CLEANING VALIDATION IN PHARMACEUTICAL INDUSTRY – AN OVERVIEW
Manufacturing of Pharmaceutical products shall demonstrate a control to reproduce consistently the desired quality of product, wherein the control of cross-contamination plays an important role. An effective cleaning shall be in place to provide documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels. Pharmaceutical manufacturers must validate their cleaning process to ensure compliance with cGMP regulations. 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 Pharmaceutical product manufacture. In this article cleaning validation and cleaning validation program discussed in brief.
Cleaning validation is documented evidence with a high degree of assurance that one can consistently clean a system or a piece of equipment to predetermined and acceptable limits. The objectives of good manufacturing practices (GMP) include the prevention of possible contamination and cross-contamination of pharmaceutical starting materials and products. Pharmaceutical products can be contaminated by a variety of substances such as contaminants associated with microbes, previous products (both active pharmaceutical ingredients (API) and excipient residues), residues of cleaning agents, airborne materials, such as dust and particulate matter, lubricants. Adequate cleaning procedures play an important role in preventing contamination and cross-contamination. Validation of cleaning methods provides documented evidence that an approved cleaning procedure will provide clean equipment, suitable for its intended use.
- To attain documented evidence, which provides a high degree of assurance that the Cleaning procedure can effectively remove residues of a product and a cleaning agent from the manufacturing equipment, to a level that does not raise patient safety concerns.
- Cleaning validation is a documented process that proves the effectiveness and consistency in cleaning a pharmaceutical production equipment
- Validations of equipment cleaning procedures are mainly used in pharmaceutical industries to prevent cross contamination and adulteration of drug products hence is critically important
ADVANTAGE OF CLEANING VALIDATION 
- Assurance of quality & safety.
- Government regulations.
- Product integrity,
- Microbial integrity,
- Cross contamination integrity,
- Batch integrity,
- Equipment reuse,
- Reduction of quality costs.
- Making good business sense.
- Less down time, fewer batch failures and may operate / clean more efficiently.
Several basic mechanisms exist to remove residues from equipment, including
Mechanical action refers to physical actions such as
- pressurized water to remove particulates.
Dissolution involves dissolving residues with a suitable solvent. The most common and practical solvent is water because of its advantages:
water is non-toxic, cheap, does not leave residues, and is environment friendly.
However, in some cases it may be preferable to use a non-aqueous solvent or a combination of both aqueous and non-aqueous solvents due to the solubility characteristics of the materials.
Alkaline or acidic solvents, for example, can enhance dissolution of the materials and could be advantageous.
Detergency requires the use of surfactant, usually in an aqueous system. Detergents act in four different ways:
- wetting agents
- emulsifiers, and
Usually detergents posses all these properties which broaden their action.
Chemical reactions such as oxidation and hydrolysis in which the residues are chemically changed. Example: Sodium Hypochloride
- Detergents should facilitate the cleaning process and be easily removable. Detergents that have persistent residues such as cationic detergents which adhere very strongly to glass and are difficult to remove, should be avoided where possible.
- The composition of the detergent should be known to the manufacturer and its removal during rinsing, demonstrated.
- Acceptable limits for detergent residues after cleaning should be defined. The possibility of detergent breakdown should also be considered when validating cleaning procedures.
- Detergents should be released by quality control and, where possible, should meet local food standards or regulations.
Example of few solvent listed below-
- aqueous cleaning- water
- organic solvent- acetone, methanol, ethyl acetae
- water surfactant- SLS,SDS
- chelants solvent(acid”EDTA,NTA,SHMP/baseNaOH,KOH)
- Acid- Glycolic acid, citric acid
- oxidant- NaOCl, H2O2
CLEANING VALIDATION PROGRAM [6,7,8,9,10,11,12,13,14]
- Selection of cleaning Level (Type)
- Selection of cleaning method
- Selection of sampling method
- Selection of Scientific basis for the contamination limit (acceptance criteria)
- Selection of Worst case related to the equipment
- Selection of Worst case related to the product
- Establishing the storage period after cleaning (hold time study)
- Selection of analytical method
A. SELECTION OF CLEANING LEVEL (TYPE)
TYPE A: MINOR à This type of cleaning take place between two batches of same product or between different strengths of the same product. For minor cleaning, cleaning validation is not required, since cross contamination is not an issue.
