primarily
covers product contact surfaces in the cleaned
equipment. Cleaning validation is not performed only 2. CLEANING MECHANISMS
to satisfy regulatory authorities. The safety of
patients is the primary goal, and product Cleaning is the process of removing unwanted
contamination presents serious liability issues for any substance or contaminant from the surface of
pharmaceutical manufacturer or contract manufacturing. There are several mechanism that
organization.5 remove or aids in removing the contaminants from

Ind Res J Pharm & Sci|2017: June.:4(2) 951

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

the equipment surfaces.12 The various cleaning 6. Hydrolysis: This involves the cleavage of
mechanisms include: different bonds in an organic molecule.
Hydrolysis is a very effective cleaning
1. Solubility: Solubility here is the dissolution procedure because it converts the large
of the contaminant in a liquid media or water insoluble molecule into smaller water-
solvent. For instance some component (salt) soluble molecule because the smaller
might be soluble in water while other in molecule formed is slightly more polar but
hexane. However the rate of solubility, the resultant hydrolyzed residues might be
insoluble form left and solvent used for either water soluble or solubilize at the pH
cleaning is considered in solubility.13 of the cleaning solution. Thus after the
hydrolysis cleaning with water or any other
2. Solubilization: Solubilization is basically solvent with specific pH may be used. 19
same as solubility the difference is it
involves the addition of some substance to 7. Oxidation: Oxidation involves the cleavage
pure solvent to make the residue soluble, of various organic bonds by the strong
such as addition of surfactant to the purified oxidizing agent such as sodium
water or pH modifier to make residue in the hypochlorite. The oxidants cleaves organic
ionized or unionized hence soluble.14 molecule at various linkages in the larger
molecule which leads to small molecules
that are more polar and increase the water
3. Emulsification: This process basically solubility of the degraded components. The
involves the breaking an insoluble liquid effect is similar to that of hydrolysis, except
residue into tiny droplets and then making that the phenomenon of oxidation is more
those droplets suspended throughout the universal (and less specific) than
water or any other specific solvent.15 hydrolysis.20

4. Dispersion: Dispersion involves the wetting 3. CLEANING AGENTS

followed by desegregation and then the
formation of suspension of solid particles in There is variety of cleaning agents available for
water. This mechanism is like cleaning processes. Cleaning agent should be selected
emulsification, difference is dispersion based on the Suitability to remove product residues,
being used for cleaning of solid residues.16 Compatibility with the equipment, Ease and
sensitivity of analytical method, Ease of removal &
5. Wetting: This involves the substitution of verification of removal and most important Toxicity
one fluid from a surface (manufacturing should be low as it may cause harmful effect to
equipment) by another fluid (the cleaning cleaning personal or might affect another batch going
solution).17 Wetting of surfaces involves to be manufactured 21 Classification of Cleaning
wetting of the soil to be removed as well as Agents:
wetting of the surface to be clean as the
Wetting of the soil to remove provides rapid 1. Organic Solvents
solubilization, emulsification or dispersion. 2. Aqueous Solvents
The main mechanism involved in wetting is i) Water
the lowering of surface tension making ii) Surfactants
equipment surface easy to clean as well as iii) Chelants
better penetration of the cleaning solution iv) Acids, bases and oxidants.22
into cracks and crevices, which are difficult 3.1. Organic Solvents: These can be used as a
places to clean.18 cleaning agent only if the drug being
manufactured is soluble in an organic

Ind Res J Pharm & Sci|2017: June.:4(2) 952

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

solvent and if organic solvent is also the and sulfuric acid are generally not used
same solvent used in the bulk active because of safety reasons or deleterious
manufacturing process. However safety effects on equipment. Acids are used to
must be taken in consideration the use of lower the pH, thus rendering certain alkaline
solvents, which may be flammability of the residues more soluble.27
solvent or the occupational exposure limit.
Examples of typical organic solvents used 4. CLEANING METHODS
are Methanol, Acetone or Ethyl acetate
etc.23 Cleaning methods are selected on the basis the extent
of disassembly of equipment and on the method of
3.2. Aqueous Solvents: Aqueous cleaning contact of the cleaning agent with the equipment to
consists of cleaning with water with or with be cleaned. Cleaning methods are broadly classified
variety of other modified solvents. into Automated Cleaning and Manual Cleaning.28

i. Water: It is the universal solvent. If water 4.1. Automated Cleaning:

