Quality by Design: A Case Study on Why You Should Care Clinton Weber, NNE Pharmaplan 1 Summary of Industry QbD History - From Regulators & Industry FDA, New initiative about Science and Risk Based Approach, 2002 – 2004, cGMP for the 21st Century New paradigm of ICH Q8, Q9 & Q10 ISPE – To lead global innovation and change in pharmaceutical technology and processes GAMP®5: A Risk-Based Approach to Compliant GxP Computerized Systems New ISPE Baseline Guide for Verification of Pharma Manufacturing Systems Expected in 2010: New Process Validation Guideline from FDA & EMEA Case Study Background • • Global Pharmaceutical Manufacturing company Over 12 sites world wide • Product and Services portfolio: • Generics, Biosimilars, APIs, Medical Devices, Crossover products, CMO services • April, 2009 FDA Inspection of one site included observations related to process validation and process control • Subsequent October, 2009 Inspection of another site yielded significant observations on process validation, and lack of science and risk-based approaches Case Study Warning Letter Language “You have not provided a scientific rationale to justify that the mixing studies conducted for Product X and Product Y are adequate and fully representative of the mixing processes for the other (b)(4) products. In addition, you have not identified the component attributes (e.g., solubility and viscosity) and process parameters (e.g., speed, temperature, and pH) that are important to produce a solution for all (b)(4) products. ” “We note that your response is also inadequate because you have not provided the statistically and scientifically sound rationale for the application of the solution tank mixing validation matrix.” “Different XYZ solutions contain different chemical ingredients, different excipients and potentially different critical process parameters. The potential critical process parameters like: pH, temperature, (b)(4) mixing time and mixing speed have not been identified and evaluated. The "worst case" validation approach utilized does not support the XYZ solutions manufacturing processes performed at your facility.” R&D Relationship to Manufacturing Operations R&D Unnecessary cost and pain + lack of scientific knowledge and understanding of products and processes What’s the Plan? • Focus on Process Validation approach • Two pronged attack – at site and in Corporate Quality Procedures Corporate Quality Site Validation •Approach must address legacy products as well as new products Site Validation • A Seven Step Approach: 1. 2. 3. 4. 5. 6. 7. Product and Process Overview Applying Knowledge Product Understanding Overview Matrix Product Assessment Summary Report Improved Understanding Validation Continued Process Verification Seven Steps for Legacy Products Product & Process Overview Product list and family Process Flow Diagram Risk based Prioritization Improved Process & Product Understanding Experimentation Data mining & analysis Use of scientific expertise Assessment of Critical Attributes and Parameters Specification (CQA) to CPP matrix scoring Identify priorities Validation Plan & Execution Scientific and risk based validation Understanding Overview Matrix Prior Knowledge Historical data Validation data Forward data Fundamental knowledge Unknowns Continued Process Verification Trending Continuous improvement Product Assessment Summary Report Prior Knowledge Historical data Validation data Fundamental knowledge Unknowns Seven Steps: Product & Process Overview Product & Process Overview Assess CQA’s and CPP’s Understan ding Overview Matrix Product Assessment Summary Report Improved Process Product Understand Step 1 – Product and Process Overview Products should be prioritized: • Rank risk to patient from a severity point of view (this could be based on therapeutic effect and mode of delivery) • Rank the products in order of how important they are to supply market • Gain high level feel of validation concerns • Group the products into product groups or families based on formulation and presentation • Gain conceptual understanding of facility process steps to final product • Use of Process Flow Diagrams to focus total plant process understanding • Walk down of process by those involved in project • Map the manufacturing process for each product group • Gain overview of existing process validation per product group. Validation Plan & Execution Continued Process Verification Seven Steps: Assessment of CQA’s and CPP’s Product and Process Overview Assess CQA’s and CPP’s Understan ding Overview Matrix Product Assessment Summary Report Improved Process Product Understand Validation Plan & Execution Continued Process Verification Step 2 – Assessment of Critical Attributes and Parameters • Initial data mine of capability • Identify what is critical to the patient and how that is impacted by the process • Identify CQAs for each product and variant • Make a risk assessment of the impact of the different unit operations on the CQAs • List for each product and variant potential CPPs for each unit operations impacting CQAs • Make a risk assessment of these potential CPPs • All these risk assessments combined in one tool • Tools such as Ishikawa and P-diagrams can be used to quickly identify CQA and CPPs if not already available. • Exercise MUST include R&D, Process Development or Product/Process SME! Seven Steps: Understanding Overview Matrix Product and Process Overview Assess CQA’s and CPP’s Understandi ng Overview Matrix Product Assessment Summary Report Step 3 – Understanding Overview Matrix • Gain overview of process understanding to justify validation approach per product variant • Assess understanding in the following categories • Prior documented knowledge from R&D, validation or manufacturing (including MBR) • Referenced fundamental first principle knowledge • Historical data and statistical knowledge • Forward looking data and statistics • Identification of unknowns •This matrix is used to pinpoint where data is. • Step 3 is used to prioritize the future process understanding, controls or validation work to close the knowledge gaps. Improved