Quality by Design and Process Analytical Technology

Pharmaceutical Manufacturing Technology

1. QUALITY BY DESIGN (QbD) & PROCESS ANALYTICAL TECHNOLOGY (PAT) Presented By V. Manikandan, Roll No. 2061050002, M. Pharm (Pharmaceutical Quality Assurance) – I Year, Department of Pharmacy, Annamalai University. Submitted to Dr. R. Murali, M. Pharm., Ph. D, Assistant Professor, Department of Pharmacy, Annamalai University.

2. Pharmaceutical Quality Quality Acceptably low risk of failing to achieve the desired clinical attributes. Pharmaceutical Quality Any drug substance or drug product should be free of contamination and reproducibly delivering the therapeutic benefit promised in the label to the consumer.

3. Quality by Design The pharmaceutical Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based sound science and quality risk management. The product is designed to meet patient needs and performance requirements The process is designed to consistently meet product critical quality attributes. 3

4. 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. Appropriate control strategies are developed. Quality by Design

5. Involves product design and process development. Risk-based, science based. Primary focus is patient safety and product efficacy. Business benefits are also drivers. Results in improved process understanding. Results in improved process capability/robustness. Systematic development. Multivariate – interactions are modeled. Requires a significant reduction in regulatory oversight post approval. The characteristics of a successful QbD program

6. Current Approaches & Limitations Aspects Traditional QbD Pharmaceutical development Empirical; univariate Experiments Systematic; multivariate experiments Manufacturing process Fixed; validation on 3 initial full-scale batches; focus on reproducibility Adjustable within design space; continuous verification; focus on control strategy & robustness Process control In-process testing for go/no-go; offline analysis w/slow response PAT utilized for feedback & feed forward, real time Product specification Primary means of quality control; based on batch data Part of the overall quality control strategy; based on desired product performance Control strategy Mainly by intermediate and end product testing Risk-based; controls shifted upstream; real-time release Lifecycle management Reactive to problems & OOS; post-approval changes needed Continuous improvement enabled within design space

7. Why QbD is Required? Higher level of assurance of product quality. Cost saving and efficiency for industry & regulators. Facilitate innovation Increase manufacturing efficiency Reduce cost/product rejects Minimize/eliminate potential compliance actions Streamline post approval changes & regulatory processes and more focused inspections.

8. Advantages Steps Synthetic development (QbD) Analytical development (AQbD) 1 QTPP identification ATP identification 2 CQA/CMA identification, Risk Assessment CQA identification, Initial Risk Assessment 3 Define product design space Define process design space Method Optimization and development with DoE 4 Refine product design space MODR 5 Control Strategy with Risk Assessment Control Strategy with Risk assessment 6 Process validation AQbD Method Validation 7 Continuous process monitoring Continuous Method Monitoring

9. Systematic Approach Predefined objectives Define Quality Target Product Profile (QTPP) Identify Critical Quality Attributes (CQA) Product and process understanding Identify critical material attributes (CMA*) and critical process parameters (CPP) Establish the functional relationships that link CMA/CPP to CQA Process control Develop appropriate Control Strategy, including justifications Sound science Science-driven development (scientific literature, prior knowledge, DOEs etc.) Quality risk management Risk-based development (ICH Q9) Advantages

10. Elements of QbD

11. Elements of QbD ICH Q8(R2) Pharmaceutical Development: Provides information on how to present knowledge gained when applying scientific approaches and quality risk management for developing and manufacturing a product. ICH Q9 Quality Risk Management: Provides information regarding systematic approaches to quality risk management.

12. ICH Q10 Pharmaceutical Quality System: Establishes a new ICH tripartite model for an effective quality management system for the pharmaceutical industry. The model is referred to as the Pharmaceutical Quality System (PQS). ICH Q11 Development and Manufacture of Drug Substance: Apply for small and large. Is focused on risk analysis and design space for reliable drug quality. Elements of QbD

13. Quality Target Product Profile (QTPP) A natural extension of Target Product Profile for product quality. Quality characteristics (attributes) that the drug product should possess in order to reproducibly deliver the therapeutic benefit promised in the label. Guide to establish formulation strategy and keep the formulation effort focused and efficient.

14. Critical Material Attribute (CMA) A physical, chemical, biological or microbiological property or characteristic of an input material that should be within an appropriate limit, range, or distribution to ensure the desired quality of output material.