alone is efficient in cleaning the product i. Clean in Place (CIPs): CIP is an
without much time or physical effort to automated process in which disassembly is
remove the residues, the water can be best not performed and in which process
solvent to be used, However the water equipment is merely flooded with cleaning
alone requires too much of time for solution.29 Generally a CIP involves spray
cleaning. Thus in these conditions the devices to distribute the cleaning solution to
other Solvents come into the picture.24 all parts of the equipment. CIP systems are
ii. Surfactants: Surfactants used for usually designed for cleaning performed
cleaning generally have a hydrophilic with the aid of Aqueous Cleaning agent.30
("water loving") polar end and a lipophilic The advantages of CIP includes that they are
("oil loving") non-polar end. The function Designed for better clean ability,
of a surfactant is for dispersion, Automated, Consistent, Water/cleaner
emulsification, wetting surfaces and savings, Time savings, Ease of validation
solubilization. As broad categories, and Safe during operation and few
surfactants are divided into nonionics, disadvantages like Lack of flexibility, High
anionic, cationics and amphoterics. initial capital cost and Uses aggressive
Nonionics are mostly used when cleaning cleaning agents.31
mechanism emulsification is required,
while anionics are used where wetting and ii. Agitated Immersion: Agitated immersion
dispersion are required.25 is basically filling the cleaning solution into
iii. Bases: Bases include hydroxides such a s the vessel to be cleaned and then agitating it
sodium hydroxide or potassium with the aid of agitator placed already in the
hydroxide. Bases are used to raise the pH, vessel, followed by multiple times rinsing
thus rendering certain acid residues more with suitable solvent.32 The cleaning
soluble. They also can assist in the solution may be an organic solvent or an
hydrolysis of esters or arnides. Finally, aqueous solvent due to which cleaning takes
bases assist in potentiating surfactants so place. This process of Agitated Immersion
that the detergency is improved.26 can be performed by using different
iv. Acids: Acids include weak to medium parameters like various times, temperatures,
strength acids such as glycolic acid, cleaning agents, and flow conditions. The
phosphoric acid, and citric acid. Strong major advantages of Agitated Immersion are
mineral acids such as hydrochloric acid Low Capital cost, Simplicity followed by
disadvantages like high process times.33

Ind Res J Pharm & Sci|2017: June.:4(2) 953

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

iii. Automated Parts Washing: In this feedback on their cleaning performance being
process the equipment is disassembled and performed.40
the equipment parts are placed in a 5. SAMPLING TECHNIQUES
mechanical washer followed by cleaning,
rinsing, and drying cycles with the aid of The Sampling Techniques must be consistent with
cleaning solution and rinsing solvent which sound scientific judgment and must support the goal
are sprayed to all surfaces of the objects to of the study, which is to prove that the amount of
be cleaned by spray jets and nozzles.34 The residue or target substance in the equipment has been
performance of the automated washer is reduced to an acceptable level.41 Equipment is
due to both the mechanical spray systems characterized into hot spots and critical sites. Hot
and due to the chemical action of the spot is the place that is likely to become dirty during
cleaner used. The major advantages of the manufacturing process and it is difficult to
Automated Parts Washing are Consistency clean.42
in performance, Time savings, safe, There are two generals types of sampling that have
Chemical and water saving. The been found acceptable which are Direct Sampling
disadvantages of automated parts washers technique and Indirect Sampling technique.43
are as follows: Initial capital cost and
Unsuitable for delicate parts.35 5.1. Direct Sampling Technique: Direct
surface sampling can be further divided
into two parts:
iv. Ultrasonic Washers: These cleaning
system work on the principle Cavitation in i. Visual Inspection (Qualitative): To
which the sound waves cause tiny bubbles physically look at and examine the direct
to form when these bubbles grow, they surface of the equipment to confirm that
eventually collapse upon themselves. This contaminants, impurities, residual product,
mechanical energy formed due to etc are removed.44 Visual Inspection
collapsing cause dislodge of the residues employs the following: eyesight of the
present on the equipment surface. 36, 37 viewer, available light for viewing, distance
Ultrasonic washers run at temperatures of the viewer from the surface, angle of the
below about 50°C. This process is most light and the viewer to the surface, naked
favorable for cleaning delicate parts that eyes (pre-qualification eyes exam is
might be damaged by other cleaning required), boroscope, mirrors, extension
processes or parts containing small holes poles, bright lighting, white and black
which are difficult to clean. The advantages cloths.45
of ultrasonic are excellent cleaning for
delicate items and low initial capital cost ii. Swab Sampling (Quantitative): It basically
but may have the disadvantages like high involves the use of Swabbing material, often
manual processing and validation issues.38 saturated with a solvent, to physically
sample the equipment surfaces. The Swabs
4.2. Manual Cleaning: are treated with the liquid medium (usually a
good solvent for the target substance to ease
There are various Process of Manual Cleaning the absorption of the residue) and then swab
processes which include wiping, high pressure is applied on a predetermined surface area
spraying, sink brushing, and equipment and then the swabs are prepared and stored
brushing.39 These all manual cleaning operations in a suitable container for further analysis. 46
has an advantage like low capital costs and It is the most preferred technique by most
disadvantage like higher variability. If done in regulatory agencies. Swab material typically
right way, they are very effective and also allow consists of polyesters, glass wool, cotton and
operators to have high degree of immediate filter paper. The swab must be compatible

