QbD.pptx

Explanation about quality by design c0ncept

1. Quality by Design CONTENTS: Introduction Aim Benefits Drawbacks Steps to implement QbD Elements of QbD Tools of QbD Applications of QbD

2. INTRODUCTION : Defined as a systematic approach to development that begins with predefined objectives emphasizes product and process understanding and process control, based on sound science and quality risk management. The concept of Quality by Design (QbD) was first mentioned by J.M. Juran , an American Engineer in his book on " Juran on Quality by Design.“ Januvia ~ 1 st drug to be developed based on QbD by Merck and company The concept was first adopted to automobiles, telecommunication, aviation industries, by 1990s adapted to medical device manufacturers and by 20004 the concept entered pharmaceutical industry

3. AIMS OF QbD : To acheive predetermined or targeted product quality specifications. To reduce the defects and failure of the end product by understanding product design and controls. To Enhance process and product development efficiencies. To Manage the root cause analysis and post-approval management

4. BENEFITS OF QbD: Better process understanding. Eliminate the batch failure. Ensure better design. Empowerment of technical staff. Continuous improvement. Organizational learning. Avoid regulatory problems. Increases the manufacturing efficiency.

5. STEPS INVOLVED IN IMPLEMENTING QbD

6. 1) QUALITY TARGET PRODUCT PROFILE {QTPP}: The QTPP is an essential component of a QbD strategy, which forms the basis for product design. QTPP is a prospective review of drug product quality, which is to be achieved, taking into account drug product safety and efficacy. The QTPP discusses how the quality, safety, and efficiency of a given drug product for the patient can be ensured. For Abbreviated New Drug Applications (ANDAs), a target should be defined at an early stage in development based on the Drug substance's properties, Reference Listed Drug (RLD) product characterization, RLD label consideration Target patient profile

7. QTPP may include the following Intended use in a clinical setting. Route of administration. Dosage form. Dosage strength(s) Container closure system. Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics ( eg . dissolution, aerodynamic performance); Drug product quality criteria ( eg. sterility, purity, stability, and drug release) When new information is collected during the development process, the QTPP can either modified or changed at different stages of its growth.

8. 2) CRITICAL QUALITY ATTRIBUTES {CQA} ~ CMA & CPP After the identification of QTPP, the next step is to identify the relevant CQAs. CQAs including physical, chemical, biological, or microbiological properties or characteristics of an output material (finished drug products) which should be in prescribed limits for the quality performance of the product. CQA includes Impact of attribute is based on the degree of harm to patient if pdt . limit exceeds the limit Identity Microbial limits Test Color Content uniformity Odor Product degradability Shape Residual solvents Morphology Drug release Friability Moisture content Score

9. a) CRITICAL MATERIAL ATTRIBUTES {CMA}: For developing a robust drug product with intended CQAs, consideration of the physical chemical, and biological CMAs of the drug substance and inactive ingredients is crucial. CMA includes PHYSICAL PROPERTIES particle size, shape, surface area, volume, density, solid-state, polymorphic form, melting point, hygroscopicity, intrinsic/aqueous solubility, and stability CHEMICAL PROPERTIES pKa , reactivity, hydrolytic, oxidative and photolytic stability. BIOLOGICAL PROPERTIES partition coefficient, permeability, bioavailability, and toxicity

10. EXAMPLE 0F CMA If the product is an immediate-release formulation, one must have to concentrate on the drug substance material attribute such as size, shape, and polymorphic forms. These attributes have a significant impact on the quality attribute 'dissolution' as less particle size has more dissolution and vice versa. In solids forms, the amorphous form has more solubility and less melting point than that of crystalline structure . However , crystalline solids are more preferred due to their stability. ICH Q8 recommends drug-excipient compatibility during the early phases of drug development for improved stability. and hence shelf-life of the product.

11. b)CRITICAL PROCESS PARAMETERS: Critical process parameters (CPP) are defined as "parameters whose variability have an impact on a CQA and therefore should be monitered / collected to ensure the process and to produce the desired quality. Process robustness is defined as the ability of a process to demonstrate acceptable quality and performance and tolerate variability in its of the same time. To demonstrate the reproducibility and consistency of a process, process capability should be studied. Process capability is a statistical measure of the inherent process variability for a given characteristics. Process capability index ( CpK ) = Upper Limit - Lower Limit 6 σ standard Deviation

12. A pharmaceutical production process usually involves several unit operations to produce the necessary products with quality. Operations in batch mode or a continuous production process may be performed. The process involves physical or chemical changes such as milling, mixing, granulation, drying, compression, and coating. The manufacturing process improvement plan should define any critical process parameters which need to be checked or managed to ensure the output is of the required qualities. A process is generally considered well-understood when the critical sources of variability are identified, managed, and controlled. The input operational parameters ( eg. speed and flow rate) or the process state variables ( eg , temperature and pressure) of a unit operation are referred to as process parameters .

