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Process Validation – What the Future Holds

Process Validation – What the Future Holds. Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011. Course Objective. Take an in depth look at the regulatory requirements (EU and FDA) for process validation FDA process validation guidance

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Process Validation – What the Future Holds

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  1. Process Validation – What the Future Holds Presented by: Karen S Ginsbury PCI Pharmaceutical Consulting Israel Ltd. For IFF February 2011

  2. Course Objective Take an in depth look at the regulatory requirements (EU and FDA) for process validation • FDA process validation guidance • Q10 – Pharmaceutical Quality System Guidance • Management Review • Ongoing product and process performance monitoring

  3. The Objective… • Gain an overall understanding of the topic of Process Validation over a product lifecycle tied in with Product Quality Review in the context of ongoing verification of process and product performance • Tie in with CAPA programs to provide an enhanced quality system

  4. To be discussed… • The GMP regulations:- EU on Product Quality Reviewand Process Validation- US on Annual Product Reviewand Process Validation • Q10 – Pharmaceutical Quality System:Ongoing Process and Product Performance Monitoring • FDA Process Validation guidance

  5. To be discussed… • What industry is currently doing • Critical Process Parameters and their review • Critical Quality Attributes and their inclusion in the review • Data trending (Use of simple statistical tools) • Validation, deviations and changes

  6. To be discussed… • Organizational Structure, escalation policy • SOPs • CAPA and Follow-up • Critical systems, support systems • Management involvement / commitment • Mobilizing resources

  7. Purpose of Validation: • To satisfy the regulators!! • Ensure you got what you intended • In accordance with design / development • Map critical elements / show reproducibility • Allow for: • Continuous Improvement / Change management • Ongoing maintenance • Ongoing qualification • CAPA

  8. The future is now

  9. The future is now • Your firm failed to provide validation protocols that evaluated the impact of the increasing batch sizes on product quality. You failed to conduct a study to demonstrate at what point each batch size is uniformly blended. You have not conducted any analysis comparing data between your validation batches. Further, your firm uses a general "Master Validation Plan" for process validation on all products. Validation must be demonstrated for each product and process. The critical controls and processing parameters must be known and shown to be in control, and a demonstration of process reproducibility with objective measures must be made.1 • 1 Further information on FDA's current thinking on process validation is available in Food and Drug Administration, Draft Guidance for Industry, Process Validation: General Principles and Practices November 2008, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf

  10. The Future is Now

  11. The Future is Now

  12. Regulatory Basis for Validation USA / FDA Sec. 211.68 Automatic, mechanical, and electronic equipment • “Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product • Such equipment shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those … inspections shall be maintained” • Input to and output from the computer or related system of formulas or other records or data shall be checked for accuracy. The degree and frequency of input/output verification shall be based on the complexity and reliability of the computer or related system

  13. Regulatory Basis for Validation – EU Annex 15 – Qualification and Validation (2001) • …a GMP requirement that manufacturers identify what validation work is needed to prove control of critical aspects of their particular operations • Significant changes to facilities, equipment and processes, which may affect the quality of the product, should be validated • A risk assessment approach should be used to determine the scope and extent of validation

  14. Warning Letters

  15. Some Concepts • Uncertainty: The lack of certainty, A state of having limited knowledge where it is impossible to exactly describe existing state or future outcome or there is more than one possible outcome • Measurement of Uncertainty: A set of possible states or outcomes where probabilities are assigned to each possible state or outcome • Risk: A state of uncertainty where some possible outcomes have an undesired effect or significant loss

  16. Uncertainty • “It is not enough to satisfy the customer…You MUST delight them” W. Edwards Deming

  17. Two More that have to be understood Critical Quality Attribute (CQA): A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality [= safety, efficacy, performance] Critical Process Parameter (CPP): A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality

  18. Production Yield (Y) is a CQA affected by the Variable Inputs (X) People Inputs to the process control variability of the Output Equipment I N P U T S (X) y = ƒ(x) Measurement y Process OUTPUT Materials Adapted from slide by Moheb Naser, FDA Environment Quality Attributes Process Parameters 18

  19. From the FDA Guide • CGMP regulations require that batch samples represent the batch under analysis e.g. § 211.160(b)(3) and that the sampling plan result in statistical confidence § 211.165(c) • in-process specifications “. . . shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate” This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability

  20. From the Guide • We recommend an integratedteam approach to process validation that includes expertise from a variety of disciplines, e.g. process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance

  21. From the Guide • The approach to PQ should be based on sound science … • we strongly recommend firms employ objective measures (e.g., statistical metrics), wherever feasible and meaningful to achieve adequate assurance

  22. From the Guide • In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny of process performance • The level of monitoring and testing should be sufficient to confirm uniform product quality throughout the batch during processing

  23. From the Guide • The increased level of scrutiny, testing, and sampling should continue through the process verification stage as appropriate, to establish levels and frequency of routine sampling and monitoring for the particular product and process • Considerations for the duration of the heightened sampling and monitoring period could include, but are not limited to: • volume of production • process complexity • level of process understanding • experience with similar products and processes

