製品開発： 例研究 の概要 - jpma.or.jp

1 Implementation of ICH Q8, Q9, Q10.. international conference on harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview . Quality by Design .. - QTPP .. - .. ICH, Tokyo, October 2010 slide 3. Quality by Design QbD . QTPP .. GMP .. CQA . CQA . CPP .. DOE CQA . DOE CPP . CQA . QRM .. PQS.. PQS & GMP. PQS QP, ..) .. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - ICH Q8 Q9 Q10 .. - .. ICH, Tokyo, October 2010 slide 5. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview . ICH, Tokyo, October 2010 slide 6. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview.

2 - .. - . - . ICH, Tokyo, October 2010 slide 7. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview . Quality Target Product Profile: QTPP).. Quality by Design QbD . ICH, Tokyo, October 2010 slide 8. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - - . - - . - - .. ICH, Tokyo, October 2010 slide 9. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - . - . - . - . - . - .. QRM .. ICH, Tokyo, October 2010 slide 10. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview QbD . QTPP.. & CQA.. ICH, Tokyo, October 2010 slide 11. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview.

3 ICH, Tokyo, October 2010 slide 12. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - . - Biopharmaceutics Classification System (BCS). 2 . - . - . In vitro-in vivo IVIVC .. ICH, Tokyo, October 2010 slide 13. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - . - Biopharmaceutics Classification System (BCS) 2 .. - . - . - . - . - . - . In vitro-in vivo IVIVC .. ICH, Tokyo, October 2010 slide 14. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview QTPP .. QTPP . 30 mg .. , .. ICH .. PSD . ICH . 2 30 C .. QTPP .. ICH, Tokyo, October 2010 slide 15. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview.

4 ICH, Tokyo, October 2010 slide 16. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. ICH, Tokyo, October 2010 slide 17. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. D- .. 6000.. ICH, Tokyo, October 2010 slide 18. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. ICH, Tokyo, October 2010 slide 19. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. no impact to CQA. known or potential impact to CQA . current controls mitigate risk known or potential impact to CQA. additional study required Drug Substance Drug Product * includes bioperformace of API and safety Semi-Continuous Moisture Control (API purity).

5 Solvent Switch Crystallization Rotary Drying Compression Manufacture Extractions Lubrication Centrifugal Packaging Distillative Coupling Reaction Aqueous Blending Filtration Coating CQA. in vivo performance*. Dissolution Assay Degradation Content Uniformity Appearance Friability Stability-chemical Stability-physical ICH, Tokyo, October 2010 slide 20. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview . no impact to CQA. known or potential impact to CQA . current controls mitigate risk known or potential impact to CQA. additional study required Drug Substance Drug Product * includes bioperformace of API and safety Semi-Continuous Moisture Control (API purity). Solvent Switch Crystallization Rotary Drying Compression Manufacture Extractions Lubrication Centrifugal Packaging Distillative Coupling Reaction Aqueous Blending Filtration Coating CQA.

6 In vivo performance*. Dissolution Assay Degradation Content Uniformity Appearance Friability Stability-chemical Stability-physical ICH, Tokyo, October 2010 slide 21. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - . - FMEA. > . - .. - .. ICH, Tokyo, October 2010 slide 22. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - DOE . - FMEA. > % . - DOE QTPP . 1/2 . - DOE .. PSD DOE . ICH, Tokyo, October 2010 slide 23. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview . PSD . What is the Impact that ------------- will have on PSD? 1) minimal 5) moderate 9) significant What is the Probability that variations in ------------ will occur?

7 1) unlikely 5) moderately likely 9) highly likely What is our Ability to Detect a meaningful variation in --------------- at a meaningful control point? 1) certain 5) moderate 9) unlikely PR T. De . t C. OB. tec Unit Operation Parameter Comments PA. IM. RPN. Prior knowledge (slowness of crystallization kinetics) ensures that the hot crystallizer feed will be well dispersed and thermally equilibrated Crystallization Feed Temperature 1 5 1 5. DOE . before crystallizing. Hence no impact of feed temp variation on crystal size. Prior knowledge (solubility data) shows that small variations in water Crystallization Water content of Feed 1 5 5 25. do not affect crystalliation kinetics. Fast addition could result in uncontrolled crystallization. Detection of Crystallization Addition Time (Feed Rate) 9 5 9 405 short addition time could occur too late to prevent this uncontrolled crystallization, and thus impact final PSD.

8 Prior knowledge (Chemical Engineering theory) highlights seed wt Crystallization Seed wt percentage 9 5 5 225. percentage variations as a potential source of final PSD variation Yield loss to crystallization already low (< 5%), so reasonable Crystallization Antisolvent percentage 1 1 1 1 variations in antisolvent percentage (+/- 10%) will not affect the percent of batch crystallized, and will not affect PSD. Change in crystallization temperature is easily detected, but rated Crystallization Temperature 9 5 9 405 high since no possible corrective action (such as, if seed has been dissolved). Prior knowledge indicates that final PSD highly sensitive to Agitation, Crystallization Agitation (tip speed) 9 5 5 225. thus requiring further study. Seed PSD controlled by release assay performed after air attrition Crystallization Seed particle size distribution 9 1 1 9.

9 Milling. Crystallization Feed Concentration 1 1 1 1 Same logic as for antisolvent percentage ICH, Tokyo, October 2010 slide 24. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - .. - . wt%. Pressure . Seed .. Temperature . DOE .. ICH, Tokyo, October 2010 slide 25. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - .. - A .. Seed wt%. - B edge . Temperature knowledge space . Seed Wt%.. Temperature ICH, Tokyo, October 2010 slide 26. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. - . - . - . - . - . - . - .. ICH, Tokyo, October 2010 slide 27. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview.

10 20 30 23 27 . 5 15 .. m/s .. % 1 2 %.. 1 % .. ICH, Tokyo, October 2010 slide 28. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview . 30 mg .. In vitro-in vivo IVIVC . - .. - . - . ICH, Tokyo, October 2010 slide 29. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. ICH, Tokyo, October 2010 slide 30. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview .. CQA . - CQA .. in vivo .. ICH, Tokyo, October 2010 slide 31. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview CQA .. - . - .. - . DOE .. - .. ICH, Tokyo, October 2010 slide 32. ICH Quality Implementation Working Group - Integrated Implementation Training Workshop Product Development: Case Study Overview.