15. Critical Quality Attribute (CQA) A quality attribute that must be controlled within predefined limits to ensure that the product meets its intended safety, efficacy, stability and performance.

16. Critical Process Parameter (CPP) A process parameter that must be controlled within predefined limits to ensure the product meets its pre-defined quality attributes. Example: Tablet – Granulation, Oral Liquids – Mixing, Aerosol – At the same dose released from last spray.

17. Reference Listed Drugs (RLD) A Reference Listed Drug (RLD) is an approved drug product to which new generic versions are compared to show that they are bioequivalent. A drug company seeking approval to market a generic equivalent must refer to the Reference Listed Drug in its Abbreviated New Drug Application (ANDA).

18. Target Product Quality Profile

19. Product and Process Design Development Define desired product performance upfront; Identify product CQAs Design formulation and process to meet product CQAs Risk Assessment and Risk Control Continually monitor and update process to assure consistent quality Identify and control source of variability in material and process Understand impact of material attributes and process parameters on product CQA s Product and Process Design Development

20. Desig n 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 (ICH Q8). 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.

21. Establishment o f a Design Space Relationship and interaction between CPPs and CQAs. Identification of those process parameters which can influence the quality of the product. Multivariate analysis in order to demonstrate within which ranges process parameters can be varied without affecting the quality of the product (quality attributes).

22. Elements o f a Design Space Selection of variables: Linkage and effect of process parameters and material attributes on product CQAs. Identifying variables and their ranges within which consistent quality can be achieved. Describing a design space in a submission. Unit operation design space(s). Relationship of design space to scale and equipment.

23. Elements o f a Design Space Design space versus proven acceptable ranges: A characterized range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria. Design space and edge of failure. Control strategy.

24. Design of Experiment (DoE) A systematic, planned approach to solving problems by gaining information through carefully planned experiments or studies. These studies have adequate statistical properties to be able to accurately measure the effects of formulation & process factors on the key response variable(s) (i.e., dissolution, content uniformity,etc.) and tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects.

25. Design of Experiment (DoE)

26. Key Steps for Design of Experiment (DoE) Set objective. Select process variables. Select an experimental design. Execute the design. Check that the data are consistent with the experimental assumptions. Analyze and interpret the results.

27. Risk Assessment Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm . A 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.

28. Risk Assessment Questions What might go wrong? What is the likelihood (probability) it will go wrong? What are the consequences (severity)?

29. Risk Assessment

30. Risk Assessment

31. Mitigation In general, mitigation means to minimize degree of any loss or harm. In insurance contracts, various clauses and conditions are specified so as to ensure minimum losses to the insurer. The actuaries are entrusted with the responsibility of underwriting the insurance policy. They employ a variety of quantitative techniques in order to assess the risk associated with the insured and decide the appropriate premiums commensurate with the risk. The primary objective of the exercise is to mitigate the risk ingrained with the insured.

32. Minimization Pharmaceutical risk-minimization programs are public health interventions that are legally mandated in certain countries as part of the pharmacovigilance strategy for specific drugs. In essence, such programs are intended to achieve a positive benefit-to-risk balance for these medications by ensuring that “the right prescriber provides the right drug to the right patient at the right dose and at the right time” under ‘real-world use’ conditions.

33. Minimization Risk-minimization programs are often needed to gain more insight into potentially concerning aspects of a product’s safety profile. These programs can also enable regulators to address unmet therapeutic needs by providing access to medicines which, due to the significant risk(s) they pose to patients, might not otherwise have been approved or permitted to retain their marketing authorization.

34. Formulations in QbD Even though the pharmaceutical industry has focus on quality, it has failed to keep up with other industries in terms of manufacturing efficiency and productivity. Current scenario in the Pharmaceutical Industry: Cost of revalidation Off‐line analysis for in‐process ‐ need based Product specifications as primary means of control

35. Unpredictable Scale‐up issues Inability to understand failures Systematic approach to development: That begins with predefined objectives Emphasizes products and process understanding Process control Formulations in QbD

36. Formulation and Design Development Not all prototype formulations can be evaluated in human subjects, which mean that developing sensitive in vitro dissolution methods is crucial to an effective development program. Manufacturing Process Design And Development: Process development and formulation design cannot be separated because a formulation cannot become a product without a prescribed process.

