Question 1

What type of variation is “Changes 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 10 (II.1 Active substance a) Manufacture): a) Minor change in the manufacturing process of the active substance. — Type IA; b) Substantial change to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product. — Type II; c) The change refers to a biological/immunological substance or use of a different chemically derived substance in the manufacture of a biological/immunological substance, which may have a significant impact on the quality, safety and efficacy of the medicinal product and is not related to a protocol. — Type II; d) The change relates to a herbal product and there is a change to any of the following: geographical source, manufacturing route or production. — Type II; e) Minor change to the restricted part of drug master file (DMF). — Type IB.

Question 2

How is “Changes in the manufacturing process of the active substance” classified in the EU?

Accepted Answer

Commission Guidelines C/2025/5045: Q.I.a.2 Change in the manufacturing process of the active substance, intermediate of an active substance or starting materials for biological active substance: a) Minor change in the manufacturing process — Type IA; b) Major change to the manufacturing process which may have a significant impact on the quality, safety or efficacy of the finished product — Type II; c) Change in the geographical source of a herbal starting material and/or production of a herbal substance — Type IB; d) Minor change to the restricted part of an Active Substance Master File — Type IB; e) Deletion of a manufacturing process — Type IA

Question 3

How is “Changes in the manufacturing process of the active substance” reported to the US FDA?

Accepted Answer

21 CFR 314.70 and FDA guidance: Adding identical parallel processing lines, with no change to in-process limits or specifications — Annual report (2014 App. A 3.4); Other change in drug substance process or process parameters (same route, before the final intermediate step, impurity profile unaffected) — CBE-30 supplement (2004 §VII.C.1.b); Change in route of synthesis, any process change after the final intermediate step, or a change that may affect the impurity profile or physical properties — Prior approval supplement (2004 §VII.B.5, §VII.B.4.b; 21 CFR 314.70(b)(2)(iv)); Natural-product (incl. botanical/protein) substance: change in source material, cell line, or virus/adventitious-agent removal — Prior approval supplement (2004 §VII.B.3; 21 CFR 314.70(b)(2)(vii)). Any process change after the final intermediate processing step is PAS, however minor (§VII.B.5). Changes to the closed part of a Type II DMF are filed by the holder as a DMF amendment; the applicant reports the change under 314.70 according to its potential for adverse effect. Protein and biological substances now follow BLA rules (21 CFR 601.12).

Changes in the manufacturing process of the active substance

SFDA Saudi Food and Drug Authority

EU European Union

Q.I.a.2 · Change in the manufacturing process of the active substance, intermediate of an active substance or starting materials for biological active substance

US FDA US Food and Drug Administration

Other items in II.1 Active substance a) Manufacture

Variant	Change	Type
a	Minor change in the manufacturing process of the active substance.	Type IA
b	Substantial change to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product.	Type II
c	The change refers to a biological/immunological substance or use of a different chemically derived substance in the manufacture of a biological/immunological substance, which may have a significant impact on the quality, safety and efficacy of the medicinal product and is not related to a protocol.	Type II
d	The change relates to a herbal product and there is a change to any of the following: geographical source, manufacturing route or production.	Type II
e	Minor change to the restricted part of drug master file (DMF).	Type IB

Variant	Change	Type
a	Minor change in the manufacturing process	Type IA
b	Major change to the manufacturing process which may have a significant impact on the quality, safety or efficacy of the finished product	Type II
c	Change in the geographical source of a herbal starting material and/or production of a herbal substance	Type IB
d	Minor change to the restricted part of an Active Substance Master File	Type IB
e	Deletion of a manufacturing process	Type IA

Change	Category	Reference
Adding identical parallel processing lines, with no change to in-process limits or specifications	Annual report	2014 App. A 3.4
Other change in drug substance process or process parameters (same route, before the final intermediate step, impurity profile unaffected)	CBE-30 supplement	2004 §VII.C.1.b
Change in route of synthesis, any process change after the final intermediate step, or a change that may affect the impurity profile or physical properties	Prior approval supplement	2004 §VII.B.5, §VII.B.4.b; 21 CFR 314.70(b)(2)(iv)
Natural-product (incl. botanical/protein) substance: change in source material, cell line, or virus/adventitious-agent removal	Prior approval supplement	2004 §VII.B.3; 21 CFR 314.70(b)(2)(vii)