modern paharmaceutics ich guidelives for .pptx

ich guidelines

1. Modern Pharmaceutics VALIDATION

2. ICH guidelines Q8 (R2): Pharmaceutical Development   Q9 : Quality Risk Management   Q10 : Pharmaceutical Quality System

3. Definition Validation is a structured approach for translating user requirements, design specification and quality aspirations into a manufacturing facility

4. Discovery New opportunity Early development stage Screening of the opportunity Manufacture small quantity for trials Late development phase Design of a scalable process Optimal productivity Safe and environment friendly Manufacturability Implementation of a robust manufacturing process manufacturing

5. PDF (Process design qualification) To ensure that engineering rigor and quality are built into the design philosophy Master validation plan (MVP) To ensure that the rigorous design philosophy is executed and implemented

6. PDF: An organized effort to integrate various aspects of process development into holistic final design ensuring appropriate rigor and quality is built into design philosophy MVP: A structured effort to execute and implement the design philosophy

7. Process design finalization team Assemble PDF team Rigorously design the process design prior to implementation Process integration Integrate the process stages Process simplifications Reduce number of process stages and material handling Process flow description Put the pieces together Risk Analysis(FMEA) Analyze and mitigate the risks Modeling Capture knowledge for capacity and knowledge improvement Process optimization Improve the process, enhancing the economic viability User requirement specifications (URS) Clearly communicate design specifications

8. Process design finalization team : Formation of a PDF team to integrate a diverse work force(Diff departments) with a common objective of successfully launching the product Process integration Process integration is integration of various stages of infrastructure into manufacturing facility Process simplification The process simplification is done in terms of robustness, safety,cost , efficiency, capacity and ease of operation

9. Process flow description It’s a systematic way of capturing manufacturing the process information Process flow chart/ equipment flow chart, unit operations for the manufacturing process Quality control strategies required to run a process with its specifications A narrative of the process

10. Risk Management It’s the risk based decision making process based on risk analysis, risk mitigation, control strategy and awareness Risk identification Risk analysis Risk mitigation Periodic review Unacceptable risk Acceptable risk

11. Failure mode and effective analysis Its an engineering technique to define, identify, eliminate known and potential failures, problems, errors, and so on from design, process, and / or service before they reach customer

12. System, design, process and service

13. Risk Management HAZOP ( For identifying the risk for health, safety and environment) Fault tree and event tree (Risk identification) FMEA (Risk management methodology) QBD & VFD (Customer requiremets ) HACCP (For determining severity rating for contamination)

14. HAZOPS It’s a structured brain storming exercise in which multidisciplinary team of experts systematically considers each piece of equipment in the plant defining its intentions to identify the possible deviations from intentions FMECA It’s a stepwise step procedure for identifying the failure modes or design weakness and criticality of the consequence of the failure for a particular system under consideration

15. Fault tree analysis it depicts the way in which a particular system failure might occur (Cause) working downwards through the branches using and /or logic gates, analysis reveals the combination of the events themselves cause the top event to occur Event tree analysis it represents the consequences

16. Hazards analysis and critical control points (HACCP) It provides documentation to ensure that company understands its product and process well enough to control or monitor the parameters that are important to produce quality products Analyze each step hazards Identify all control points (CCP S ) Verify the limits for each CCP Verify monitoring and testing of limits verify corrective actions Verify operational procedures for CCPs Verify records of each CCPs are documented in the batch record

17. QFD It provides a systematic approach to determine, prioritize and translate customer’s need to product design parameters, which arranges the facts so that important issues, relationship among these issues, significance of each and their measures of success can be readily displayed VFD This focus on value

18. Modeling

19. URS URS is a documentation of design intentions and sets the functional requirements; requirements for product quality and business drive it include all stake holders system of performance requirements such as operations, maintenance, environment, health, safety, engineering, validation , QC, and automation URS will form the basis for system for equipment operational qualification and performance qualification (PQ)

