VALIDATION PROTOCOL STANDARDS.

Validation Protocol standards must be used for writing the Functional Test (FT) if it is to be a stand alone document that can be executed and reviewed as part of the operational qualification. The FT should first be written at the FAT stage. This means that your vendor should write it, and so the vendor does in a high percentage of instances. It is criminal that having spent hundreds of hours authoring, developing and finally executing a detailed FAT at the factory, the document is allowed to die and never be used again. For instance in a project Validation Online was closely involved in, 87 people spent nearly one year in raising, approving and executing the FAT for a Distributive Control System, while on site, 30 people spent over a year writing the OQ’s. The FAT reviewed and condensed would have done a much better job, partly because it was written by staff who had direct access to the design staff who designed the DCS, but mainly because it was ready, and should have been freely available from the vendor. The FAT and the FT, are the same as the re-qualifying tests that are carried out on laboratory and process equipment. It becomes a little obvious that if these documents were written to normal validation protocol standards, then, the one document could be used for the testing section in documents like, the FAT, FT, qualify and re-qualifying of equipment.

Validation Protocol Standards

The following method of construction must be used. The over all protocol standards are shown in the SOP’ for the different protocols, here we are concerned about the testing element alone. All testing must be detailed and pre-approved by a qualified person to ensure the system under test has been adequately tested. Each test must comprise of ;

Main Sub-headings in Test Script.

• A Rationale, giving the reason and or object of the test.
• A detailed Test Method.
• A detailed Acceptance criteria that the tests must produce.
• A Test Result confirming whether the test result, satisfied the acceptance criteria.

General details that must be adhered to.

• The test result must be initialled by the person executing the tests, on completion or at each significant stage.
• Each test must be designed to verify an element of the equipment functionality.
• Each test must a have a result that is clear, unambiguous and known.
• The test method must call up for the recording of the test result parameters. (no ticks or tick boxes, no generalities).
• Each test must be witnessed or the results must be reviewed by a competent person.
• The overall test results must be approve by a competent person.

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STANDARD PROTOCOL RELATIONSHIPS.

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FULL LIFE CYCLE DOCUMENTATION RELATIONSHIPS.

SIX Golden Rules of Validation

1.0 DRAFT A PERFECT PLAN FOR VALIDATIONS

Normally, entire validation activities in any organization is performed using

Master Validation Program. If MVP is perfect, success in validation is assured. Exercise following precautions in drafting MVP

Avoid Critical Miss Outs:

Many of MVP,s have critical miss outs. Very often atypical MVP includes Equipment validation, Process validation, HVAC & Water system validations and Method validation but misses out Computer System validation. Some MVP,s even do not provide scope for revalidation. Retrospective validations for the existing system and equipments are also missed out many times.

Specify frequency of Validation/ Revalidations.

Master validation Plan shall provide clear statement of frequency of Validation / Revalidation so as to ensure that systems are maintained in validated state through out their life cycle.

Provide detailed information on validation team

MVP shall clearly state Name/ Designation of validation team members and their individual and joint responsibilities.

Cover all the critical validation activities

The validation activities require the following steps

· Drafting validation protocol

· Approval of the protocol.

· Experimentation and observation as per the protocol.

· Recording of results

· Interpretation of results

· Comparison of results with acceptance criteria.

· Remarks

· Final validation report(validation summary and recommendation

Final certification and approval by all team members

Ten Keys For Drug Development

Mr. R M Gupta and Mr. S Vishweshwar

(Perfect Pharmaceutical Consultants Pvt. Ltd. Pune)

Kulkarni Sumant S.

(M. Pharm. (II) Student, J. S. S. College of Pharmacy Ooty)

Directive 1. “Write a clear SOP on drug development”.

Presenting a quality drug in the shortest development time is the goal of drug development. Start the project only after you have clear, concise drug development procedures and objectives. It shall be backed-up with cleaning, process and analytical validation.