Process Product Understand Validation Plan & Execution Continued Process Verification Seven Steps: Product Assessment Summary Report Product and Process Overview Assess CQA’s and CPP’s Understand Overview Matrix Product Assessment Summary Report Improved Process Product Understand Validation Plan & Execution Continued Process Verification Step 4 – Product Assessment Summary Report • Product specific CQA and CPP risk matrix (step 2) • Product specific Understanding Overview Matrix (step 3) • Validation performed and relevance • Short summary and collation of information to demonstrate what knowledge supports the conclusions 42 Lots Seven Steps: Improved Process and Product Understanding Product and Process Overview Assess CQA’s and CPP’s Understand Overview Matrix Product Assessment Summary Report Improved Process Product Understand Validation Plan & Execution Continued Process Verification Step 5 – Improved Process and Product Understanding This step uses the following expertise, tools and methodologies to strengthen product or validation understanding: • Further historical data analysis • Use of experts to gain additional fundamental understanding • Use forward looking data analyses such as DoE and EVOP (Evolutionary Operations) Process Development Process improvements based on science and risk Changes to operating procedures Control Strategy Development Use of increased in process testing for control Data driven use of control and sampling Seven Steps: Validation Plan & Execution Product and Process Overview Assess CQA’s and CPP’s Understand Overview Matrix Product Assessment Summary Report Improved Process Product Understand Validation Plan & Execution Continued Process Verification Step 6 – Validation Plan/Execution (Process Qualification) This step builds on the science and risk based approaches to design a smart, science and risk based validation plan which takes account of steps 1 to 5 in making decisions as to what should be validated and how. • Project Execution Plan for what should be Revalidated (missing pieces, lack of understanding) • Revalidate using science and risk based approaches (use of traditional approaches, DoE, science & risk and any other appropriate methods) • It is essential that the validation plan and it’s execution should take account of steps 2 to 5 which document product and process understanding. This should ensure only the gaps are validated to strengthen position and not wholesale mass validation. • Use the information from the revalidation to: • Update the Understanding Overview Matrix • Update the risk assessment (CQA / CPP) • Identify if further risk mitigation or risk control activities are needed • Update summary report Seven Steps: Continued Process Verification Product and Process Overview Assess CQA’s and CPP’s Understand Overview Matrix Product Assessment Summary Report Improved Process Product Understand Validation Plan & Execution Continued Process Verification Step 7 – Continued Process Verification Continuously verify data going forward for scientific justification of production of safe and efficacious product for marketplace. Trend relevant data and make needed continuous improvement or CAPA activities. Relevant data is determined through Risk Assessment and knowledge gained during the Validation/Qualification Execution phase. Corporate Quality Procedures Closing The Gap 1. Establish Understanding of FDA’s Draft Process Validation Guidance 2. Develop Gap Analysis Tool for Comparison of Existing Procedures 3. Create Prioritization Matrix of Procedures 4. Identify New Corporate Quality Procedure Structure 5. Modify / Create New Procedures 6. Develop Execution Plan for Each Site New FDA Process Validation Guidance Revisited R&D / PD As Stakeholders CQA’s / CPP’s Defined Process Design 1 Align with Risk Assessments Process Qualification 2 Based upon Science Not calendar year Continued Process Verification 3 Gap Analysis Tool • PV Guidance broken down into consumable sections • Top Priority Procedures evaluated against Guidance • Qualitative evaluation performed • Allowed for orthogonal approach to understanding gaps Corporate Procedures Final “Look” at a Glance INPUTS Approvers: R&D Engineering Manufacturing Approvers: Manufacturing Validation Manufacturing Validation R&D Site Quality Corp.Quality Ø Ø Ø Ø Approvers: Product List: Grouping / Families Quality Target Product Profile defined Process / Product Development Knowledge Ø DOE’s documentation / review Ø Technology Transfer document approved Ø Ø Defining CQAs, CPPs Ø Ø Site Quality Ø Risk Assessment: Direct vs. Indirect equipment Ø Ø Control Strategy defined (equipment / unit operations defined) Process Flow Chart Total # of parameters defined Variation defined (ranges estimated) Ø Ø Quality Risk Assessment: PV Enhance sampling strategy defined per CPP Product grouping strategy Equipment bracketing strategy Qualification Reports approved Operational ranges defined PQ PQ PQ SIP CIP Mix · · Continued process verification Continuous improvement Process Qualification Stage PQ Equipment, Facilities, Utilities Qualification DQ/IQ/OQ PV Report Ongoing Verification RA PQ Ø · · Approvers: Risk Assessment: CQA’s / CPP’s R&D defined Total product parameters listed, Manufacturing evaluated - CPP’s identified Validation Unit Operations defined Site Quality Corp. Quality · · · · DQ IQ Qualification of equipment OQ End to end PV Report approved Ø Non-product performance qualified Functionality, control ranges verified SOP’s approved, trained Routine statistical analysis Ties into Change Control Ties into APQR Approvers: Ø · · Risk Assessment: Ongoing R&D verification / monitoring strategy SamplingManufacturing strategy defined per CPP Product grouping strategy confirmed Validation Quality OUTPUTS · · · Corp. Quality Periodic Requal or Revalid. The Payoff 1. Consistent Approach, specialized focus 2. Elimination of unnecessary testing 3. Better alignment with other proactive strategies (e.g., ASTM E2500) 4. Allows for Reduction in Corp. procedures 5. PROCESS IMPROVEMENT
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