Process Robustness: Development to Life Cycle Management. Presented By J. Richard Creekmore US Technology Manager AstraZeneca Pharmaceuticals

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1 Process Robustness: Development to Life Cycle Management Presented By J. Richard Creekmore US Technology Manager AstraZeneca Pharmaceuticals

2 Introduction You ve heard it before: Complaints about the robustness of the manufacturing processes used to manufacture your products. Process robustness leads to: Higher efficiency Increased profit Less regulatory hassles Happier employees Robustness can be done right if you start at the beginning of development. We have the tools to do it better and more efficiently. Starts with ICH Q8 and Q9

3 Process Robustness Principles 1. Definition 2. Critical Quality Attributes 3. Critical Process Parameters 4. Process and Material Variability 5. Tolerance Limits 6. Operating Ranges: Normal, Known operating space, relation to ICH Q8

4 What is robustness? The ability of a process to demonstrate acceptable quality and performance while tolerating variability in inputs. Many factors affect robustness: Formulation Materials Measurements People Environmental conditions Place in development process

5 Critical Quality Attributes (CQAs) CQAs are quantifiable properties that are critical to the safety, efficacy, and purity of the intermediate and final product. Other attributes may be described as Key Attributes, not critical, but important in the manufacture of the product. Some disagreement about what is and isn t CQA. Each company has its own philosophy. Important to be able to defend list of CQAs for each product. Unnecessary CQAs can be troublesome-choose carefully.

6 Critical Quality Attributes Examples (tablets) Product Attributes Assay Content Uniformity Dissolution Appearance Tablet Hardness Thickness Weight Uniformity Friability Yield Moisture Blend Particle Size Stability CQA X X X X X

7 Critical Process Parameters (CPP s) Process input variable that must be maintained within a proven acceptable or predetermined range in order to ensure that an intermediate or final product will be within its CQA limits. Generally does not include factors that are related to efficiency, yield, safety/health/environment, business objectives unless the factor affects product quality or is a GMP concern, e.g. yield.

8 Variability Sources include equipment, raw materials, human factors, testing methods, manufacturing procedures. Important to control as many as possible Understanding raw materials and specification is important: compendial testing, manufacturing process, stability, interactions. Procedures and methods: Must be clear and easy to reproduce.

9 Tolerance Limits Understanding of tolerances comes from experimentation (DOE) and experience. Best to have ranges for as many variables as possible, but not practical. Decide which ones are more important (QRA) Some cannot be determined because no method can determine the difference. Only downstream processing and testing might work, e.g. blend uniformity of a non-flowing mixture.

10 Operating Ranges Zone Proven acceptable range or design space may not fill the operating range completely

11 Operating Ranges Zone marked in Yellow ( Zone) represents the level of assurance that the normal operating is far/near the level of failure. Development plan should be designed to maximize this distance. Maximizing this distance will generate process understanding. Risk assessment, statistical tools, DOE (ICH Q9) are helpful in understanding which processing parameters need more work in maximizing the distance between the NOR and PAR ( Zone).

12 Developing a robust process- Development During development knowledge increases from near zero to nearly complete. Preferred tool to document and guide development teams is risk assessment at key stages ICH Q9.

13 ICH-Q9 Initiate Risk Management Process Risk Assessment Risk Identification Re-evaluation Risk Analysis Risk Evaluation Risk Management tools Risk Control Risk Reduction Risk Acceptance unacceptable Risk Communication Risk Review Risk Communication acceptable Risk Acceptance Output / Results of the Risk Management Process Review Events

14 Steps for Developing A Robust Product 1. Form the team 2. Define the process (process flow diagram, inputs, outputs) 3. Prioritize experiments 4. Analyze measurement capability 5. Identify functional relationships 6. Identify critical quality attributes and critical process parameters 7.Identify the design space.

15 Steps for Developing A Robust Product 1. Form the team Teams should be multidisciplinary including formulators, engineers, analysts, statisticians, and other scientists. Team membership should be flexible as development proceeds. Team should include those with knowledge of development and large scale manufacturing Team s focus should change as development proceeds over time.

16 Steps for Developing A Robust Product 2. Define the process Process takes shape as development progresses Process diagram is a must; basic version in IND Process diagram should reflect process at a given time Process diagram basis for QRA and other activities related to product Helps in focusing the CPPs and CQAs

17 Process Diagram

18 Steps for Developing A Robust Product 3. Prioritize experiments Speeds development. Provides clarity. More efficient use of resources. Quality Risk Assessment (FMEA, PHA, or similar) Helps in prioritizing areas needing work Provides written record of thinking into developing product Another history of development process Reports

19 ICH-Q9 Risk Assessment Initiate Risk Management Process Risk Identification REPORTS DATA EXPERIMENTS Re-evaluation Risk Analysis Risk Evaluation Risk Management tools Risk Control Risk Reduction Risk Acceptance unacceptable Risk Communication Risk Review Risk Communication acceptable Risk Acceptance Output / Results of the Risk Management Process Review Events

20 PHA Example more appropriate for early stages Uncertain Event Handing of high hazard materials in Product Development Risk/Opportunity Description Example: Decontamination procedures not clearly defined Threat Opportunity Probability Impact T H H 16 Product Mitigation or Maximization Review decontamination procedures for other sites, put procedures in place for decontamination which are proven to eliminate risk for decontamination Wider training required, risk of inexperienced operators and eliminate fear of unknow Further monitoring required for clarification that bags can be used reproducibly Documentation: protection of batch records, laptops, log books, calculators, pens, etc T M L 6 Completed department training T M M 9 Budgets need to be agreed upon for further testing to ensure consistent use of containment and generation of data from monitoring. Is there a cheaper way to get monitoring? T M L 6 More investigation required Mitigation procedures if containment breached, fogger use, evacuation of room, training on procedures, containing Safety, working alone New containment design speeds processing by 50% T H H 16 O H H 16 Portable door entry system, modular degowning rooms Document time savings by manufacturing batches, report results to R&D management, present results at meetings like Interphex

21 FEMA Example More appropriate for later stages

22 Summary bar graph FEMA example Needs more attention

23 Steps for Developing A Robust Product 4. Analyze measurement capability Understanding of the measurement capability is key to process understanding and troubleshooting Analytical procedure capabilities are generally well known. Process measurements such as temperature, speed, etc are more exact. Other types of measurements may not correlate as well, e.g. motor load analysis. Some measurement values may need mathematical treatment.

