Validation Master Plan, Cleaning Validation and FDA 21 CFR Part 11

Prepared By: Shayana Gora M.Pharm~2nd sem Quality Assurance

VALIDATION MASTER PLAN
Objectives of Part 1
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To provide an introduction to the subject of Validation To provide information on the Validation Master Plan

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INTRODUCTION

Three basic principles of Quality Assurance:
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Quality, safety, effectiveness Cannot inspect quality into a product Processes must be under control

WHO validation definition
The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.

Qualification or validation?

A system must be qualified to operate in a validated process ´ Qualify a system and/or equipment ´ Validate a process ´ Qualification versus validation,
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e.g. you qualify an autoclave, whereas you validate a sterilization process

Qualification and validation work require: ´ ´ ´ Collaboration of experts Budget Meticulous and careful planning A Validation Master Plan helps the manufacturer and inspectorate .

The Validation Master Plan (VMP) Philosophy Content Strategy .

Validation Master Plan ´ ´ ´ ´ Recommendation only Cover manufacturer·s validation policy and needs Provides information on validation organization It should describe: « why? « what? « where? by whom? how? when? .

Validation Master Plan ‡Prospective validation ‡Concurrent validation ‡Retrospective validation ‡Revalidation ‡Change control .

The VMP helps: Management Validation team members Project leaders GMP inspectors .

systems) Defines nature and extent of testing expected Outlines test procedures and protocols Summary document Management agreement ´ ´ ´ . processes.The VMP ´ ´ Identifies validation items (products.

Validation Activities in VMP Every validation activity included ´ ´ ´ Revalidation Validation of new process cycles Large validation projects have separate VMPs Include reasonable unexpected events ´ .

The VMP: ´ Enables overview of entire validation project Lists items to be validated with the planning schedule as its heart Is like a map ´ ´ .

The ´Introductionµ to the VMP ´ ´ ´ ´ ´ Validation policy Project scope Location and timing (including priorities) Validation procedures Standards .

VMP should state who is responsible for:        Preparing the VMP The protocols and SOPs Validation work Report and document preparation and control Approval/authorisation of validation protocols and reports in all stages of validation process Tracking system Training needs in support of validation .

VMP should contain: Cross references to documents ´ Specific process considerations ´ Specific characteristics briefly outlined ´ Validation list (What to validate) ´    premises. systems and equipment processes products .

VMP should contain: ´ Descriptions of plant (where to validate)  processes  products  ´ Personnel attributes  expertise and training ´ Key acceptance criteria .

VMP should contain: ´ ´ ´ ´ ´ ´ Format for protocols and other documentation List of relevant SOPs (How) Planning and scheduling (When) Location (Where) Estimate of staffing requirements (Who) A time plan of the project (When) ´ Annexes .

VMP should contain change control ´ ´ ´ ´ Policy and procedure Risk assessment Authorization Failure to properly document changes to the system means invalidation of the process .

Controllers ´ Site changes. Operational changes ´ Change of source of material ´ Change in the process ´ Significant equipment change ´ Production area changes ´ Support system changes ´ .Changes that require revalidation Software changes.

equipment. a VMP should contain at least: ´ ´ ´ ´ ´ ´ ´ Validation policy Organizational structure Summary of facilities. systems.In summary. processes to be validated Documentation format for protocols and reports Planning and scheduling Change control Training requirements .

Part 2 Cleaning validation .

Objectives To review: y General requirements y Validation protocol requirements y How to check limits y Analytical requirements y Sample methods .

Why cleaning validation is so important y Pharmaceuticals can be contaminated by y y y y potentially dangerous substances Essential to establish adequate cleaning procedures Particular attention should be accorded to the validation of cleaning procedures (WHO) Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure (PIC/S) The data should support a conclusion that residues have been reduced to an acceptable level (FDA) .

Product residues Cleaning agent residues and breakdown Lubricants . mould and pyrogens Decompos -ition residues Airborne matter C O N T A M I N A N T S . ancillary Bacteria.

