Validation of Pharmaceutical Manufacturing Process Focus: APIs.

Transcription

1 Validation of Pharmaceutical Manufacturing Process Focus: APIs

2 Validations: Regulatory History (US FDA) Sterilisation 1977 Aseptic processing 1979 Water Systems 1981 Non-sterile Mfg Process 1987 Revised PV Guidance 2011 (Jan)

3 Validation Quality tool to establish, High degree of assurance Consistency Documented proof Built-in Quality

4 Validation : Definitions WHO: Establishment of Documented Evidence that a Systemdoes whatitissupposedtodo US FDA: Process of Establishing Documented Evidence to Demonstrate with High Degree of Confidence That a System Performs Consistently as per Design. ICH Q7: Section 12

5 Benefits Of Validation Reduction in Failures - Less reprocessing Reduction in Costs -Less modifications (utilities) Reduced Testing Better documentation for future review Regulatory Compliance

6 Process Validation 1987: To Demonstrate with Documented Evidence that a Specific Manufacturing Process is Capable of Performing in a Reliable and Consistent Manner to Deliver a Homogenous Product Meeting Defined Quality Attributes Consistently. Jan 2011: 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.

7 Basis for Current Strategy for PV Thorough understanding of the process (from Process development to Plant scale) Understand the source of variation at every stage Detect the presence & degree of variation Impact of variation on Process & Product Control of variation based on Risk Analysis

8 Finished Dosage Form v/s API S Physical Processing - Complex chemistry Drying, Homogenizing - Chemical synthesis, Blending etc. Extraction, Distillation, Crystallisation, etc. No purification - Involves purification No by products - By products likely Degradation products - Degradation products more likely No flexibility in API Some flexibility in RM charges possible and solvent charges Batch Homogeneity Homogenity more robust

9 Sequence to Validation Process Development (Lab scale) Experimental Batches ( Pilot ) Validation of Sub-Systems (Analytical methods, Lab instruments; Equipment Qualification, Utility Qualification) Process Sale up (Experimental Plant Batches) Plant Validation batches

10 Focusing on Process Qualification efforts without understanding the Manufacturing Process may not lead to adequate assurance of Quality Stages of Process Validation : Process Validation: Current Perspective 1. Process Design: - Lab trials; Pilot plat trials 2. Process Qualification: - a. Facility, Equipment/ Utility Qualfn. b. Process Performance Qualification 3. Continued Process Verification: After commercial release

11 Process Validation: Current Perspective Stages of Process Validation :

12 Process Design Stage A thorough process development work in lab and pilot plant/ process knowledge is the basis for a successful Process Validation. - Critical raw materials / intermediates - Impurities, its origin, detection & control - Critical steps & Control parameters - Impact of deviations from critical parameters - Contingency plans (in case of deviations!) - Batch Parking & storage life of intermediates - Process Optimization

13 Stage -2 : Process Qualification a. Facility /Equipment / Utility qualification b. Process Performance qualification

14 Process Qualification : Sequencing Process Qualification Equipment Test Method Cleaning Water System AHU Qualification validation validation validation Qualfn (IQ, OQ, PQ) (In-process (Reactor Impurities Granulator Intermediate) Drier Sampling Qualification Qualification Blender) method ( IQ, OQ) (IQ, OQ) Instrument Validation DQ DQ Qualification of detection (IQ,OQ) method

15 Validation Master Plan Overview of entire validation project Validation policy Responsibilities for key activities Equipments/ Utilities qualification Systems/ processes to be validated Validation sequence and planning schedules Validation protocols& responsibility Revalidation requirements

16 Validation Approach Multi Functional activity Team approach (ex: R&D, Prdn, Maint, QC, QA) QA Co-ordination Protocol Driven (Planning)

17 Qualification Ensure Critical equipments, Utilities and instruments are qualified/ calibrated. i.e. Fit for the Purpose.

18 Process Qualification: b. Process Performance Qualification(PPQ) - Must be completed before commercial dispatch - Process parameters fixed based on knowledge in all stages so far. - Effects of scale up on Process parameters - Carried out under normal operating conditions - Driven by approved protocol - Concurrent to be addressed in protocol

19 Satge 3: Continued Process Verification - Continue monitoring batches to verify state of control -Same level of sampling and testing as stage 2. - Systems to capture & evaluate unplanned deviations - Statistical tools to evaluate variations: - Product quality - Input quality (RMs) - Process control parameters (Intra and Inter batch)

20 Types of validation (ref: ICH Q7A) Prospective : Prior to Market Dispatch Concurrent : Release before completing PPQ or deviation during Regular Production Retrospective : Data Analysis from Previous Batches

21 Prospective Validation Prior to commercial dispatch Three consecutive batches minimum Batches failing due to reasons unrelated to process to be removed & fresh batch included Validation Protocol

22 Concurrent Validation Concurrent validation is carried out, when: Only limited number of batches possible Changes in existing validated process Deviation in critical parameter in a validated batch Based on extensive in-process, finished product Analysis and process monitoring.

