Open Science Journal of Pharmacy and Pharmacology

2015; 3(4): 28-32

Published online July 20, 2015 (http://www.openscienceonline.com/journal/osjpp)

Cleaning Validation and Its Protocol in

Pharmaceutical Industry
Yasir Mehmood*
Faculty of Pharmacy, University of Central Punjab, Lahore, Pakistan

Email address
yasirmehmoodamjad@gmail.com

To cite this article

Yasir Mehmood. Cleaning Validation and its protocol in Pharmaceutical Industry. Open Science Journal of Pharmacy and Pharmacology.
Vol. 3, No. 4, 2015, pp. 28-32.

Abstract
Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. Minimizing
equipment downtime has the potential to impact the efficiency and economics of pharmaceutical production. The main purpose
of cleaning validation is to improve the effectiveness and consistency of cleaning in a given pharmaceutical production
equipment or prevent cross contamination and adulteration of drug products with other active ingredients like unintended
compounds or microbiological contamination, leads to prevent several serious problems and also useful in related studies like
packaging component cleaning validation. So it is necessary to validate the cleaning procedures to ensure safety, efficacy,
quality of the subsequent batches of drug product and regulatory requirements in Active Pharmaceutical Ingredients (API)
product manufacture. The benefits due to cleaning validation are compliance with federal regulations, identification and
correction of potential problems, previously unsuspected which could compromise the safety and efficacy of drug products. In
this article cleaning, validation and importance are discussed in brief.

Keywords
Validation, Regulation, API, Safety, Cleaning, Compliance

1. Introduction 2. Procedure
Cleaning validation is a documented process that proves 2.1. Factory Premises
the effectiveness and consistency in cleaning a
pharmaceutical production equipment [1]. Validations of Twice a day by using phenyl water for mopping and at the
equipment cleaning procedures are mainly used in end of working day finis oil or phenyl is poured in drain
pharmaceutical industries to prevent cross contamination and holes. Insecticidal spray used when ever required.
adulteration of drug products hence is critically important [2]. Testing Procedure: Visual examination and record should
The prime purpose of validating a cleaning process is to be maintained.
ensure compliance with federal and other standard Facility: Insectocutor and air curtain, fans, tube lights, AC
regulations [3]. The most important benefit of conducting plants, doors, windows, wall etc.
such a validation work is the identification and correction of Frequency: Cleaned on weekly basis by using duster or
potential problems previously unsuspected [4], which could brush.
compromise the safety, efficacy or quality of subsequent Equipment: Possible contaminants of equipment are:
batches of drug product produced within the equipment [5]. Active Ingredient: The first concern in cleaning validation
This paper provides a review of the current trends in cleaning is the removal of residue having pharmacological actively,
validation and its related importance. the absence of each is necessary.
29 Yasir Mehmood: Cleaning Validation and its protocol in Pharmaceutical Industry

Active Decomposition Material: Likely degradation on membrane filter using FPA occupational dust practices
materials created during either product formulation or by can be success fully employed for cleaning validation
contact with cleaning materials. purposes.
Excipients: Colors, flavours and other excipients and Environmental Surface Samples: Swabs and rinse of non-
decomposition materials from excipients could also be product contact surfaces. The surfaces could be either on the
considered to be cleaned. Residue of detergents used for equipment proper or elsewhere in proximity to it.
cleaning purpose. Removal of objectionable organism such Consideration as to open or crevices apply as outlined above.
as staphylococcus aures and Ecoli. The presence of large The use of non solvent to facilitate recovery is also possible.
numbers of other organism is also problematic. Temperature and humidity specification: The Company
Particulate contamination: Presence of specks, flaks, fiber. has determined and managed the entire work environment
Sanitizing Agents: Where utilized on or near the product like temperature and relative humidity controls, which are
contact surfaces. required for manufacturing of quality products. These
Environment Dust: Fine Particulates suspended in the air conditions are being maintained by comprehensive HVAC
which may contain any number of materials. system.
Equipment related Contamination: Gasket and packaging
materials fine pieces of metal, worn platings etc. Table 1. Controlled environmental conditions is as follows.
Residual Rinse Water: In instances where the equipment is Temperature Humidity
used in the formulation of a product where the trace amount Section Area B.P B.P
of moisture could be detrimental to product quality, the Specifications Specifications
presence of even small amounts of residual moisture could be Injectable section human
problematic. The cleaning procedure in this case must leave Washing area 25 ºC ± 5 ºC NMT 50 %
the equipment free of any trace of the final rinse solution. Solution preparation 25 ºC ± 5 ºC NMT 50 %