21 CFR 211.Regulatory Requirements yFDA.65. July 1993 Guide to inspection for validation of cleaning process yApplication regulation and requirements: 21CFR 211.67 jWritten cleaning procedure. 21CFR 211.182 .

Strategy on cleaning validation y Product contact surfaces y After product changeover y Between batches in campaigns y Bracketing products for cleaning validation y Periodic re-evaluation and revalidation .

LEVELS OF CLEANING y Levels of cleaning depends on .The stage of manufacture .The nature of the potential contamination Level Cleaning required Level 0 i. In campaign batch to batch.The equipment usage . . Not essential.e.

2)Early step to intermediate in product sequence. Level 2 1) Product change over of equipment used in final step.Level Level 1 1)Intermediates or final product to intermediate of another. . Cleaning required Progression between level 0 to level 2 depending on processes and nature of contaminant based on scientific region. Yes essential. 2) Intermediates of one batch to final step of another batch.

Cleaning validation protocol ‡ ‡ ‡ ‡ ‡ ‡ y y y Objective of the validation Responsibility for performing and approving validation study Description of equipment to be used Interval between end of production and cleaning. and commencement of cleaning procedure Cleaning procedures to be used Any routine monitoring equipment used Number of cleaning cycles performed consecutively Sampling procedures used and rationale Sampling locations (clearly defined) .

Record of cleaning validation y y y y y y Data on recovery studies Analytical methods including Limit of Detection and Limit of Quantitation Acceptance criteria and rationale When revalidation will be required Must have management and QA involvement Management commitment and QA involvement .

Results and reports y Cleaning record signed by operator. checked by production and reviewed by QA y Final Validation Reports. including conclusions .

Personnel y Manual cleaning methods are difficult to validate y Cannot validate people. can measure proficiency y Must have good training y Must have effective supervision .

Microbiological aspects y Include in validation strategy y Analyse risks of contamination y Consider equipment storage time y Equipment should be stored dry y Sterilization and pyrogen contamination .

How to sample y Swab/swatch y Rinse fluid y Placebo The sample transport and storage conditions should be defined .

Possible to recover dried residues y Indirect sampling (rinse method ) . .SAMPLING PROCEDURE y Direct surface sampling (swab method) .Sampling from wide area is possible . Sample shall be taken after the final cleaning of equipment.Sampling is possible from a position not accessible by hand.

Possible to recover dried residues and insoluble substances 1.Sampling from a wide area is possible. must extrapolate sample area to whole surface Rinse method 1. 2. 2.Swab method 1. Possible to confirm pollution or residual substances per area. Dilution effect . 2. inconsistent Recovery 3. Advantages Disadvantages 1.Sampling is possible from a position not accessible by hand.In some cases residual substances pollutants may not be dissolved. assumes uniformity of contamination surface 3. inability to access some areas 2. Unreliable.

y Validate analytical method y Must be sensitive assay procedure: y HPLC. selectivity y Limit of Detection (LOD) y Limit of Quantitation (LOQ) y Recovery. linearity. GC. HPTLC y TOC y pH y UV y ELISA y conductivity Check: y Precision. by spiking y Consistency of recovery Analytical method .

achievable and verifiable y Allergenic and potent substances y Limit setting approach needed y Uniform distribution of contaminants not guaranteed y Decomposition products to be checked y Setting limits.1% of therapeutic dose . cleaning criteria: y visually clean y 10ppm in another product y 0.Setting limits y Regulatory authorities do not set limits for specific products y Logically based y Limits must be practical.

Setting limits: ´Visually cleanµ y Always first criteria y Can be very sensitive but needs verification y Use between same product batches of same formulation y Illuminate surface y Spiking studies Setting limits: ´10ppmµ Historical In some poisons regulations Pharmacopoeias limit test Assumes residue to be harmful as heavy metal Useful for materials for which no available toxicological data Not for pharmacologically potent material .