Ind Res J Pharm & Sci|2017: June.:4(2) 954

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

with the diluent and must give greater ii) May lower test sensitivity.
flexibility in choosing the proper solvent to iii) Residues may not be homogenously distributed.
check the removal of the targeted substance iv) Inability to detect site of residues.
than swab sticks.47 The amount of solvent v) Rinse volume is critical to make sure correct
used to extract the swab should be interpretation of results.53
accurately determined. The choice of the
solvent is taken into consideration the 6. ACCEPTANCE CRITERIA
solubility of the residue in the solvent, the
time needed for the residue to be solubilized, The establishment of meaningful criterion is very
the potential interference/interactions effects important for a cleaning validation program.
between rinsing agents and residue, impact Acceptance criteria is the foundation stone of the
of solvent on the sample surface.48 overall program as they give direction as to the
effectiveness of cleaning procedure and influence the
Advantages of Swab Sampling: limits of the analytical method validation.54
i) Dissolve and physically remove sample.
The FDA does not set specific acceptance criteria for
ii) Adaptability to wide variety of surfaces.
level of residue due to different variety of processes,
iii) Economically and widely available.
equipment and products in pharmaceutical country,
iv) May allow sampling of a defined area.
however FDA quotes that “The firm’s rationale for
v) Applicable to active, microbial, and
the residue limits establishment should be logical
cleaning agent residues.49
based on the manufacturer’s knowledge of the
materials involved and be practical, achievable, and
Limitation:
verifiable”.55
i) An Invasive technique that may
introduce fibers. Thus, Acceptance criteria should be scientifically
ii) Results might be technique dependent. justifiable, pacifically achievable, and methodically
Swab material and design may inhibit verifiable.56
recovery and specificity of the method.
iii) Evaluation of large, complex and hard There can be possible 3 types of limits if illustrated
to reach areas difficult.50 below:

5.2. Indirect Sampling or Rinse Sampling: 1. Visually clean Approach

Rinse Sampling involves passing a known 2. Chemical Approach
volume of solvent over a large area and 3. Microbiological Approach
analyzing the recovered solution.51 The 6.1. Visually clean Approach: GMPs require
Rinse sampling is more commonly used in inspection for visual cleanness before
bilk pharmaceuticals Rinse sampling manufacture of any product. Visual inspection is
involves using a liquid to cover the surfaces an active observation of the visually accessible
to be sampled. It is one of the easy and product contact surfaces of the pharmaceutical
widely used sampling methods; most manufacturing equipment
preferable liquid for rinsing is water and .
rinse volume is an important factor that has Few key points to be considered in this approach
to be determined.52 may be angle of view of the inspector, distance
from equipment, surface Lighting conditions,

Rinse volume α (1/Residue conc. in rinse sample) and viewer’s knowledge. During inspection
Limitation: viewer can use visual aids which may be limited
i) Limited information about real surface to additional lighting, magnifying glass, fiber-
cleanliness in some cases. optic scope or UV light based on the product
being inspected and severity.57

