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Review Article
Raval. EUROPEAN JOURNAL OF PHARMACEUTICAL
European Journal of Pharmaceutical and Medical Research
AND MEDICAL RESEARCH ISSN 2394-3211
www.ejpmr.com EJPMR

A REVIEW ON CLEANING VALIDATION SAMPLING TECHNIQUES

*Dr. Kashyap Raval

Asst. Professor, Department of QA, Noble Pharmacy College, Junagadh.

*Corresponding Author: Dr. Kashyap Raval

Asst. Professor, Department of QA, Noble Pharmacy College, Junagadh.

Article Received on 12/05/2016 Article Revised on 01/06/2016 Article Accepted on 22/06/2016

ABSTRACT
Pharmaceutical industries are vital segment of healthcare system. Manufactures of products which are life-saving,
life maintaining drugs. Not to fail its client by releasing substandard or adulterated drugs. Quality product should
be maintained throughout its product lifecycle. It is essential to validate and maintain all the critical process
parameters within the limit as per specification. So it is essential to establish adequate equipment cleaning
procedures to prevent cross contamination due to remnants of product residues. In Cleaning Validation, Sampling
is Very crucial thing for any sample. Mainly three types of techniques are there like Swab, Rinse & Visual.

KEYWORDS: Cleaning Validation, Procedure, Swab, Rinse, Visual.

INTRODUCTION Pharmaceutical products and active pharmaceutical

Cleaning Validation is documented evidence which gives ingredients (APIs) can be contaminated by other
a high degree of assurance that cleaning procedure pharmaceutical products or APIs, cleaning agents,
should consistently clean a system or a piece of microorganisms or by other material (e.g. air-borne
equipment to predetermine and acceptance limits. particles, dust, lubricants, intermediates, auxiliaries). In
Cleaning validation is required to verify the effectiveness many cases, the same equipment may be used for
of cleaning procedures and to ensure no risks are processing different products. To avoid cross
associated with cross contamination of active ingredients contamination of the pharmaceutical product, adequate
or detergent/sanitizer.[1-3] Equipment cleaning validation cleaning procedure must be strictly followed and
procedures are mainly used in pharmaceutical industries validated. This applies equally to the manufacture of
to prevent contamination of drug products; hence it is pharmaceutical products and active pharmaceutical
critically important as per federal and other standard ingredients (APIs). In any case, cleaning process has to
regulations. The most important benefit of conducting be designed such a way thatcontamination is reduced to
validation study is identification and correction of an acceptable level.[3]
potential problems that are previously unsuspected,
which may compromise with quality of subsequent The first step in designing a cleaning validation study is
batches of drug product. The basic need of quality to define the key elements-products, equipment,
assurance that product produced must meet the quality manufacturing processes, cleaning procedures,
requirements; i.e. Safety, Identity, Strength, Purity and acceptance limits, sampling and testing procedures,
Quality.[4, 5] personnel and responsibilities. The next step includes
designing the cleaning validation process, generating the
There are different levels or degrees of cleanliness protocol and conducting the study.[8] The cleaning of
required in pharmaceutical operations and naturally the “difficult to reach ‟surface is one of the most important
specifications for each of the cleaning will differ considerations in equipment cleaningvalidation.
substantially. Cleaning validation procedures are carried Equipment cleaning validation in an API facility is
out in order to ensure that product residues are within extremely important as cross contamination is one of the
acceptable limits after the cleaning process. The product pharmaceutical dosage forms, will multiply the problem.
residues which are in highly diluted state after rinsing Therefore, it is important to do a step-by-step evaluation
procedure. This makes it difficult to find appropriate of API process to determine the most practical and
analytical methods that are sensitive enough to detect the efficient way to monitor the effectiveness of the cleaning
product residues. It is advantageous that analytical process. It is necessary to validate cleaning procedure for
method selected to be simple, accurate and give results the reasons like:(1) it is regulatory requirement in
quickly.[6, 7] ActivePharmaceutical Ingredient product manufacture.
(2) It is prime customer requirement since it ensures the
purity and safety of the product. (3) It also assures the

