LectureItechnology transfer6thJanuary2022 (1).pptx

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1. Product Development & Technology Transfer Development of technology by R & D Technology transfer from R & D to production, Optimization and Production , Qualitative and quantitative technology models. Documentation in technology transfer: Development report, technology transfer plan and Exhibit.

2. Trevor M. Jones, CHAPTER 1:Preformulation Studies , in  Pharmaceutical Formulation: The Science and Technology of Dosage Forms , 2018, pp. 1-41 DOI:  10.1039/9781782620402-00001 eISBN : 978-1-78262-040-2 From Book Series:  Drug Discovery

3. Technology Transfer Plans and Reports Technology transfer plans and reports are used by a research and development organization in order to document their official ‘‘transfer’’ of a newly developed or recently upgraded product/process from the developmental area and facilities to an operations unit and site, usually located in separate buildings, or at an entirely separate and different manufacturing sites . While the format and content has not been formally prescribed by FDA, companies generally include the following information[12] in these documents : Definition of responsibilities for key departments ; documentation review, approval, and storage requirements. Summary of developmental activities completed . Summary of scale-up activities; summary of formulation , synthesis , process, and analytical method changes ; establishment of impurity specifications ; establishment of critical process parameters; identification of validation plans and activities.

4. Technology Transfer Plans and Reports Definition of component, container/closure, and product attributes. Analytical methods development and validation summary . Descriptions, specifications, design parameters and requirements of facilities, and major equipment and utility systems. Definition of the manufacturing process. Stability and expiry dating information. Change control. Reprocessing. Cleaning processes, including methods development and validation of the processes and methods. Summary of Regulatory Affairs activities, including regulatory commitments, key data and information to be summarized in regulatory filings.

5. Key aspects of Technology Transfer Whether a tablet, a transdermal patch, a topical ointment, or an injectable, the transformation of a pharmaceutical prototype into a successful product requires the cooperation of many individuals Integration of personnel process & machine & materials

6. Key aspects of Technology Transfer The success of development efforts is measured by the ease of technology transfer and scale-up to largescale manufacturing. Small-scale studies in the laboratory need to incorporate influencing factors of largescale manufacturing. The intent is to develop a process that is safe, effective, efficient, and sufficiently robust where the manufacturing technology can be transferred to routine large-scale commercial production. Product-design objects are efficacy, stability, safety, and ease of use

7. Key aspects of Technology Transfer The scope and extent of the validation studies expand as batch sizes increase with the progression from development to commercial manufacturing. Knowledge of manufacturing capacities and capabilities, appropriate and adequate processing conditions for a robust process, coupled with careful control of starting material and processing conditions are necessary for successful technology transfer in achieving the predefined processing conditions and predicted finished product qualities.

8. Key aspects of Technology Transfer Processing at larger batch sizes provides an opportunity to verify the suitability of the processing parameters identified during development and focus on assessing the distribution of behavior and uniformity of finished product qualities at a larger scale.

9. Key aspects of Technology Transfer A complete and comprehensive development report is an invaluable resource for technology transfer. This document preserves the body of knowledge and experience gained during product design and process development activities. Information including characteristics of the API, formulation, and finished product outlined in the preceding sections are part of a comprehensive development report. As well, the knowledge and experience in initial scale-up for processing clinical material is also valuable. The expected behavior, finished product attributes, and any difficulties that arise in scaling-up provide useful insight as larger batch sizes are integrated into routine manufacturing. Obtaining consistent desired properties of the drug product are the final assessment of a successful scale-up and technology transfer.

