Process validation.pptx_Process validation and inspection method with Example of Process validation protocol and report
- 1. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Zerlealem Tsegaye February 2024 Process validation and inspection method with Example of Process validation protocol and report
- 2. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Presentation outline Process validation, definition and purpose General principle Traditional vs new paradigm Risk assessment as part of process validation Validation scheme: Monitoring and Sampling Specific topics: Blend uniformity and validation of compression step Process validation: other dosage forms Process validation: sterile products Process validation : Biological products Retrospective validation Summary: How to review protocol and report List of References used
- 3. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation Definition 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 products. (FDA) Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets predetermined specifications and quality characteristics. (WHO) The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.(EMA) Which one of the 3 definition is Ethiopian FDA PV definition????
- 4. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Purpose of PV To show that critical steps are under control and lead continuously to the desirable quality Mandatory for processes including all critical steps Examples of critical steps ????
- 5. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa General principle • Manufacturing processes may be developed using a traditional approach or a continuous verification approach. – Irrespective of the approach used, processes must be shown to be robust and ensure consistent product quality before any product is released to the market • Manufacturing processes using the traditional approach should undergo a prospective validation programme. – Retrospective validation is no longer an acceptable approach.
- 6. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa General principle • Process validation of new products should cover all intended marketed strengths and sites of manufacture. • Bracketing could be justified for new products based on extensive process knowledge from the development stage in conjunction with an appropriate ongoing verification programme.
- 7. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa General principle • Normally batches manufactured for process validation should be the same size as the intended commercial scale batches and the use of any other batch sizes should be justified • Equipment, facilities, utilities and systems used for process validation should be qualified. • Test methods should be validated for their intended use.
- 8. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa General principle • Process validation batches should only be manufactured by trained personnel in accordance with GMP using approved documentation. • It is expected that production personnel are involved in the manufacture of validation batches to facilitate product understanding. • The suppliers of critical starting and packaging materials should be qualified prior to the manufacture of validation batches; otherwise a justification based on the application of quality risk management principles should be documented.
- 9. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa General principle • For process validation of products which are transferred from one site to another or within the same site, the number of validation batches could be reduced by the use of a bracketing approach. – However, existing product knowledge, including the content of the previous validation, should be available. • Different strengths, batch sizes and pack sizes/container types may also use a bracketing approach, if justified.
- 10. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Traditional vs new paradigm • Traditional process validation is normally performed when the pharmaceutical development and/or process development is concluded, after scale-up to production scale and prior to marketing of the finished product. • Process validation studies may be conducted on pilot scale batches if the process has not yet been scaled up to production scale.
- 11. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Traditional vs new paradigm • Formal process validation studies to be conducted on production scale batches • The number of batches used would depend on the variability of the process, the complexity of the process / product and the experience of the manufacturer but would usually be a minimum of 3 consecutive batches.
- 12. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Traditional vs new paradigm • Continuous process verification is an alternative approach to traditional process validation in which manufacturing process performance is continuously monitored and evaluated . • Continuous process verification may be applicable to both a traditional and enhanced approach to pharmaceutical development. • Continuous process verification can be used in addition to, or instead of, traditional process validation.
- 13. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Traditional vs new paradigm • Companies should perform, as relevant, extensive in- line, on-line or at-line controls and monitor process performance and product quality on each batch. • Data on quality attributes of incoming materials or components, in-process material and finished products should be collected. – This should include the verification of attributes, parameters and end points, and assessment of CQA and critical process parameter (CPP) trends.
- 14. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Traditional vs new paradigm Ongoing Process Verification Lifecycle • Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated. • The extent and frequency of ongoing process verification should be reviewed periodically. • At any point throughout the product lifecycle, it may be appropriate to modify the requirements taking into account the current level of process understanding and process performance. • Ongoing process verification should be conducted under an approved protocol or equivalent documents • Statistical tools should be used, where appropriate, to support any conclusions with regard to the variability and capability.
