intoduction of validation in pharmaceutical

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A SEMINAR ON INTRODUCTION OF PHARMACEUTICAL VALIDATION Prepared By: Guided by : Pooja R. Savaliya Dr. Rina H. Gokani M.Pharm Sem. III Associate professor Q.A. department S.J.Thakkar College Of Pharmacy Opp. NRI Bungalows , Rajkot. \ “ Education is the Chief Defense of the Nation” Monday, September 05, 2011 9/5/2011 9/5/2011 QA department,sjtpc,rajkot . 2

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Validation is an essential part of good manufacturing practices (GMP). It is an element of the quality assurance programed associated with a particular product or process. Establishing documented evidence. Provide a high degree of assurance. INTRODUCTION 9/5/2011 QA department,sjtpc,rajkot. 3

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validation defined as to establishing documented evidence that a process or system, when operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its pre-determined specifications and quality attributes. DEFINATION OF VALIDATION 9/5/2011 QA department,sjtpc,rajkot. 4

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Specificity Linearity Range Accuracy Precision Repeatability Intermediate Precision Reproducibility Limit of Detection Limit of Quantitation Robustness Validation Parameters 9/5/2011 QA department,sjtpc,rajkot. 5

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Following are the area were validation can be implied : Analytical test methods, Instrument calibration, Process utility services, Raw materials, Packaging materials, Facilities , Manufacturing, Product design, Cleaning and Operators. SCOPE OF VALIDATION 9/5/2011 QA department,sjtpc,rajkot. 6

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VALIDATION PRINCIPLES The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. In order to meet this principle, a good understanding of the processes and their performance is important . Quality should be built into the manufacturing processes . Careful design and validation of system and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications. 9/5/2011 QA department,sjtpc,rajkot. 7

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Increased throughput Reduction in rejections and reworks Reduction in utility costs Avoidance of capital expenditures Fewer complaints about process related failures Reduced testing in process and finished goods More rapid and accurate investigations into process deviations More rapid and reliable start-up of new equipment Easier scale-up from development work Easier maintenance of the equipment Improved employee awareness of processes More rapid automation Benefits of validation 9/5/2011 QA department,sjtpc,rajkot. 8

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V MODEL CONCEPT Universally accepted model popularly known as V model The left arm of the V always deals with defining the requirement and detailing the change and the right arm of the V ensure that for each item in the left arm, There is a corresponding activity which verifies that the change done is as per the requirement, design etc . 9/5/2011 QA department,sjtpc,rajkot . 9

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Figure 2: Validation Process (adapted from the typical V-Model 9/5/2011 QA department,sjtpc,rajkot. 10

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Validation activity is not the responsibility of any one single department in an organization. The organization must have a group of people pulled from various department and convert It into a good homogenous team. The team member may be taken from research and development. Any one person who has a basic understanding of validation and capability and maturity of a manager should head this team. A clear communication system should be developed amongst the team member and the other members of the organization The validation activity is a highly challenging and each member of the team has to accept this challenge. Organization for validation 9/5/2011 QA department,sjtpc,rajkot. 11

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The Validation Master Plan is a document that describes how the validation program will be executed in a facility. I t is the document that outlines the principles involved in the qualification of a facility, defines the areas and systems to be validated . provide the format required for each particular validation document (IQ, OQ, PQ for EQ and systems; process validation, analytical assay validation) VALIDATION MASTER PLAN (VMP) 9/5/2011 QA department,sjtpc,rajkot. 12

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indicate what information is to be contained within each document. indicate why and when revalidations will be performed. who will decide what validations will be performed. order in which each part of the facility is validated . indicate how to deal with any deviations. state the time interval permitted between each validation. VALIDATION MASTER PLAN (VMP) 9/5/2011 QA department,sjtpc,rajkot. 13

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VMP should reflect the key elements of the validation programmed. It should be concise and clear and contain at least the following A Validation policy O rganizational structure of validation activities. summary of facilities, systems, equipment and processes validated and to be validated documentation format (e.g. protocol and report format) planning and scheduling, change control. References to existing documents . 9/5/2011 QA department,sjtpc,rajkot. 14

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The VMP describes clearly and concisely the company’s philosophy, expectations and approach to be followed.. Identifies the systems and controls to be validated. The level of testing required. Covers all aspects of the project as equipment qualification. Developed in the early stages of a production. Object and allow a logical progression from plan to validation schedule. The VMP can also assist in monitoring and tracking the progress of the project by performing periodic audit reviews v/s the approved version of the VMP. Importance of the VMP: 9/5/2011 QA department,sjtpc,rajkot. 15