2.2. Sampling Procedure Filling room1 25 ºC ± 5 ºC NMT 50 %

Filling room 2 25 ºC ± 5 ºC NMT 50 %
From Equipment Surfaces: Swab [in open area] an easy Optical checking 25 ºC ± 5 ºC NMT 50 %
sample to obtain, but may not demonstrate overall cleanliness
Blistering 25 ºC ± 5 ºC NMT 50 %
as open areas are also the easiest location to clean. Usually a
fixed size location is sampled using a mask. Cotton balls and Packaging 25 ºC ± 5 ºC NMT 50 %
other specialized swabs are used to avoid wood or glue. General Tablets Section For Human
Swabs are generally wet with water of final rinse quality. Wet Granulation 25 ºC ± 5 ºC NMT 55 %
Non aqueous solvent also used to wet the swabs. Dry Granulation 25 ºC ± 5 ºC NMT 50 %
Swabs [In inaccessible areas] these locations around
Compression 25 ºC ± 5 ºC NMT 50 %
threads, in crevices, in corners are more difficult to sample
Film Coating 25 ºC ± 5 ºC NMT 55 %
and more difficult to clean. Quantification is extremely
difficult as the sample areas are unknown. The use of a swab Blistering 25 ºC ± 5 ºC NMT 50 %
in this area is a worst case evolution relative to swab taken in Packaging 25 ºC ± 5 ºC NMT 50 %
an open area.
Final Rinse: The removal of liquid sample from the last General Capsule Section
Portion of the final rinse of the equipment is a common
Capsule Mixing 25 ºC ± 5 ºC NMT 45 %
approach. If the materials of concern are insoluble in water,
Capsule Filling 25 ºC ± 5 ºC NMT 45 %
this approach may give a false sense of security.
Placebo Product: Gives best indication of what carry over Blistering 25 ºC ± 5 ºC NMT 50 %
might be in to next product. Expensive due to the cast of Packaging 25 ºC ± 5 ºC NMT 50 %
materials and time consuming in the analysis of sufficient Stores
units, this approach gives the most direct indication of clean Raw Material Bulk 30 ºC ± 2 ºC NMT 60 %
lines. Next production lot introduces significant risk for
Active Materials 25 ºC ± 5 ºC NMT 50 %
product rejection should any residual be found.
Weighing and
Solvent Extraction: The use of a solvent extraction may be Dispensing
25 ºC ± 5 ºC NMT 50 %
the only satisfactory means for determining product residuals Finished Products 25 ºC ± 5 ºC NMT 50 %
for materials that are poorly soluble in water. This practice
Quality Control Department
will raise questions regarding the adequacy of aqueous
cleaning methods. Solvent extraction would follow final Retained Samples Area 25 ºC ± 5 ºC NMT 50 %
aqueous rinse. Instrument Room 25 ºC ± 5 ºC NMT 50 %

2.3. Environment 2.4. Testing Procedure

Environment Air Samples: Samples obtained by impaction Assays [For each component] [6] Using adaptations of the
 Open Science Journal of Pharmacy and Pharmacology 2015; 3(4): 28-32 30

product assay or more sensitive methods targeted at the lower quantity of material likely to be present after cleaning.

Figure 1. Sketch of HVAC system.

Prefilter: G4, 65%, First Filter 95%, Final filter H11 99%
VCD = Volume Control Damper
HVAC = Humidity Ventilation and Air Conditioning
AHU = Air Handling Unit
M = Monometer

Total Organic Carbon: (TOC) [7] A rapid means of useful. The acceptance criteria utilized are usually extremely
evaluating samples that require only limited sample subjective in nature.
preparation. The TOC test identifies only organic carbon and Specific Ion Meters [16, 17]: Rapid means for quantifying
therefore should be corrected to more specific analytical test low levels of specific ions generally from ionic materials.
methods. This test does not identify the specific residue This method is useful for confirming the level of residual
material. The TOC test is useful for shop floor evolution of from acidic or basic detergents in the final rinse.
clean lines before use in next production lot. Visible, Infrared or ultra violet scan [18]: Provides for an
Total Solids [8]: Quantities non volatile materials liquid in evolution of residue of various types in a single test. These
liquid extracts, either in rinses or swabs results of the surface. tests are reasonably quick way to establish the presence of
Use full for both organic and in organic materials, but non- various organic materials. Some degree of qualification and
specific results limits use fullness. correlation assay residuals is possible.
PH [9]: The PH test is easy to perform and can be readily
adopted to the production area. The PH test is primarily 2.5. Frequency of Validation
useful for determining the presence of alkaline or acid Initial Validation: Three initial runs for any new cleaning
cleaning materials in the final rinse. procedure, product or item of equipment are considered
Osmolarity [10]: Meters can detect the presence of low sufficient for automated systems.
levels of ionic material in aqueous solution. Osmolarity Routine Monitoring: After each manual cleaning procedure,
determination is easy to perform and require little or no some form of quantitative evolution using a rapid test
sample preparation. Not suited for organic materials. procedure seems desirable as a safeguard against variation in
Purified Water Test [11]: USP analysis using the incoming operator performance.
final rinse water as a standard. The post rinse sample is Product Change Over: When converting a piece of
expected to provide comparable results. Tests performed are equipment, room or facility from one product to another
only the required USP compendia tests for the appropriate sampling is generally necessary. This practice associated with
water. Water analysis is poorly corelatable to concentrations the campaigning of different products in the same piece of
of materials other than those in the monograph. equipment.
Conductivity [12, 13]: A rapid means for determining the Change in Cleaning Procedure: Whenever there is a
ionic connection of water sample. change in cleaning method eg. Detergent change, formulation
Particulate Count [14, 15]: The Counting of Particulates in change, cleaning equipment change, procedure change etc.
the final rinse using an automated particle counter is also Operator Qualification: To initially and periodically
31 Yasir Mehmood: Cleaning Validation and its protocol in Pharmaceutical Industry