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quality of the process through an internal control and procedures on how cleaning processes will be validated
compliance. Once the cleaning procedure for a particular and these procedures” should address issues such as
piece of equipment (for a particular product following a sampling procedures, analytical methods to be used,
specific manufacturing process) is validated, it should including the sensitivity of those methods.[12]
consistently produce the same results.
Validation of cleaning processes should be based on a
TYPES OF CLEANING PROCEDURE worst-case scenario including: challenge of the cleaning
Product Change over from one batch to next batch of process to show that the challenge soil can be recovered
same product/potency and of similar product with in sufficient quantity or demonstrate log removal to
ascending potency with same colour. Cleaning ensure that the cleaning process is indeed removing the
procedures involves removal of powder of previous soil to the required level and the use of reduced cleaning
product by dry cleaning procedure by using vacuum or parameters such as overloading of contaminants, over
lint free cloth.[6] drying of equipment surfaces, minimal concentration of
cleaning agents, and/or minimum contact time of
For changeover of products with different API / colour, detergents. At least three (3) consecutive applications of
descending potency, after maintenance equipment, after the cleaning procedure.
production of several batches of same product and when
next product batch is not known. Here the cleaning Should be performed and shown to be successful in order
procedure involves removal previous product residues by to prove that the method is validated. Equipment which
dry cleaning procedure and then with wet cleaning is similar in design and function may be grouped and a
procedure using water as cleaning solvent.[6] Cleaning is worst case can be established for validation.[13]
like any other critical process that requires validation.
However, it is generally not well understood or studied. SAMPLING TECHNIQUES
It is essential that adequate cleaning procedures should In developing the sampling plan for a validation study, it
be established and validated.[9] The selection of cleaning makes scientific sense to incorporate an understanding of
method is depends upon the solubility and difficulty of the acceptance criteria and the limitations of the
cleaning of active ingredient. The calculations of product sampling method relative to the surface to be sampled.
residue limit are based on potency, toxicity and stability The two methods of sampling generally employed are
of active ingredient. swab and / or rinse sampling. (If neither or these methods
are shown be a scientifically sound method for testing in
The selection of cleaning method is depends upon the a specific instance then an alternative is to consider
solubility and difficulty of cleaning of active ingredient. testing the next Product.) The selection of either of these
The calculations of product residue limit are based on techniques must be consistent with sound scientific
potency, toxicity and stability of active ingredient. The judgment and must support the objective of the study,
ability to successfully clean a piece of equipment is which is to demonstrate that the amount of residual
closely related to the solubility of materials being material in the equipment has been reduced to acceptable
removed in washes and stages of cleaning. Materials levels.[14]
which are soluble freely in water can be rapidly reduced
in concentration through repetitive dilution of the surface EACH METHOD IS DESCRIBED IN BRIEF
with additional washes. Materials which are poorly BELOW
soluble are most likelyremoved from the surfaces by the 1. SWAB
force of wash and rinse spray against the
equipmentsurface. The ability to remove the relatively
insoluble materials can be enhanced by the introduction
of surfactant, co-solvents etc to the cleaning process. The
basic mechanisms involved in the removing the residues
and contaminants from the equipment are mechanical
action, dissolution, detergency and chemical reaction, so
the cleaning procedure should be validated.[10, 11, 3]

Now-a-days pharmaceutical industries are increasingly

using the multipurpose equipment and automated clean-
in-place procedures; it has become more important to
establish evidence that cleaning procedure is effective.
FDA has placed an increased emphasis on the cleanliness
of the equipment to minimise the risk of cross
contamination and adulteration of drug products made
subsequently using the same equipment.FDA” s July SWABBING[14]
1993 “Guide to Inspections, Validation of Cleaning In a typical pharmaceutical manufacturing environment,
processes requires companies to have “written general cleaning might be performed by using 70% isopropyl