Ind Res J Pharm & Sci|2017: June.:4(2) 955

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

However, there is no such quantifiable limit set

by regulatory agencies but most of the industrial Step 1 – Calculation of the ADE
experts consider a typical visual limit as not less (Acceptable Daily Exposure)
than 4 µg/cm2 and also PIC/S advocates × BW
=
considered to do spiked coupon study for × ×
determination of visual limits.
Where,
NOAEL - No Observed Adverse Effect
This approach has various advantages like easy
Level (mg/kg/day) , BW - Is the weight of
to do, can be time and money-saving but it
an average adult in Kg, UFc - Composite
should not be considered for potent drug,
Uncertainty Factor: combination of factors
microbiological contamination or endotoxin
which reflects the inter- individual
because trace amount of these cause a serious
variability, interspecies differences, MF -
health hazard.58
Modifying Factor: a factor to address
uncertainties not covered by the other
6.2. Chemical residue Approach: 59 This
factors and PK - Pharmacokinetic
approach may be based on following criteria’s –
Adjustments
i. Therapeutic dose based criteria: Based on
the assumption that 1/1000 part of
Step 2 – Calculation of MAC from ADE
therapeutic dose does not have any clinical
(Previous) × MBS (Next)
impact on human (animal) body and found =
to be Most suitable for drug product ( )
(finished product) manufacturing facility. In
iii. LD50 based criteria: In cases where no
this criterion the limit for Maximum
other data is available (e.g. ADE etc) and
Allowable Carryover (MAC) is calculated
only LD50 data is available (e.g.
by the formula given below) of Product A
chemicals, intermediates, detergents etc),
(Previous) to Product B (Next):
the MAC can be based upon LD50 data.
(Previous) × MBS (Next)
= Step 1 – Calculation of NOEL
× ( )
50 × BW
Where, =
2000
STDDprevious - Standard Therapeutic
Daily Dose of the investigated product (in Where,
the same dosage from as TDDnext)
(mg/day) , STDDnext - Standard NOELprevious - No Observed Effect Level
Therapeutic Daily Dose for the next product (mg/day), LD50 - Lethal Dose 50 in mg/kg
(mg/day) , MBSnext - Minimum batch size animal (mg/kg), BW - Is the weight of an
for the next product(s) (mg) , SF - Safety average adult (e.g. 70 kg) (kg) and 2000 is
factor an empirical constant.

ii. Health-based data based criteria: Step 2 – Calculation of MAC

Based on the toxicological information
(Previous) × MBS (Next)
available in Material Safety Data Sheets. =
× ( )
Most suitable for active drug (API)
manufacturing facility, where cleaning
agents are used other than water.

Ind Res J Pharm & Sci|2017: June.:4(2) 956

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

Safety factors: Safety factors for different dosage forms is given in Table-1
Table I - SAFETY FACTORS FOR DIFFERENT DOSAGE FORMS

Approach Approach Typically Applicable To

0.1 to 0.01 Topical products

0.01 to 0.001 Oral products

0.001 to 0.0001 Parenterals, opthalmic products

0.0001 to 0.00001 Research, investigational products

iv. 10 PPM criteria:60 This criteria is

based on the hypothesis that 10 ( / )
parts of previous product is ( )
=
therapeutically ineffective if ( )
presents in million parts of next
product, this approach is CGMP 6.2.2. Rinse Limit:62 The residue amount in
requirement and is widely equipment after cleaning can also be
applicable determined by taking rinse samples.
The Target value for the Rinse
10 × BS samples can be calculated by formula:
=
1000000

Where,
( / )
BS – Smallest batch size to be available
( )
=
( )
After the successful calculation of MAC (Maximum
Allowable Carryover) the next necessary step is the 6.3. Microbiological criteria:63 This criteria is
establishment of the Swab and Rinse limits which are given in USP Official specifications USP
generally used as sampling methods, the <1111> “Microbial Examination of non-
establishment of the limit are illustrated below: sterile Products: Acceptance criteria for
Pharmaceutical Preparations and
6.2.1. Swab Limits: 61 A recommended Substances for Pharmaceutical Use” and is
value for the Swab can be set; if it is widely used at the Industrial Scale during
assumed that there is homogenous cleaning validation and it is also an
distribution on all the surfaces. If the important regulatory requirements.
total direct contact surface is known,
the target value for residue per square The various regulatory agencies like
meter can be calculated which can be European GMP has recommended the
used as vital information for microbiological monitoring of the
developing a method of analysis and production area during manufacturing of
setting up the detection limit. Swab the Pharmaceuticals and generally
limit can be calculated using the calculated using the formula:
formula:

