GUIDELINE TO CLEANING VALIDATION

By – Mr. R.M. Gupta ; Mr. Vishnu P. Choudhari ;

(Perfect Pharmaceutical Consultants Pvt. Ltd. Pune)

(Maharashtra Institute of Pharmacy, Pune)

Contact www.perfect-consultants.com for ready to use Validation Protocols at an affordable price.

Validation of cleaning procedures has generated considerable interest to avoid adulteration or cross contamination in Bulk drugs, Pharmaceutical formulations, Biotechnology product and in Microbiological processes etc.

Benefits associated with validation

1	Identification and correction of potential problem previously unidentified, which could compromise safety, efficacy or quality of subsequent batches of drug product processed with the Equipments.
2	Prevention of serious problems arising from cross contamination

GENERAL CLEANING METHODS AND CONCEPTS

Methods used for cleaning may be classified as

· Manual cleaning procedure,

· Semiautomated procedure,

· Fully Automated procedure (CIP system).

Steps Involved in Manual cleaning procedures: -

1	Equipment disassembly (If required)
2	Pre-washing inspection
3	Washing
4	Initial rinse
5	Final rinse.
6	Reassembly (If required)

Steps Involved in Semiautomated cleaning process (cabinet type stationary machines with plumbed utilities)

1	Loading of cleaning agents in the machine
2	Automatic cleaning of the vessels
3	Unloading of excess cleaning agent from the machine

Steps involved in Fully Automated cleaning procedures:-

Used mostly for cleaning of large stationary piece of equipment’s.

1	DQ,IQ,OQ , PQ of CIP system.
2	PQ for cleaning Process Sampling consideration i.e. Addition of sampling port maybe required for ease of sampling of wash or rinse fluid. Pause capabilities may have to be changed or added to the cleaning program to allow inspection and / or sampling.
3	Material supply:- Fully automated system require hard plumbed supply lines and tank for water, cleaning agents, acids or bases etc
4	Actual automated cleaning

General cleaning procedure and systems (Pre-validation Verification)

Before switching to actual cleaning validation one should insure that the cleaning procedures, controls & documentation systems are logical, controlled & properly documented. Therefore cleaning procedure must consistently meet the limits set. The steps taken for these are,

A) Documentation & Tractability :-

This includes -

1	Identification of equipment
4	Cleaning Equipment’s should be suitably calibrated wherever required, cleaned and maintained and SOPs made available for the same.

B) Utilities Used: -

Utilities like WFI, D.M. Water, Compressed air should be qualified and operated as specified.

C) Control of cleaning material: -

Production or Purchase, testing & use of cleaning material should be effectively

Controlled to ensure reproducibility in the cleaning, these materials include

Solvent, cleaning agents, ancillary utilities like steam compressed air, potable

Water, scrubbing agents, etc.

1

Solvent : Water is a primary solvent required & quantity of water in cleaning use will depend on purpose. Minimum water quantity required for the given steps have to be clearly specified. The water system itself should be qualified and operated as per established (validated) procedures. Source & quality of non-aqueous solvent where used should be controlled & should be used only if absolutely necessary due to their safety, cost & environmental considerations.

2	Cleaning Agents: - Use of these agents introduce another potential contaminant that must be removed by the cleaning procedure. Control of composition of cleaning agent is difficult as commercial preparations are proprietary and compositions are changed without user’s knowledge. Now a days trend is to manufacture the cleaning agent in house for in house use.
3	Ancillary utilities: - Steam under pressure, compressed air is used to aid in or facilitate cleaning & should be free from particulate matter, oil, microbes & other potential contaminants.
4	Scrubbing Agents: - Removal of residual actives from the encapsulation machines is better achieved by running placebo formulation. Placebo formulation to be used should be clearly identified & quality or Raw material used should be adequately controlled.

D) Control of ancillary tools & equipments for cleaning:-

1	Cleaning Tools:- Brushes, rags , sponges and other cleaning tools should be selected to avoid contamination. Appropriate cleaning method for these tools should be evaluated & followed to avoid contaminant being introduced due to use of these materials.
2	Cleaning Equipment:- Equipment should be maintained, calibrated & controlled as like processing equipment & should be subject to routine maintenance & calibration.

E) Frequency of Cleaning :-

1	Cleaning between batches of same product & strength or ascending strength (provided color is same):- This is also called type ‘A’ cleaning provided non-aqueous solvents not used for cleaning or for product is not non-aqueous. When the cleaning process is used only between batches of same product the firm need only meet criteria of “visibly clean” for the equipment. Such between batch cleaning do not require validation
2	Cleaning during change over of product with different actives, color, descending potency, and after not more than ‘6 ‘ times “A” type of cleanings,
3	Cleaning after maintenance
4	Cleaning after accidental contamination
5	General criteria can be summarized as – “ Minor cleaning for same product “or “Major cleaning for different product”. Also the manufacturer may have one process for removing water-soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios.

Validation Protocol: - This shall include

1	Scope and objectives
2	Introductory information of background
3	Actual procedure
4	Results
5	Normal and Statistical Analysis of results
6	Acceptance criteria
7	Validation Report

Equipment cleaning validation may be performed either after normal use of

equipment for desired product or by chanllenging the cleaning procedure by

deliberately contaminating the equipment.

Cleaning limits :

Limits for the following contaminants may be set:

· Active Ingredient

· Excipients used in the formulation

· Residues of the cleaning agent

Analytical Method:- Method developed:

* Should be able to detect the substance/ingredient selected for cleaning

evaluation and its some of major degradation products.

* The same shall be fully validated.

Acceptance Criteria:- There are many basis for establishing limits for

cleaning processes. Some of them are:-

1	Based on medical dose
2	Based on toxicity
3	Based on analytical delectability
4	Based on process capability of the cleaning process
5	Microbial Load on the cleaned container
6	No of particles recovered from the cleaned equipment

Evaluation:- Following methods can be used

1	Swab sampling
2	Rinse sampling
3	Placebo samples
4	Visual Evaluations

Microbiological contamination:-

This type of contamination has concern in sterile as well nonsterile formulation. Poor cleaning process lead to increased bioburden and pyro-burden, which have serious concern with use of such equipments.

Unlike residual actives and cleaning agent’s, microbes have capacity to proliferate on the poorly cleaned surface therefore matter of prevention is of more concern.

Time limits allowable between process end and start of cleaning must be specified. Cleaned equipment should be protected from subsequent microbial contamination.

Particulate matter contamination:- Smaller visible particles and microscopic particle are of concern for parentral and ophthalmic preparations. To avoid presence of such particles with the cleaned equipments final rinse solvent should be appropriately filtered.

For evaluation of particulate matter load with cleaned container, standard procedures should be used e.g. microscopic evaluation, electronic particular counters (Coulter Counter), etc.

Revalidation:- Revalidation need for these cleaning validation arises due to various reasons. One reason is to perform routine validation based on time period elapsed after validation. But more pragmatic and practical approach is to revalidate for cause. And this links revalidation to change control in an important way. These incidences where revalidation required are:

1	Change in processing equipment
2	Significant changes in cleaning equipment used to clean the processing equipment
3	Change in cleaning agent(s) used
4	Change in cleaning procedure
5	Change in location of the equipment

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