TYPE B: MAJOR à This type of cleaning take place between two products.
In this case, validation of the effectiveness of the cleaning procedure in removing residues to the required level is mandatory.
B. SELECTION OF CLEANING METHOD
- Manual cleaning
- Semi automatic procedures
- Automatic procedures
- CIP (Clean-in-place)
- COP (Clean-out-of-place)
Clean-In-Place (CIP) Method
- Cleaning of the equipment is performed in place without disassembling
- Cleaning process may be controlled manually or by an automated program.
- Very consistent and reproducible cleaning method.
- Can be validated readily.
- Being a closed system visual inspection of all components is difficult.
Clean-Out-Of-Place (COP) Method
- Cleaning of disassembled equipment is performed in a central washing machine.
- The washing machine also requires validation such as the temperature, ultrasonic activity, cycle time, cleaning operation sequence, detergent quantity dispensed etc.
Manual Cleaning Method
- Difficult to validate
- Most extensive and elaborate cleaning procedures are required.
- A high quality and extensive training program is required.
The risk involved in manual cleaning processes is taken care of with following:
- Proper washroom design with drying, protection and storage requirement.
- Detailed cleaning SOP
- Training / Qualification of cleaning operators
C. SELECTION OF SAMPLING METHOD
Generally there are two types of sampling that are accepted. The most desirable is the direct method of sampling the surface of the equipment, another method being the use of rinse sampling.
1. Rinse samples (indirect method)
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.
- Ease of sampling.
- Evaluation of entire product contact surface.
- Accessibility of all equipment parts to the rinsing solvent.
- Best fitted to sealed or large scale equipment and equipment which is not easily or routinely disassembled.
- No physical removal of the contaminant.
- The rinsing solvent may not reach inaccessible or occluded part of equipment.
- Use of organic solvents for water insoluble materials.
2. Swab sampling
It is also know as direct surface sampling method. This method is based on the physical removal of residue left over on a piece of equipment after it has been cleaned and dried. A swab wetted with a solvent is rubbed over a previously determined sample surface area to remove any potential residue, and thereafter extracted into a known volume of solvent in which the contaminant active ingredient residue is soluble. The amount of contaminant per swab is then determined by an analytical method of adequate sensitivity.
- Direct evaluation of surface contamination.
- Insoluble or poorly soluble substances may be physically removed from the equipment surfaces.
- Hard-to-clean but accessible areas are easily incorporated into the final evaluation.
- Difficult to implement in large-scale manufacturing equipment.
- Extrapolation of results obtained for a small sample surface area to the whole product contact surface area.
Sampling Method Selected
Looking at the advantages and disadvantages of both the sampling methods swab sampling method was selected. The cleaning procedure uses water as a solvent and we have dosage forms having active ingredient which is insoluble in water.
Sampling Location and Number of Samples
The sample locations are dictated by worst-case conditions. The equipment’s hard to clean locations are identified based on cleaning experience and the design of equipment. The number of samples should take into consideration the equipment surface area, design, shape, operating principle and construction material.
Sample Surface Area
Sample surface areas usually vary from 25 sq.cm to 100 sq.cm.
Swab Recovery Study
A swab recovery study is performed to determine the ability of the swab to quantitatively remove the contaminant from the surface sampled.
Once the acceptance limit of cleaning validation is determined swab recovery study should be carried out. Product solutions of 50%, 100% and 150% of the acceptable limit of area are prepared and spiked on the model surface equivalent to the swab surface area. Surface is dried under gentle airflow. Surface is sampled as per the standard swabbing technique, which will be used for sampling. The swab is tested as per the Validated Analytical procedure.
Test result reported
% Recovered by the swab=——————————————————X 100
Known amount of product spiked
There should be evidence that samples are accurately recovered.
For example, a recovery of > 80% is considered good, > 50% reasonable and < 50% questionable.
Recovery factor shall be taken into consideration while calculating the Acceptable limit for residue.