Quality by design (QbD) and process analytical technology (PAT)

Quality by design (QbD) and process analytical technology (PAT) (QA) M.pharm 2 SEM 1 year PHARMACEUTICAL MANUFACTURING TECHNOLOGY

1. Quality by design ( QbD ) and process analytical technology Presented by Shreyash P. Chaudhari M.Pharm Quality Assurance, 2 nd Sem Subject Pharmaceutical Manufacturing Technology ( mqa 201t) Dr. Rajendra Gode College Of Pharmacy, malkapur

2. Contents Introduction Current approach and its limitations Why QbD is required Advantages Elements of QbD Terminology QTPP CMA CQA CPP RLD Design space Design of Experiments Risk Assessment and mitigation/minimization.

3. Contents Quality by Design Formulations by Design QbD for drug products QbD for Drug Substances QbD for Excipients Analytical QbD . FDA initiative on process analytical technology PAT as a driver for improving quality and reducing costs quality by design ( QbD ) QA QC GAMP. PAT guidance standards and regulatory requirements

4. Introduction Qbd (quality by design) is defined in the ICH Q8 guideline as " a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and understanding and process control, based on sound science and quality risk management "

5. Current approach and its limitations

6. 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.

7. Advantages

8. Elements of QbD

9. 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. 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.

10. Terminology 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. 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. 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. 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.

11. 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). Design space (DS) 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. 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.

12. 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. 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. 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.

13. 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 Unpredictable Scale-up issues. Inability to understand failures. Systematic approach to development: That begins with predefined objectives. Emphasizes products and process understanding. Process control

14. 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). 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.

15. 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 ."

16. QbD For Drug Excipient "The word excipient is derived from the Latin excipiere , 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."

17. 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, analyses, and control pharmaceutical manufacturing processes through the measurement of Critical Process Parameters (CPP) which affect Critical Quality Attributes (CQA)".

18. QA 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 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 analyses the impact..

19. QC 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.

20. GMP Good manufacturing practice (GMP) is a system for ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product.

21. PAT Standards and Regulatory Requirements Regulatory aspects to QbD FDA perspective ICH guideline and QbD Regulatory challenges and inspection 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 Clinical Genetics. Problems in adoption of QbD

22. 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 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 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.

23. 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 materialsIn gel manufacturing QbD for ANDAS In tableting process Impact of genotoxic impurities on process development In analysis of excipients and API 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

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