20. User requirement Design intentions System classification Direct vs Indirect impact Physical completion Construction Commissioning Qualification Direct impact critical system qualified Validation Manufacturability Functional system VMP

21. Direct impact critical component Direct impact Noncritical component Indirect impact Critical component Direct impact Noncritical component COMPONENTS Indirect or direct

22. Commissioning Commissioning is the startup activities, typically occurs between construction, physical completion and turn over to either operations end users or validation team Start up activities: FAT, functional test, SAT etc The tests performed during commissioning should be designed to provide assurance that the system has constructed and will perform to the intended design criteria; Both functional and performance tests

23. A validation plan is a comprehensive document describing applicable validation requirements for the facility and providing plan for meeting those requirements FDA Definition Establishing a documented evidence that provides high degree of assurance that the specific process will consistently produce product meeting its predetermined specifications and quality attributes As per regulatory agencies the quality attributes of the product to be identified After CPP, the companies must perform the studies to test the parameter ranges; operating and validated

24. The operating range is the range in which the product is manufactured- narrowest Validated range :falls outside of operating range and is the range in which the process will still perform adequately Once CPP is determined, the critical product or operating parameters ( time , tem , pressure, pH) to be controlled and monitored during process validation studies

25. VMP A list of all studies that will validate manufacturing process the question of what and how to validate a manufacturing process

26. VMP Design qualification Installation qualification Operational qualification Performance qualification Process validation Cleaning validation Computer validation Analytical validation Validation report Monitoring , maintenance , change control Revalidation

27. Design qualifications Also called as equipment qualification Documentation of design aspects checked and approved Design aspects contains a plant description and shows that plant design agrees with customer design specifications The scale up exercise leads to equipment specification for the manufacturing process The equipment and process flow are captured process flow chart ; summary of manufacturing process and equipment requirements These requirements are specified and documented in URS; forms the basis of qualification stage

28. Objectives of DQ To built quality into design To assure that the design is consistent with development and scale up activity in the preceding stages of commercialization as specified in the URS The quality aspects of DQ include cGMP The documentation audit will include review of development history, URS, training plan, SOPS, engineering and relevant facility Reviews by design and process engineers, scientists, QA& QC, operating personnel

29. Installation qualification (IQ ) The focus of IQ is to ensure that equipment is installed as intended in the design and in accordance with Vendor’s recommendations This includes system completion, security or utility connections, documentation, inventory, equipment inventory, electrical requirements, material qualifications, drawing validation, main equipment features, instrument calibration , spares and maintenance Installation qualification process, written evidence is given that all parts of equipment is installed according to the equipment supplier and purchase specifications

30. It includes FAT, It documents that operating criteria for equipment is installed, and in compliance with process and installation diagram, (P& I), plant functional specifications and process flow diagrams IQ is the stage where the completeness and correctness of all requirements are checked

31. Operational qualification OQ provides the assurance that equipment operates as intended throughout the anticipated operating ranges This involves testing of equipment during operations using non product materials such as air and water In OQ the documented evidence shows that all parts of plant and equipment work within its specifications Process parameters are within the acceptable criteria PLC (Programmable logic control ) will be qualified during OQ process Computerized process controls should be qualified in CV A simulation of normal production conditions must be done to ensure that OQ are successful

32. Performance qualification (PQ) PQ is the evaluation of overall equipment to confirm the system operates throughout anticipated ranges as intended PQ is performed close to production conditions as possible and performed without the real product The documentation of PQ includes approved protocol, system description , purpose, sampling regimen, testing regime, acceptance criteria, deviation and corrective action PQ provides documented evidence that all parts of the plant and process validated can operate as intended in the design

33. PQ includes critical variable studies ; simulating conditions of upper and lower processing, processing at the operating limits of equipment, circumstances, and worst case conditions It should show that such conditions do not necessary induce process or product failure OQ: all parts of the plant and equipment are qualified separately PQ: qualify the entire plant with respect to production process ALL SOPS to be approved Values of critical and noncritical parameters to be recorded

