A Review On Cleaning Validation in Pharmaceutical Industry
A Review On Cleaning Validation in Pharmaceutical Industry
A Review On Cleaning Validation in Pharmaceutical Industry
INTRODUCTION
Cleaning and decontamination is one of the major and critical activities in pharmaceutical
operation. The four basic requirement of cGMP are Identity, Safety, Strength, Purity. The
[1]
concept of purity is directly related to the cleaning operation .The process of providing
documented evidence that the cleaning methods employed within a facility consistently controls
potential carryover of product (including intermediates and impurities), cleaning agents and
extraneousmaterial into subsequent product to a level which is below predetermined levels
[2]
.Cleaning validation is primarily used for the cleaning of process manufacturing equipment in
[3]
the pharmaceutical industries .The basic reason for having good, effective, consistent
cleaningprocedures is toprevent the contamination ofproducts made subsequently in the
sameequipment. The goal is to provide pharmaceuticalproducts of the highest quality to our
patients. Thisis the basic regulatory requirement as well as thegoal of all of those suppliers of
products andservices [4].
OBJECTIVE
The objective of the cleaning validation is to verify the effectiveness of the cleaning procedure
for removal of product residues, degradation products, preservatives, excipients, and/or cleaning
agents as well as the control of potential microbial contaminants. In addition one need to ensure
there is no risk associated with cross contamination of active ingredients. Cleaning procedures
must strictly follow carefully established and validated methods [2].
It is necessary to validate cleaning procedure for the following point reasons[2]:
1) It is a customer requirement- it ensures the purity and safety of the product.
2) It is a regulatory requirement in Active Pharmaceutical Ingredient (API) product.
3) It also assures from an internal control and compliance point of view the qualityof the
process.
general and somewhat vague, and are centered around 21 CFR 211.67 that states: Equipment
and utensils be cleaned, maintained and sanitized at appropriate intervals to prevent malfunctions
or contamination that would alter the safety, identity, strength, quality or purity of the drug
product [4].
According to this law each and every pharmaceutical and food industry should followthe
cleaning validation programmed to avoid malfunctioning, contamination and cross
contaminationof finished product.
A. Bracketing procedure
The total manufacturing process is grouped such as early step, critical step and API. Each group
of process is further grouped as per equipment usage similarities. All the processes are then
divided as per the solubility and worst case scenario rating is made. If two or more equipment
trains are used for a given manufacturing process, a choice made for the same purpose. The
combination of substance in a train can be chose based upon one or more the following
strategies, or combination of them.
Substances with the same cleaning procedure produce in the same train.
Substance with low therapeutic daily dose/ low batch size (and the opposite), produce in the
same train.
Non toxic substances produce in the same train
Substance with high solubility produce in the same train
CONTAMINATIONS [8,9]
Contamination is a condition in which the product contains any material that is not intended to
present and not listed in a current formulation as an ingredients.
Types of contaminations
1. Cross contamination with active ingredients.
Cross contamination with active ingredients may cause potential higher level of synergistic
interactions between pharmacologically active chemicalsand it causes unintended
pharmacological activity. So contamination of one batch of product with residue of active
ingredient of different batch or previous batch should not be tolerated if the residue is more than
that of acceptance limit.
B. 10 ppm Criteria
NMT 10 ppm of any product to appear in another product.
Limitations
An invasive technique that may introduce fibers
Results may be technique dependent
Swab material and design may inhibit recovery and specificity of the method
Evaluation of large, complex and hard to reach areas difficult (e.g., crevices, pipes, valves,
large vessels)
B. Rinse Sampling
This method is based on the analytical determination of a sample of the last rinsing solvent
(generally water) used in the cleaning procedure. The volume of solvent used for the last rinse
must be known to allow for the quantitative determination of the contamination. Thus, collection
of rinse samples should consider location, timing, and volume. It is important to ensure chosen
solvent has appropriate recovery for residues being quantified. The solvent rinse occurs after
cleaning has been completed. This method is not as direct as swabbing but will cover the entire
surface area (and parts inaccessible to swabs).
Advantages
Adaptable to on-line monitoring
Easy to sample
Non-intrusive
Allows sampling of a large surface area
Allows sampling of unique surfaces
Limitations
Limited information about actual surface cleanliness in some cases
May lower test sensitivity
Residues may not be homogeneously distributed
Inability to detect location of residues
Rinse volume is critical to ensure accurate interpretation of results
Sampling methodology must be defined since rinse sampling method and location can
influence results
May be difficult to accurately define and control the areas sampled, therefore usually used
for rinsing an entire piece of equipment, such as a vessel
Reduced physical sampling of the surface
C. Placebo Sampling
Placebo sampling can be used to detect residues on equipment through the processing of a
placebo batch subsequent to the cleaning process. It is appropriate for active residue, cleaning
agent, particulates and microbial testing. Placebos are used primarily to demonstrate the lack of
carryover to the next product. The placebo should mimic product attributes. The equipment
characteristics also impact the choice of the placebo batch size.
Advantages
Placebo contacts the same surfaces as the product
Applicable for hard-to-reach surfaces
There are many analytical techniques available but selection of appropriate tool depends on the
parameter to be measured. Analytical methods are categories into Specific and non-specific to
detect any compound. The choice of using a specific or non specific method can be difficult. If a
drug active is highly toxic, a specific method is always recommended. Chromatographic methods
are preferred for cleaning validation studies because of their sensitivity, specificity, and ability to
quantify
A. Specific method
It is a method that detects a unique compound in the presence of potential contaminants. Some
examples of specific methods are high performance liquid chromatography (HPLC), Ion
chromatography, Atomic absorption, Capillary electrophoresis, and other chromatographic
methods.
B. Non-specific method
It detects any compound that produces a certain response. Some examples of non specific
methods are Total Organic Carbon (TOC), pH, Titration, and conductivity.
REFERENCE
[12] Pawar H.A, Banerjee N.D, Pawar S, Pawar P. Research Article on Current Perspectives
On Cleaning Validation In Pharmaceutical Industry: A Scientific And Risk Based
Approach. Int.J.Pharm.Phytopharmacol.Res. 2011, 1(1): 8-16. Available
online on www.eijppr.com.
[13] Harsshavardhan K.,ThiruvengadaRajan V.S.,Amrut Kumar
N.,AngalaParameswari.,MadhusudhanaChetty C. A Review On Role Of Cleaning
Validation Protocol In Pharmaceutical Manufacturing Unit Int. J. Rev. Life. Sci., 1(3),
2011, 151-158.Available online on www.ijrls.pharmascope.org
[14] Patel P.K., Patel N.M., Patel P.M. Review article on An over View on Cleaning
Validation. Int. J. Pharm. & Bio. Arch.2011; 2(5):1332-1336.
Available online at www.ijpba.info