- 15. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Traditional vs new paradigm • The first stage in the product lifecycle. process design • the second stage in the product lifecycle. Continuous process verification • The third stage on-going process verification
- 16. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Traditional vs new paradigm Enabler • Process analytical technology (PAT) applications • The use of PAT enables disturbances to be detected in real time. • Example applications include in-line UV flow cells to monitor therapeutic protein concentration in-line near-infrared spectroscopy to assess blend uniformity or water content on-line HPLC to monitor conversion of a chemical reaction. • Multivariate Statistical Process Control (MSPC)
- 17. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation phases Pre-validation phase Protocol Preparation Information from product development studies (identification of critical attributes) Information from primary/clinical manufacturing (scale up information) Process risk assessment information (identification of critical steps) Validation phase Protocol execution Post valdn phase: Review of process, deviations, failures, need for improvement, scale up etc…
- 18. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation protocols A short description of the process and a reference to the respective MasterBatch Record; Functions and responsibilities; Summary of the CQAs to be investigated; Summary of CPPs and their associated limits; Summary of other (non-critical) attributes and parameters which will be investigated or monitored during the validation activity, and the reasons fortheir inclusion; List of the equipment/facilities to be used (includingmeasuring/monitoring/recordin g equipment) together with the calibration status; List of analytical methods and method validation, as appropriate. Proposed in-process controls with acceptance criteria and the reason(s) why each in-process control is selected. Additional testing to be carried out with acceptance criteria; Sampling plan and the rationale behind it; Methods for recording and evaluating results; Process for release and certification of batches (if applicable).
- 19. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Risk assessment • Part of process development and protocol preparation – Risk matrix- usually as part of process development • Critical quality attributes (CQA) vs processing stages, e.g. dissolution vs granulation • CQA vs critical process parameters, e.g., dissolution vs kneading time – Failure mode analysis- usually as part of process validation • To identify critical attributes, processes and parameters • To establish control strategy
- 20. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Example: risk matrix for low dose capsule (CQA vs process stages) Sifting/sizing blending lubrication Capsule filling Assay Low Medium Medium Medium Content uniformity High High High High Dissolution Low Low High Low Stability Low Low Low Low
- 21. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process steps to be validated • All steps that are generally considered critical (medium and high risk steps) should be monitored – by summarizing actual process parameters applied and observations recorded • e.g. sifting stage, wet and dry granulation stages – observations serve as feedback for future refinement of process parameters • In addition, where feasible, sampling and testing should be performed • e.g. drying, mixing steps, compression, filling • results measure effectiveness and consistency of the immediate as well as preceding steps- e.g. final blend characteristics are mainly shaped by wet/dry granulation process
- 22. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Validation scheme- example Processing steps Critical parameters Validation scheme Dispensing Weight checks Monitored Sifting Mesh size Monitored Wet Granulation and drying Amount and addition rate of granulating agent, mixing speed, time, as well as sequence of events Monitored, Drying uniformity to be tested Dry Granulation Slugging /compaction parameters Monitored only or Monitored and sampled? Blending mixing speed, time Monitored; Blend uniformity to be established Lubrication mixing speed, time Monitored; Blend uniformity from mixer and bulk container Compression Initial set up parameters, speed, applied pressure, Monitored; Several samples to be sampled and tested for IPQC parameters Fluidized bed coating Spray rate, inlet and product temp, etc… Monitored; appearance, weight gain and full testing Primary packaging, protocol requested on case by case basis Sealing temperature, speed Monitored; leak test
- 23. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Monitoring- Example: Compaction – Any comment with the difference between BMR set range and actual applied inputs? BMR Set parameters Batch 1 Batch 2 Batch 3 e.g. of parameters Cycle 1 Cycle 2 Cycle 1 Cycle 2 Cycle 1 Cycle 2 Roller speed (RPM) 8-15 10 10 10 10 10 10 Roller pressure (Bars) 40-60 41-42 42-43 41-43 41-42 41-42 41-43 Vertical feed screw (RPM) 50-100 75 75 75 75 75 75 Horizontal feed screw (RPM) 10-20 15 15 15 15 15 15
- 24. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Example: Monitoring and sampling: Drying Monitoring Set parameter Observation Batch X Batch Y Batch Z Inlet temperature 60+/-10oC 62-65 52-63 52-60 Outlet temp 29-44 31-47 28-36 Total drying time (min) (for information) 65 65 80 Sampling and testing Spec Batch X Batch Y Batch Z Location 1 0.75-2.25% 1.54 1.53 1.70 Location 2 1.94 2.01 1.80 Location 3 2.03 1.30 2.05 Location 4 1.89 1.87 2.20
- 25. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Blend uniformity Uniform blend with good flow and compressibility characteristics Compression with optimum conditions Tablets meeting criteria for uniformity of dosage units Note: Blend uniformity is a routine test for low dose products (i.e. active load <=5% or 5mg)
