Saturday, March 4, 2023

Cleaning Validation detail information

Cleaning Validation: to understand cleaning validation it is important first to understand, how cleaning is done in pharmaceutical manufacturing?

Important aspect of cleaning in pharmaceutical manufacturing is to prevent cross contamination of one product to another, and to prevent microbial contamination, proper and efficient cleaning procedure is one aspect by which the pharmaceutical company can ensure that contamination of one product to another product does not occur.

It’s just not sufficient to have a proper and effective cleaning procedure but the cleaning procedure should be easy and should yield results meeting the limit or complying with the limits to minimum carry over limit of previous product and limit for traces of cleaning agent and rinse water and swab tests results consistently. Almost a nondeductible level of previous product is desirable, and the rinse water or swab test also has no detectable, very negligible amount of the cleaning agent that is provided in the specifications. As well as the microbial load over the surface of the equipment should meet the requirements of good manufacturing practices guidelines.

Cleaning procedure:

Initial cleaning of equipment is done with raw water and scrubbing the surfaces of the equipment. Followed by soap solution and scrubbing, Suitable solution of soap or surfactant with suitable concentration is added on the surfaces of the equipment and again scrubbing is done.

In case of CIP systems, the soap solution is added in a soap solution tank, from which it is sprayed through a spray ball into the manufacturing equipment covering every point inside the equipment.

How to decide the concentration of soap solution for cleaning in pharma manufacturing?

Molecule deactivating agents:

In case of steroid drugs and potent drugs manufactured in equipment, the manufacturing vessels are added with a strong oxidizing agent and solution of dilute sodium hydroxide or dilute solution of acid, to break down the molecule so that the byproduct if any is easily removable and easily cleaned away with soap solution.

Soap solutions or pharmaceutical cleaning agents are formulated which includes such deactivating agents, which easily allow the traces of such potent or peculiar smells like methyl salicylate or any fragrances added in topical preparations can be deactivated and removed easily during washing with water.

How to decide the concentration of cleaning agent solution for cleaning in pharmaceutical manufacturing?

Concentration of cleaning agents should be initially decided upon by using it by making different concentrations on empty or equipment which are not used or yet to be used, by adapting the same procedure as that of regular procedure in the SOP.

The best fit lowest and optimal concentration should be considered after observation of the results obtained from cleaning of equipment with different concentrations. And different cleaning agents.

One cleaning agent will be effective for cleaning after a particular product and that may not be effective for cleaning of other product, evaluation of same should be done in small scale and identify a broad spectrum effective cleaning agent and product specific, hard to clean product cleaning agent in small scale pilot plant, while cleaning validation should confirm the efficacy of these cleaning agents.

Contact period of soap solution and equipment surface is important in achieving cleaning, therefore even if CIP systems circulation of soap solution in manufacturing vessels, equipment’s, is done for a defined period, about 15 to 30 minutes, and after which soap solution is drained off and removed by circulation of hot water. Transfer pipes, accessories, transfer systems ducts, pipes, storage bins, pressurized vessels, etc. are circulated with cleaning agent solution for appropriate time.

In CIP you need to provide input for the circulation time for soap and rinsing water and final rinsing.

Number of washing with hot water to remove soap solution and debris of previous product:

Higher or more the number of washing better is the solubility of material, hence giving the number of washing to equipment with hot water after application of soap should be identified so that the removal of all traces of soap is facilitated completely. Final rinsing with purified water:

Final rinsing of equipment with purified water is done to remove the traces of raw water, hot purified water is circulated through CIP and from piping and ducts through which the product transfer and handling is done.

Cleaning validation What is cleaning validation?

Cleaning validation is validation of cleaning procedures adapted for the equipment, in manufacturing, filling etc. Validation is the process of gathering data as documentary evidence and reviewing and verifying through documentary evidence that the adapted procedure, process CIP is capable of producing predetermined, desired consistent results of cleaning, and reducing the microbial contamination from surface of the equipment to the acceptable level.

For cleaning validation, a pharmaceutical manufacturing company has to decide on which product should be considered first for validation of cleaning procedure for equipment after manufacturing of that product.

There are two most important criteria for selection of product for doing cleaning validation.

1.       LD 50 value

2.       Worst to clean product.

Above two criteria when considered during selection of the product it will fulfill the objective of the process of cleaning validation.

Consideration of LD 50 value for consideration of product for doing validation of its cleaning:

LD 50 value is a value that indicates dose of a drug that is lethal to 50 % of the population of animals in the study. It is determined during initial safety study while doing acute toxicity study of a drug molecule.

Lower is the LD 50 value of its highly toxic molecule, therefore during considering any product for doing cleaning validation first matrix of all products and the LD 50 values of the API used in the product, since the excipients mostly are inert and do not have any toxic effects. In this table the product with API with lower LD 50 value is arranged on top and goes down in the table in increasing order.

Worst to clean product, Hard to clean product:

A product with higher level of water insoluble API or excipients, odoriferous product imparting staining like coloration example of colored API ivermectin, Beta carotene etc.

These products should be included in the validation master plan for doing cleaning validation.

A matrix of hard to clean products and products with API with lower solubility in water should be prepared.

A comprehensive matrix presenting a LD 50 matrix and matrix of hard to clean product and product with API with lower solubility in water should be prepared.

Hard to clean and products with API insoluble or lower solubility in water should be placed on along with lower LD 50 products.

In event there are two products coming on top one with lowest LD 50 value and product with insoluble API then both products can be considered in cleaning validation depending on the nature of product.

Minimum carry over limit for residue after cleaning.

Regulatory aspects:  US FDA guidelines on cleaning validation are provided in 21 CFR PART 211.67 mentioned that periodic cleaning and sterilization of equipment must be done so as to prevent cross contamination, to prevent threat of contaminants going into drug products and alter its safety and efficacy.

Standard operating procedure should be available with training on how to conduct cleaning validation, a protocol for doing cleaning validation is required to be prepared and approved by Quality assurance.

Sampling plan sampling procedure sample points and method of estimation of residues, collected data and its tabulation and method of evaluation should be provided in protocol for cleaning validation and in the report of cleaning validation.

Responsibilities of each unit or persons functioning should be clearly defined.

Cleaning methods:

Clean in place: as it is known as CIP automated systems and used in this method.

Clean out of place: where the equipment parts are disassembled and taken into the washing area and cleaned.

Sampling for testing for cleanness:

Direct samples taken with swab from the surfaces, sometimes the swab cannot be taken from the inner part of equipment therefore indirect samples like water rinsed over those parts are taken and tested for residue.

Quality assurance should first Annalise the worst to clean spots and corners and a sampling for swab and rinse water sampling plan and location is decided.

Evaluation of cleaning:

Physical observation:  Physical observation with naked eyes and with magnifying glasses can be done, facility for light, or torch used to observe the inner side of the surface. Quality assurance person should do this physical observation after cleaning along with the doer department.

Estimation of residues left over: HPLC method used for estimation of the API and drug product under the cleaning validation activity is used, traces of soap can be estimated with HPLC or spectrophotometric.  IR can be used for identification of soap residue if required.

Limit residues left over: Not more than 0.1% of the normal therapeutic dose of a product should appear in the maximum daily dose of another product.

Microbial load test: Swab test, contact plate techniques can be used for microbial evaluation of cleaned equipment. The area also is cleaned therefore the microbial load test for the respective area should also be done.

Limit for Microbial load over cleaned equipment:  no more than 20 CFU (colony-forming units) for bacterial counts, no more than 2 CFU for molds, and/or no more than 25 CFU/25cm2 of contaminants in a sample

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