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Quality by Design
- 1. QUALITY BY DESIGNIN PHARMACEUTICAL DEVELOPMENT Guided by: S. Rajarajan Assistant professor Department of Pharmaceutics Karnataka college of pharmacy Presented by: Mahesh Kumar Mishra M. Pharm (Pharmaceutics) 2nd Semester
- 2. CONTENTS Introduction QbDin product development Design space Important QbD aspects and development flow. QTTP DOE Manufacturing process development.
- 3. INTRODUCTION QUALITY The commonelement of the business definitions is that the quality of a product or service refers to the perception of the degree to which the product or service meets the customer’s expectations. The suitability of a drug product or a drug substance for its intended use. The term includes attributes such as identity, purity and strength.
- 4. QUALITY BY DESIGN A more systematic approach to development can include, for example, incorporation of prior knowledge, result of studies using design of experiments, use of quality risk management and use of knowledge management throughout life cycle of the product. Product quality life cycle is all about the practical means for the implementation of ICH guidance’s on ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk management) and Q10 (Pharmaceutical Quality System) based on sound scientific, engineering and business principles. It is the concept introduced by the ICH-Q8 guidelines, Aa a systemic approach to development that begins with predefined objectives and emphasizes product, process understanding and process control, based on sound science and quality risk management. Quality by Design (QbD) is emerging to enhance the assurance of safe, effective drug supply to the consumer, and also offers promise to significantly improve manufacturing quality performance.
- 6. What QbD doesin product development QbD identifies characteristics that are critical to quality from the perspective of patients, translates them into the attributes that the drug product should possess, and establishes how the critical process parameters can be varied to consistently produce a drug product with the desired characteristics.to consistently produce a drug product with the desired characteristics. For this the relationships between formulation & manufacturing process variables (i.e. CMAs of API and excipient and CPPs) and product characteristics (QTPP) are established and sources of variability identified (CQAs). This knowledge is then used to implement a flexible and robust manufacturing process that can adapt and produce a consistent product over time. The increased process knowledge and product understanding resulting from QbD can increase the efficiency of manufacturing processes; reduce product recalls and compliance actions, resulting in cost savings for product recalls and compliance actions, resulting in cost savings for pharmaceutical companies.
- 7. Cont….. By reducinguncertainty and risk, QbD can allow industry and regulators to focus their resources in the most critical areas. Because much more process understanding has been demonstrated and expressed in dossier. QbD filings also can help facilitate GMP inspections by the regulators and decrease the number of post- approval regulatory submissions required to make process changes. The QbD-based pharmaceutical manufacturing process will be adjustable within a design space, providing a robust process that is managed with a control strategy developed using modern process control methods (DOE) and enabling a lifecycle approach to verification/continuous process verification. Product specifications will be based on desired product performance characteristics and will be part of a risk- based quality control strategy. QbD principles increase product understanding and process knowledge.
- 9. What is QbDin brief Pharmaceutical QbD is a systematic, scientific, risk-based, holistic and proactive approach to pharmaceutical development that begins with predefined objectives and development and emphases product and processes understanding and process control. In other words …. A systematic and knowledge based scientific approach of maintaining CQAs by well defined control strategy and design space by establishing combination and interaction of CMAs and CPPs to provide predefined QTPP.
- 10. What is DesignSpace ? It is a multidimensional combination and interaction of input variables (CMAs––critical material attributes) and process parameters (CPPs––critical process parameters that have been demonstrated to provide assurance of quality. Most Important…. Out of Design Space Initiation of Post Approval
- 11. Important QbD Aspects& Development Flow… Defining Quality Target Product Profile (QTPP) Identification of Critical Quality Attributes (CQAs) : Critical/Non Critical. Identification of Critical Material Attributes (CMAs). Initial Risk Assessment for Drug Substance Attributes. Justification for Initial Risk Assessment for Drug Substance Attributes. Selection of Excipients (Provide Rationale / Justification). Excipients Compatibility Studies. Development of Q&Q formula for initial Formulation Development. Initial Risk Assessment for Formulation Components.
- 12. Cont….. Designing DevelopmentStrategies. DOE for Optimization of Formulation. Defining Design Space for CQAs, CMAs or Formulation Components. Pilot Bioequivalence Studies. Update of Initial Risk Assessment for Drug Substance Attributes. Update of Initial Risk Assessment for Formulation Components. Justify the Levels of Risks changed. Well Defined Control Strategy.