23 Retrospective Validation Process well established Sufficient data available System and records in place Analyses of data from identical batches Revalidation: - After Significant Change - Periodic Review

24 Which Stages need to be validated?

25 Validation - Multiple stage Process Which Stages need to be validated? KSM Crude API API A B C D E Considerations: 1. Quality - Final Stage & N-1 Stage - Impurity Control - Complexity of process (ex: Hydrogenation, Grignard reaction) - Complexity of operation (ex: Bromination, Phase transfer reactions) 2. Safety 3. Cost / Yield 4. Risk Analysis Approach

26 Methodology 1. Define API quality: Chemical purity / Assay Physical attributes (ex: Particle size, Bulk density) Impurity Profile Batch Homogeneity Residual solvents Microbiological purity - Define Alert and Action limits

27 Define Process:- Methodology Methodology.Continued Reaction Scheme Description of process Flow chart Batch production instructions Key equipments Batch size

28 Define RM Quality Focus on KSM and critical RMs Specifications & Test methods (validated) Avoid or Justify changes in Supplier of KSM & Critical RMs Solvents: Fresh / Recovered? Ensure that KSM & all Critical raw materials conform to specifications

29 Define Responsibilities Identify Team - Multifunctional Responsibilities : - Monitoring Critical parameters - Sampling & Analysis - Data Collection & Report Ensure that Personnel are trained in Critical Operations.

30 In-process Controls In-process specifications Sampling (more extensive than routine, if required ) Ex: Extraction Layers, Centrifuge cake washings, Driers, Micronisation...etc) Test methods (validated) Acceptance limits

31 Critical Process Steps / Parameters Process steps which are critical to product quality, yield and safety. Process parameters having Impact on product quality Based on scientific judgment or lab / pilot trials, Past experience. Ensure that critical steps are supervised

32 Examples for Critical Steps: Critical Steps / Parameters (.continued) Phase changes: Extraction, Washings, Crystallisation etc. Chemical Rxn: - Formation of Drug molecule / Key intermediate - Key Impurity Formation / Removal - Protection from moisture / Air - Exothermic Reactions - Addition of Catalysts - Vacuum distillation Physical change: Drying Distilling Blending (Colour, degradation etc.) (Quality of fractions) (Homogeneity)

33 Critical Steps / Parameters (..continued) Examples for Critical Parameters: Parameter Impact of Deviation Reaction time - Incomplete reactions Rate of addition - Side product, Exotherms etc. Reaction temperature - Exotherms, degradations Reaction Pressure - Incomplete Rxn, Safety etc Cake washings in - Impurity not removed centrifuge / Nutche Drying temp, time - Degradation, colouring..etc.

34 Concurrent Validation When? 1. Limited batches only possible 2. During regular production due to changes 3. Deviations in critical Parameters Should be limited to exceptional cases

35 Training: Operators must know critical steps / parameters Identify any special training needs

36 Acceptance Criteria Criteria for Validation to be Successful: CriticalQuality Attributes (Assay, Impurity, Particle size etc.) Yield / Efficiency Critical Process Parameters In-Process Test Results

37 Implementation of Validation Identify validation team Approve protocol Execute & Monitor Closely Record relevant data Evaluate Data Validation Report

38 Evaluation of Validation Data Evaluate deviations; Assignable causes Statistical Tools: Trend analysis - Critical process parameters - In-process results - Yields Control / Alert limits Process Capability Analysis (Cp& Cpk values)

39 Format for Validation Protocol 1. Purpose & Scope 2. Type of Validation & Justification 3. Responsibilities 4. Batch Selection Criteria 5. Process description / Master formula/ flow chart 6. Batch Manufacturing Instructions 7. Key equipments, reference to qualification 8. Quality of critical raw materials

40 Format for Validation Protocol 9. Critical Steps & Process parameters, Justification 10. Acceptance Criteria 11. Format for validation report 12. Revalidation requirement 13. Approval by concerned authority & QA

41 Recycles & Recovery Issues Recycling of extraction layers Recycling of M/L s from centrifuge / Nutsche wash Second crops Reprocessed / Reworked batches Acceptable if, Quality as good as API from regular batch (colour, impurity, stability etc) Consistent Standardised and validated Traceability in records maintained

42 Recycle & Recovery Issues Validation Issues: - Standardise in-put of recycles to each batch - Monitor the input (Quality, Impurity) - Standardise BMR and Validate -Monitor build up of impurities over repeated recycles - Fix Process Cycles for recycling

43 Process Capability