37. Formulation and Design Development Process design is the initial stage of process development, in which an outline of the commercial manufacturing processes is documented, including the intended scales of manufacturing. The outline should include all the factors that need to be considered for the design of the process, including facility, equipment, material transfer, and manufacturing variables. Other factors to consider during process development are the QTPP and CQAs.

38. QbD For Drug Products Quality characteristics (attributes) that the drug product should possess in order to reproducibly deliver the therapeutic benefit promised in the label guide to establish formulation strategy and keep the formulation effort focused and efficient .. It facilitates identification of what’s needed/critical for the patient/consumer in the Quality Target Product Profile(such as Critical Quality Attributes, CQAs)

39. A drug product designed, developed and manufactured according to Quality Target Product Profile with specification (such as dissolution/release acceptance criteria) consistent with the desired in vivo performance of the product. QbD For Drug Products

40. QbD For Drug Substance Drug substance means “an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates use in the synthesis of such ingredient.” 

41. QbD For Drug Excipient “The word excipient is derived from the Latin  excipere , meaning ‘to except’, which is simply explained as ‘ other than ‘. Pharmaceutical excipients are basically everything other than the active pharmaceutical ingredient. Ideally, excipients should be inert, however, recent reports of adverse reactions have suggested otherwise.” 

42. Process Analytical Technology (PAT) “A system for designing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes for raw and in process materials and also processes with the goal of ensuring final product quality into the product and manufacturing processes, as well as continuous process improvement. Process analytical technology (PAT) has been defined by the United States Food and Drug Administration (FDA) “as a mechanism to design, analyse, and control pharmaceutical manufacturing processes through the measurement of Critical Process Parameters (CPP) which affect Critical Quality Attributes (CQA)”.

43. Process Analytical Technology (PAT) PAT is a system and application at following sites Designing, analysing and controlling manufacturing. Timely measurements. Critical quality and performance attribute. Raw and in-process material. End processes. RM Testing (warehouse based).

44. Packaging Components. Blending (at- line or on- line). Drying. Tableting (potency and CU). Encapsulation (Coating thickness). Packaged product. Equipment cleaning. Equipment cleaning (surface monitoring). Process Analytical Technology (PAT)

45. The objective for PAT implementation could be one or more of the following  Better process understanding Improved yield because of prevention of the scrap, rejects, and reprocessing Real-time release of the batches From an implementation perspective, perhaps, PAT can be visualized as the three-step process. The design phase starts early in process development when the given unit operation is being designed and then later optimized and characterized. Process Analytical Technology (PAT)

46. In this phase, the critical quality attributes (CQA) that are being affected by the process step are identified along with the critical process parameters (CPP) that have been determined to affect the CQA. This process understanding is the essence of PAT and critical for the next two phases. Discuss the need for general FDA guidance to facilitate the implementation of the PAT. Process Analytical Technology (PAT)

47. Process Analytical Technology (PAT) PAT Goals Approaches recognize Product quality and performance are ensured through the design of effective and efficient manufacturing processes. Product and process specification are based on a mechanistic understanding of how formulation and process factors affect product performance. Continuous “real time” quality assurance. Relevant regulatory policies and procedures are tailored to accommodate most current level of scientific knowledge. Risk-based regulatory.

48. Process Analytical Technology (PAT) Four key elements in PAT implementation: Building a science Process monitoring and control Validation of PAT system.  Regulatory strategies. 

49. Elements in PAT Implementation Building a science – based knowledge base: The PAT guidance emphasizes the need to develop a deep understanding of the underlying scientific principles behind pharmaceuticals manufacturing processes to determine the parameters critical to process and product quality. The knowledge base provided by the PAT approach is valuable in three main ways: It is a foundation for robust process and product design. It facilitates continuous learning throughout the product life cycle.

50. It is supports and justifies flexible regulatory paths for innovative new approaches. Elements in PAT Implementation The design of experiments, and the capture and evaluation of analytical measurement data are essential parts of building the knowledge base.