34. Process validation Check list of validation and control documentation in respect to cGMP Introduction Organization – establishment of facility installation and qualification Buildings and facilities- plant and facility installation and qualification ,maintenance and sanitization, microbial and pest controls, Equipmen t :installation qualification and cleaning methods Control of raw materials, in process and product : incoming components, manufacturing nonsterile products Production and process controls : process control systems , instrumentation and computers Packaging and labeling controls : de pyrogenation sterile packing filling and closing Holding and documentation: facilities Laboratory controls :analytical methods Records and reports : computer systems Returned and salvaged drug product : batch processing: water treatment and steam systems, A ir and water quality : water treatment, air heat and vacuum handling Sterilization: LVPS, , autoclaves and process, parameters , aseptic facilities, devices, sterilizing filters

35. Objectives Good engineering sense Fewer product recalls and trouble shooting assignments in manufacturing operations Technically and economically sound products

36. Key stages of a product and process development sequence

37. Pilot plant scale up Development laboratory Pilot plant Production Development laboratory Pilot batch request Pilot batch complete report Production

38. New product development and pilot plant scale up

39. Pilot plant scale up and process validation Development activities Formulation design, selection and optimization Preparation of first pilot lab batch Conduct of initial accelerated stability testing If the formulation is found to be stable, additional pilot batch for expanded non clinical use Pilot plant scale up program is the scale up operations conducted subsequent to the product and process leaving the development laboratory an prior to its acceptance by the full production manufacturing unit

40. Process validation: order priority Sterile products and their process Large volume parentrals Small volume parentrals Ophthalmic and other sterile products and medical device Non sterile products and their process Low dose / High potency tablets and capsule Drugs with stability problems Other tablets and capsules Oral liquids, topicals and diagnostic aids

41. Process validation : specific responsibilities Engineering : install qualify and certify plant, facilities equipment and support systems D evelopment : Design, optimize, qualify manufacturing process within design limits, specifications, and / or requirements ; establishing process capability information Manufacturing: operate and maintain plant, facilities, equipment, support system, and specific manufacturing process within its design limits, specifications and requirements QA: Establish approved validation protocols, conduct process validation by monitoring, sampling testing, challenging, auditing for compliance with design limits, specifications and or requirements

42. Process capability studies: These studies determine critical process parameters(CPP) or operating variables that influence process output and range of numerical data for each of these parameters results acceptable process output Determination of number and relative importance of CP The numerical data generated for each CPP are within the least statistical QC limits (plus or minus sd deviation) Process qualifications It represents to actual studies or trials conducted to show that all systems, subsystems, or unit operation of manufacturing process perform as intended that all CPP operates within the assigned control limits, such studies form the basis of process capability design and testing (OQ/PQ)

43. Basic information is obtained from (1x ) size Lab batch Formula, rationale for inert ingredient Critical specification, test methods, acceptance criteria for each raw material, Proposed specification, test methods and acceptance criteria for finished dosage form Interim stability of (1x) size lab batch Detailed operating instructions for preparing 10 x size batch Preparation of simple flow diagram of process Using flow diagram, list of process and control variables are next drawn up for each operation step in the process Determine which process variable and /or unit operations are critical with respect to product outcomes by process characterization

44. Process characterization Cause and effect or fish bone diagram Constraint analysis Pareto principle

45. Constraint analysis Previous successful experience Major processing equipment published scientific and technical literature Pareto analysis Based on 80: 20 principle

46. Process Qualification Replication of optimal or mid range values Pilot lab batch , SOPS and protocols for in processing Measures the outcomes, check within in process specification Process is continued to next step Representative finished product sample is subjected to end process testing The same process is done several times Fractional factorial design