- 13. Cont….. Development ofManufacturing Process Initial Risk Assessment for Manufacturing Process DOE for Optimization of Manufacturing Process Defining Design Space for identified CQAs or CPPs Pilot Bioequivalence Study Justify the Levels of Risks changed Well Defined Control Strategy
- 14. Cont….. Scale-up fromLab to Pilot Scale & then Commercial Scale Pre-exhibit / Exhibit Batch Update of Initial Risk Assessment for Manufacturing Process Pivotal Bioequivalence Control Strategy for Drug Product Container Closure System Development Studies to be supported with Stability Studies
- 15. Defining Quality TargetProduct Profile (QTPP) It contains prospective summary of the desired product features with respect to quality, safety, efficacy. The QTPP is a product description that summarizes the characteristics expected during the development to respond to the therapeutic drug target. QTPP Element Target Justification Dosage form, Route of Administration, Strength, Pharmacokinetics, Stability, Drug product quality attribute, Container Closure system, etc. Product Specific Pharmaceutical equivalent requirement or specific
- 16. Identification of CriticalQuality Attributes (CQAs) and defining its criticality Summarize the CQAs on the basis of quality attributes identified as a target along with the justification for being CQA Drug Product CQAs: Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation Products, etc. QA of DP Target Is it CQA? Justification It should include product and process specific quality attributes Desired quality Based on impact of attribute on QTPP Statement should clearly justify the CQA criticality level scientifically as well as technically.
- 17. Identification of CriticalMaterial Attributes (CMAs) Physical characterization of Drug Substance Physical, pH-solubility, Hygroscopisity, MP, Flow, Solid State Form, Polymorphism, etc. Chemical Characterization of Drug Substance pH, pKa, Stability, etc. Biological Characterization of Drug Substance Partition coefficient, BCS, etc. --------to identify the CMAs.
- 18. Initial Risk Assessmentfor Drug Substance Attributes It involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based on safety and efficacy linked to scientific knowledge ultimately Drug Substance Attributes: Moisture, Hygroscopisity, Solubility, Flow, Chemical Stability, etc. Drug Product CQAs: Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation Products, etc. Drug Product CQAs Drug Substance Attributes A B C D X LOW Y MEDIUM Z HIGH
- 19. Important QbD Aspects& Development Flow… Selection of Excipients (Provide Rationale / Justification) Excipients Compatibility Studies Development of Q&Q formula for initial Formulation Development
- 20. Formulation Development….. DesigningDevelopment Strategies Design of Experiments (DoE) for Formulation Development (This information includes DOE implementation in Product Development by using commercially available DOE software e.g. Minitab, Design Expert, Stat Graphics, etc.) DOE should be carried out at, two main stages of Product development 1.To optimize formulation 2.To optimize manufacturing process
- 21. Design of Experiments(DoE) for Formulation Development Why DoE? To find answers of following common questions, 1.What is an optimum formulation? 2.How does the optimum change if changes are made to formulation or process? 3.Which variables is sensitive to the machine or process? 4.For performance consistency , what are the limits for these variables? 5.How one design can effectively troubleshoot the problem? To save Time, To Reduce Cost, To get Reliable Quality. The factors to be studied in a DoE could come from the risk assessment exercise or prior knowledge.
- 22. Cont….. DoE tobe apply and discuss in brief with respect to Design Steps as follows 1.Screening DoE: Selection of only vital factors from the factors identified in initial risk assessment. 2. Characterization DoE: Choice of experimental design which gives potential interactions in selected vital factors. 3.Performance of experiments. 4.Statistical analysis of data. 5.Conclusion along with recommendations if any. DoE in terms of factors, levels, response variables, design applied, significance and non significance (p-value)
- 23. Cont….. Three basicprinciples of statistical experimental designs, 1. Randomization By properly randomizing the experiments, the effects of uncontrollable factors that may be present can be “averaged out”. 2.Blocking It is the blocking arrangement of experimental units into groups (blocks) that are similar to one another. Blocking reduces known but irrelevant sources of variation between groups and thus allows greater precision in the estimation of the source of variation under study. 3.Replication It allows the estimation of the pure experimental error for determining whether observe differences in the data are really statistically different.
- 24. Design of Experiments(DoE) for Formulation Development Factorial Designs – Identify the vital factors that affect your process or product. Then you can make break through improvements. Response Surface Methods (RSM) – Find the ideal process settings. Achieve optimal performance. Mixture design techniques – Discover the optimal formulation. Combined designs - Combine process variables, mixture components and categoric factors in one design!
- 25. Manufacturing Process Development It involves identification of all possible known material attributes and critical process parameters that could impact the performance of the process. Initial Risk Assessment for Manufacturing Process: Risk assessment can be done for each unit operation of manufacturing process steps separately depends up on the critical considerations for process optimization. Based on the selected process and CMAs, Initial risk assessment can be done. (Stage of risk assessment is not fixed. Risk assessment is depends on the criticality of manufacturing process steps.)
- 26. Initial Risk Assessmentfor Manufacturing Process Manufacturing Steps: Mixing, Granulation, Lubrication, Compression, Coating, etc. Drug Product CQAs: Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation Products, etc. Drug Product CQAs Manufacturing Process Steps (Each unit operation process step should be cover) I J K L X LOW Y MEDIUM Z HIGH
- 27. CONCLUSION There isan ever growing need for better understanding of the formulation and process development by pharmaceutical scientists. Benefits of QbD application for both regulatory agencies and manufacturers have been proven. It is clear the QbD will become a necessity, therefore all the stakeholders should adapt to its implementation