10. Key aspects of Technology Transfer Formula handling and safety considerations Raw materials Manufacturing equipment Manufacturing precautions Manufacturing procedures Packaging Process validation Specifications for raw materials, packaging components, and in-process and finished product Validated analytical methods Regulatory considerations Rework procedures Transportation

11. Activities leading to Technology transfer Product development (PD) is the first step to TT Objective of PD is to develop product that meets with QTTP & CQA so as to obtain product that is safe, stable & is complying with efficacy requirement. PD activity includes conduct of experimental trials resulting in understanding of input variables and process variables. In order to develop product with consistent quality, ICH guidelines are followed

12. ICH guidelines for product life cycles management ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System

13. Product development strategy PD starts with identifying a suitable dosage form on the basis of : properties (physical, chemical & biological) of the drug substance Patient need Market need Regulatory & IPR consideration After QTPP & CQA are identified, the next step is to identify CMAs composition variables, CPPs

14. Raw material selection Raw materials include API, excipients, packaging material The properties of API – polymorphic form, particle size, surface area, impurity profile Depending on the desired CQA of drug product, risk assessment of CMA of APIs is done. Quality attributes of APIs should be within the specified acceptance limit set as per the official compendial limits

15. API selection Raw materials include API, excipients, packaging material The properties of API – polymorphic form, particle size, surface area, impurity profile Depending on the desired CQA of drug product, risk assessment of CMA of APIs is done. Quality attributes of APIs should be within the specified acceptance limit set as per the official compendial limits Follow the ICH guidelines or in-house specifications Initial risk assessment of CMA of API on CQA done

16. API selection It is preferable to select at least 3 sources of API for qualification based on their compliance API supplier should provide OPEN PART OF DMF information about - ROS, impurities, degradants, analytical data, stability data 3 lots of API of product batch are obtained from the supplier and evaluated for the compliance PD is done in RD atleast with 2 sources It is better to register the product with 2 sources of API so that during commercial phase reliability & continuity of supply chain is mainitained

17. Project Case study: Sr. No. Parameter Observation 1. Manufactured for Company ABC 2. Country USA 3. Strength 40 mg Drug A, 25 mg Drug B 4. Dosage form Tablet 5. Description Pink, oval, film-coated tablets, approximately 15*7 mm 6. Composition Hydroxypropyl Cellulose, Hypromellose, Lactose, Low substituted Hydroxypropyl Cellulose, MCC, Red Iron Oxide, Talc, Titanium Dioxide, Yellow Iron Oxide 7. Shape Oval shaped 8. Average weight (Coated) 432.60 mg 03-03-2022 22 Analysis of Innovator’s Product

18. 03-03-2022 23 Sr. No. Parameter Observation 9. Thickness of tablet 4.70-4.75 mm 10. Length of tablet 15.20 mm 11. Breadth of tablet 7.20 mm 12. Hardness 16.0-22.0 kP 13. Disintegration time 3 min 15 seconds 14. Dissolution Medium: 0.05M pH6.8 phosphate buffer, Volume: 900 mL, Apparatus: USP Type II, Speed: 50 rpm Time (min) % Drug dissolved Drug A Drug B 5 56 80 10 69 94 15 71 98 20 74 100 30 77 102 45 79 103 60 80 103 15. Tablet scoring Unscored 16. Storage Store at 20-25˚C 17. Pack Bottles of 30’s 18. Related substance Active moiety of Drug A: NMT 1.0% ND Drug A related Compound-A: NMT 0.5% ND Benzothiadiazine Related Compound-A: NMT 0.5% 0.16 Any Unspecified Impurity: NMT 0.2% 0.1 Total Impurities: NMT 0.3% 1.00

19. 03-03-2022 24 Sr. No Excipients Function Tentatively % w/w used 1. Hydroxypropylcellulose Binder/Film, coating polymer 2-5 % 2. Hypromellose Binder/Film coating polymer 1-3 % 3. Microcrystalline Cellulose Diluent 4-8 % 4. Low-substituted Hydroxypropyl Cellulose Binder & Disintegrant 4-15 % Sr. No Excipients Function Tentatively % w/w used 5. Talc Glident 1-2 % 6. Lactose Diluent 80-90 % 7. Magnesium Stearate Lubricant 2-10% 9. Red Iron Oxide Colourant   2-3 % 10. Titanium Dioxide Opacifier 11. Yellow Iron Oxide Colour Innovator’s Product Composition- function and tentative quantity

