Qb d 1
- 1. Quality by design: an overview of basic concepts and its applicability By, Mr. Gunjan Reddiwar
- 2. What is quality? Janet Woodcock(Director for the centre for Drug Evaluation and research) defined Pharmaceutical quality as a product that is free from contamination and reproducibly delivers the therapeutic benefit promised in the label to the consumer. FDA’s emphasis on quality by design began with the recognition that increased testing does not improve product quality. Pharmaceutical quality=ƒ(drug substance, excipients, manufacturing, packaging)
- 3. What is Quality by Design (QbD)? Systematic approach to development Begins with predefined objectives Emphasizes product and process understanding and process control Based on sound science and quality risk management Ref- ICH Q8(R1)
- 4. In a Quality by Design system: The product is designed to meet patient needs and performance requirements. The process is designed to consistently meet product critical quality attributes. The impact of starting raw materials and process parameters on product quality is understood. The process is evaluated and updated to allow for consistent quality over time. Critical sources of process variability are identified and controlled and appropriate control strategies are developed.
- 5. The International Conference on Harmonization of Technical requirements for Registration of Pharmaceuticals for Human use (ICH) has released certain documents for implementing QbD to ensure drug product quality. These include Pharmaceutical Development (ICH Q8), Quality Risk Management(ICH Q9) and Pharmaceutical Quality Systems (ICH Q10).
- 6. Current VS. QBD Approaches to Pharmaceutical Development
- 7. Pharmaceutical Development & Product Lifecycle
- 9. Elements of QbD Target the product profile Determine critical quality attributes (CQAs) Link raw material attributes and process parameters to CQAs and perform risk assessment Develop a design space Design and implement a control strategy Manage product lifecycle, including continual improvement
- 10. Quality Target Product Profile(QTPP): What is QTPP? – A set of elements that defines the drug product – The target or goal set in advance – A guide to Drug Product development What forms the basis for QTPP? – The RLD and its label – Applicable regulatory guidelines When to define QTPP? – At the start of development – Knowledge gained in development may change some elements
- 11. Components of QTPP Components related to safety, efficacy, identity, purity and potency Critical and non-critical components, e.g. – Critical: Assay, content uniformity – Non-critical: Appearance Fixed and variable components – Fixed elements must be present e.g. Dosage form, strength – Variable elements may have a range of acceptable values e.g. Tablet weight, assay
- 12. Quality Target Product Profile QTPP Element Target Justification Dosage form MR/IR Pharmaceutical equivalence requirement: Route of administration Oral Pharmaceutical equivalence requirement: Dosage strength X mg Pharmaceutical equivalence requirement: Dissolution Should be within appropriate limits Drug product quality attributes Identification Content Uniformity Drug Release Pharmaceutical equivalence requirement: Meeting the same compendial or other applicable (quality) standards (i.e., identity, assay, purity, and quality)
- 13. Critical Quality Attributes – CQAs CQAs are a subset of the QTPP Include critical parameters that are likely to change based upon variations in raw materials and processes -Identity test for dosage form – Not a CQA -Assay, Content uniformity – CQAs CQAs are monitored throughout the DP development. CQAs ensure that DP remains within safe and effective levels.
- 14. Critical Quality Attributes: Quality Attributes of the Drug Product Target Is it a CQA? Justification Physical Attributes Appearance Color and shape acceptable to the patient. No visual tablet defects observed. Color, shape and appearance are not directly linked to safety and efficacy. Therefore, they are not critical. The target shall be set to ensure patient acceptability. Odor No unpleasant odor In general, a noticeable odor is not directly linked to safety and efficacy, but odor can affect patient acceptability and lead to complaints. Size Similar to RLD (Innovator) Tablet size correlates to swallowability; therefore, it is critical. For comparable ease of swallowing as well as patient acceptance and compliance with treatment regimens, the target for tablet size and volume is set similar to the RLD Friability (whole) Not more than 1.0% w/w A target of NMT 1.0% mean weight loss is set according to the compendial requirement and to minimize post- marketing complaints regarding tablet appearance. This target friability will not impact patient safety or efficacy. Content Uniformity Uniformity of Dosage Units Variability in content uniformity will affect safety and efficacy of tablet. Drug Release Similar drug release profile as RLD similar drug release profile to the RLD so as to have same bioequivalence.
