内資系企業のQbD取り組みの経験から - nihs.go.jp

1 QbD 2016 2 3 18 2 2011 4 DVT 15 mg, 30 mg RTRT ( ) CONFIDENTIAL 2014 9 AF/VTE 15 mg, 30 mg, 60 mg RTRT CONFIDENTIAL CMA QbD 3 CMA QbD CONFIDENTIAL CMA , , , CQA (ex. , ) CMA (ex. ) Design space RTRT RTRT 4 CONFIDENTIAL CPP / CMA EMA-FDA QbD Pilot program 5 6 Box Behnken design, 30kg API/100kg batch CPP CMA Inlet air temp.

2 Spray rate Hardness API particle size Inlet air temp. Spray rate Inlet air temp. Spray rate Inlet air temp. Spray rate API 390 kg CMA Pilot CPP Plant CPP Plant CPP Plant API 390 kg API 39 kg API 90 kg API 90 kg Equipment change Equipment change 390 kg 390 kg Total 780 kg 129 kg 90 kg Total 219 kg CPP Plant Center point is optional CONFIDENTIAL CONFIDENTIAL CMA ( ) Link CPPs directly to CQAs. Make CMAs only applicable to input material attributes of the API and excipients.

3 It is not necessary and even not helpful to force the discussion of PP effects to first consider effects on "MAs"(QAs) of intermediates and finally QAs of the product. Completely agree. We tried at the QbD Workshop to also show how a control strategy focus could manage change and how a control strategy can be site, scale and equipment dependent. This paper is very supportive to our overall current thinking. 7 CQA MA MA MA MA MA MA MA p- CMA PP PP PP PP PP PP PP PP PP p-CPP p-CPP p-CPP p-CPP MA MA MA MA MA MA p-CMA p- CMA p-CMA CMA CMA CPP PP PP Fish bone, PHA, FMEA FMEA Fish bone, PHA, FMEA FMEA CPP 1) / ( ) 2) CPP CMA(/p-CMA) ( ) PAT 3) 1)+2) CMA CPP CQA: Critical Quality Attribute CMA: Critical Material Attribute p-CMA: Potential Critical Material Attribute CPP: Critical Process Parameter p-CPP.

4 Potential Critical Process Parameter PAT/ CONFIDENTIAL 8 CQA-CMA PAT CONFIDENTIAL CMA QbD 9 10 CONFIDENTIAL CONFIDENTIAL 70 80 D QbT vs QbD ( ) QbT QbD 90 A,B,C (%) 11 = f ( , , ) CONFIDENTIAL CQA (CMA) CQA Std Max Min Trend change Feed back (CMA ) Actual Predict CMA-CPP CMA PP CQA-CMA CMA 12 CMA CQA Std Max Min Feed back (CPP )

5 Trend change CONFIDENTIAL 13 14 NIR CONFIDENTIAL NIR 2 1 L 2 4 H 3 4 H 3 3 H 2 1 L 2 1 L 3 4 H 4 1 L 4 1 L 3 1 L CONFIDENTIAL 15 PAT 16 OK NG CONFIDENTIAL NIR CONFIDENTIAL CMA QbD 17 CONFIDENTIAL SST ,QA RTRT 18 ( ) CONFIDENTIAL 19 Q.

6 IDEF0 20 GMP / GMP A B C / ? ? A0 ( ) IDEF0 Integrated DEFinition for functional modeling 0) CONFIDENTIAL (1/2) RACI 21 A1A2A3A4A5R: ( )r: ( )A: ( )a: ( )C: ( )I: ( ) RIRRR I-rr- aIa-- aAI-- aRI-r A-A-- C-CC- R A r a 4 Responsible Accountable Consulted Informed CONFIDENTIAL 21 (2/2)

7 22 Unit Operation Unit Operation PAT Unit Operation PAT IT Data Information Knowledge Action RTRT Feed back/ Feed forward PAT CONFIDENTIAL CONFIDENTIAL CMA QbD 23 24 CONFIDENTIAL CMA PAT RTRT CMA ( 25 1/2 60mg CONFIDENTIAL A B 26 2/2 A Q=75% 75 70 80 85 90 kgf X50 mm 10 30 5 15 13 kgf X50 mm B Q=80% A B 75 85 80 90 95 10 30 5 15 28 CONFIDENTIAL 27 QbD (Q / Q12 ) RTRT ( ))

8 ( QbD PAT Enhanced QbD CONFIDENTIAL)