Guidance for Industry Process Validation: General Principles and Practices; A Contract Manufacturing Organization's Approach

Transcription

1 May -3, 202 Javits Center New York, NY Guidance for Industry Process Validation: General Principles and Practices; A Contract Manufacturing Organization's Approach Sandra Lueken Director of Quality Baxter Pharmaceutical Solutions Title Date Javits Center New York, NY

2 Outline 2 Guidance Background FDA Expectations Lifecycle Approach Roles and Responsibilities Guidance Recommendations Process Design and Case Study Process Qualification, Performance, and Verification The Rest of the Story

3 Guidance Background 3 The latest process validation guidance for industry was issued January 20 with the goal of fostering innovation and advancing the science of pharmaceutical manufacturing. Aligns process validation activities with the product lifecycle and Quality by Design (QbD). Builds on the concepts delineated in the 987 guideline; replacing the 987 guidance.

4 Final Process Validation Guidance 4 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 Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20; (emphasis added)

5 FDA Expectations 5 Quality, safety, and efficacy are designed or built into the product. Quality cannot be adequately assured merely by in-process and finished-product inspection or testing. Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

6 Lifecycle Approach A series of activities taking place over the lifecycle of the product and process. 6

7 Lifecycle Approach (con t) 7 The guidance clearly states - Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

8 CMO Roles and Responsibilities 8 Unless carefully managed a CMO may have 90% of the manufacturing responsibilities with only 0% of the decision authority. This leads to the age old dilemma of the client owning the license/filing and most decision rights while the CMO owns the 483 observations. Ultimately, there must be a set of Joint manufacturers roles and responsibilities.

9 Manufacturers Roles and Responsibilities (con t) 9 A successful validation program depends upon information and knowledge from product and process development. Manufacturers should: Understand the sources of variation Detect the presence and degree of variation Understand the impact of variation on the process and ultimately on product attributes Control the variation in a manner commensurate with the risk it represents to the process and product Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

10 Manufacturers Roles and Responsibilities (con t) 0 Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product. This must be done in partnership with the Pharma Partner/license holder. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

11 Manufacturers Roles and Responsibilities (con t) Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate the state of control of the process. These programs may identify process or product problems or opportunities for process improvements that can be evaluated and implemented Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

12 Manufacturers Roles and Responsibilities (con t) (a), states that; There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality and purity they purport or are represented to possess. Code of Federal Regulations; Subpart F Production and Process Controls, 2.00 Written procedures; deviations, Revised April 2008.

13 Key Points 3 Well-designed processes must include in-process control procedures to assure final product quality. Sampling plans must result in statistical confidence (2.65(c)) and the batch must meet its predetermined specifications(2.65(a)). Manufacturers need to analyze process performance and control batch-to-batch variability. Data about product quality and manufacturing experience must be periodically reviewed to determine whether any changes to the established process are warranted (2.80(e)). Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

14 Guidance Recommendations 4 In all stages of the product lifecycle, good project management and good archiving that capture scientific knowledge will make the process validation program more effective and efficient. The FDA recommends: an integrated team approach project plans full support of senior management Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

15 Guidance Recommendations (con t) 5 The FDA recommends : Studies should be conducted according to sound scientific principles, approved in accordance with established procedure appropriate for the stage of the lifecycle Attribute criticality should be thought of as a continuum rather than a binary state Evaluate attributes in terms of risk management rather than a one size fits all approach Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

16 Process Design 6 is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The manufacturer is expected to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

17 Process Design (con t) 7 Generally, early process design experiments do not need to be performed under the CGMP conditions required for drugs intended for commercial distribution that are manufactured during : Stage 2 (process qualification) Stage 3 (continued process verification) Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

18 Case Study: CMO and Pharma Partner Collaboration 8 Commercial Product Transfer Complex formulation containing several APIs Continued Process Verification (Stage 3) Continuous Improvement Process Design (Stage ) Process Qualification (Stage 2) Aseptic addition of sterile adjuvant

19 Case Study: CMO and Pharma Partner Collaboration (con t) 9 Commercial Product Transfer Continued Process Verification (Stage 3) Continuous Improvement Process Design (Stage ) Cross-site media challenge including all aspects of the aseptic process Process Qualification (Stage 2) Cross-site filing: 2 Pharma Partner facilities & CMO Harmonization across all sites