Ind Res J Pharm & Sci|2017: June.:4(2) 957

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

cfu/plate/{π × (5.5/2)2} × swab area measurement of that target substance by the

aid of ultraviolet (UV) spectroscopy,
7. ANALYTICAL METHODOLOGY conductivity, or evaporative light-scattering
detector.68
When the Acceptance criteria of the target substance ii. Ultraviolet Spectroscopy: Drug substances
is established, the analytical method to test for the in which active chromophoric group is
targeted substance residues in each swab or rinse present can be analyzed by this method; it is
sample must be developed or selected which must be the most widely available analytical
consistent with the acceptance criteria.64 instrument.69
iii. Atomic Absorption Spectroscopy: This
Regulatory authorities require that the accuracy, limit
method is specific to metal ions. Generally
of Quantitation (LOQ), specificity, linearity and
used for estimation of sodium or potassium
precision of test methods opted for cleaning
ions during drug residue analysis.70
validation should be established which must be
iv. Ion Chromatography: In Analysis of drug
accomplished in accordance with ICH guidelines.
residue, this method can be specifically used
These guidelines also applied to the validation of
in determination of anions and cations. It
analytical methods that are used to measure residues
enables the different methods for separation
on the manufacturing equipment.65
and measurement of anions, which may be
The basic requirements are: present in the detergents or cleaning agents
used during cleaning of pharmaceutical
 The ability to detect the target substance(s) manufacturing equipment.71
at levels consistent with the acceptance v. Enzyme-Linked Immunosorbent Assay
criteria (ELISA): ELISA is mainly used for the
 The ability to detect the target substance(s) determination of protein which if analyzed
in the presence of other materials that may from any other analytical method might
also be present in the sample (selectivity).66 degrade during sample preparation. So, this
method is very specific in determination of
Types of Analytical Method: proteins present in Pharmaceutical
72
formulations.
1. Specific methods
2. Non – Specific methods 7.2. Non - Specific Methods:

The selected analytical method must allow i. Total Organic Carbon: This method uses
qualification of low levels of residue. On the basis of the oxidation of the substance and
type of Sampling, consideration must be done on how measurement of the carbon dioxide
sample preparation may have its influence on generated by using methods such as infrared
method’s sensitivity and must relate to the acceptance spectrometry or conductance. The method
criteria.67 has disadvantage that it consider that all the
measured carbon is due to target substance
7.1. Specific Methods:
being analyzed thus making it highly non
specific. However this method is generally
i. HPLC: Most preferred method, with this
used in Biotechnological drug residue
method the Drug residue on Pharmaceutical
analysis.73
equipments can be quantified. High
Performance Liquid Chromatography
ii. Conductivity: Conductivity measures
(HPLC) make use of injecting sample
specifically ions in solution because charge
injection into the separation column ,
on ions facilitates the conductance of
separation of the target substance from other
electric current but the conductance will be
components in the sample, and then
due all the ions present in the solution,
Ind Res J Pharm & Sci|2017: June.:4(2) 958
 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

which makes this method non specific as contamination, safe and efficacious in turn
unable to detect the nature or type of ion. It controlling the potential carryover of product,
can be used for the estimation of an alkaline intermediates, cleaning agents, microbiological
or an acid cleaning agent.74 contaminants and extraneous material in subsequent
product to the extent which is under acceptable
8. DISCUSSION limits. Therefore, the articles covers all the aspects
which are required to have an effective cleaning
The Cleaning Validation is an ever-increasing validation program which includes cleaning
challenge and the topic of interest in the mechanisms, cleaning agents used, cleaning methods
Pharmaceutical industry and is recommended by employed, sampling techniques to be used,
regulatory agencies like US-FDA, the Cleaning calculation of acceptance limits and the subsequent
validation demonstrate that manufacturing facilities analysis of the residues using appropriate analytical
produce a product which is pure, free from method.

