Quality by design pptx.pdf
- 1. J Club Presentation TOPIC NAME: Quality by Design for M. Pharmacy Submitted By: Name: Chaitali Agrawal Roll no:2350981204 M.Pharmacy (Pharmaceutical Regulatory Affairs) Submitted To: Dr. Sonia Dhiman Professor & HOD (PRA) Chitkara College of Pharmacy Chitkara University 1
- 2. CONTENT • Introduction • Concepts and Background of QBD • Advantages of QBD • Principles of QBD • Key Aspectsof QBD • Regulatory Aspects of QBD • Current Approaches for QBD • Six-Sigma Introduction • Six-Sigma Implementation • Tools and Techniques of Six Sigma • Benefits of Six-Sigma • Six-Sigma Adoption • Conclusion 2
- 3. Introduction • Quality Quality can not be tested into products it has to be built in by design. Quality means customersatisfaction in terms of service, product, and process. Many of these quality related activities reflect need for companies to excel in global competition. The features like performance, trustworthiness,robustness, ease of use, and service- ability have to built in the product and such product should be free from deficiencies. • Definition of QBD • Systematicapproach to development that begins with predefined objectives which emphasizes product and process understanding and process control, based on sound science and quality risk management. 3
- 4. Concepts and Background of QBD • During the industrial revolution, mass-production techniques came into light. Throughout these years the quality of the product was tested by the end product only. By 1930’s Shewart, an American Statiscian bought the approach that emphasize on the improvement of the quality of the process the lead us to the quality end product. Along with Shewart, Deming & Juran bought the concept of management into the quality. The history of Qbd with Pharmaceutical industry started in 1950s when J.M. Juran took over the management of Takeda Pharma, Japan. • In 2002 the Qbd was adopted by FDA’s regulatory framework for the 21st century “Quality SystemsApproach to Pharmaceutical cGMPs” and the ICH Q10 Guideline on “Pharmaceutical Quality Systems”– and then by pharmaceuticals. 4
- 5. Advantages of QBD • Benefits for industry 1.QbD helps in providing safer, quality, and more efficient drug products. 2. QbD helps in safer and faster drug development. 3. It provides a proper understanding of Critical process parameter and critical material attributes and their effect on the final quality of the drug product. 4. Using QbD helps companies achieve greater batch-to-batchconsistencyand reduces batch-to-batch variation. 5. The QbD approach builds quality into the manufacturing process by designing, and controlling the critical parameters. 6. It provides in-between checkpointsfor in-process evaluation of the product so that the root cause analysis is easy. 5
- 6. Principles of QBD • Principles of quality by design 1. Risk and knowledge-based decisions. 2. Systematicapproach for process development. 3. Continuous Improvement leads to “capable” processes. • ICH’s role in quality by design- ICH implemented 4 guidelines for maintaining the quality of pharmaceutical product development. Q8- Pharmaceutical Development Q9- Quality Risk Management Q10- Pharmaceutical Quality System Q11- Development and Manufacture of Drug Substances 6
- 7. Key Aspects Of QBD 7 611 × 581
- 8. The Target Product Quality Profile ( TPQP) • Defining the quality target product profile (QTPP) as it relates to quality, safety, and efficacy, considering e.g., the route of administration, dosage strength, container closure system, therapeutic moiety release, strength,and stability. It is a prospective summary of the ideal quality characteristics of the drug product taking into account safety & efficacy) will be defined based on the voice of patient. • It is an element for setting the target for drug product development. QTTP is worldwide used in development planning, and setting up of targets. Clinical strategies and commercialoutcomes,regulatory requirements,and risk management. • Examples of final quality targets that the product should always have to satisfy compliance: 8
- 9. QTPP elements Target 9 Solid Liquid Parenteral Dosage Form Uncoated, coated, The solution,suspension, emulsion Injection Dosage Design Immediate release, Modifiedrelease etc Immediate release formula Immediate release formula Route of administration Oral Oral, Topical Parenteral Dosage strength X mg X mg/ml X mg/ml
- 10. Critical Quality Attribute (CQAs) • “A property or characteristic that when controlled within a defined limit, range, or distribution ensures the desired product quality.” • CQAs are the physical, chemical, biological, or microbiological properties that should be within an appropriate limit, range or specification to ensure the desired product quality. • Potential CQAs are derived from the QTPP and guide product and process development. • CQAs are identified by quality risk management and experimentation to determine the effect of variation on product quality. 10
- 11. Determination of Critical quality attributes- Substance quality attributes Productquality attributes Is this a CQA? 11 Particle size Identification Solid state Assay Assay Organic impurity Impurity Inorganic impurity Uniformity of dosage Residualsolvent class Disintegration Water content Water content Essay Residualsolvent Hygroscopicity Microbiallimit YES
- 12. Risk Assessment • Identification of Critical material attributes and Critical process Parameters: • Risk assessmentis an important element used in quality risk management that can aid in identifying which critical material attributes and critical process parameters potentially have a significant impact on product CQAs. • Risk assessmentis typically performed early in the pharmaceutical development process and is repeated as more information becomes available and greater knowledge is obtained. • It can be further divided into three phases: 12