confirm the operator satisfactory performance of the Coverage of System: In complex systems, it may be
changing procedure. necessary to establish that all portions of the vessel interior
Change in Products, Process or Equipment: When there is are contacted by the wash and rinse liquid. The ability to
a product reformulation, process change or modification to adequately clean locations which may be behind baffles,
the equipment where a validated cleaning procedure is inside nozzles, under agitators etc must be confirmed. The
already exists. use of a fluorescing dyes to highlight. Contamination in
After Maintenance: Evolution is completed to assure that potentially difficult to clean areas is wide spread.
the equipment has been properly cleaned after scheduled or
non scheduled maintenance procedure. The presence of 3. Limit of Acceptance
atypical contaminants in the system may complicate the
cleaning process. Percentage of lowest Therapeutic Dose [20]: (LTD) This
After shutdown periods: Sampling is performed to method utilized a medical opinion along with an arbitrary
establish that the equipment is sufficiently clean before the safety factor to set a limit. The safety factor is generally in
reception of operations. Similar to the maintenance concern the range of 0.01% to 10% of LTD. The higher safety factors
with added complication during shutdown periods normal are employed for serial cleaning between different lots with
environment contract may not be in place. save active ingredients.
After contamination of Area: To prove acceptable clean Percentage of Toxic Dose [21-23]: This approach employs
lines after a contamination problem i.e. bag splits open, a medical opinion along with an arbitrary safety factor to set
persistent microbial level in excess of monitoring limits, a limit. The safety factor is usually greater than selected for
difficulties with water system etc. This may involve a severe the LTD. This type of limits is used for non actives such as
contamination potential in the presence of routine detergents sanitizers, degradation materials etc.
environmental controls. Percentage of lowest marketed dose [24]: This practice
Periodically: A portion of the cleaning validation effort utilizes a marketing decision along with an arbitrary safety
should be repeated on a periodic basis. factor to set a limit. The safely factor is generally in the same
range as that used for LTD or 0.01% to 10% of lowest
2.6. Parameters of the Cleaning Procedure marketed dose.
Evaluated

Following are the parameter which should be considered 4. Conclusions/Summary

as part of the cleaning validation. Identification and control
over these may be essential to assure cleaning effectiveness. A cleaning validation program should contain the
Wash and Rinse Volume [19]: The volume of all washes assessment of equipment and products, assessment of the
and rinses utilized in the cleaning process. Temperature impact of a process on routine process, determination of an
(in/out) control over the wash and rinse inlet temperature appropriate cleaning agent and method, determination of
may be necessary to assure proper cleaning. acceptance criteria for the residues, determination of a degree
Flow rate Pressure: The measurement of both inlet flow of evaluation required to validate the procedure, decisive on
rate and delivery pressure of washes and rinses is the residues to be tested based on solubility and toxicity,
recommended. Operating outside of demonstrated ranges can development of sampling and analytical methods for
impede cleaning procedure. recovery and detection of residues. acceptance criteria for the
Detergent Concentration: Confirmation of detergent validation, compilation and approval of the validation
concentration within the acceptable range is a common protocol, scope for the validation studies to be performed in
practice. accordance with the protocol, compilation and approvals of
Wash and rinse water quality: Chemical and micro validation reports, documented studies, conclusions,
biological information on the quality of the water used to recommendations and revalidation policy.
wash and rinse the tank. Final rinses are almost always either
purified water. Initial washes and rinses could be city water, References
well water or other water types to reduce treatment cost.
[1] Prabu, L. and T. Suriyaprakash, Cleaning validation and its
Time and Sequence: The duration of the various steps in importance in pharmaceutical industry. Pharma times, 2010.
the cleaning procedure and the sequence in which they are 42(7): p. 21-5.
performed.
Gas Purges, Evacuation and Drain periods: There are [2] Trivedi, H. K., N. Kshtri, and M. C. Patel, A Rapid, Validated
RP-HPLC Method for the Simultaneous Determination of
common steps in many cleaning procedures. Where these Cleaning Validation and Cross-Contamination of 12 Beta-
practices are used, appropriate measurement of parameters Lactam Compounds. Scientia pharmaceutica, 2013. 81(1): p.
associated with these steps should be considered. The 151.
microbial quality of the gas purge should be confirmed.
[3] Tangri, P. and P. S. Rawat, Validation: A Critical Parameter for
Agitation: Where agitators or pumps are part of system Quality Control of Pharmaceuticals. Journal of Drug Delivery
being cleaning the RPM and duration of use during the and Therapeutics, 2012. 2(3).
cleaning procedure should be known.
 Open Science Journal of Pharmacy and Pharmacology 2015; 3(4): 28-32 32