20 Case Study: CMO and Pharma Partner Collaboration (con t) 20 Enhanced knowledge sharing of joint expertise Commercial Product Transfer Continued Process Verification (Stage 3) Continued partnership between Pharma Partner & CMO to address new challenges, product characteristics, API and process changes Continuous Improvement Process Qualification (Stage 2) Process Design (Stage )

21 Case Study: CMO and Pharma Partner Collaboration (con t) 2 Commercial Product Transfer / Expansion Collaboration to expand product line to new configuration Continued Process Verification (Stage 3) CMO personnel visits at Pharma Partner facility to gain best practices Continuous Improvement Process Qualification (Stage 2) Expansion project to meet additional product demand Process Design (Stage ) Extensive Pharma Partner presence to provide on-site support and decision making

22 Legacy Products 22 Grandfathered products have their own set of challenges; product history files basic validation packages Many companies choose to alleviate these products if the ROI is not commensurate with the cost to find, rebuild, or create proper validation packages that would meet today s standards.

23 Document, document, document 23 It is essential that activities and studies resulting in process understanding be documented. Documentation should reflect the basis for decisions made about the process. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

24 Process Qualification Facility & Equipment Design of a facility and qualification of utilities should be a shared responsibility CMO Facility Equipment: Utilities, HVAC, WFI Autoclaves Filling Equipment Lyophilizers Terminal Sterilizers Container Prep, Closure, & Labeling Packaging Equipment Client Specialized Equipment Tanks Specialized mixing equipment Diafiltration Filter skids Homogenizers Specialized parts Secondary Packaging; dispensers 24

25 Process Performance Qualification PPQ 25 The PPQ combines the actual facility, utilities, equipment (each now qualified), and the trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches. A successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

26 Statistics 26 The approach to PPQ should be based on sound science and the manufacturer s overall level of product and process understanding and demonstrable control. In addition, we strongly recommend firms employ objective measures (e.g., statistical metrics) wherever feasible and meaningful to achieve adequate assurance. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

27 Statistical Confidence 27 The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches. The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

28 PPQ Execution and Report 28 Execution of the PPQ protocol should not begin until the protocol has been reviewed and approved by all appropriated departments, including the quality unit. How many lots/batches? Three is no longer the magic number. Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

29 Continued Process Verifications 29 Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control. This is more than control charts and APRs Guidance for Industry Process Validation: General Principles and Practices U.S. Department of Health and Human Services, Food and Drug Administration, January 20

30 Variation Example 30 Overall % Rejects (December February) 5 Variation identified and evaluated % Rejects % Stopper Position (December February) Mfg Batch Number UCL AVG LCL UCL AVG % Stopper Position LCL Decision to implement stopper position tool during filling operations (implemented on January 2). Tool implementation correlates with significant reduction in Stopper Position in February Mfg Batch Number February Batches

31 Regulatory Success 3 2 Regulatory Inspections in 20; 4 of 5 FDA Inspections = No 483 Obs. Most favorable European Inspection in site history Major, 8 Other (minor) observations Major, Other observations Major, 0 Other observations 2008 Major, 3 Other observations 20 Major, 8 Other observations Improved Pharma Partner Audit Performance Observations/Audit, 3 Critical, 69 Major Observations/Audit, Critical, 57 Major Observations/Audit, 0 Critical, 3 Major Continued Improvement for Corporate Audits Major, 0 Minor Observations 20 0 Major, 2 Minor

32 Regulatory Success 32 Product Approvals Since 2007: 5 Approved Products 8 Pre Approval Inspections (with inspections covering 76 product / country applications) 02 Countries approved

33 Conclusion 33 The FDA s most recent process validation guidance is a good road map for CMOs and pharma partnerships to navigate through the technical transfer process. FDA Consumer Safety Officers are training with this guidance; as an industry, we can expect to see inspectors looking for evidence that we are in compliance with the CGMPS and following their recommendations.

34 34 Thank You! Baxter is a registered trademark of Baxter International Inc.