- 13. Three phases of risk assessment Phase 1 • Risk identification- material attributes and process parameters • are diagnosed using (process map or fishbone) Phase2 • Risk analysis- MA’s and PPs are analysed by relative risk-based • matrix analysis (RRMA) or failure mode and effect analysis Phase3 • Risk evaluation- Evaluation of risk based upon risk priority number (RPN Threshold) 13
- 14. Identification of Critical Process Parameter • Process Parameters which has a significant impact on the critical quality attribute, whose variation will directly impact the quality of the finished product. CPPs are responsible for ensuring the CQAs & it is identified from a list of potential CPPs using risk assessment. • Further, CPPs can be classified into 2 types • 1. Critical parameter- A realistic variation in parameter can cause the product to fail to achieve CQAs and QTPP. • 2. Non-critical parameter- No failure in QTPP determined within the potential operating space & no interactions with other parameters in the established suitable range. 14
- 15. Some of the Critical Process Parameters during tablet formulation- S. No ManufacturingProcess Step Input ProcessingParameter Output Quality Attributes 1 Co-sifting Screen size Milltype Sifting speed Particle size distribution Flowability Powder bulk density 2 Wet granulation Impeller speed Chopper speed Dry-mixing time Granule PSD Flowability 3 Drying Inlet air volume Inlet air temperature Filter type Granule PSD Loss on drying 4 Sizing Milltype Oscillationspeed Screen size Granule PSD Flowability Granule uniformity 15
- 16. Qualitative risk base matrix analysis- Can be further divided into 3 categories Low risk Broadly acceptablerisk Medium risk The risk may be acceptable,and may not impact product quality High risk Risk is unacceptableand will havesignificant impact on quality 16
- 17. Design space • Design space can be established by the implementation of the design of the experiment. It is the systematic series of experiments in which purposeful changes are made to input factors for screening and optimization of CMA’s and CPPs concerning CQA’s. • Methods for presenting design space included graphs (surface-responsecurves and contour plots), a linear combination of parameter ranges, equations, and models are: STEP 1 STEP 2 STEP3 STEP 4 STEP 5 17 Defining the objective Measuring CQAs Analyzing model Designing space Verifying design space
- 18. Continuous improvement throughout product life cycle • Product quality can be improved throughout the product life-cycle; companies have opportunities to opt inventive approaches to improve quality. Process performance can be monitored to make sure consistencyin quality. • The QbD approach avails the continuous improvement throughout products’ life cycle this is distinguishing point from the conventional method which is much frozen process. • Life cycle approach differs from that of the traditional approach of method development. According to Morefield it includes continuousimprovement of method performance and the design space allow flexibility for continuous improvement in analytical method can be done without prior regulatory approval because of design space made previously. 18
- 19. Analytical Method Development in QBD 19 Risk Assessment Continuous Improvement Pareto analysis Monitor method performance Technique Selection Control Strategy Method performance criteria Define control space Analytical Target Profile Method Development What where and when to measure DOE/Design space
- 20. Regulatory aspects of QbD • FDA perspective • FDA also statesthe importance of quality of pharmaceutical products by giving Process Analytical Technology (PAT)which is a Framework for Innovative Pharmaceutical Development,Manufacturing and Quality Assurance. • QbD ultimately helps to implement Q8 and Q9. FDA’s view of QbD is ‘‘QbD is a systematic approach to product and process design and development’’. • This concept was accepted by FDA in 2004 and detailed description was given in ‘pharmaceutical cGMPs for 21st century – a risk based approach’. • Product quality and performance can be assured by designing efficient manufacturing processes. • Risk-based regulatory approaches are for scientific understanding and control related process for product quality and performance. 20
- 21. Regulatory challenges and inspection • Traditionally, inspections have been conductedusing the FDA system-based approach and in accordance with CDER’s Compliance Program ‘‘Inspection of Licensed Bio-logical Therapeutic Drug Products’’. • The inspection will evaluate the quality system and its effectiveness regarding consistent productquality, change in control procedures, process improvements, deviation management, and knowledge and risk management during the product lifecycle. • But design, testing, and monitoring programmes that demonstrate robustness and consistencywould be highlighted. 21
- 22. Current approach of QBD 22 • Design of Experiment: • Design of experiment is a systematic method used to determine the relationship between factors affecting a process and the output of that process. • Using statisticalmethods like factorial designs and response surface methodologies to systematically explore the impact of process variables on the product quality. DOE helps in understanding the relationship between input variables and output responses. • Process Analytical technology: • PAT refers to a system for designing, analyzing and controlling manufacturing process through timely measurements of critical quality and performance attributes of raw and in process materials.
