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Validation :

Validation Presented By: Ms. Dolita Shah M.Pharm (Q.A, Gold medalist), Assistant Professor, Smt. R. B. Patel Mahila Pharmacy College, Atkot 1 Dolita Shah

Introduction :

Introduction 2 Dolita Shah


Definitions Prospective validation- for new product Retrospective validation- for established products manufactured for several years without any complaints Concurrent validation- when process , equipments, material inputs or any other change that may effect the quality of product Revalidation- In case of quality problems 3 Dolita Shah

Who is involved ?:

Who is involved ? Research & development / process development / formulation development / scale up dept Production dept Engineering department Quality control Quality assurance 4 Dolita Shah

Where do we start ? :

Where do we start ? Decide the product and type of validation required to be carried out Decide the team from the concerned department Write down the protocol before proceeding for the actual work 5 Dolita Shah

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Raw material Equipments Process Utilities Analytical procedure QC equip PRODUCT 6 Dolita Shah

Raw materials :

Raw materials Set specification for physical / chemical parameters Specifically for impurity profile Polymorphs Select vendor – approve vendor Should not change the source of the materials for economic reasons Carry out technical audit from where you source the materials 7 Dolita Shah

Equipments :

Equipments New equipments Design qualification Installation Qualification Operational Qualification Performance qualification Existing equipments Operational Qualification Perfomance Qualification Periodic calibration 8 Dolita Shah

Process validation ( Prospective ):

Process validation ( Prospective ) Define the source of raw materials, formula, manufacturing process step wise,- equipments used, Determine the critical steps and boundary parameters. Establish the in process controls, sampling points and methodology of testing Test the product at the end to specification already predetermined Should be carried out on at least three batches of API of actual production size. One of them can be a pilot batch of size 1/10 th of the proposed batch size Keep the same three batches for stability studies 9 Dolita Shah

Utilities used :

Utilities used Water Steam Compressed Air Environment D.Q., I.Q., O.Q., P.Q. for all the systems at the time of starting the plant. Followed by periodic checking & calibration procedure 10 Dolita Shah

Types of water:

Types of water Raw Water Dematerialized Water Potable Water Distilled Water Water for Injection 11 Dolita Shah

Water system :

Water system Water for chemical – microbiological purity, Establish sampling point, Determine specs & method of testing Frequency of testing 12 Dolita Shah


Environment System as a whole design qualification Protocol for validation, Filter integrity test- by DOP, Particle Counts Microbiological Monitoring , Settle plate count, air samples No of air changes Air distribution 13 Dolita Shah

QC equipments :

QC equipments DQ, OQ, IQ, & PQ Periodic Calibration & Installation , Establish calibration procedure, and limits for compliance, frequency of calibration, state calibration status Check column performance System suitability test 14 Dolita Shah

Analytical Procedure :

Analytical Procedure Accuracy , Precision, Specificity, Linearity Limit of detection Limit of quantification Robustness Ruggedness Analytical method transfer procedure ( AMTP protocol) 15 Dolita Shah

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Some definitions……….. 16 Dolita Shah

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EQUIPMENT QUALIFICATION (qualification de l’équipement ): Studies which establish with confidence that the process equipment and ancillary systems are capable of consistently operating within established limits and tolerances. The studies must include equipment specifications, installation qualification, and operational qualification of all major equipment to be used in the manufacture of commercial scale batches. Equipment Qualification should simulate actual production conditions,including "worst case"/ stressed conditions. INSTALLATION QUALIFICATION (qualification d'installation ): The documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed . OPERATIONAL QUALIFICATION (qualification opérationelle ): The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications. 17 Dolita Shah

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PROCESS QUALIFICATION (qualification du procédé ): The phase of validation dealing with sampling and testing at various stages of the manufacturing process to ensure that product specifications are met. PROCESS RE-VALIDATION (revalidation du procédé ): Required when there is a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricators, major equipment or premises. Failure to meet product and process specifications in sequential batches would also require process re-validation. PROCESS VALIDATION (validation du procédé ): Establishing documented evidence with a high degree of assurance, that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics. Process validation may take the form of Prospective, Concurrent or Retrospective Validation and Process Qualification or Re-validation. 18 Dolita Shah

