Quality-By-Design In Pharmaceutical Development

1) Introduction
2) ICH Q8 guidline
3)Regulatory and Industry views on QbD
4)Scientifically Based QbD
5) Example of application

1. Quality-by-Design In Pharmaceutical Develpoment Presented By : Under the Guidance of: Shubhangi Parbhane Dr. Nalanda Borkar First Year M Pharm (Sem-II) HOD (Department Of Pharmaceutics ) Department of Pharmaceutics Alard Collage of Pharmacy, Marunji Sub: CADD Alard Collage of Pharmacy, Marunji 1

2. QbD: 2

3. Content : 1)Introduction 2)ICH Q8 guideline 3)Regulatory and industry views on QbD 4)Scientifically based QbD-Example of application 3

4.    QULITY – “Quality can not be tested into products; it has to be built in by design”  DEFINATION OF QBD - ‘systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management’  Quality by Design is a concept first outlined by Joseph M. Juran in various publications.  He supposed that quality could be planned. The concept of QBD was mention in ICH Q8 guidelines, which states that, “To identify quality can not be tested in products, i.e. Quality should be built in to product by design.” 4

5.  Benefits for Industry:  Better understanding of the process.  Less batch failure.  More efficient and effective control of change.  Return on investment / cost savings.  Additional opportunities:  Reduction of post-approval submissions.  More efficient technology transfer to manufacturing.  Risk-based approach and identification.  Innovative process validation approaches . 5

6.  The main objectives of QBD is to ensure the quality products, for that product & process characteristics important to desired performance must be resulting from a combination of prior knowledge & new estimation during development.  From this knowledge & data process measurement & desired attributes may be constructed.  Ensures combination of product & process knowledge gained during development. ICH Q8- Pharmaceutical Development  Quality by design (QBD) is a concept introduced by the international conference on harmonization (ICH)Q8 guideline, as a systematic approach to development, which begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management 6

7. QBD Approach:  Quality Target Product Profile (QTPP): According to the ICH Q8 guideline, QTPP is a prospective summary of the quality characteristics of a drug product to ensure the desired quality, taking into account safety and efficacy of that drug product.  Through the scientifically based process of product development, critical process parameters (CPPs), and critical quality attributes (CQAs) of the product are identified.  CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.  CPP is a process parameter whose variability has an impact on a CQA.   7

8. ICHQ8(R2): Pharmaceutical Development Guideline: • The ICH Q8 guideline describes GOOD PRACTICES FOR PHARMACEUTICAL PRODUCT DEVELOPMENT. •ICHQ8 Pharmaceutical Development describes the principles of QbD, outlines the key elements, and provides illustrative examples for pharmaceutical drug products. •It is often emphasized that the QUALITY of a pharmaceutical product should be BUILT IN BY DESIGN RATHER THAN BY TESTING ALONE. • The ICH Q8 guideline suggests that those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality, should be DETERMINED AND CONTROL STRATEGIES justified. • Some of the tools that should be applied during the design space appointment include experimental designs, PAT(Process Analytical Technology) ,prior knowledge, quality risk management principles,etc. 8

9. 9 • PAT(Process Analytical Technology) is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality . • Pfizer was one of the first companies to implement QbD and PAT concepts. Contents for 3.2.P.2 of CTD Quality Module 3 1.Components of drug product (drug substance/ excipients) 2 . Formulation Development. 3 . Manufacturing Process Development 4 . Container Closure System 5 . Microbiological Attributes 6 . Compatibility

10. 10 COMPONENTS OF DRUG PRODUCT GIVEN BY ICH Q8 Drug substances- “ The physicochemical and biological properties of the drug substance that can influence the performance of the drug product and its manufacturability.” Examples of physicochemical and biological properties that might need to be examined include- Solubility,Water content,Particle size,Crystal properties,Biological activity,Permeability Excipients - The excipients chosen, their concentration, and the characteristics that can influence the drug product performance or manufacturability should be discussed relative to the respective function of each excipients. The compatibility of the drug substance with excipients should be evaluated. For products that contain more than one drug substance, the compatibility of the drug substances with each other should also be evaluated. Formulation development - A summary should be provided describing the development of the formulation, including identification of those attributes that are critical to the quality of the drug product and also highlight the evolution of the formulation design from initial concept up to the final design. •Information from comparative in vitro studies (e.g., dissolution) or comparative in vivo studies (e.g., BE) that links clinical formulations to the proposed commercial formulation.