Directive 2.”Run controlled pilot studies”

U

ncontrolled studies like non-validated assays generally give the wrong guidance. To evaluate a potential bioequivalent product with a fully validated analytical assay/ metabolite/impurity procedure a controlled pilot study often works out more cost effective. Never do uncontrolled studies!

Directive 3. “Write and Report Facts Faithfully”

A failed result highlights a wrong development route hence it is a positive endpoint. Faithful reporting of Failed results is a duty of Investigator. Avoid average results as it may give wrong picture about the out-of-spec-results.

Directive 4. “Remember the 5C’s of documentation”

Write Clear statements, aims, objectives, conclusions and results.

Concise – Prepare a report that is to the point ; its all that’s needed.

Compact, avoid any padding - period!

Write Controlled prospective protocols and procedures for studies or processes. It will produce well-controlled documents.

Certify & Check - review and audit every document produced. Documents that have passed a careful and thorough audit review process shall be Signed, dated and stamped.

Directive 5. “Be Open and Direct “

Never hide a bad study report or a poor result. Review your firm’s out-of-specification SOP and check that there are no organization omissions.

Directive 6. “Investigate all abnormalities”

Test results that are out-of-specification, the result may well be a sampling or technician error.

Directive 7.

“Make your Application really clear, concise and user friendly “
Well prepared and assembled print or electronic files and dossiers are equally important as that of Experimental Findings. Make the reports attractive, stimulating, and interesting to read and review.

A document can entice or repel a reader simply by its construction - it can also be made a scientific work-of-art.

Directive 8.

“Treat regulators like your key personnel treat you”
Listen to regulators - they may know regulations that you don’t. Listen to their concerns clearly - it’s in your product’s interest.

Work with regulators - or they will work against you and your product may not get to the market place on time.

Treat regulators with respect - as you would like to be treated.

Remember an agency never looses an argument - the product only suffers and gets delayed due to incomplete data or regulatory requirements.

Directive 9.

“Talk to the regulators regularly.”

Allow regulators to review protocols prior to starting the work. Get their opinion and express your concerns openly. Regulators like openness and honesty - and work well with polite, respectful and professional personnel.

Directive 10.

“Take a hard look at your cGMPs “
The absence of GMP compliance simply adulterates your drug development pipeline.

Always follow cGMP Guidelines.

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This Article is brought to you by Perfect Consultants (India) Regulatory Affairs, for more detailed information please visit our site at:

1) www.perfect-consultants.com

2) www.perfect-consultants.com/services.html

3) www.perfect-consultants.com/products.html

Or email us at

info@perfect-consultants.com , gupta1@vsnl.com

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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This Article is brought to you by Perfect Consultants (India), for more detailed information please visit our site at:

1) www.perfect-consultants.com

2) www.perfect-consultants.com/services.html

3) www.perfect-consultants.com/products.html ( For ready to use protocols)

Or email us at

info@perfect-consultants.com , gupta1@vsnl.com

IEST tutors on cleaning validation

Contamination control professionals keen to learn more about swabbing protocols for cleaning validations can boost their knowledge by attending a tutorial on the subject next month.

Developed from the Institute of Environmental Sciences and Technology (IEST), the Swabbing Protocols for Cleaning Validation tutorial aims to enhance working skills and expose professionals to real-world experiences.

The tutorial will feature hands-on demonstrations detailing proper swabbing techniques for high performance liquid chromatography (HPLC) and total organic carbon (TOC) for cleaning validation. Topics to be covered include proper methodology of sampling, review of cleaning validation challenges, and current industry practices. Participants will also learn about sampling materials requirements, swab material selection, vial handling, instrument loading, and how to improve recovery rates.

The tutorial is scheduled for 6 May during the 54th Annual Technical Meeting and Exposition, ESTECH 2008 at the Hilton Chicago/Indian Lakes Resort in Bloomingdale (Northwest Suburban Chicago), Illinois.

contact

IEST
F+1847 9814130
iest@iest.org