1. IJPRD, 2011; Vol 4(02): April-2012 (175- 179) International Standard Serial Number 0974 – 9446
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CLEANING VALIDATION: IMPORTANT ASPECT IN PHARMACEUTICAL INDUSTRY
Udhan Ravindra1*,Vijayalaxami Chavan1, Neelam Saraf1, Preeti Sable1
*1 Shri Bhagwan college Of pharmacy,Auranagabad, MH, India
ABSTRACT
The objective of cleaning and sanitization in pharmaceutical Correspondence to Author
industry is to ensure that product is not cross contaminated
with cleaning agent and manufactured product. Residue behind
affect the quality of the finished product. Cleaning validation is
documented proof that a particular pharmaceutical facility
consistently and effectively cleans a system or equipment item.
Cleaning validation program is required by regulation of GMP and
enforced by U.S Food and Drug Administration. This review intent
the importance of cleaning validation in pharmaceutical industry,
various regulatory requirements, types of sampling, residual
Udhan Ravindra
detection method and their acceptance criteria.
Shri Bhagwan college Of
Key words: GMP, WHO, API, cleaning validation etc.
pharmacy,Auranagabad, MH, India
Email: ravi.udhan403@gmail.com
INTRODUCTION goal of all of those suppliers of products and
The cleaning processes used in pharmaceutical services. [1]
operations have achieved an increasing emphasis
in the past decade both by the regulatory agencies Cleaning continuum is concept advocated by the
and industry itself. At this time it is generally Klenzaid G.M.P academy and can be defined as “an
regarded as just as critical to have effective international organizational model which helps to
cleaning processes as to have consistent, validated draft the operational details of specific cleaning
manufacturing processes. The basic reason for validation programme”. The cleaning validation is
having good, effective, consistent cleaning highly complex process and it refers to cleaning
procedures is to prevent the contamination of activities viz.
products made subsequently in the same
equipment. The goal is to provide pharmaceutical • Establishing critical parameters.[2]
products of the highest quality to our patients. This • Developing grouping philosophies.
is the basic regulatory requirement as well as the
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2. International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
• Establishing the scientific rationale for possible contamination and cross
cleaning programme. contamination.
• Determining the process, equipment and 5. Cleaning validation is not necessarily
products that represent the greatest required for non-critical cleaning such as
concern. that which takes place between batches of
• Establishing the criticality of cleaning limits the same product (or different lots of the
and methods. same intermediate in bulk process),or of
floors, walls, the outside of vessels, and
PRINCIPLE AND NEED OF CLEANING VALIDATION following some intermediate steps.
[3] 6. Cleaning validation should be considered
1. The objective of good manufacturing important in multiproduct facilities and
practices (GMP) includes the prevention of should be performed among others, for
possible contamination and cross equipment, sanitization procedures and
contamination of pharmaceutical starting garment laundering.
material and product by cleaning validation.
REGULATORY REQUIREMENTS FOR CLEANING
2. Pharmaceutical product can be
VALIDATION
contaminated by variety of substances such
The Food and Drug Administration
as contaminants associated with microbes,
establishes the regulations and policies relating
previous products (both active
o pharmaceutical grade products distributed
pharmaceutical ingredients (API) and
commercially in United States. These
excipient residues),residue of cleaning
regulations are called current Good
agent, airborne materials, such as dust and
Manufacturing Practices and are classified in
particulate matter, lubricants and ancillary
Title 21, Part 211 of the Code of Federal
materials, such as disinfectant, and
Regulation (CFR). The applicable laws at this
decomposition residue from:
time are general and somewhat vague, and are
• Product residue breakdown
centered around21 CFR 211.67 that states:
occasioned by, e.g. the use of
“Equipment and utensils be cleaned,
strong acids and alkalis during the
maintained and sanitized at appropriate
cleaning process; and
intervals to prevent malfunctions or
• Breakdown procedures of the
contamination that would alter the safety,
detergents and alkalis that may be
identity, strength, quality or purity of the drug
used as part of the cleaning
product”.[4]
process.
According to this law each and every
3. Adequate cleaning procedures play an
pharmaceutical and food industry should follow
important role in preventing contamination
the cleaning validation programme to avoid
and cross contamination. Validation of
malfunctioning, contamination and cross-
cleaning method provides documented
contamination of finished product.
evidence that an approved cleaning
procedure will provide clean equipment,
TYPES OF CONTAMINANTS [5]
suitable for it’s indeed use.