[4] Moody, D. L. and G. G. Shanks, Improving the quality of data [14] Parsons, T. R., A Manual of Chemical & Biological Methods
models: empirical validation of a quality management for Seawater Analysis2013: Elsevier.
framework. Information systems, 2003. 28(6): p. 619-650.
[15] Horrocks, D., Applications of liquid scintillation counting2012:
[5] Ballermann, M. A., et al., Validation of the Work Observation Elsevier.
Method By Activity Timing (WOMBAT) method of
conducting time-motion observations in critical care settings: [16] Bauder, T. A., et al., Irrigation water quality criteria2011:
an observational study. BMC medical informatics and Colorado State University Extension Fort Collins, CO.
decision making, 2011. 11(1): p. 32.
[17] Folegatti, M. V., et al., Calibration of cardy-ion meters to
[6] Riley, C. M. and T. W. Rosanske, Development and validation measure nutrient concentrations in soil solution an in plant sap.
of analytical methods. Vol. 3. 1996: Elsevier. Scientia Agricola, 2005. 62(1): p. 8-11.

[7] Nelson, D. and L. E. Sommers, Total carbon, organic carbon, [18] Islam, K., B. Singh, and A. McBratney, Simultaneous
and organic matter. Methods of soil analysis. Part 2. Chemical estimation of several soil properties by ultra-violet, visible,
and microbiological properties, 1982 (methodsofsoilan2): p. and near-infrared reflectance spectroscopy. Soil Research,
539-579. 2003. 41(6): p. 1101-1114.

[8] Sluiter, A., et al., Determination of total solids in biomass and [19] Toetschinger, M. J. and M. M. Dawson, Portable wash and
total dissolved solids in liquid process samples. National rinse system with dilution, 1999, Google Patents.
Renewable Energy Laboratory, Golden, CO, NREL Technical
Report No. NREL/TP-510-42621, 2008. [20] Investigators, E., Platelet glycoprotein IIb/IIIa receptor
blockade and low-dose heparin during percutaneous coronary
[9] Ang, W. S., S. Lee, and M. Elimelech, Chemical and physical revascularization. The New England journal of medicine,
aspects of cleaning of organic-fouled reverse osmosis 1997. 336(24): p. 1689.
membranes. Journal of membrane science, 2006. 272(1): p.
198-210. [21] Plaza, S. M., The safety and efficacy of high-dose chromium.
Alternative medicine review, 2002. 7(3): p. 218-235.
[10] Greyson, J. and S. N. Stiso, Device and Method for the
Determination of the Specific Gravity or Osmolality of a [22] Robichaux, T. BACTERICIDES USED IN DRILLING AND
Liquid, 1977, Google Patents. C0MPLETI0N 0PERATI0NS. in Environmental aspects of
chemical use in well-drilling operations: conference
[11] Andreozzi, R., et al., Advanced oxidation processes (AOP) for proceedings: May 1975, Houston, Texas. 1975. Office of
water purification and recovery. Catalysis today, 1999. 53(1): Toxic Substances, Environmental Protection Agency.
p. 51-59.
[23] Nassani, M., Cleaning validation in the pharmaceutical
[12] Hem, J. D., Study and interpretation of the chemical industry. Journal of validation technology, 2005. 11(4): p. 286.
characteristics of natural water. Vol. 2254. 1985: Department
of the Interior, US Geological Survey. [24] GEOLA, F. L., et al., Biological Effects of Various Doses of
Conjugated Equine Estrogens in Postmenopausal Women*.
[13] Chau, R., et al., Electrical conductivity of water compressed The Journal of Clinical Endocrinology & Metabolism, 1980.
dynamically to pressures of 70–180 GPa (0.7–1.8 Mbar). The 51(3): p. 620-625.
Journal of Chemical Physics, 2001. 114(3): p. 1361-1365.