9. REFERENCES 10. Food and Drug Administration “Guide to

Inspections, Validation of Cleaning Processes”
1. Sharma A, Saini S, Process Validation of Solid Office of Regulatory Affairs, FDA, Rockville, MD,
Dosage Form A Review, International Journal of 1993.
Research in Pharmacy and Science, 3 (2), 2013, pp. 11. Robert Fredrick, the Basic Facts of Cleaning
12- 30. Validation. Canada, Pharmainfo.net, 2004.
2. Kaur H, Singh G, Seth N, Pharmaceutical Process 12. Rosen M J, Detergency and its modification by
Validation: A Review, 3 (4), 2013, pp. 189-194. surfactants. In Surfactants and interfacial
3. Potdar MA; Pharmaceutical Quality Assurance. 2nd phenomena, New York, John Wiley and Sons Inc,
Edition, Nirali Prakashan, 2009, pp. 6-20. 1978, pp. 272-293.
4. Sharma PP, How to practice GMPs, A Guide for 13. Morgan JJ and Stumm W, Water in Encyclopedia of
CGMP Compliance along with PAT & HACCP, 5, chemical technology, 4th edition, volume 25, New
2005, pp. 28-35. York, John Wiley and Sons, 1998, pp. 383-388
5. Kumar V S, Sanjeev T, Overview of cleaning 14. Rosen M J, Emulsification by surfactants in
validation in pharmaceutical manufacturing unit, surfactants and interfacial phenomena, New York,
International Journal of Advanced Research in John Wiley and Sons Inc, 1978, pp. 123-148.
Pharmaceutical & Bio sciences, 1(2), 2012, pp. 154- 15. Rosen M J, Solubilization by solutions of
164. surfactants: Micelles catalysis in Surfactants and
6. 21 CFR 210: Current good manufacturing practice interfacial phenomena, New York, John Wiley and
in manufacturing, processing, packing, or holding Sons Inc, 1978, pp. 224-250.
of drugs, 1 April 1997. 16. Rosen M J, Dispersion and aggregation of solids in
7. EPA, Fact sheet: Final air toxics rule for liquid media in Surfactants and interfacial
pharrnaceutical production, Washington, D.C, phenomena, New York, John Wiley and Sons Inc,
Environmental Protection Agency, Office of Air 1978, pp. 251-271
and Radiation, 1998. 17. Rosen M J, Wetting and its modification by
8. Watson D. G, Pharmaceutical Analysis- A surfactant in Surfactants and interfacial phenomena,
Textbook for Pharmaceutical students and New York, John Wiley and Sons Inc, 1978, pp.
Pharmaceutical chemists, 2nd Edition, Edinburgh 174-199.
Elsevier, 2005, Pg.no 11-13. 18. Rosen M J, Reduction of surface and interfacial
9. PIC, Recommendations on cleaning validation, tension of surfactants in Surfactants and interfacial
document PR1/99-1, Geneva, Switzerland, phenomena, New York, John Wiley and Sons Inc,
Pharmaceutical Inspection Convention, 1999. 1978, pp. 149-173.