47. Process optimization Parametric statistical design Selection of a suitable experimental design Selection of variables Performance of a set of statistically designed experiments Measurement of responses Development of a prediction polynomial equation based on statistical nad regression analysis of the experiential data Development of set of optimized requiems for the formula based on mathematical and graphical analysis of data Non parametric search methods EVOP REVOP(Random)

48. PROCESS VALIDATION OPTIONS PROSPECTIVE PROCESS VALIDATION RETROSPECTIVE PROCESS VALIDATION CONCURRENT VALIDATION REVALIDATION

49. Prospective validation In PPV, an experimental plan called as validation protocol is executed (Following the completion of qualification trials) before the process is put into commercial use This type of validation carried out in connection with introduction of a new drug product and manufacturing process

50. A formalized process validation program should never be undertaken without Facilities and equipment ( IQ) Operators and supervising personnel , who will be running validation batches have an understanding of process and its requirements The design, selection and optimization of the formula have been completed The qualification trials using (10x size) pilot batches have been completed, in which CPS, CPV been identified and provisional operational control limits for each test parameter have been provided

51. Detailed technical information on product and manufacturing process have been provided including stability Finally at least one qualification trial of a pilot production (100xsize) has been made and shows, upon scale up, there were no significant deviation from the expected performance of the process

52. Use of different lots of raw materials should be included ; API and major excipients Batches should run in succession and on different days and shifts Batches should be manufactured in the equipment and facility designed for eventual commercial production Critical PV should be set within the ranges and should not exceed upper and lower limits during process operation Output response should be within FP specification In case of failures to meet requirements of validation protocol, requalification or revalidation should be done

53. Retrospective validation Retrospective validation is chosen for established products whose manufacturing process are considered stable Economic considerations, prospective validation trails can not be established Numerical in process and end product data of historic production batches are subjected to statistical analysis Equipment facilities, subsystems used in connections with manufacturing process must be qualified and validated in conformance with cGMP requirements

54. Steps involved Gather the numerical values from completed batch record and include assay values, end product test results, and in process data Organize these data in chronological sequence, according to batch manufacturing data using a spread sheet format Include data from at least the last 20-30 manufactured batches for analysis, if less than 20, all manufactured batches in your analysis Trim the data by eliminating test results from noncritical processing steps delete all gratuitous numerical information Subject the resultant data to statistical analysis and evaluation Draw conclusion to state of control of manufacturing process based upon the analysis of retrospective validation data Issue a report of your findings

55. Solid dosage forms Individual assay results from content uniformity testing Tablet hardness values Individual thickness Tablet or capsule variation Individual capsule or tablet dissolution time (t 50%) or DT Individual tablet capsule moisture

56. Semi solid and liquid dosage form pH values Viscosity Density Color or clarity values Average particle size or distribution Unit weight variation and/ or potency values

57. Statistical methods Basic statistics (SD, tolerance limits) Analysis of variance Regression analysis Cumulative analysis Cumulative difference analysis Control charting (averages and range)

58. Concurrent validation In processing n critical processing steps and end products testing current production can provide documented evidence to show that manufacturing process is state of control

59. Revalidation Change in a critical component or raw materials Change or replacement in a critical piece of modular (capital)equipment Change in a facility and /or plant (usually)location or site Significant (usually order of magnitude)increase or decrease in batch size Sequential batches that fall to meet product or process specification

60. In process and final product testing, depends on sampling size(larger the better) Establishment of tighter ‘in house’ specifications limits that hold the product and manufacturing process to a more demanding standard will reduce the need for more sampling Applications of zero defect – Japanese quality principle; (6 sigma ) NMT 3or 4 defects/ I million units

61. Computer system validation (CSV) Software verification SV provide an objective that evidence that the design outputs of particular phase of software development cycle meet all the specified requirements for that phase consistency, completeness and correctness of the software and supporting documentation that and provides supports that subsequent conclusion that software is validated Software validation Confirmation by examination and provision of objective evidence that software specification conform to the user need and intended uses and that particular requirements implemented through software can be consistently fulfilled