- 26. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Blend uniformity- Sampling location and method • Sampling location -usually predetermined as part of qualification of the mixer – we at least check if periphery, center positions and various other positions are considered – Samples from each location are usually taken in triplicate • Samples should also be taken from the blend container- to evaluate impact of transfer – important for low dose products and particularly for DC processed blend • Sampling should be done consistently and in away that does not disturb the bulk blend state – such aspects (e.g. type of sampling thief used) are better addressed at the time of inspection
- 27. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Blend uniformity- Sample size • What is an acceptable amount for samples taken at each location? • Normally 1-3 time of the FPP unit dose weight
- 28. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Blend uniformity- acceptance criteria • Commonly used criteria – Individual assays: 90.0-110.0% of label claim, RSD NMT 5.0% • In case of very low dose products – Individual assays: 85.0-105.0% of the label claim/mean value, RSD: NMT 5.0% May be acceptable provided that uniformity of dosage units is satisfactorily demonstrated on tablets/capsules manufactured from blend lot with close to limit blend uniformity results
- 29. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Sampling and testing plan- Lubrication- example missing parameter? Do you agree with the acceptance criteria? Sample location Sample size Sample analysed Tests Acceptance limits Lubrication 10 position from Octagonal blender and blend container 850-2550mg in triplicate 10 Individual samples Blend uniformity Mean: 95.0- 105.0%, individual: 90-110%, RSD: NMT 5% Samples from top, middle and bottom 50gm Composite samples Complete analysis as per routine blend spec As per blend spec Particle size distribution, bulk and tapped density For information What are the minimum tests we expect to see in blend spec? Acceptable?
- 30. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Compression • Good compression outcome is a measure of – Granule/powder mix properties • bulk and tapped density-granulation • particle size and particle size distribution-granulation • moisture content- drying • extent of lubrication- lubrication time – Machine and tooling attributes • appropriate selection and adequate lubrication of punches and dye • machine speed • applied compression pressure
- 31. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Compression – Sampling frequency and size • depends on the length of the run time/ batch size – we expect frequent sampling than the normal IPQC frequency – the number of tablets/capsules taken should be greater than those taken during a normal IPQC sampling
- 32. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Compression- Challenge studies • Certain variations in compression speed and hardness than the target set points may happen – what would be the impact of such variations? – speed affects dwell time- which intern affects several tablet parameters (thickness, hardness, as well as weight variation) • Therefore, robustness should be demonstrated C. Morten, PIAT programme, University of Manchester
- 33. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Extensive sampling- example (there are several other approaches) IPQC testing schedule Normal production batch Validation batches 48 station machine, batch size of 170,000 tabs, target speed 25rpm Group weight and appearance, every 30 minutes; others every 1 hour (at least 3 times) About 300 tablets About 300 tablets All in process parameters at start, middle and end of compression (different hopper fill levels) - About 360 tablets Additional samples at high, low speed; at high and low hardness levels - About 480 samples Total number of tablets sampled 300 tablets 1140 tablets
- 34. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa How to demonstrate consistency?
- 35. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation-oral solutions Validation focuses on – mixing time and conditions to clear solution, if deemed relevant • bulk liquids: pH, specific gravity, clarity of solutions; assay – filling process • filled units:- Volume/Wt variation and as per FPP specs
- 36. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process Validation- Oral suspensions Focuses on – API micronization processes (if applicable) – colloidal milling process (as applicable), – homogenization – filling • Viscosity, fill volume/weight variation, • Other critical attribute that may be affected by filling process? • Other parameters as per FPP spec including, PSD, pH, dissolution,
- 37. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation- sterile products Products mfd by Terminal sterilization and Aseptic processing Container and component sterilization and depyrogenation - Depyrogenation by tunnel depyrogenator (e.g. ampoules) or washing (e.g. rubber stoppers, plastic bottles) * - Depyrogenation by washing- for stoppers, seals, accessories* - Validation of steam sterilization – for stoppers, seals, accessories* - Dry heat sterilization and depyrogenation- for glass vials or ampoules*
- 38. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation- sterile products-Contd Products mfd by Terminal sterilization Products mfd by Aseptic processing Product sterilization Terminal sterilization by Steam sterilization, radiation or ETO (as applicable)* Filter validation (as part of dev’t pharm) Pseudomonas diminuta. Process simulation - Media fill Full batch processing (other aspects of the mfg process, e.g. valdn of bulk prepn, filling and sealing quality) 3 production batches mfd at proposed scale 3 production batches mfd at proposed scale *validation should be on three runs to demonstrate reproducibility.