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It provides the total pictures of the project. It is a management tool for tracking progress. Assignment of responsibility, which promote team work. It identifies acceptance criteria before the start of validation . Benefits of VMP: 9/5/2011 QA department,sjtpc,rajkot. 16

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Cover page ( approvals) Scope of project (which process being validated) Objectives / backgrounds Description Installation qualification (IQ), Operational qualification (OQ), Performance qualification ( PQ) Role and responsibilities. SOP’s requirement. Process monitoring . Format for validation protocol : 9/5/2011 QA department,sjtpc,rajkot. 17

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Acceptance criteria /test methods . Deliverables. Documentation requirement Additional information- -A flow chart of the process -Sampling methods to be used -In process samples to be collected and details of collection -Testing to be conducted on samples collected -Sample size ,type of container, and swab techniques -Tools and precautions 9/5/2011 QA department,sjtpc,rajkot. 18

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9/5/2011 QA department,sjtpc,rajkot. 19 Type of validation The field of validation is divided into a number of subsections including the following: Cleaning Validation Process Validation Analytical Method Validation Computer System Validation

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“Process validation is defined as the collection and evaluation of data , from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.” PROCESS VALIDATION 9/5/2011 QA department,sjtpc,rajkot. 20

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Process validation decision TREE 9/5/2011 QA department,sjtpc,rajkot. 21

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type of the process validation There are four type of the process validation: Prospective process validation (also called premarket validation), II. Retrospective process validation, III. Concurrent validation and Revalidation 9/5/2011 QA department,sjtpc,rajkot. 22

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In prospective process validation , validation protocol is executed. Before the process is put into commercial use. Generate validation support data. I ntroduction of new drug products and their manufacturing processes . The formalized process validation program should undertaken after some operations and procedures have been completed satisfactorily I ) Prospective Process Validation 9/5/2011 QA department,sjtpc,rajkot. 23

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The retrospective validation option is chosen for established products whose manufacturing processes are considered stable and when on the basis of economic considerations alone and resource limitations, prospective validation programs cannot be justified . Using either data-based computer systems or manual methods, retrospective validation may be conducted in manner. II ) Retrospective validation 9/5/2011 QA department,sjtpc,rajkot. 24

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In-process monitoring of critical processing steps and end-product testing of current production can provide documented evidence to show that the manufacturing process is in a state of control . Concurrent validation may be the practical approach under certain circumstances. The systems and equipment to be used have been fully validated previously. The justification for conducting concurrent validation must be documented and the protocol must be approved by the Validation Team . III ) Concurrent validation: 9/5/2011 QA department,sjtpc,rajkot. 25

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Almost all GMP texts recommend that whenever there are significant changes in the facility, equipment or process, revalidation should be carried out . In following Conditions revalidation should be carried out: Change in a critical component Change or replacement in a critical piece of modular equipment Change in a facility and/or plant Significant increase or decrease in batch size Sequential batches that fail to meet product and process specifications . IV ) Revalidation 9/5/2011 QA department,sjtpc,rajkot. 26

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Clearly defined procedures are required in order to control any changes in the production processes. These procedures should control all the planned changes and ensure the presence of sufficient supporting data that show that modified process will result in a product of the desired quality. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorized. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the Validation. Change control 9/5/2011 QA department,sjtpc,rajkot. 27

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There are two basic approaches to validation Prospective and concurrent validation Retrospective validation APPROACHES TO VALIDATION 9/5/2011 QA department,sjtpc,rajkot. 28

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Qualification define as Action of proving and documenting that any premises, systems and equipment are properly installed, and/or work correctly and lead to the expected results. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation . There is five type of Qualification. Qualification: 9/5/2011 QA department,sjtpc,rajkot. 29

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Defines the functional and operation specification of the instrument , program, or equipment and details the rationale for choosing the supplier DQ should ensure that instruments have all the necessary functions and performance criteria that will enable them to be successfully implemented for the intended application and to meet user requirements. Design Qualification (DQ ) 9/5/2011 QA department,sjtpc,rajkot. 30

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D Q considerations include: Description of the analysis problem. Description of the intended use for the equipment. Description of the intended environment. Preliminary selection of the functional and performance specification (technical , environmental, safety ). Preliminary selection of the supplier. Final selection of the supplier and equipment. Development and documentation of final functional and operational specifications. 9/5/2011 QA department,sjtpc,rajkot. 31

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Written for critical processing EQ and systems list all the identification information, location, utility requirements, and any safety features of EQ verify that the item matches the purchase specifications II Installation qualification (IQ): 9/5/2011 QA department,sjtpc,rajkot. 32