13. Steps to establish CPP and CMA Identify all possible known material attributes and process parameters that could impact the performance of the product and process. Use risk assessment and scientific knowledge to identify potentially high-risk material attributes and process parameters. Establish levels or ranges of these potentially high-risk material attributes and process parameters. Using DoE, Design and conduct experiments. Analyze the experimental data. Link CMAS and CPP to CQAs when possible. Develop a control strategy .

14. 3)QUALITY RISK MANAGEMENT {QRM}: As there are many CMAs and CPPs that may impact the CQAs of the intermediate and finished drug material Formulation scientist can't examine all the content characteristics described in the formulation optimization studies. QRM help identify the significant attributes and parameters to study further. The exam will depend on existing scientific expertise and the abilities of the formulator

15. QRM is defined as the systematic process for the assessment, control, communication, and review of risks to the quality of the drug product across the product lifecycle. -ICH guidelines Q8 QRM helps in identifying the extent of the impact of CMAS and CPPs on CQAs; therefore, it is an integral part of QbD . The initial list of potential parameters which can affect CQAs can be quite extensive but can be reduced and prioritized by quality risk management(QRM ).

16. 4) DESIGN SPACE : After screening and justifying different quality attributes using QRM, the evaluation of boundaries in newly designed and operational space should be specified to predict the probability of failure of any factor concerning quality objectives for the final products. When such analyzes take place in carefully planned experimental studies, an integrated connection between the material attributes CMA, process parameters CPP, and product attributes can be more readily established. Design space is defined as the multidimensional combination and interaction of input variables ( eg. material attributes) and process parameters that have been demonstrated to assure quality. -ICH guideline Q8

17. EXAMPLE 0F DESIGN SPACE: A tablet preparation consists of the unit operations of milling, mixing, granulation, drying, and compression . In this instance, the scientists have the choice of creating separate design spaces for one or more operations or a single, multi-operative design. Although a different design space is often more comfortable to develop for each unit operation individually, a design space that spans the entire product life cycle may offer greater operational versatility . Design space is proposed by the applicant and is subject to regulatory assessment and approval . The movement out of the design space is considered to be a change and that would normally initiate the regulatory post approval change process . METHODS TO PRESENT: Graphs , Linear combination of parameters, equations, parameters

18. 5)CONTROL STRATEGY: Controlled strategy is defined as the planned set of controls derived from the current product and process understanding that assures process performance and product quality. - ICH guidelines Q10 To keep producing the product of the required quality consistently, a control strategy is designed. It is necessary to describe and clarify how raw materials (APIs and excipients) relate to the final product quality and intermediates (in-process materials) controls package closure processes drug components

19. Control strategy includes , Control of input material attributes ( eg. drug substance, excipients, primary packaging materials Product specification Controls for unit operations that have an impact on product quality ( eg. the impact of drying on degradation, the particle size distribution of the granulate on dissolution0 In-process or real-time release testing instead of end-product testing ( eg. measurement and control of CQAs during processing) A monitoring program

20. 6) PRODUCT LIFECYCLE MANAGEMENT Using the product lifecycle, manufacturers may analyze novel strategies to maximize product quality The product performance can be tracked and ensured its working according to the design space to generate characteristics of product quality This tracking could include trend analysis of the production process A set of tasks performed by the applicant to enhance production capacity to meet criteria is continuous improvement which may include defining the problem & project goals, measuring the critical aspects of the process, analyze the data to establish the cause & relationship further improvement/ optimization of the current process control over the deviation from the target

21. TOOLS OF QUALITY by DESIGN: Risk management methodology Steps: Risk assessment Risk control Risk review 2. Process analytical technology

22. 1.QUALITY MANAGEMENT METHODOLOGY : QRM definition as per ICH Q8. Risk assessment tools can be used to identify and level parameters ( eg. process, equipment, input material) with potential to have an impact on product quality based on prior knowledge and primary experimental data. Steps of Risk Management: Risk assessment Risk control Risk Review

23. a) Risk assessment: Systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. It is the first step of quality risk management process COMPONENTS: Risk identification Risk analysis Risk evaluation

24. 1.RISK IDENTIFICATION: The systematic use of information to identify potential sources hazards that are referring to the risk question or problem description, which can includes of historical data, theoretical analysis, informed opinions, and the concerns of stakeholders. 2. RISK ANALYSIS: The estimation of the risk associated with the identified hazards. 3 RISK EVALUATION: The comparison of the estimated ride to given risk criteria using quantitative or qualitative scale to determine the significance of the risk.