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alcohol (IPA) and/or other chemicals, detergents and Swab sampling does not cover the entire equipment
sanitizing agents in order to remove residues from the surface area therefore sites must be chosen with care. It
previous batch run. The areas thus cleaned must now be is important that, as a minimum, the swab sites
sampled adequately and appropriately in order to validate represents worst case locations on the equipment and that
the cleaning protocol. the result is then extrapolated to account for the total
product contact surface area. This calculation makes it
While the FDA guidance indicates a preference for the possible to make a worst case determination of potential
more direct swabbing method, more recent carryover into subsequent product.
communication from the International Conference on
Harmonisation (ICH) ICH Q7A5 states that sampling  Due to the nature of this method which employs
methods need to be comprehensive enough to quantitate physical forces as well as chemical forces it may be
both soluble and insoluble residues that are left behind necessary to perform sampling technique evaluation.
on the surfaces after cleaning. The exact protocols  Swabbing efficiency (% recovery) for the swabbing
prescribed will necessarily vary depending on the nature method must be determined.
of the products, residues and surfaces. These protocols  It is necessary to ensure that extractible of the swab
must be tailored to the needs of each environment. do not interfere with the sampling method.
 Using this technique it is possible to sample
THE SWABBING PROCEDURE – insoluble residues due to the physical action
CONSIDERATIONS[14] associated it.
The swab to be used for sampling is typically pre-wetted  Swabbing technique involves the use of a swabbing
with water or another appropriate solvent in order to material, often saturated with solvent, to physically
remove residues from the surface. Squeezing the sides of sample the surfaces.[3]
the swab against the inside of the vial upon pre-wetting
prior to sampling removes excess solvent. This is Advantages
important because excess solvent can itself serve as a · Dissolves and physically removes sample
source of residues leading to variable results. There is a · Adaptable to a wide variety of surfaces
direct, physical interaction between the swab, the solvent · Economical and widely available
and the residues to be removed; therefore, the choice of · May allow sampling of a defined area
swab is critical to the effectiveness of the sampling · Applicable to active, microbial and cleaning agent
process. The swab used must offer ultra-low particulates residues[16, 3]
and fibers, high absorbency and minimal extractable
interferences. Polyester swabs are specially processed to 2. RINSE
meet the stringent requirements associated with cleaning Rinse samples allow sampling of a large surface area. In
validation protocols. addition, inaccessible areas of equipment that cannot be
routinely disassembled can be evaluated. However,
The physical nature of the swabbing process implies that consideration should be given to the solubility of the
significant levels of operator training be conducted prior contaminant.[18]
to implementation of cleaning validation protocols. This
training should serve to minimize the subjectivity that is Rinse Sampling involves passing a known volume of
inherent to such sampling activity. The recommended solution over a large area and analyzing the recovery
directions and motions used in actual swabbing of an solution.
area as and should be detailed in the training to ensure  The solvent rinse occurs after cleaning has been
the highest levels of consistency. Alternate swab completed
sampling patterns may certainly be used if they would
 This method is not as direct as swabbing but will
help maximize percent recovery.
cover the entire surface area (and parts inaccessible
to swabs)
The swabbing pattern used is critical to ensure an
 It is important to ensure chosen solvent has
accurate and reproducible collection of residues. A
appropriate recovery for residues being quantified
typical sampling pattern employing two swabs.
 This method allows much greater ease of sampling
1. The first side of the first swab is swiped horizontally
than swabbing
ten times.
2. The swab head is flipped over and the second side is  A reduced no of samples are required to generate a
swiped vertically ten timesover the same surface. carryover figure.[16,3]
3. The swab is deposited in the vial.  Sampling and testing of rinse samples for residual
4. The first side of the second swab is swiped diagonally active ingredient is a commonly adopted method to
upwards ten times. evaluate cleanliness. This is a fairly convenient
5. The swab is flipped over and the second side is swiped method in many cases and requires control over the
diagonally downward ten times. solvent used for rinsing, the contact time and mixing
6. The second swab head is deposited in the vial.[15] involved. The solvent used should be selected based
on the solubility of the active ingredients and should

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either simulate a subsequent batch of product or at Advantages

least provide adequate solubility. A disadvantage of Adaptable to on-line monitoring, Easy to sample, Non-
rinse samples to that the residue or contaminant may intrusive, Less technique dependent than swabs.
not be soluble or may be physically occluded in the Applicable for actives, cleaning agents and
equipment. An analogy that can be used is the “dirty excipients.[16,3]
pot”. In the evaluation of cleaning a dirty pot,
particularly with dried out residue, one does not look 3. VISUAL CLEANING METHOD
at the rinse water to see that it is clean: one looks at It is important to use visual inspection in addition to
the pot. analytical methodology to ensure the cleaning process is
acceptable. The study involves finding out criteria for
 Testing Methods[19] visual cleanliness limit for selected drug by applying
The basic requirements of the analytical methods should known amount of drug on SS plate before taking swab
have the following criteria. samples for chemical analysis.
1) Testing method should have the ability to detect target
substances at levels consistent with the acceptance The use of visual inspection as a criterion for equipment
criteria. cleanliness has always been a component of cleaning
2) Testing method should have the ability to detect target validation programs. Mendenhall proposed the use of
substances in the presence of other materials that may only visual examination to determine equipment
also be present in the sample. cleanliness as long ago as 1989. He concluded that
3) The testing analytical method should include a visible cleanliness criteria were more rigid than
calculation to convert the amount of residue detected in quantitative calculations and clearly adequate. The US
the sample to 100%if the recovery data generated Food and Drug Administration limited the use of visually
indicates a recovery outsides the allowed range. clean criterion between lots of the same product.
Selection of analytical techniques it mainly depends on a
variety of factors. The most important factor is to A visible-residue limit (VRL) currently is used in a
determine the specifications or parameters to be clinical pilot plant for the introduction of new
measured. The limit should always be established prior compounds (4, 5) in cases for which the VRL is lower
to the selection of the analytical tool. than the acceptable-residue limit (ARL). TheARL is the
amount of a formulation component that can be carried
Sampling from rinses is the most commonly used over to the next formulation with no pharmacological or
technique for evaluation of cleanliness. It has become adulteration concerns. The initial use of an active
popular because of its ease, the only control required is pharmaceutical ingredient (API) in the facility is
solvent used and rinsing and contact/mixing. In the rinse followed by cleaning and a visual inspection against the
sample, volume of rinse solvent is important. In the previously determined VRL. Visually clean equipment
equipment designed to hold liquid, either the volume of means the current cleaning procedure is effective and the
rinse solvent should be sufficient to ensure contact with new API is not a new worst case that would require
all product contact surface or method of introduction of cleaning validation.[17]
solvent should be such that solvent make contact with
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