- 39. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation : Biological products • Flow of Manufacture for Biotechnological Products Manufactured in a Microbial Cells e.g. E. Coli, Human insulin. – Develop host cell – Develop expression vector – Establish a cell bank – Protein production – Purification(DSP) – Characterization/Analysis – Formulation of DP(Drug Product)
- 40. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation : Biological products Control of al starting materials, (medium nutrients, cell viability & density). Cell expansion using shake flask(125ml, 500ml 2000L; Contamination Check, pH, Wet Cell Weight ). Fermentation – (critical process parameters eg , pH, PCO2, temp, stir rate, batch phase, fed batch phase(fed rate NMT 11 g/Llh), continuous cell density, viability, Contamination Check, pH, Wet Cell Weight , Product content of Insulin). Centrifugation – rpm Lysis crude – (Temperature, time, pH, endotoxin level, yield etc.)
- 41. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Process validation : Biological products Capture and Elucidation –columns/resins for capture, Buffer, flow rate of buffers, Load, viscosity, pH, conductivity & temperature, Bioburden. Purification – Chromatography Enzymatic conversion of human proinsulin to human insulin– type of enzyme used (Pancreatic Porcine trypsin, recombinant porcine trypsin. Pancreatic Bovine trypsin and recombinant bovine trypsin. Multimodal Chromatographic Purification of human insulin : UF/DF – Concentration of product Crystallization of insulin with zinc solution(pH, % solids, Product content, purity and impurity profile) Drug substance → Human insulin
- 42. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Matrixing/bracketing approach • Multiple strengths of same product (common blend) – until stages of final granules: 3 consecutive batches of the common blend (instead of 3 separate blend batches for each strength) – compression: 3 consecutive batches of each strength • Primary packaging of tablet/capsule products – blistering of hygroscopic or moisture sensitive products however should always be individually validated
- 43. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Retrospective validation for established products • Tries to demonstrate process effectiveness and consistency via trend analysis: – extent of deviations – extent of OOS or OOT – extent of batch rejection – extent of product complains – extent of changes/ improvements introduced – See Appendix 2 of medicine registration guideline
- 44. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Review of protocol- main aspects to check • Scope of the validation (type, batch size, reason)- do they reflect the planned validation? Highest batch size to be validated? • Major equipments identified (in line with BMR) and a provision for recording their Q status included? • Reference to current master production record included? • Summary of critical steps identified? is this convincing ? • Monitoring and sampling plan provided?- Do you agree with the steps monitored/sampled? • Sampling schedule, schematics, tests and acceptance criteria, as well as current specification codes included ? Are these acceptable?
- 45. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Review of protocol- main aspects to check-cont. • For solid orals: final blending, compression/encapsulation, coating stages must be adequately sampled and tested. Are these being reflected? – Blend uniformity: Sampling schemes and blend uniformity acceptance criteria specified? Are these acceptable? – Compression/encapsulation at lower, target and upper speeds included? • Provision for performance of dissolution profile testing and comparison with the biobatch included?
- 46. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Review of validation report • Is the reported data relevant for the proposed manufacturing process and scale – equipment used, process parameters applied • All critical steps adequately monitored/sampled? • Level of sampling and size are acceptable? • All results within acceptable limits? Particular trend? • Deviations appropriately evaluated and discussed? • Is the overall process in sufficient control? Is there any thing that should be improved or refined for future production batches
- 47. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa Some of the References used to prepare the PPT • Guideline for Registration of Medicines fourth edition • EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use volume 4 EudraLex https://health.ec.europa.eu/system/files/2016-11/2015-10_annex15_0.pdf • Guideline on process validation for finished products - information and data to be provided in regulatory submissions https://www.ema.europa.eu/en/documents/scientific-guideline/guideline- process-validation-finished-products-information-and-data-be-provided- regulatory-submissions-revision-1_en.pdf • Guideline on manufacture of the finished dosage form https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-manufacture-finished- dosage-form-revision-1_en.pdf • WHO published PPT
- 48. We protect the safety of our people! To be a center of excellence in food and health products regulation in Africa
Editor's Notes
- #14: real-time approach to verify and demonstrate that a process that operates within the predefined specified parameters consistently produces material which meets all its critical quality attributes (CQAs) and control strategy requirements.
- #24: Normally, the protocol should require validation of the BMR range, but once validation is executed either the BMR set up parameters should be revised to reflect the validated range or set point or new validation should be done.
- #35: i.e, in sigma process, the whole area within +/-3 of SD will be within spec limit, while in case of 4 sigma, +/4 SD of the curve area is within spec limit (and in this case Cpk is roughly equal to 1.33).