20. 03-03-2022 25 Drug product CQAs Drug Substance Attributes Solubility Related substances Assay Residual Solvents Particle size distribution (PSD) LOD (Loss on drying) Flow properties Dissolution High Low Low Low High Low Low Assay Low Low Low Low Medium Low Medium Content uniformity(CU) Low Low Low Low Medium Low High Related substances Low Low Low Low Low Low Low Table 9.8: Initial risk assessment of drug substance attributes- For Drug A

21. 03-03-2022 26 Drug substance attribute Drug product Critical Quality Attribute (CQA) Initial Risk Assessed Justification Solubility Dissolution High As Drug A exhibited low solubility across the physiological pH range, its solubility will strongly impact dissolution. The risk is assessed as High. The formulation process will be designed to mitigate the risk. Justification of risk assessment Particle Size Distribution (PSD) Dissolution High As API being a BCS class II drug, PSD can impact dissolution, so risk identified is high. Assay Medium Small particle size of API may impact blend flowability . In extreme cases, poor flowability may cause an assay failure. The Risk identified is medium. CU Medium PSD has a direct impact on drug substance flowability and ultimately tablet CU. The Risk identified is medium.

22. 03-03-2022 27 Flow properties Dissolution Low The flowability of the drug substance is not related to its solubility. Hence will not impact dissolution. Therefore, the risk is low. Assay Medium Drug A has poor flow properties. In extreme cases, poor flow may impact assay. The risk is medium. CU High The poor flow properties of API may lead to poor tablet CU. The risk is high. RS Low The flowability of the drug substance is not related to its degradation pathway or solubility. Therefore, the risk is low.

23. Specification of API Quality attributes of API as per ICH Q6A, as per pharmacopoeia & manufacturer CMA s are identified as per the risk assessment Specifications for the CMAs are decided on the basis of experiments conducted during formulation development using API with varying parameters As you proceed with the development activity, specifications evolve and are fine tuned The objective is to minimize the risk of failure in the drug product during scale up & technology transfer

24. Excipients Criteria of excipient selection – type of dosage form ,route of administration, safety profile, manufacturing process, regulatory aspects & IPR Route of administration: for parenterals excipients to be sterile & pyrogens free Safety profile: Acceptable daily intake, IIG Limits (IID – USFDA), if used beyond ADI justification required. Excipient gives safety & toxicity data of excipients especially for new excipient

25. Excipients Regulatory aspects : compendial grade excipients to be used, in case of co processed excipients ( Ludipress , Prosolv ) – regulatory status in intended market to be checked GRAS status required Compatibility : between drug & excipient to be checked. Selection of excipients should be based on basic mechanistic understanding of structure of drug molecule, impurities, degradation pathway, processing conditions

26. Excipients Manufacturing process : choice of excipients is driven by type of mfg process . For example for DC, directly compressible excipients are used RISK ASSESSMENT – based on impact of CMA on CQA done based on that material attributes and specifications are set and requirements given to excipient vendor. 3 lots of excipients of production batch are obtained from the supplier and evaluated for the compliance PD is done in RD at least with 2 sources It is better to register the product with 2 sources of excipients so that during commercial phase reliability & continuity of supply chain is mainitained

27. Packaging materials Primary pkging materials are most relevant from regulatory perspective as they are in direct contact

28. Analytical Method Development Analytical Method Development: method dev & validation as per ICH Q2A&B QbD – QATP Accuracy, precision, linearity, robustness, recovery, repeatability, sensitivity, Pharmacopoeal / Inhouse

29. Analytical Method Development Method development for API Method Development for Drug Product Impurities as per ICH Q3A & Q3B Dissolution Method development & setting specifications with/without clinical relevance

30. Prototype Formulation Development Preliminary experimental trials with understanding of QTPP CQAs CMAs CPPs Screening designs – Plackett Burman, Factorial & Fractional Factorial design Charging of R& D batches on short term stability and stress conditions

31. Pilot Clinical Study After satisfactory data of accelerated study of 3 months of R&D batches – pilot clinical batch is taken In case of NDA :