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PROSPECTIVE VALIDATION (validation prospective): Conducted prior to the distribution of either a new product or a product made under a modified production process, where the modifications are significant and may affect the product’s characteristics. It is a pre-planned scientific approach and includes the initial stages of formulation development, process development, setting of process specifications,developing in-process tests, sampling plans, designing of batch records, defining raw material specifications, completion of pilot runs, transfer of technology from scale-up batches to commercial size batches, listing major process equipment and environmental controls. RETROSPECTIVE VALIDATION (validation rétrospective): Conducted for a product already being marketed, and is based on extensive data accumulated over several lots and over time. Retrospective Validation may be used for older products which were not validated by the fabricator at the time that they were first marketed, and which are now to be validated to conform to the requirements of Division 2, PartC of the Regulations to the Food and Drugs Act. 19 Dolita Shah

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VALIDATION (validation): The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment. VALIDATION MASTER PLAN (plan maître de validation): An approved written plan of objectives and actions stating how and when a company will achieve compliance with the GMP requirements regarding validation . VALIDATION PROTOCOL ( protocole de validation): A written plan of actions stating how process validation will be conducted; it will specify who will conduct the various tasks and define testing parameters; sampling plans, testing methods and specifications; will specify product characteristics, and equipment to be used. It must specify the minimum number of batches to be used for validation studies; it must specify the acceptance criteria and who will sign/approve/ disapprove the conclusions derived from such a scientific study . VALIDATION TEAM ( équipe de validation): A multi-disciplinary team of personnel primarily 20 Dolita Shah

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21 Dolita Shah

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Dolita Shah 22 Installation Qualification (I.Q) Operational Qualification (OQ) Performance Qualification (PQ) and protocol approval Calibration Operator Training Data Analysis Validation Report and Conclusion Approval of conclusion Prospective process Validation

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The activities relating to validation studies may be classified into three phases : Phase 1 : Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, Equipment Qualification, Installation Qualification, master production documents, Operational Qualification, Process Capability. Phase 2: Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the “worst case” conditions. 23 Dolita Shah

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Phase 3 : Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modification to the production process, and that all SOPs have been followed, including Change Control procedures. 24 Dolita Shah

Validation protocol:

Validation protocol This document provides guidance on issues and topics related to systems, equipment qualification, product and process validation for sterile and non-sterile dosage forms . These topics reflect an area in pharmaceutical, biological, and, radiopharmaceuticals manufacture that is noted as being important by both the Inspectorate and the pharmaceutical industry . A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. 25 Dolita Shah

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This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested. The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol should list the selected process and control parameters, state the number of batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. The date of approval by the validation team should also be noted. In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a change must be documented. 26 Dolita Shah

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The validation protocol should be numbered, signed and dated, and should contain as a minimum the following information: objectives, scope of coverage of the validation study validation team membership, their qualifications and responsibilities Type of validation: prospective, concurrent, retrospective, re-validation N umber and selection of batches to be on the validation study a list of all equipment to be used; their normal and worst case operating parameters outcome of IQ, OQ for critical equipment requirements for calibration of all measuring devices critical process parameters and their respective tolerances description of the processing steps: copy of the master documents for the product sampling points, stages of sampling, methods of sampling, sampling plans statistical tools to be used in the analysis of data 27 Dolita Shah

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Training requirements for the processing operators validated test methods to be used in in-process testing and for the finished product specifications for raw and packaging materials and test methods forms and charts to be used for documenting results format for presentation of results, documenting conclusions and for approval of study results. 28 Dolita Shah

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Validation Master Plan A validation master plan is a document that summarises the company’s overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management. Validation in general requires meticulous preparation and careful planning of the various steps in the process. In addition, all work should be carried out in a structured way according to formally authorised standard operating procedures. 29 Dolita Shah

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All observations must be documented and where possible must be recorded as actual numerical results. The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations,relevant to product and process controls within a firm should be included in the validation master plan . It should comprise all prospective, concurrent and retrospective validations as well as re-validation . The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOP’s and validation protocols and reports 30 Dolita Shah