Ind Res J Pharm & Sci|2017: June.:4(2) 959

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

19. Tau K D, V Elango and J A McDonough, Organic 32. Duchi P J et al, Cleaning PCBs in Electronics
in Encyclopedia of chemical technology, 4th edition, understanding today’s needs, Inventac Performance
volume 9, New York, John Wiley and Sons, 1994, Chemicals, Bry sur Marne, France.
pp.783-786. 33. Quality Assurance in Industrial parts Cleaning
20. Kumar S, A review on concept of cleaning Basics Chemistry and Processes, 2013, SurTec
validation in pharmaceutical Industry, International Deutschland, pp. 32-35.
Research Journal of Pharmaceutical Sciences, 3(7), 34. Best Technology, Precision Cleaning,
2012, pp. 17-19. Passivation & Finishing Systems.
21. Michael P, Cleaning validation & Regulatory URL:
compliance an introduction and overview, Merck http://www.besttechnologyinc.com/industria
milipore, pp. 11-18. l-parts-washers-cleaning-systems/part-
URL:http://www.dcvmn.org/IMG/pdf/cleaning_vali cleaning-guide/
dation_michael_payne_.pdf
22. LeBlanc, D. A., D. D. Danforth, and J. M. Smith, 35. Varghese G and P Lopolito, Cleaning Engineering
Cleaning technology for pharmaceutical and Equipment Design, Cleaning and Cleaning
manufacturing. Pharmaceutical Technology, 1993, Validation, Volume 1, PDA/DHI, Bethesda,
17 (7): 84-92. Maryland, 2009, pp. 126-127 and 141-142.
23. Health product and food branch inspectorate, 36. Azar and Lawrence, Cavitation in ultrasonic
Cleaning validation guidelines, 2008, pp. 1-16. cleaning and cell disruption, Controlled
24. Lynn J L, Detergency in Encyclopedia of chemical Environments, 2009.
technology, 4th edition, volume 7, New York, John URL:
Wiley and Sons, 1997, pp. 1073-1081. http://www.absotecthailand.com/Cavitation.pdf.
25. Lynn J L and B H Bory, Surfactant in Encyclopedia 37. Williams and Douglas, Guide to Cleaner
of chemical technology, 4th edition, volume 23, Technologies: Cleaning and Degreasing Process
New York, John Wiley and Sons, 1997, pp. 478- Changes, Washington DC, United States
541. Environmental Protection Agency, 1994, pp. 19.
26. Ghosh A and Dey S, Overview of Cleaning 38. Fuchs F J, the key to Ultrasonics-Cavitation and
Validation in Pharmaceutical industry, International implosion Precision Cleaning, 1995, 3(10), pp. 13-
journal of Pharmaceutical Quality Assurance, 2010, 17.
2(2), pp. 26-30. 39. Anindya G, Sanjay D, Overview of Cleaning
27. Patel Payal K et al, An Overview on Cleaning Validation in Pharmaceutical Industry, International
Validation, International Journal of Pharmaceutical Journal of Pharmaceutical Quality Assurance, 2010,
& Biological Archives, 2011, 2(5), 1332-1336, 2(2), pp. 26-30.
ISSN 0976 – 3333. 40. Imtiaz HS, Validation standard operating
28. Adams D G and Aggarwal D, CIP system design procedures: a step-by-step guide for achieving
and installation, Pharmaceutical Engineering 10(6), compliance in the pharmaceutical, medical device
1990, pp. 9 15. and biotech industries, 2006, pp. 1045-1060.
29. Stewart J C and D A Seiberling, Clean in place 41. Sandeep K, why the Swab Matters in Cleaning
Chemical Engineering, 1996, 103 (1), pp.72-79. Validation Controlled Environments, Health
30. Seiberling D A, Alternatives to conventional Canada guideline, 2010.
process/CIP design for improved cleanability. URL: www.n-
Pharrnaceutical Engineering, 1992, 12 (12), pp. 16- genetics.com/file/Controlled_Environments_2010.p
26. df
31. PDA Biotechnology Cleaning Validation
Subcommitte, Cleaning and cleaning validation A 42. Fourman G L and Mullen M V, Determining
biotechnology perspective, Bethesda, Parenteral cleaning validation acceptance limits for
Drug Association, USA, 1996, pp. 65-84. pharmaceutical manufacturing operations,
Pharmaceutical Technology, 1993, 17 (4), pp. 54-
60.

