Cleaning Validation in the Pharmaceutical Industry

Validation
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Introduction:
Cleaning validation is a documented evidence which assures high level of assurance for
cleaning procedures for removing all type of residues from the formulaiton and cleaning
agent from the manufacturing equipment to a minimum level which does not produce risk to
the patient. Cleaning validation is also documented process which assures efficiency and
uniformity in cleaning a pharmaceutical production equipment. Cleaning validation is
primarily useful for preventing cross contamination and adulteration in the pharmaceutical
products.
Food and Drug Administration (FDA) inspections in the pharmaceutical manufacturing units
reported need for the rationale and valid implementation of the cleaning validation
programme. Moreover, Good Manufacturing Practice (cGMP) also made mandatory to
validate the cleaning procedures for products and equipments in the pharmaceutical
manufacturing industries. It is mandatory for the FDA inspectors to inspect functioning of the
proper cleaning validation programme and its appropriate documentation (Sargent et al.,
2016). It is mandatory for the pharmaceutical manufacturing units to use clean and sterile
equipments prior initiation of the manufacturing process. It is extremely important for the
pharmaceutical manufacturing units to decontaminate equipments because cross
contamination is major problem in pharmaceutical industry because it would lead to multiple
problems.
Validation of the cleaning procedures need to be done for the following reasons:
 Pure and safe product is the prime requirement of the customer and cleaning
validation programme ensure safety and purity of the formulation.
 It is the regulatory requirement for manufacturing of Active Pharmaceutical
Ingredient (API) and finished formulation.
 It also ensures quality of the implemented process through internal quality control and
compliance.
Cleaning validation is an important and time-consuming programme in the pharmaceutical
industry. Repeatability and reliability are the important aspects of the cleaning validation in
the pharmaceutical industry. Process validation is usually categorised into three parts like
Installation Qualification (IQ), Operational Qualification (OQ), and Performance
Qualification (PQ). Cleaning validation can be categorised under Performance Qualification
(PQ). It is important to develop, plan and implement validated methods for cleaning products
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and equipments. Systematic approach needs to be implemented for successful cleaning
validation. Hence, in this paper systematic approach is discussed for the implementation of
cleaning validation programme.
Aim and Objective:
Objectives of this validation programme is to establish comprehensive foundation for the
cleaning validation policy and programme. It includes determination of requirements,
procedures, acceptance limits and documentation necessary for implementing cleaning
validation procedures.
Body:
Cleaning validation programme in the pharmaceutical industry comprises of different steps
like selection of cleaning level, selection of cleaning method, selection of sampling method,
selection of Scientific basis for the contamination limit, selection of Worst case related to the
equipment, selection of Worst case related to the product, establishing the storage period after
cleaning, selection of analytical method and documentation.
Selection of cleaning level:
Cleaning level for products and equipments was validated for cleaning validation. Cleaning
level is based on the type products for which cleaning need to be done. Cleaning level is
mainly categorised into type A and type B. Type A cleaning is also called as minor cleaning.
Type A cleaning is usually performed on the two batches of the same product or same
product with the varying strength. In type A cleaning, there is no scope of cross
contamination; hence, validation of the cleaning process is not necessary. Type B cleaning is
also called as the major cleaning. Major cleaning is usually performed on two different
products. In major cleaning, validation is mandatory. Validation in the major cleaning
ensures removal of the residues from the product to the required minimum quantity (Tanyous,
2018).
Selection of cleaning method:
Different types of cleaning methods applicable to the pharmaceutical industry include manual
cleaning, semi-automatic procedures, automatic procedures, CIP (clean-in-place) and COP
(clean-out-of-place). All these cleaning procedures need to be evaluated during the cleaning
validation in the pharmaceutical industry. CIP, COP and manual cleaning holds more
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significance in the pharmaceutical industry. In CIP method, equipments need to be cleaned at
its place without disassembling. This method can be monitored both manually and with
automated programme. Since, this method is reliable and reproducible; validation can be
easily performed. However, visual checkup is difficult due to closed system. In COP method,
equipments need to disassembled and cleaned in the central washing machine. Different
validation parameters like temperature, ultrasonic activity, cycle time, cleaning operation
sequence and detergent quantity dispensed need to be evaluated during validation of COP
method. Manual cleaning method is problematic to validate due to extensive cleaning
procedures. Elaborate training is necessary for the validation of the manual cleaning
procedure (Tanyous, 2018; Lodhi et al., 2014).
Selection of sampling method:
Two types of sampling methods like rinse sampling and swab sampling was evaluated during
the validation of the sampling method of cleaning validation in the pharmaceutical industry.
Rinse samples are also called as the indirect samples and contain samples obtained through
last rinsing solvent. Usage of the last rinsing solvent of the cleaning procedure is useful
determining amount of contamination. Swab sampling is also known as direct surface
sampling method. Swab sampling is usually performed by removing residue on the surface of
the equipments. Wetted swab with the suitable solvent need to be rubbed over surface of
equipment and residue from the swab need to be removed by extracting with the
predetermined known volume of suitable solvent. Analytical technique with the optimum
sensitivity needs to be used for determining number of contaminants. In this study, swab
sampling technique was used and water was used as the solvent because active ingredient of
the formulation is water insoluble. Equipment was selected for the cleaning procedure based
on the worst-case condition. Equipment which was difficult to clean has been selected for the
validation study of the cleaning procedure. Number of samples for the validation were
selected based on the equipment surface area, design, shape, operating principle and
construction material. Selected sample surface area was between 50 sq. m. to 100 sq. m
(Moradiya et al., 2013).
Swab recovery study:
Swab recovery study was carried out to monitor the capacity of the swab to quantitatively
take away contaminant from the equipment surface. Swab recovery study should be carried
out after the determination of acceptance limit of cleaning validation procedure. Sample
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