51. Process monitoring and control The understanding of the interaction between process and product is the basis for the design of the process monitoring, process control and QA strategies used in Manufacturing PAT is an integrated approach in which the results obtained from the real time analysis of critical process control points are used to control the process in some way. During manufacturing, process parameters are adjusted (within clearly defined limits) to produce the desired product quality attributes at the process end point. Elements in PAT Implementation

52. Elements in PAT Implementation Validation of PAT system The validation plan for a PAT system will typically include the validation of Software packages for data analysis Process analyser hardware and software Process control software IT systems for the management, storage and backup of results.

53. Elements in PAT Implementation Regulatory strategies A PAT policy development team of four subject matter experts has been established to work with industry to facilitate discussion on proposed pat approaches at an early stage and support FDA’s sciences and risk based approaches to PAT. PAT is a joint initiative of the centre for Drug Evaluation and Research (CDER), Office of Regulatory Affairs (ORA) and the Centre for Veterinary Medicine (CVM) within the “cGMPs for the 21st Century "framework.

54. Functions of QA in Pharmaceutical industry Raw materials used in the manufacturing are approved and procured from approved vendor. All data's are recorded as per cGMPs and is reviewed for accuracy and traceability. Procedures are in place for performing the activities, operating and calibrating the equipment. Quality is built up in the plant, process, product. That a Robust Quality system is in place. Trainings like induction, On job, Scheduled and after any changes are conducted to respective individuals on time.

55. Functions of QA in Pharmaceutical industry To prepare and approve Quality Policy, Quality Objectives, Quality Manual and Validation Master Plan. Periodic Monitoring of the Quality Objectives. Monitors all validation & stability activities are completed as per the schedule. Ensures that all changes impacting the product and the established systems are documented and reviewed to analyse the impact.

56. Ensures that all deviations, OOS/OOT & Market complaints are logged, investigated to identify the root cause so as to take CAPA to prevent recurrence. Preparation of Annual product quality reports, trending of data, determining product and process performance. To arrange and conduct the self inspection, identify gaps and take CAPA. Review of related batch manufacturing records and QC testing data Prior to release of any batch . Functions of QA in Pharmaceutical industry

57. Functions of QC in Pharmaceutical industry Preparation of specifications for testing of materials and products. Carrying out Sampling and testing of materials or products. Environment Monitoring Conducting stability studies. Investigating test failures such as OOS / OOT. Analytical method validation. Evaluation of complaint samples. All the quality control activities are performed adherence to the GLP.

58. PAT Standards and Regulatory Requirements Regulatory aspects to QbD FDA perspective ICH guideline and QbD Regulatory challenges and inspection

59. Basic considerations of QbD Elements of pharmaceutical development Define an objective Determination of critical quality attributes.(CQA) Risk assessment Development of experimental design Designing and implementing control strategy Continuous improvement throughout product life cycle PAT Standards and Regulatory Requirements

60. PAT Standards and Regulatory Requirements Application of QbD in analytical methods of measurement Aspects of application of QbD to analytical method, Analytical target profile (ATP) Method design Critical quality attributes (CQA) Risk assessment Method qualification Control strategy Life cycle approach

61. PAT Standards and Regulatory Requirements Literature reports of application QbD For chromatographic technique In determination of impurity In screening of column used for chromatography In development of HPLC method for drug products/substances In capillary electrophoresis In stability studies In UHPLC

62. PAT Standards and Regulatory Requirements For hyphenated technique In LC–MS method development In bio analytical method development In dissolution studies For spectroscopic measurements In handling complex spectroscopic data In mass spectroscopy In near infrared.

63. PAT Standards and Regulatory Requirements Other applications of QbD or elements of QbD Pharmaceuticals In sterile manufacturing In solid oral dosage form Contribution of (SEM/EDX) to QbD by investigation of pharmaceutical materials In gel manufacturing QbD for ANDAs In tableting process Impact of genotoxic impurities on process development In analysis of excipients and API

64. PAT Standards and Regulatory Requirements Biopharmaceuticals In manufacturing of protein In production and characterization of monoclonal antibody For chromatographic technique used for purification PAT and QbD for biopharmaceutical In Nano medicine Challenges and solution for application of QbD to

65. Clinical Genetics Problems in adoption of QbD PAT Standards and Regulatory Requirements

66. References ICH guideline Q 8 –pharmaceutical development, http://www.ich.org U. S. FOOD and DRUG administration for industry. PAT – a framework for innovative. Review article of quality by design (QBD).

67. THANK YOU