25. RISK ASSESSMENT TOOLS: The pharmaceutical industry and regulators can evaluate and manage risks by using well-known risk management tools viz, Basic risk management facilitation methods Failure mode effects analysis Failure mode, effects and criticality analysis Fault tree analysis Hazard analysis and critical control points Preliminary hazard analysis Risk ranking and filtering Supporting statistical tools

26. a) Basic risk management facilitation method Flow charts, check sheets, process mapping, case and effect diagrams, etc., are the most commonly used and simple method for RA and management. Process mapping is a technique which relates critical process parameters and/or critical material attributes and critical product quality to a response surface derived from an experimental data. Cause effect diagram or also called Ishikawa diagram or Fishbone diagram. The diagram will be having horizontal line, the end - product quality. diagonal lines-Major influencing factors sub lines for the diagonal lines – Influence of critical process parameters & critical material attributes Examples of basic fish bone diagram.

27. b) Failure mode effects analysis This tool can be used to identify any inadequacies in the development of the product. The method systematically identifies, prioritizes, and estimates the risk and prevents failure. The risk involved in changing a process can also be limited using failure mode effects analysis (FMEA) c)Failure mode, Effects and Criticality analysis Failure mode, effects, and criticality analysis mode and associated with manufacturing processes. This criticality analysis probability of failure modes This, criticality analysis is used to chart the probability of failure modes against the severity of their consequences

28. d)Fault tree analysis Fault tree analysis (FTA) is a structured, graphical, quantitative assessment tool which makes modeling of complex system easy. It is an excellent tool for evaluating multiple factors affecting product quality. It is used for both RA and monitoring Software can be used to calculate failure probabilities from fault trees. e)Hazard analysis and critical control points Hazard analysis and critical control points (ACCI) was approach for assuring product quality, reliability, and safety as means of prevention rather than finished product inspection HACCP can be used to identify and manage risk associated with physical, chemical, and biological hazards. HACCP is best utilized when product and process understanding is sufficiently comprehensive .

29. f) preliminary hazard analysis This can be used in the early stages of product development when there is little information on design details or operating procedures. Hazards identified in the preliminary hazard analysis (PHA) are usually further assessed with some other RA tools. g)Risk Ranking and Filtering : It is used for comparing and ranking risks. For each risk, multiple diverse quantitative and qualitative factors are evaluated. This is useful to prioritize manufacturing sites for inspection/audit by regulators or industry h)Supporting Statistical Tools : These are used for effective data assessment, determining the significance of the data, and decision making. It includes control charts (acceptance control charts, control charts with arithmetic average and warning limits, cumulative sum charts, Shewhart control charts, weighted moving average, etc.), design of experiments, histograms, Pareto charts etc.

30. b)RISK CONTROL Control includes decision making to reduce and / or accept risks. The purpose of the risk control is to reduce the risk to an acceptable limit C) RISK REVIEW At the final stage , the output / results of the risk management process should be reviewed to take into account new Knowledge and experience

31. 2) PROCESS ANALYTICAL TECHNOLOGY (PAT): PAT is defined as the system for designing, analyzing, and controlling manufacturing process through timely measurements of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. ~ FDA The process involves the identification of scientific and engineering principles and variables that affect product quality. PAT is useful in the reduction of cycle times, prevention of reject product and waste, real-time product release, greater use of automation and facilitation of continuous processing.

32. TOOLS FOR PROCESS ANALYRICAL TECHNOLOGY: # Multi variate tools for design, data acquisition, analysis # Process analyzers # Process control tools MULTI VARIATE TOOLS FOR DESIGN , DATA ACQUISITION,ANALYSIS: Management systems results in scientific understanding of the relevant multifactorial relationships. Design of experiments, response surface methodologies, process simulation; and pattern, recognition tools can be used a multivariate mathematical approaches PROCESS ANALYSERS: Process analyzers are able to provide much data. Real-time control and quality assurance during manufacturing are possible with modern process analyzers. It involves at-line, on-line, or un-line measurements PROCESS CONTROL TOOLS: According to PAT. a process end point is the achievement of desired material attribute rather than a time-defined and point. Process control tools ant used to ensure effective control of all products CQA. It also measures the ability and liability of process analyzers to measure critical attributes

33. Design of Experiments (DoE) Design of experiments (DoE) is a structured and organized method to determine the relationship among factors that influence outputs of a process. With the help of DoE maximum information can be obtained from a minimum number of experiments in a fraction of the time. It is a valuable tool for choosing experiments efficiently and systematically to give reliable and coherent information. Moreover DoE can be used for comparative experiments, screening experiments, response surface modeling, and regression modeling