Question 1

What type of variation is “Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance” under the SFDA Guidelines for Variation Requirements?

Accepted Answer

SFDA Guidelines for Variation Requirements v6.3, item 11 (II.1 Active substance a) Manufacture): a) Up to 10-fold increase compared to the currently approved batch size — Type IA; b) Downscaling down to 10-fold — Type IA; c) The change requires assessment of the comparability of a biological/immunological active substance — Type II; d) More than 10-fold increase compared to the currently approved batch size — Type IB; e) The scale for a biological/immunological active substance is increased/decreased without process change (e.g. duplication of line) — Type IB.

Question 2

How is “Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance” classified in the EU?

Accepted Answer

Commission Guidelines C/2025/5045: Q.I.a.3 Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance: a) An increase to the originally approved batch size — Type IA; b) Downscaling of the approved batch size — Type IA; c) The change in batch size of a biological active substance/intermediate requires assessment of the comparability — Type II; d) The scale for a biological active substance/intermediate is increased/decreased without process change (e.g. duplication of line) — Type IB

Question 3

How is “Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance” reported to the US FDA?

Accepted Answer

21 CFR 314.70 and FDA guidance: Scale change made by combining previously separate batches of in-process material (all meet IPC limits, traceability kept) — Annual report (2014 App. A 3.2); Scale-up or scale-down of a synthetic drug substance on equipment of the same design and operating principle, with no change to process parameters or specs — Annual report (2004 §VII.D.1 (drug-product rule applied by analogy)); Scale change that requires different equipment design or changed process parameters (synthetic drug substance) — CBE-30 supplement (2004 §VII.C.1.b); Natural-protein substance: scale change in finishing steps that involves different equipment — CBE-30 supplement (2004 §VII.C.1.c; 21 CFR 314.70(c)(2)(ii)(A)); Aseptically processed sterile substance: scale change that extends processing or bulk hold time by more than 50% beyond validated limits — Prior approval supplement (2004 §VII.B.2). FDA guidance has no scale example for a synthetic drug substance (§VII.D.1 covers drug products). Same-design equipment with unchanged parameters and specifications has minimal potential for adverse effect (AR, 314.70(d)(1)); a parameter change is CBE-30 (§VII.C.1.b). No fold limit applies. Natural-protein scale changes without new equipment are AR (§VII.D.7), but protein products are now BLAs (21 CFR 601.12).

Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance

SFDA Saudi Food and Drug Authority

EU European Union

Q.I.a.3 · Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance

US FDA US Food and Drug Administration

Other items in II.1 Active substance a) Manufacture

Variant	Change	Type
a	Up to 10-fold increase compared to the currently approved batch size	Type IA
b	Downscaling down to 10-fold	Type IA
c	The change requires assessment of the comparability of a biological/immunological active substance	Type II
d	More than 10-fold increase compared to the currently approved batch size	Type IB
e	The scale for a biological/immunological active substance is increased/decreased without process change (e.g. duplication of line)	Type IB

Variant	Change	Type
a	An increase to the originally approved batch size	Type IA
b	Downscaling of the approved batch size	Type IA
c	The change in batch size of a biological active substance/intermediate requires assessment of the comparability	Type II
d	The scale for a biological active substance/intermediate is increased/decreased without process change (e.g. duplication of line)	Type IB

Change	Category	Reference
Scale change made by combining previously separate batches of in-process material (all meet IPC limits, traceability kept)	Annual report	2014 App. A 3.2
Scale-up or scale-down of a synthetic drug substance on equipment of the same design and operating principle, with no change to process parameters or specs	Annual report	2004 §VII.D.1 (drug-product rule applied by analogy)
Scale change that requires different equipment design or changed process parameters (synthetic drug substance)	CBE-30 supplement	2004 §VII.C.1.b
Natural-protein substance: scale change in finishing steps that involves different equipment	CBE-30 supplement	2004 §VII.C.1.c; 21 CFR 314.70(c)(2)(ii)(A)
Aseptically processed sterile substance: scale change that extends processing or bulk hold time by more than 50% beyond validated limits	Prior approval supplement	2004 §VII.B.2