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The format and content should include: introduction: validation policy, scope, location and schedule organizational structure: personnel responsibilities plant/ process /product description: rational for inclusions or exclusions and extent of validation specific process considerations that are critical and those requiring extra attention list of products/ processes/ systems to be validated, summarized in a matrix format, validation approach re-validation activities, actual status and future planning key acceptance criteria documentation format reference to the required SOP’s time plans of each validation project and sub-project . 31 Dolita Shah

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Installation and Operational Qualification The detail and scope of a qualification exercise is in many respects related to the complexity of the equipment involved and the critical nature of that equipment with respect to the quality of the final product. Installation and Operational Qualification exercises assure through appropriate performance tests. The basic principles are: equipment be correctly installed in accordance with an installation plan requirements for calibration, maintenance and cleaning be covered in approved SOP’s tests be conducted to assure that equipment is operating correctly, under normal and “worst case”conditions operator training requirements pertaining to new equipment be conducted and documented. At various stages in a validation exercise there is need for protocols, documentation, procedures, equipment, specifications and acceptance criteria for test results. All these need to be reviewed, checked and authorised . It would be expected that representatives from the appropriate professional disciplines, eg . Engineering , Research and Development, Manufacturing, Quality Control and Quality Assurance be actively involved in these undertakings with the final authorisation given 32 Dolita Shah

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Installation Qualification (IQ ): I.Q. is the method of establishing with confidence that all major processing, packaging equipment and ancillary systems are in conformance with installation specifications, equipment manuals, schematics and engineering drawings. This stage of validation includes examination of equipment design, determination of calibration, maintenance and adjustment requirements. For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a predelivery check of the equipment at the supplier’s assembly facility. This pre-delivery check cannot substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and documented at this stage may duplicate a number of the checks conducted at the I.Q. stage, thus leading to a reduction in the scope of the I.Q. checks. All equipment, gauges and services should be adequately identified and should be given a serial number or other reference number. This number should appear in the reports for the equipment validation studies 33 Dolita Shah

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Installation qualification requires a formal and systematic check of all installed equipment against the equipment supplier’s specifications and additional criteria identified by the user as part of the purchase specifications. These checks, tests and challenges should be repeated a significant number of times to assure reliable and meaningful results. At the I.Q. stage the company should document preventive maintenance requirements for installed equipment. The preventive maintenance schedule should be incorporated into the routine maintenance schedule. 34 Dolita Shah

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Operational Qualification (OQ ): The conduct of an Operational Qualification should follow an authorised protocol. The critical operating parameters for the equipment and systems should be identified at the O.Q. stage. The plans for the O.Q.should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met. Studies on the critical variables should include a condition or a set of conditions encompassing upper and lower processing and operating limits referred to as “worst-case” conditions. The completion of a successful O.Q. should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment. The completion of satisfactory I.Q. and O.Q. exercises should permit a formal “release” of the equipment 35 Dolita Shah

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The completion of satisfactory I.Q. and O.Q. exercises should permit a formal “release” of the equipment for the next stage in the process validation exercise as long as calibration, cleaning, preventive maintenance and operator training requirements have been finalised and documented. Re-Qualification: Modifications to, or relocation of equipment should follow satisfactory review and authorization of the documented change proposal through the change control procedure. This formal review should include consideration of re-qualification of the equipment. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system of the preventative maintenance progress. 36 Dolita Shah

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Process Validation: It would normally be expected that process validation be completed prior to the distribution of a finished product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary to validate processes during routine production (Concurrent Validation). Processes which have been in use for some time without any significant changes may also be validated according to an approved protocol (Retrospective Validation). 37 Dolita Shah

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Change Control: Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment, processing site, method of production or testing or any other change that may affect product quality or support system operations. All changes must be formally requested, documented and accepted by the Validation Team. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be determined. 38 Dolita Shah

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Commitment of the company to control all changes to premises, supporting utilities, systems, materials,equipment and processes used in the fabrication/packaging of pharmaceutical dosage forms is essential to ensure a continued validation status of the systems concerned. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised . Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the Validation Team. The Team should decide if a re-validation must be conducted prior to implementing the proposed change. 39 Dolita Shah

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Thank you………………. for your attention 40 Dolita Shah

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