J = maxim number of dose units of product B (next product) administrated / day. .Setting limits: not more than 0.1% y Proportion of MINIMUM daily dose of current product carried over into MAXIMUM daily dose of subsequent product y Need to identify worst case MAXIMUM ALLOWABLE CARRY OVER (MACO) MAC = I/J x K/L x M where I = smallest strength of product A' (previous product) manufactured (safety factor 1000).

Oral Products 1/1000th to 1/10.Topical Products 1/100th to 1/1000th of a Normal Daily Dose. SAFETY FACTOR 1/10th to 1/100th of a Normal Daily Dose.Injections. Ophthalmic Products .000th of a Normal Daily Dose. M= sampling surface area ( product A is previous product &product B is next product).K= number of dose units per batch of product B. L= equipment surface area in common between products A and B expressed as square centimeters.

INVESTIGATION OF WORST CASE Hardest to clean Solubility in used solvent Highest toxicity Lowest Therapeutic dose smallest strength dose most insoluble drug product dose Worst case study is taken as standard .

Other issues y Clean-In-Place (CIP) systems y Placebo studies y Detergent residues. composition should be known y Scrubbing by hand .

Questions for the GMP Inspector to ask y How is equipment cleaned? y Are different cleaning processes required? y How many times is a cleaning process repeated before acceptable results are obtained? y What is most appropriate solvent or detergent? y At what point does system become clean? y What does visually clean mean? .

Cleaning validation strategy Assess situation on merits ‡ Scientific rationale must be developed Contaminant Significance equipment selection contamination distribution .

Part 3 FDA 21 CFR Part 11 .

‡ defines the criteria under which electronic records and electronic signatures are considered to be trustworthy. ‡ also applies to submissions made to the FDA in electronic format (e.g..e. reliable and equivalent to paper records. the paper documents can be considered to be the authoritative document for regulatory purposes and the computer systems need not meet these requirements.. . ‡ If a regulated firm keeps "hard copies" of all required records. faxes). a New Drug Application) but not to paper submissions by electronic methods (i.

Electronic Signatures. Electronic Records: Electronic Signatures ± Scope and Application (2003) ‡ Guidance for Industry Computerized Systems ‡ used in Clinical Investigations(2007) .History ‡ FDA Title 21 CFR Part 11:Electronic Records. Final Rule (1997) ‡ FDA Guidance for Industry Part 11.

system validations. . with some specific exceptions. audit trails. medical device manufacturers.‡ Part 11 requires drug makers. and other FDA-regulated industries. electronic signatures. biologics developers. and documentation for software and systems involved in processing electronic data that are (a) required to be maintained by the FDA predicate rules or (b) used to demonstrate compliance to a predicate rule. including audits. biotech companies. to implement controls.

reliable. and generally equivalent to paper records and handwritten signatures executed on paper. and other general signings as required by agency regulations.  electronic signatures to be equivalent to full handwritten signatures. controls. .  Computer systems (including hardware and software). and subject to. initials. Scope  criteria ~ trustworthy.Subpart A ² General Provisions 1. and attendant documentation shall be readily available for. FDA inspection.

Definitions . For records required to be maintained but not submitted to the agency b. Implementation a.2. For records submitted to the agency. 3.

Signature manifestations 4. . copied. Controls for closed systems ensure that the signer cannot readily repudiate the signed record as not genuine 2. 3.Subpart B ² Electronic Records 1. Controls for open systems confidentiality of electronic records from the point of their creation to the point of their receipt. or otherwise transferred to falsify an electronic record by ordinary means. Signature/record linking Electronic signatures and handwritten signatures executed to electronic records shall be linked to their respective electronic records to ensure that the signatures cannot be excised.

Subpart C ² Electronic Signatures General requirements Electronic signatures and controls Controls for identification codes/passwords .

H.Code of Federal Regulations Title 21 US FDA Swarbrick J.com CFR . ´Encyclopedia Of Pharmaceutical Technologyµ Vol I 3rd Edition .A.References      US FDA: General Principles Of Validation Nash R. Wachter A.wikipedia. . An International 3rd Editionµ Vol 129 www. ´Pharmaceutical Process Validation.

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