- 23. • This enables immediate adjustmentsif any deviations from the desired quality are detected. Multivariate data analysis: • Multivariate data analysis helps in identifying patterns, correlations, and outliers in large sets of data, aiding in process optimization. 23
- 24. Conclusion • Qbd is emerging as an important element providing significance for quality improvement. The objective of quality by design method in pharmaceutical product development is to formulate a reliable method that gives assurance of the ultimate quality and efficacy of the product and minimizes batch-to-batch variation or inconsistencyand to reduce errors. QbD is emerging as a promising scientific tool in quality affirmation in the pharmaceutical industry. Qbd successfullyprovides a layout or the path from the initial defining objective and finally successfully commercializes the product. 24
- 25. Six Sigma : Introduction • In contrast, Six Sigma tools rely on data-driven, statistical techniques, for example, Hypothesis Testing, ANOVA, Regression Analysis, and Statistical Process Control (SPC) while aiming to reduce variations and defects to improve process performance. • The DMAIC (Define, Measure, Analyze, Improve, Control) roadmap provides a structured approach to achieving these goals and isan integral part of Six Sigma. • The benefits of six sigma: 1)reduced cost (2) reduced errors/defects (3) improved product/service quality (4) reduced non-value-added steps (5)improved cycle time (6) increased customersatisfaction 25
- 26. Phases of Six Sigma Phase 1 Define Defining the targets or the objective of drug product development,these targets or objectives should be achieved to ensure the desired qualityof the drug product required for safety and efficacy. Phase 2 Measure Phase Measuring the critical quality attributesout of qualityattributes(QA’s) because deviationor out of specificationof CQA’s will have a definite impact on safety and efficacy of customer or patient. Phase 3 Analyze Phase Identifying critical process parameters (CPPs)and critical material attributes(CMAs) and further analyzingrisk factors through SIPOC, RRMA, FMEA, ANOVA. Phase 4 Improve Phase Designing the design of the experiment and developingand verifying design space. It can be done by first screening experiments and then optimizing experiments. Phase 5 Control Phase Implementationof controlstrategy and control critical factors with controlspace and continue improvement. 26
- 27. Six Sigma Implementation • Many of the publications suggest the Design, Measure, Analyse, Improve, Control (DMAIC) and the Design for Six Sigma (DFSS)methods as the two most common methodologies to implement Six Sigma. • While DMAIC is a problem solving method which aims at process improvement, DFSS is defined as “a process to define, design and deliver innovative products provide competitively attractive value to customers in a manner that achieves the critical-to-quality characteristics for all the significant functions”. • There are several variations for DMAIC (even if it remains the most commonly adopted methodology) such as P-DMAIC (Project DMAIC), E-DMAIC (Enterprise- DMAIC) and DMAICR (DMAIC Report). The differences are mostly in terms of the number and type of phases, rather than the tools used. DMAICR, for instance, adds the final step of “Reporting the benefits of the reengineered process” into DMAIC . 27
- 28. Tools and techniques of Six Sigma • Basic tools of DMAIC, typically used at the Yellow-Belt level of competenceinclude flowcharts, check sheets, Pareto diagrams, cause/effect diagrams, scatter diagrams, histograms and StatisticalProcess Control. • More advanced tools such as regression analysis (e.g. with indicator variables, curvilinear regression and logistic regression), hypothesis testing, control charts and Design of Experiments typically feature at the Black-Belt level. • Even though tools and techniques vary, it is essential to apply the right tool in the right situation in order to achieve successfulresults. 28
- 29. Flowchart 29
- 30. Checksheet 30
- 34. Histogram 34
- 36. Benefits of Six Sigma • Reduced costs,reduced project time, improved results and improved data integrity are some of the benefits of Six Sigma. • It could enhance product development cycles and process design, shorting product lead times by reducing the cycle time of the overall manufacturing process. • Six Sigma can be used to find and eliminate the root causes of the problem, so reducing the variability in the process in order to prevent defects. • There are also organisational implications. • Indeed Six Sigma methodologies provide guidelines which could help the workers understand how to carry out the job and train them to solve potential problems. 36
- 37. Six Sigma Adoption • The first generation of Six Sigma (1987-1994) was focused on reduction of defects and saw successwith Motorola. • The second generation (1994-2000) was concentrated on 15 cost reduction and was adopted by companies such as General Electric, Du Pont and Honeywell. • The third generation (2000 onwards) is oriented to creating value for the customers and the enterprise itself, and finds its application within companies like Posco and Samsung. • It also emerged that many large companies, e.g. Xerox, Fidelity Investments, integrate Six Sigma with other techniques such as Lean, Quality Management System and Kaizen/Continuous Improvement. 37
- 38. Conclusion • It is possible to identify four interpretations of Six Sigma: a set of statisticaltools, an operational philosophy of management, a business culture and an analysis methodology. • The main goals of Six Sigma, however, remain unchanged, i.e. improving efficiency, profitability and capability in the process. • The initial methodology of Six Sigma was focused on process improvement and accordingly DMAIC approach was universally adopted, but as time progressed, the need of implementing Six Sigma at design stage of product (or process) was felt crucial and hence the concept of Design for Six Sigma (DFSS) was developed. 38
- 39. THANK YOU 39