4. The objective of cleaning validation is to
The manufacturing of API and pharmaceutical
prove that the equipment is consistently
products involves series of processing steps and
cleaned of product, detergent and microbial
use of various equipments. Equipments or ancillary
residues to an acceptable level, to prevent
systems may be used for manufacturing multiple
product or single dedicated product. The
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3. International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
inadequate cleaning process may leads to the fact potential impact on the test data is
that following residue may carry forward as important as the sampling material may
contaminant in the next batch to be manufactured interfere with the test. (For example, the
in the same equipment. adhesive used in swabs has been found to
1. Precursors to the Active Pharmaceutical interfere with the analysis of samples.)
Ingredient II. Factors that should be considered include
2. By-products and/or degradation products of the the supplier of the swab, area swabbed,
Active Pharmaceutical Ingredient number of swabs used, whether they are
3. Contamination of one batch of product with wet or dry swabs, swab handling and
significant levels of residual active ingredients from swabbing technique.
a previous batch III. The location from which the sample is
4. Microbiological contamination: Maintenance, taken should take into consideration the
cleaning and storage conditions may provide composition of the equipment (e.g. glass or
adventitious microorganisms with the opportunity steel) and the location (e.g. blades, tank
to proliferate within the processing equipment. walls or fittings). Worst case locations
5. Contamination with unintended materials or should be considered. The protocol should
compounds such as Cleaning agents, lubricants , identify the sampling locations.
surfactant etc. IV. Critical areas, i.e. those hardest to clean,
should be identified, particularly in large
SAMPLING METHOD USED IN CLEANING [6-8] systems that employ semi-automatic or
fully automatic clean-in-place systems. The
Equipment should normally be cleaned as soon as sampling medium and solvent used should
possible after use. This may be especially important be appropriate to the task.
for operations with topical products, suspensions
and bulk drug or where the drying of residues will b) Rinse samples (indirect method)
directly affect the efficiency of a cleaning I. This method allows sampling of a large
procedure. Two methods of sampling are surface, of areas that are inaccessible or
considered to be acceptable. These are direct that cannot be routinely disassembled and
surface sampling and rinse samples. A combination provides an overall picture. Rinse samples
of the two methods is generally the most desirable. may give sufficient evidence of adequate
The practice of resampling should not be used cleaning where accessibility of equipment
before or during cleaning and operations and is parts can preclude direct surface sampling,
acceptable only in rare cases. Constant retesting and may be useful for checking for residues
and resampling can show that the cleaning process of cleaning agents, e.g. detergents.
is not validated because these retests actually II. Rinse samples should be used in
document the presence of unacceptable residue combination with other sampling methods
and contaminants resulting from an ineffective such as surface sampling.
cleaning process. III. There should be evidence that samples are
accurately recovered. For example, a
a) Direct surface sampling (direct method) recovery of >80% is considered good, >50%
I. This method of sampling is the most reasonable and <50% questionable.
commonly used and involves taking an ANALYSING CLEANING SAMPLE
inert material (e.g. cotton wool) on the end There are many analytical techniques available that
of a probe (referred to as a “swab”) and can be used in cleaning validation. But choosing the
rubbing it methodically across a surface. appropriate analytical tool depends on a variety of
The type of sampling material used and its
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4. International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
factors. The most important factor is to determine Very low levels of cleaning agents can be detected
the specifications or parameters to be measured. by using this technique.[13]
The limit should always be established prior to the
selection of the analytical tool. ANALYTICAL METHOD VALIDATION[14]
a. High performance Liquid Chromatography The analytical method should be validated before
the cleaning validation is performed. The method
The High performance Liquid Chromatography chosen should detect residuals or contaminants
technique is widely used in the analyzing of specific for the substance being assayed at an
cleaning sample . The process have applied to a appropriate level of cleanliness. The validation of
wide variety of natural product such as nucleic analytical method should include appropriate:
acid, urine, serum, carbohydrates, lipid, amino • Precision
acid, bile salt, and manufactured product such as • Linearity
pharmaceuticals, pesticides, surfactant and • Selectivity
antioxidants.[9] • Limit of Detection
• Limit of Quantitation
b. TOC • Robustness
One analytical technique that provides an excellent • Ruggedness
mean of conducting whole detergent product ESTABLISHING ACCEPTABLE LIMITS[15-16]
analysis is that referred to as Total Organic Carbon
analysis. Using this technique, organic compound I. The limit-setting approach can be product-
are oxidized to CO2 which is then quantitated, specific group products into families and
typically by non-dispersive infrared absorption or choose a worst case product, Group
conductivity. TOC analysis is non-specific and offers products into groups according to risk, e.g.
