Question 1

What type of variation is “Change in the manufacturing process of the finished product” under the SFDA Guidelines for Variation Requirements?

Accepted Answer

SFDA Guidelines for Variation Requirements v6.3, item 28 (II.2 Finished product b) Manufacture): a) Substantial changes to a manufacturing process that may have a significant impact on the quality, safety and efficacy of the medicinal product. — Type II; b) The change relates to a biological/immunological medicinal product. — Type II; c) Introduction of a non-standard terminal sterilization method. — Type II; d) Introduction or increase in the overage that is used for the active substance. — Type II; e) Minor change in the manufacturing process of an aqueous oral suspension. — Type IB; f) Minor change in the manufacturing process — Type IA(IN).

Question 2

How is “Change in the manufacturing process of the finished product” classified in the EU?

Accepted Answer

Commission Guidelines C/2025/5045: Q.II.b.3 Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product: a) Minor change in the manufacturing process — Type IA; b) Major change to a manufacturing process of the finish product that may have a significant impact on the quality, safety and efficacy of the finished product — Type II; c) Introduction of a non-standard terminal sterilisation method — Type II; d) Introduction of, or change in, an overage that is used for the active substance — Type II; e) Change in the holding time and/or storage conditions of an intermediate or bulk product used in the manufacture of the finished product — Type IB

Question 3

How is “Change in the manufacturing process of the finished product” reported to the US FDA?

Accepted Answer

21 CFR 314.70 and FDA guidance: Listed low-risk changes: mixing/drying times (IR solid oral; mixing for solutions), non-aseptic sieving step, order of addition in solutions — Annual report (2014 App. A 3.1.1–3.1.3; App. B 3.2; 2004 §VII.D.5); Any other change in process, process parameters or equipment not listed elsewhere (e.g., a minor change for an oral suspension) — CBE-30 supplement (2004 §VII.C.1.a); Fundamental change in process or technology (e.g., dry to wet granulation, new type of drying process) or a change that may affect modified release/metering — Prior approval supplement (2004 §VII.B.4, §VII.B.1); Change affecting sterility assurance, including a new sterilization method (aseptic to terminal, gas, dry heat, irradiation) — Prior approval supplement (2004 §VII.B.2; 21 CFR 314.70(b)(2)(iii)); Natural-source product: change in virus/adventitious-agent removal, source material or cell line, or a new master cell bank — Prior approval supplement (2004 §VII.B.3; 21 CFR 314.70(b)(2)(vii)); Introduction or increase of an active-substance overage (quantitative batch-formula change) — Prior approval supplement (2004 §V; 21 CFR 314.70(b)(2)(i)). The 2004 and 2014 guidances list only eliminating or reducing an overage (AR, 2014 App. A 1.1); introducing or increasing one changes the quantitative formulation (PAS, 314.70(b)(2)(i)). Any process change needing a new in vivo BE study is PAS (314.70(b)(2)(ii)). For natural-protein products most process changes are CBE-30 (§VII.C.1.c); BLA biologics follow 21 CFR 601.12.

Change in the manufacturing process of the finished product

SFDA Saudi Food and Drug Authority

EU European Union

Q.II.b.3 · Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product

US FDA US Food and Drug Administration

Other items in II.2 Finished product b) Manufacture

Variant	Change	Type
a	Substantial changes to a manufacturing process that may have a significant impact on the quality, safety and efficacy of the medicinal product.	Type II
b	The change relates to a biological/immunological medicinal product.	Type II
c	Introduction of a non-standard terminal sterilization method.	Type II
d	Introduction or increase in the overage that is used for the active substance.	Type II
e	Minor change in the manufacturing process of an aqueous oral suspension.	Type IB
f	Minor change in the manufacturing process	Type IA(IN)

Variant	Change	Type
a	Minor change in the manufacturing process	Type IA
b	Major change to a manufacturing process of the finish product that may have a significant impact on the quality, safety and efficacy of the finished product	Type II
c	Introduction of a non-standard terminal sterilisation method	Type II
d	Introduction of, or change in, an overage that is used for the active substance	Type II
e	Change in the holding time and/or storage conditions of an intermediate or bulk product used in the manufacture of the finished product	Type IB

Change	Category	Reference
Listed low-risk changes: mixing/drying times (IR solid oral; mixing for solutions), non-aseptic sieving step, order of addition in solutions	Annual report	2014 App. A 3.1.1–3.1.3; App. B 3.2; 2004 §VII.D.5
Any other change in process, process parameters or equipment not listed elsewhere (e.g., a minor change for an oral suspension)	CBE-30 supplement	2004 §VII.C.1.a
Fundamental change in process or technology (e.g., dry to wet granulation, new type of drying process) or a change that may affect modified release/metering	Prior approval supplement	2004 §VII.B.4, §VII.B.1
Change affecting sterility assurance, including a new sterilization method (aseptic to terminal, gas, dry heat, irradiation)	Prior approval supplement	2004 §VII.B.2; 21 CFR 314.70(b)(2)(iii)
Natural-source product: change in virus/adventitious-agent removal, source material or cell line, or a new master cell bank	Prior approval supplement	2004 §VII.B.3; 21 CFR 314.70(b)(2)(vii)
Introduction or increase of an active-substance overage (quantitative batch-formula change)	Prior approval supplement	2004 §V; 21 CFR 314.70(b)(2)(i)