11. 11 Container and closure system: • The choice for selection of the container closure system for the commercial product should be discussed. • A possible interaction between product and container or label should be considered . Microbiological attributes : • The selection and effectiveness of preservative systems in products containing antimicrobial preservative or the antimicrobial effectiveness of products that are inherently antimicrobial. • The lowest specified concentration of antimicrobial preservative should be justified in terms of efficacy and safety, such that the minimum concentration of preservative that gives the required level of efficacy throughout the intended shelf life of the product is used . Compatibility: • The compatibility of the drug product with reconstitution diluents (e.g., precipitation, stability) should be addressed to provide appropriate and supportive information for the labelling. • This information should cover the recommended in-use shelf life, at the recommended storage temperature and at the likely extremes of concentration. Similarly, admixture or dilution of products prior to administration ( e.g.,product added to large volume infusion containers) might need to be addressed.

12. REGULATORY VIEWS ON QbD “The QbD concept represents product and process performance characteristics scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches.” “Another FDA representative (Shah, 2009) states that introduction of the QbD concept can lead to cost savings and efficiency improvements for both industry and regulators.” REGULATORY VIEWS ON QbD facilitate: • enhance opportunities for first cycle approval, • streamline post approval changes and regulatory processes, • enable more focused inspections, • provide opportunities for continual improvement (Shah, 2009). • innovation, • increase manufacturing efficiency, • reduce cost/product rejects, • minimize/eliminate potential compliance actions, 12

13. REGULATORY VIEWS ON QBD EMA representatives) point out that it is preferable for a design space to be complemented by an appropriate control strategy. The review of variations regulations and the revised Variations Classifications Guideline (2008) has taken into account QbD submissions, to enable easier updates of the registration dossier. EMA templates and guidance documents used for the assessment of any new drug application in the centralized procedure include the possibility of design space appointment.   REGULATORY VIEWS ON QBD EMA, FDA, and ICH working groups have appointed the ICH quality implementation working group (Q-IWG), which prepared various templates, workshop training materials, questions and answers, as well as a points- to-consider document (issued in 2011) that covers ICH Q8(R2), ICH Q9, and ICH Q10 guidelines. This document provides an interesting overview on the use of different modeling techniques in QbD. 13

14. 14 Scientifically Based Example of Application : Quality by Design [QbD] is a science based approach widely used in industry to continually monitor and improve the quality of product. It is a modern risk based strategic framework of all the aspects related to quality. ICH guidelines Q8 to Q11 summarizes all the different perspectives of quality by design system in required depth along with ways to implement it . This review in all focuses on the general terms of QbD its meanings and application along with different wide range applications of the QbD to pharmaceutical fields like Analysis, Formulation, Design and Technology development, Control Strategies etc .

15. Example of QbD Application in Japan  MSD presented at the ISPE Annual meeting in 2014;  By introducing RTRT(Real Time Release Testing) to Januvia tablets which they market worldwide,  They were able to save up to 20 million US dollars in 5 years Example of Januvia®  Januvia®  Active Ingredient : Sitagliptin Phosphate Hydrate  Approved : Oct. 2009  Indication : Type 2 diabetes mellitus  DPP-4 inhibitor 15

16. Example of Januvia 16

17. Manufacturing Floor 17

18. 18 At-line NIR analyzers perform at the process line with samples removed by hand and fed into the machine, allowing the analysis done on samples from many lots or stages of production. This technology is especially useful for at-line analysis because at-line NIR analyzers can use fairly large samples with no extra preparation needed. An at-line NIR analyzer uses near infrared radiation to cause vibrations in the molecules of the sample which create spectra that can be used to determine the chemical components of the sample. The at-line NIR analyzer works best when the machine has been calibrated to look for a specific substance.

19. Example of Januvia®  They were able to save up to 20 million US dollars in 5 years  Opportunities exist to develop more flexible regulatory approaches, for example, to facilitate:  risk-based regulatory decisions (reviews and inspections)  manufacturing process improvements, within the approved design space described in the dossier, without further regulatory review  reduction of post-approval submissions  real-time quality control, leading to a reduction of end product release testing 19

20. Reference: 1) https://www.slideshare.net/chetanpawar2829/introduction-to-quality-by-design-qbd /Assessed Date : 28 May 2021 . 2)https://www.slideshare.net/NavaneethakrishnanPa4/quality-by-design-qbd-162665917 /Assessed Date : 28 May 2021 . 3 ) https://www.slideshare.net/Rohitkumar2988/ich-q8-guidelines-of-quality-by-designproduct-developement /Assessed Date : 29 May 2021 . 4) https ://www.pmda.go.jp  /Assessed Date : 30 May 2021 . 5)https :// database.ich.org./ Assessed Date :02 May 2021. 20

21. Thank You ! 21