Quality by Design

A comprehensive learning on the aspect of quality by design which is a tool used to produce more safe and effective pharmaceutical drug products.

1. QUALITY BY DESIGN UNIT I – CHAPT 4 Ms. TENY SARA THOMAS MOUNT ZION COLLEGE OF PHARMACEUTICAL SCIENCES AND RESEARCH, ADOOR, KERALA ASSISTANT PROFESSOR B.PHARM SIXTH SEMESTER PHARMACEUTICAL QUALITY ASSURANCE

2. CONTENTS Introduction Objectives of QbD Benefits of QbD Elements of QbD Steps of QbD Tools of QbD

3. INTRODUCTION The Pharmaceutical Quality by Design is a systematic approach to development that begins with predefined objectives an emphasizes product and process understanding and process control, based on sound science and quality risk management. 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.

4. OBJECTIVES OF QbD Achieve meaningful product quality specifications that are based on clinical performance. Increase process capability and reduce product variability and defects by enhancing product and process design, understanding, and control. Increase product development and manufacturing efficiencies. Enhance root cause analysis and post approval change management.

5. BENEFITS OF QbD Better understanding of the process Less batch failure Return on investment or cost savings Reduction of post approval submissions More flexible regulatory approaches. E.g. – manufacturing changes within the approved design space without further regulatory review. Better innovation due to ability to impress processes without resubmission to the FDA. Less validation burden More drug availability and less recall Improved yields, lower cost, less investigations, reduced testing Time to market reductions

6. ELEMENTS OF QbD TARGET PRODUCT QUALITY PROFILE CRITICAL QUALITY ATTRIBUTES MATERIAL ATTRIBUTE DESIGN SPACE CRITICAL PROCESS PARAMETER CONTROL STRATEGY RISK ASSESSMENT

7. The Target Product Profile (TPP) has been defined as a – prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and thus, the safety and efficacy, of a product is realised. TARGET PRODUCT QUALITY PROFILE

8. A critical quality attribute (CQA) is a physical, chemical, biological, or microbiological property, or characteristic that should be within an appropriate limit to ensure the desired product CQAs are generally – drug substance Excipients Intermediates Drug product CRITICAL QUALITY ATTRIBUTES (CQA)

9. Material – raw materials, starting materials, solvents, process aids, intermediates, packaging and labelling materials. Attribute – a physical, chemical, or microbiological property Material Attribute – can be quantified, typically fixed, can sometimes be changed during further processing E.g. – porosity, moisture level, specific volume, impurity profile. MATERIAL ATTRIBUTES (MA)

10. A process parameter whose variability has an impact on a CQA and therefore should be monitored or controlled to ensure the process produces the desired quality. CPPs have a direct impact on CQAs Process parameter can be measured and controlled. Examples of CPP – temperature, cooling rate, rotation speed , pH, agitation, feed type, rate. CRITICAL PROCESS PARAMETER (CPP)

11. The multidimensional combination and interaction of input variables ( e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. Design space is proposed by the applicant and is subjected to regulatory assessment and approval. 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

12. DESIGN SPACE DETERMINATION First – principles Approach – combination of experimental data and mechanistic knowledge of chemistry, physics, and engineering to model and predict performance. Empirical Approach – statistically designed experiments – linear or multiple – linear regression. Scale – up Correlations – translate operating conditions between pieces of equipment. Risk analysis – determine significance of effects. Any combination of the product

13. Knowledge gained through designed development studies reaches a highest point which lead to establishment of a control strategy. Control strategy includes three levels of control:- Level 1 – uses automatic engineering control to monitor the CQAs. This level of control is adaptive. Input material attributes are monitored and process parameters are automatically adjusted. Level 2 – consists of pharmaceutical control with reduced end – product testing and flexible MA and CPP within the established design space. Level 3 – is a level of control traditionally used in pharmaceuticals. This level relies on extensive end – product testing and tightly constrained MAs and CPPs. CONTROL STARTEGY

14. Risk – is defined as the combination of the probability of occurrence of harm and severity of that harm. Risk Assessment – a systematic process of organising 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. RISK ASSESSMENT

15. STEPS of QbD

16. TOOLS OF QbD The concept of QbD has two components – the science underlying the design and the science of manufacturing. After understanding the elements an steps of QbD, it is important to be familiar with the tools of QbD – Design of Experiment (DoE) Process Analytical Technology (PAT) Risk Assessments (include about risk assessment as mentioned before)

17. A structured, organised method for determining the relationship between factors affecting a process and the output of that process – DoE. Excellent tool that allows pharmaceutical scientists Reasonable tool to determine the relationship between input and output. Can help identify the optimal conditions, CMAs. CPPs and design space DoE is effective in the design of different dosage forms and unit operations, Guarantee high research efficiency and improved product quality. DESIGN of EXPERIMENT (DoE)

18. PAT is defined as tools and systems that utilize real time or rapid measurements during processing, of evolving quality and performance attributes of in-process materials to provide information to ensure optimal processing to produce final product that consistently confirms to established quality and performance standards. PAT steps There is a 3 step process in the design and optimisation of drug formulations and manufacturing process – 1. Design stage 2. Analyze stage 3. Control stage PROCESS ANALYTICAL TECHNOLOGY (PAT)

19. Design step - in this step, experimentation is performed to understand which CQAs are related to a given unit operations and CPPs and MAs have the most impact on the final product quality. Here the TPP, CQA, and CPP are identified. Analysis step - in this step, identified the chosen CQA, CPP, and MA, all the parameters are monitored using direct or in-direct analytical methods with appropriate analytical tools. Control step – control strategies provide adjustments to ensure control of all attributes and set up the understanding of relationships among all the elements of QbD so as to decide what action to take in case the process performance deviates from the optimal path.