Ind Res J Pharm & Sci|2017: June.:4(2) 960

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

43. Agallaco J. Frederick Carelton J, A Text Book of 55. FDA, Inspection guide: Cleaning validation.
Validation of Pharmaceutical Process, Spring Rockville, Md., USA: Food and Drug
Publisher, 3rd Edition, 2008, pp. 525-565. Administration, 1992.
44. Forsyth R J et al, Visible Residue limit for Cleaning 56. GMP guide for API”, (ICH, Q7). ICH Good
Validation and its Potential Application in Manufacturing Practice Guideline for Active
Pharmaceutical Research facility, Pharm Pharmaceutical Ingredients, July 23 1999, on
Technology, 2005, 28(10), pp. 58-72. Cleaning Validation, Health Canada
45. LeBlanc D A, Visually Clean as solo acceptance 57. S.W. Harder, The Validation of Cleaning
criteria for cleaning validation protocols, Journal of Procedures, Pharm. Technol. 1984, 8 (5), pp.
Pharmaceutical Science and Technology, 2002, 29-34.
56(1), pp. 31-36.
46. Lombardo S et al, Development of surface 58. Fourman G and Mullin M, Determining Cleaning
swabbing procedures for a cleaning validation Validation Acceptance Limits for Pharmaceutical
program in a biopharmaceutical manufacturing Manufacturing Operations, Pharmaceutical
facility, Biotechnology and Bioengineering, 1995, Technology, 1993, pp. 54-60
pp. 513-519. 59. Mendenhall D, Cleaning Validation, Drug
47. Cooper D W, using swabs for cleaning validation: Development and Industrial Pharmacy, 1989,
A review in cleaning validation, Institute for 15(13), pp. 2105-2114.
Validation Technology, USA, 1997, pp. 74-89. 60. Active Pharmaceutical Ingredient Committee
48. Bodavula Samba Siva Rao, cleaning validation of (APIC) group of EEFIC, 1999, Guide to cleaning
albendazole tablet 400 mg, Pharma Innovations, validation in API plants. APIC Publications, pp. 2-
2012, 1(4), pp. 76-9. 23.
49. Patel Hiren, Popat bhai et al, Process validation of 61. Justification of limit for cleaning validation in the
Benzepril HCL 5 mg tablet, International Research manufacture of active pharmaceutical ingredient,
Journal of Pharmaceutical and applied sciences, 2007, GMP news.
2012, (4), pp. 1-16. 62. Mc Arthur, Vasilevsky, Cleaning validation for
50. Lakshmana P, et al, Cleaning validation and its biological products case study, pharmaceutical
importance in Pharmaceutical Industry, Pharma engineering, 1995.
Times, 2010, 42(07), 21-25. 63. USP <1111> “Microbial Examination of nonsterile
51. Bodavula Samba Siva Rao, Cleaning validation of Products: Acceptance criteria for Pharmaceutical
albendazole tablet 400 mg, Pharma Innovations, Preparations and Substances for Pharmaceutical
2012, 1(4), pp. 76-9. Use”.
52. Babita Lodhi et al, Cleaning validation for the 64. Guidelines for Single-Laboratory Validation of
pharmaceuticals, biopharmaceuticals, cosmetic and Analytical Methods for Trace-Level Concentrations
neutraceuticals industries, Journal of Innovations in of Organic Chemicals Special Publication - Royal
Pharmaceuticals and Biological Sciences, 2014, Society of Chemistry: Principles and Practices of
Volume-1, (1), 2014, pp. 27-38. Method Validation, 2000, 256, pp. 179- 252.
53. LeBlanc D A, Rinse sampling for cleaning 65. Irsch R B, Validation of Analytical Methods Used
validation studies, Pharmaceutical Technology, 22 in Pharmaceutical Cleaning Assessment and
(5), 1998, pp. 66-74. Validation, Pharmaceutical Technology
54. Recommendation on VMP, IQ and OQ, non-sterile (Supplement), 1998, pp. 40-46.
process validation and cleaning validation, 66. Shifflet M and Shapiro M, Development of
Pharmaceutical Inspection Convention, Analytical methods to accurately and precisely
Pharmaceutical Inspection Co-Operation Scheme, determine residual Active pharmaceutical
2007.
URL: ingredients and cleaning agents on Pharmaceutical
https://www.picscheme.org/layout/document.php?id Surfaces, Am Pharm, 2002, pp. 35–39.
=152. 67. Kumar nitin et al., Development and Validation of a
Simple and Rapid Reversed Phase Liquid

Ind Res J Pharm & Sci|2017: June.:4(2) 961

 Indian Research Journal of Pharmacy and Science; P. Tomar et.al. June’17

Chromatography Method for Estimation of Pharmaceutical Sciences and Drug Research, 2010,
Pregabalin from Equipment Surfaces Used for 2(1), pp. 45-47.
Pharmaceutical Manufacturing, Ann Chromatogr 71. Dennis Jenke, Application of Ion Chromatography
Sep Tech, 2016, 2(3), pp. 1023. in Pharmaceutical and Drug Analysis, volume 49,
68. Goti pp et al, Development and Validation of Journal of Chromatographic Science, 2010.
Analytical Method for estimation of Declofenac 72. Samarajeewa U et.al, Application of immunoassay
Sodium in Swab samples, International Journal of in the food industry. Critical Reviews in Food
Pharmaceutical Sciences and Research, Volume, Science and Nutrition, 1991, pp, 403–434.
2013, 4(2), pp. 741-744. 73. Jenkins K M., et al., Application of Total Organic
69. Sofia Ahmed, Nafeesa Mustaan, et al, Validation of Carbon Analysis to Cleaning Validation," PDA J.
a UV Spectrometric Method for the Assay of Pharmaceutical Sciences & Technology, 1996, 50
Tolfenamic Acid in Organic Solvents, Journal of (1), pp. 6-15.
Pharmaceutics, 2015. 74. Zeyad G. Yasseen, On the Interactions of Bovine
70. Jawla Sunil, Jain Sandeep, Atomic Absorption Serum Albumin with Some Surfactants: New
Spectrometric Method for Estimation of Diclofenac Insights from conductivity Studies, Journal of
sodium and Mefenamic acid in Pharmaceutical Chemical and Pharmaceutical Research, 2012, 4(7),
Formulations, International Journal of pp. 3361-3367.

conflict of interest reported: nil; source of funding: none reported

Ind Res J Pharm & Sci|2017: June.:4(2) 962