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Equipment design features Installation conditions Calibration, preventative maintenance, cleaning schedules Safety features Supplier documentation, prints, drawings and manuals Software documentation Spare parts list Environmental conditions Important IQ considerations are: 9/5/2011 QA department,sjtpc,rajkot. 33

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F ollow an authorized protocol. The critical operating parameters for the equipment and systems should be identified at the OQ stage. The plans for the OQ 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 . pH meter, incubator, centrifuge, freezer; IQ,OQ Operational Qualification (OQ) 9/5/2011 QA department,sjtpc,rajkot. 34

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Process control limits Software parameters Raw material specifications Process operating procedures Material handling requirements Process change control Training Short term stability and capability of the process OQ considerations include: 9/5/2011 QA department,sjtpc,rajkot. 35

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In this phase the key objective is to demonstrate the process will consistently produce acceptable product under normal operating conditions. PQ considerations include: Actual product and process parameters and procedures established in OQ Acceptability of the product Assurance of process capability as established in OQ Process repeatability, long term process stability Performance qualification 9/5/2011 QA department,sjtpc,rajkot. 36

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Process and product data should also be analyzed to identify any variation due to controllable causes. Depending on the nature of the process and its sensitivity, controllable causes of variation may include: Temperature Humidity Variations in electrical supply Vibration 9/5/2011 QA department,sjtpc,rajkot. 37

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Environmental contaminants Purity of process water Light Human factors (training, ergonomic factors, stress, etc.) Variability of materials system: air (HVAC), compressed air, pure steam, raw steam, purified water, WFI, central vacuum; IQ, OQ, PQ EQ: autoclave, oven, lyophilizer, continuous flow centrifuge; IQ, OQ, PQ 9/5/2011 QA department,sjtpc,rajkot. 38

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CQ is a relatively new term developed in 2005. This term refers to the manufacturing of auxiliary components to ensure that they are manufactured to the correct design criteria. CQ considerations include: packaging components such as folding cartons , shipping cases, labels or even phase change material . Component qualification (CQ) 9/5/2011 QA department,sjtpc,rajkot. 39

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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 program. 9/5/2011 QA department,sjtpc,rajkot. 40

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PHASES OF VALDATION The activities relating to validation studies are classified into three phases. Phase 1: Pre-validation phase or the qualification phase, which covers all activities relating to product research and development Phase 2: Process validation phase (process qualification phase ) designed to verify that all. Phase 3: Validation maintenance phase requiring frequent review of all process related documents . 9/5/2011 QA department,sjtpc,rajkot. 41

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“ Establishing documented evidence, which provide a high degree of assurance that a specific process will consistently produce a product meeting with its pre-determined specifications and quality characteristics ”. Good validation documentation A way to minimize mistakes and variables. Compliance to GMP requirement and ensure reproducibility On FDA validation documentation 9/5/2011 QA department,sjtpc,rajkot. 42

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The main components of the report are as follows Cover page. Over view. Product name. Description of the process being validated. Location. Number of batches being validated. Validation reports: 9/5/2011 QA department,sjtpc,rajkot. 43

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It is clear from the above that it is necessary to perform process validation in drug manufacturing, not only because it is a regulatory requirement but also because it makes good technical and economic sense. However , the way validation is currently performed in industry involves a lot of variability, and is thus not optimal. There is potential for improvement in terms of the effciency , quality and cost effectiveness of the activity. Conclusion 9/5/2011 QA department,sjtpc,rajkot. 44

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“ FDA ”, “Current Good Manufacturing Practices; Proposed Amendment of Certain Requirements for Finished Products: Supplementary Information,” Federal Register 61(87 ), p. 20104 (3 May 1996 ). 2. “GUIDANCE FOR INDUSTRY: PROCESS VALIDATION”: General Principles and Practices . U.S. Department of Health and Human Services, Food and Drug Administration , Center for Drug Evaluation and Research , Center for Biologics Evaluation and Research , Center for Veterinary Medicine (CVM), November 2008. 3. “Robert A .Nash, Alfred H. Wachter”, “Pharmaceutical Process Validation”, Vol.129, Third Edition, Marcel Dekker, Inc, New York, 2003. 4 “James Agalloco, Frederick J. Carleton”, “Validation of Pharmaceutical Processes”, Third Edition, Informa Healthcare USA, Inc., New York, 2008. cGMPC CURRENT GOOD MANUFACTURING PRACTICES for pharmaceuticals M.A . Patodar; Pharmamed Press, Hydrabad .,p.413(1985) reference 9/5/2011 QA department,sjtpc,rajkot. 45

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