  24. From the Guide • The extent to which some materials, such as column resins or molecular filtration media, can be re-used without adversely affecting product quality can be assessed in relevant laboratory studies • The usable lifetimes of such materials should be confirmed by an ongoing PPQ protocol during commercial manufacture

  25. Life Cycle Approach PROCESS VALIDATION

  26. No more magic #3!

  27. Process Validation – FDA • Current Process Validation is from 1987 • Guidance is out-dated and no longer reflects current GMPs • The new document is closer to ICH Q8, 9 and 10 philosophy of lifecycle approach to product (risk) management

  28. Process Validation - EU

  29. Process Validation - EU • The current guideline was developed before ICH Q8/9/10 • Additional means are available to verify the control of the process by alternative means to the traditional process validation batches • The main objective is that a process design yields a product meeting its pre-defined quality criteria • Q8/9/10 provide a structured way to define CQAs, design space, manufacturing process and the control strategy • Continuous process verification can be utilised in process validation protocols for the initial commercial production and for manufacturing process changes for the continual improvement throughout the remainder of the product lifecycle

  30. Surprised?…You Shouldn’t be! • Q10, section 1.6 Enablers: • 1.6.1 Knowledge management“…process validation studies over the product lifecycle” • Q10, section 3.1 Lifecycle Stage Goals: • 3.1.2 Technology Transfer“This knowledge [from tech transfer] forms the basis for manufacturing process, control strategy, process validation approach and ongoing continual improvement”

  31. Surprised?…You Shouldn’t be! • Q10, section 3.2 Quality System Elements: • 3.2.1 Process Performance and Product Monitoring System“…provide knowledge to enhance process understanding, enrich the design space (where established), and enable innovative approaches to process validation”

  32. Definition: 1987 Guide • Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics

  33. Current Definition: January 2011 Proposed definition: 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 Preapproved Protocols? Completion of Optimization?

  34. Revised Process Validation Guide • Three phases to the validation: • Process Design • Process Qualification • Continued Process Verification • Lifecycle Approach • No more magic “three” • Can use data from lab scale / pilot batches to support process qualification

  35. FDA Process Validation Guide

  36. Worst Case • A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions • Such conditions do not necessarily induce product or process failure - Annex 15 glossary

  37. FDA Guide • Each step of a manufacturing process is controlled to ensure that the finished product meets all design characteristics and quality attributes including specifications • Each step of a manufacturing process is controlled (Product Control Strategy) to assure that the finished product meets its Critical Quality Attributes and Performance Characteristics as defined in the Quality Target Product Profile

  38. Stages of Validation - Process Design Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities This is a pre-requisite for process validation

  39. Process Qualification • During the process qualification the process design is confirmed as being capable of reproducible commercial manufacture. This stage has two elements: • Design of facility and qualification of equipment and utilities • Process Performance qualification (PQ)

  40. Continued Process Verification • Ongoing assurance is gained during routine production that the process remains in a state of control

  41. Continued Process Verification

  42. Complaints Annual Product Review Critical Systems Review Environmental Monitoring OOS / Out of trend results Deviations (planned / not) Rejected Batches Change Control Validation /Calibration Status Maintenances Batch Records (statistics) Audits Stability Ongoing Verification / Reports / CAPA

  43. Demonstrating Ongoing Control • A 10 year old car will notperform in the same manneras a brand new one • BUTif you can demonstrate, byongoing process monitoringthat product performanceis unchanged (within thelimits of the specification)then the old car is still validated

  44. Demonstrating Ongoing Control • Which means looking after the equipment: • Maintenance records:preventive and breakdown • Cleaning records • Use logs • Calibration logs • And periodically performingreview of the logs looking for: • Increased frequency / severity of breakdown • Failed calibrations • Failed or non-conforming batches of product • Borderline product – close to specification

  45. What about Grandfather Products • Grandfather products shouldn’t be a concern: Product Quality Review and vast knowledge accumulated over years should provide an excellent basis for ongoing process validation – if you don’t have it already…you should have (more or less)But – new products, IMPs…when will regulators expect to first hear the term Process Validation and see data?

  46. Quality Review - GMP Requirements • USA • 21 cfr part 211.180 General Requirementsection (e) • EU Guide • Chapter 1 to the EU Guide to Good Manufacturing Practice (October 2005)[since updated to include Quality Risk Management]

  47. 21 cfr 211.180 (e) Written records required by this part shall be maintained so that data therein can be used for evaluating at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. Written procedures shall be established and followed for such evaluations and shall include provisions for:

  48. 21 cfr 211.180 (e) cont/ (1) A review of a representative number of batches, whether approved or rejected, and where applicable, records associated with the batch. (2) A review of complaints, recalls, returned or salvaged drug products, and investigations conducted under 211.192 for each drug product.

  49. Chapter 1 – (1.4) Product Quality Review • Regular periodic or rolling quality reviews of all licensed medicinal products, • including export only products • Such reviews should normally be conducted and documented annually, taking into account previous reviews

  50. (1.4) PQR Objective Verify • The consistency of the existing process • The appropriateness of current specifications for: • starting materialsand • finished productto highlight any trends and to identify product and process improvements

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