low detection limits, potentially down to low non- very soluble products, products with similar
specific and offers low detection limit, potentially potency, highly toxic, or difficult to detect
down to low parts per billion levels. Further more, products, use different safety factors for
TOC analysis is theoretically capable of quantitating different dosage forms based on
any carbon containing compound.[10] physiological response (this method is
essential for potent materials).
c. FTIR Spectroscopy II. Limits may be expressed as a concentration
A systematic procedure was described recently by in a subsequent product (ppm), limit per
Smith. He used FTIR spectroscopy to identify the surface area (mcg/cm2), or in rinse water as
component of a formulated cleaning agent that ppm.
was the last to rinse from stainless steel and III. The sensitivity of the analytical methods
borosilicate glass surfaces.[11,12] should be defined to enable reasonable
limits to be set.
d. ION Chromatography IV. The rationale for selecting limits for carry-
over of product residues should meet
Ion chromatography can be used for the analysis of defined criteria.
inorganic, organic and surfactants present in the V. The three most commonly used criteria are:
cleaners. Most cleaners contain sodium and/or a. Visually clean. (No residue should be visible
potassium. The ion chromatography detection on equipment after cleaning.) Spiking
technique of suppressed conductivity is more studies should determine the concentration
sensitive to potassium ions than to sodium ions.
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5. International Journal of Pharmaceutical Research & Development ISSN: 0974 – 9446
at which most active ingredients are visible. 6) Quality assurance of pharmaceuticals
This criterion may not be vollume2,second updated , good manufacturing
b. suitable for high-potency, low-dosage practices and inspection,WHO,Pharma med press,
drugs; no more than 10 ppm of one product page no: 126-127
will appear in another product (basis for 7) Food And Drug Administration, Guide to
heavy metals in starting materials); and inspection to validation of cleaning process, July
c. no more than 0.1% of the normal 1993
therapeutic dose of one 8) Jenkins M, Vanderweilen AJ. Cleaning
validation: An overall perspective. Pharma Tech.
1994; 18(4): 60-73.2.632
CALCULATIONS FOR SWAB SAMPLING 9) Instrumental method of chemical analysis
,Gurudeep R. Chatwal & Sham K.Anand,Himalaya
Total residue = publication house, Revised first edition 2008,page
no:2.632
10) Development and validation of Analytical
method, by Cristopher M. Rileyand Thomas W.
Rosanske, Pergamon Press an imprint of Elsevier
2009, page no;298-299
11) J.M Smith, Pharma Tech.,17960,88-(1993)
REFERENCES 12) Biwald CE. Gavlick WK, “Use of Total
1) Pharmaceutical process validation, an Organic Carbon Analysis and Fourier-Transform
international third edition, edited by Robert A. Infrared Spectroscopy to determine Residues of
Nash, Alfred H. wather, page no : 501 Cleaning agent on Surfaces”, J AOAC International.,
2) Pharmaceutical quality assurance ,by prof 1997, 80: 1078-1083.
Manohar S. Potdar , Nirali Prakashan, page no: 13) Nair LM, Saari-Nordhaus R. Recent
8.266-8.2667 Developments in Surfactant Analysis by Ion
3) Quality assurance of pharmaceuticals Chromatography. J Chrom. 1998; 804: 233-239.
vollume2,second updated , good manufacturing 14) ICH Harmonised Tripartite Guideline,
practices and inspection,WHO,Pharma med press, Validation of Analytical procedure: Text And
page no: 120-121 Methodology Q2(R1),2005
4) Code of federal regulation Title 21 part 211, 15) ICH: Good Manufacturing Practice Guideline
“current good manufacturing practices for finished for Active Pharmaceutical Ingredients. (July 23
pharmaceuticals,” U.S Government printing Office 1999)
Washington. 16) WHO ,Good manufacturing practices,2nd
5) APIC: Cleaning validation inactive edition, PharmaMed press, page no: 128.
Pharmaceutical ingredient manufacturing plants,
1999, 3-7
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