24 Steps for Developing A Robust Product 5. Identify functional relationship between inputs and outputs Key to understanding process. Relationship is usually complex. Requires Design of Experiments (DOE) to understand or at least relate input and outputs DOE saves time and resources; more efficient than studying 1 variable at a time. Helps in planning experiments and using resources.

25 Steps for Developing A Robust Product 6. Confirm CQAs and CPPs CPPs are developed from Steps 2 & 5. List becomes more complete during development. List should be complete when manufacturing ICH stability batches. May need adjustment at tech transfer-more work at small scale maybe needed later based on large scale experience (stuff happens!). Clearly noted in development reports especially final development report and tech transfer report.

26 Steps for Developing A Robust Product 7. Identify the Design Space Culminates from all development work. Should be complete or nearly complete for tech transfer. Develops over the development process. May change during tech transfer. Information needed for NDA/MAA. Key to understanding manufacturing process along with gaining efficiencies and cost savings.

27 Technology Transfer Success depends on how well characterized the formulation and process are at time of tech transfer. Changes to some operating parameters may require change during tech transfer. Should challenge operating parameters, CPPs, and CQAs. Based on tech transfer data, adjustments to operating parameters, CPPs, and CQAs should be done before validation. After validation, a new risk assessment should be completed (Did I mention ICH Q9?).

28 Manufacturing Process Robustness Very important to maintain to keep costs down and minimize risk of OOSs, 483s, shortages, etc. Requires effort and commitment from management. Has significant payoff when problems do arise. 3 parts to maintaining robustness Monitoring Product improvement Facility/plant improvement

29 Manufacturing Process Robustness: Monitoring (1) Important part of manufacturing, but not commonly done correctly - usually done as a reactionary response, not as a proactive activity. Data and labor intensive (easier to do over time). Requires participation of many disciplines, e.g. engineers, analysts, statisticians, QA, etc. Typical tools used are: C p /C p k Control charts for key values (process parameters and product characteristics) Trend charts

30 Manufacturing Process Robustness: Monitoring (2) A tool that could be better used: Quality Risk Assessment: Continues QRA from Tech Transfer (ICH Q9) Organizes improvement and troubleshooting projects Should be held at regular intervals and after any improvements or changes Brings out hidden problems Prioritizes product improvement projects Creates a written record of projects related to product

31 Manufacturing Process Robustness: Product Improvement Problems identified by OOSs, trending, or QRAs. Root cause must be identified. Tools for investigation: QRA reports Ishikawa diagrams Kepner-Tregoe Statistical analysis: trending and other data Pareto charts

32 Ishikawa Diagram

33 Manufacturing Process Robustness: Facility Improvement Plan Monitoring and improvement of items related to all products (common items). These include: Personnel training/assessment Facilities (e.g. layout, systems) Materials Calibration and Maintenance Batch records (Are they clear? More detail doesn t lead to better execution.) Quality program-integration of findings. Studies of equipment variation vs operator variation (Repeatabity & Reproducability).

34 Conclusion (1) Robustness is the ability of a process to demonstrate acceptable quality and performance while tolerating variability in inputs. Process robustness starts at beginning of the development and continues through the life of the product. Principles of ICH Q8 and Q9 are key to developing and maintaining a robust process. Critical Quality Attributes are related to safety, efficacy, and purity; other attributes maybe described as key attributes.

35 Conclusion (2) Critical process parameters are process input variables that ensure the product/intermediate within CQA limits Steps for developing a robust product 1. Form the team 2. Define the process 3. Prioritize experiments 4. Analyze measurement capability 5. Identify functional relationships 6. Identify critical quality attributes and critical process parameters 7.Identify the design space.

36 Conclusion (3) Development of a robust product continues into tech transfer and validation-changes to CPPs, CQAs, and key parameters may be necessary at scale-up. Robustness is maintained by: Monitoring Product improvement Facility improvement Developing and maintaining robustness is a process that requires long term commitment.

37 References (1) 1. Process Robustness, PQRI White Paper, Draft 2. Process Robustness - A PQRI White Paper, Pharmaceutical Engineering, November/December 2006, Vol. 26, No. 6. ( Making Risk Assessment Part of Technology Transfer, Presentation at Interphex 2012, New York, New York, 1 May How to Define Design Space, Lynn Torbeck, pharmstat.com/files/design-space.ppt

38 References (2) 6. Quality Risk Management, ICH Q9, /Scientific_guideline/2009/09/WC pdf 7. Quality Risk Management for the Pharmaceutical Industry, Kirupakar, B.R., 8. Pharmaceutical Development, ICH Q8, s/guidelines/quality/q8_r1/step4/q8_r2_guideline.pdf

Control Strategy. Implementation of ICH Q8, Q9, Q10

Control Strategy. Implementation of ICH Q8, Q9, Q10 Implementation of ICH Q8, Q9, Q10 Control Strategy International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Introduction Structure of this session