- 15. Risk Assesment Risk Assesment of Drug Substance Attributes Low Broadly acceptable risk. No further investigation is needed Medium Risk is accepted. Further investigation may be needed in order to reduce the risk. High Risk is unacceptable. Further investigation is needed to reduce the risk. Risk assessment of the drug substance attributes Drug Product CQAs Solid State Form Particle Size/ Bulk Density Hygroscopicity Solubility Process Impurities Physical Attributes (size) Content Uniformity Drug Release Table- Risk assessment of drug product CQA`s
- 16. Justification for the risk assessment Drug substance Attributes Drug product CQAs Justification Solid state Drug release The drug substance may convert to amorphous state. This transformation may impact the drug release therefore Tablets containing amorphous drug can crystallize during storage which can change the release profile of drug. Hygroscopicity Physical attributes If drug is Non-hygroscopic risk of sorbed water to impact tablet physical attributes, assay, C.U and drug release is (L/M/ H) C.U Drug Release Solubility Physical Attributes If the Drug substance solubility has no impact on tablet physical attributes, assay, risk may be (L/M/ H). If the Drug substance has high intrinsic dissolution rate and a high solubility may migrate polymer film and potentially impact the drug release profile HIGH risk. Assay Content Uniformity Drug release Process Impurity Physical attributes Assay Drug release The risk of process impurity in drug substance is LOW
- 17. Tools used in quality risk management Basic risk management facilitation methods (flowcharts, check sheets etc.) Failure Mode Effects Analysis (FMEA) Failure Mode, Effects and Criticality Analysis (FMECA) Fault Tree Analysis (FTA) Hazard Analysis and Critical Control Points (HACCP) Hazard Operability Analysis (HAZOP) Preliminary Hazard Analysis (PHA) Risk ranking and filtering Supporting statistical tools.
- 18. Failure Mode Effects Analysis (FMEA) FMEA relies on product and process understanding. FMEA methodically breaks down the analysis of complex processes into manageable steps. It is a powerful tool for summarizing the important modes of failure, factors causing these failures and the likely effects of these failures. Some benefits of performing FMEA analysis include higher reliability, better quality, increased safety and its contribution towards cost saving includes decreased development time and reduced waste and non value added operations.
- 19. Failure Mode Effects Analysis (FMEA)
- 21. Risk assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those. three fundamental questions are often helpful: 1. What might go wrong? 2. What is the likelihood (probability) it will go wrong? 3. What are the consequences (severity)? • Information can include historical data, theoretical analysis, informed opinions, and the concerns of stakeholders.
- 22. Quality Risk Management Process (Q9)
- 23. Risk analysis is the estimation of the risk associated with the identified hazards Risk evaluation compares the identified and analysed risk against given risk criteria Risk control includes decision making to reduce and/or accept risks. It should focus on the following questions: • Is the risk above an acceptable level? • What can be done to reduce or eliminate risk? • What is the appropriate balance among benefits, risks and resources? • Are new risks introduced as a result of the identified risks being controlled?
- 24. Design Space The multidimensional combination and interaction of input variables (e.g., material attributes and process parameters) that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval.
- 25. Design Space Determination • First-principles approach – combination of experimental data and mechanistic knowledge of chemistry, physics, and engineering to model and predict performance • Non-mechanistic/empirical approach – statistically designed experiments (DOEs) – linear and multiple-linear regression • Scale-up correlations – translate operating conditions between different scales or pieces of equipment • Risk Analysis – determine significance of effects • Any combination of the above
- 26. • Application of DOEs – Scope out initial formulation or process design – Optimize product or process – Determine design space, including multivariate relationships • DOE Methodology
- 27. Real Time Release Testing Real Time Release Testing (RTRT) is the ability to evaluate and ensure the quality of in-process and/or final product based on process data Typically includes a valid combination of measured material attributes and process controls
- 28. Control Strategy A control strategy is designed to consistently ensure product quality. Elements of a control strategy can include: –Control of input material attributes –Product Specifications –Controls for unit operations that have an impact on downstream processing or end-product quality –In-process or real-time release testing in lieu of end-product testing –A monitoring program for verifying multivariate prediction models
- 29. Control strategy
- 30. 1. Guidance for Industry: Q8(R2) Pharmaceutical Development 2. Guidance for Industry: Q9 Quality Risk Management 3. Guidance for Industry: Q10 Pharmaceutical Quality System 4. Guidance for Industry PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance 5. Quality by Design for ANDAs: An Example for Modified Release Dosage Forms 6. Quality by Design for ANDAs: An Example for Immediate Release Dosage Forms 7. GPhA presentations 8. Draft QbR updated References for QbD
- 31. Envisioning the Factory of Future