B. QUALITY CHANGES – B.I ACTIVE SUBSTANCE – B.I.b) Control of active substance (obsolete version)

B.I.b.1 Change in the specification parameters and/or limits of an active substance, starting material / intermediate / reagent used in the manufacturing process of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Tightening of specification limits for medicinal products subject to Official Control Authority Batch Release	1, 2, 3, 4	1, 2	IA_IN
b) Tightening of specification limits	1, 2, 3, 4	1, 2	IA
c) Addition of a new specification parameter to the specification with its corresponding test method	1, 2, 5, 6, 7	1, 2, 3, 4, 5, 7	IA
d) Deletion of a non-significant specification parameter (e.g. deletion of an obsolete parameter)	1, 2, 8	1, 2, 6	IA
e) Deletion of a specification parameter which may have a significant effect on the overall quality of the active substance and/or the finished product			II
f) Change outside the approved specifications limits range for the active substance			II
g) Widening of the approved specifications limits for starting materials/intermediates, which may have a significant effect on the overall quality of the active substance and/or the finished product			II
h) Addition or replacement (excluding biological or immunological substance) of a specification parameter with its corresponding test method as a result of a safety or quality issue		1, 2, 3, 4, 5, 7	IB
i) Where there is no monograph in the European Pharmacopoeia or the national pharmacopoeia of a Member State for the active substance, a change in specification from in-house to a non- official Pharmacopoeia or a Pharmacopoeia of a third country		1, 2, 3, 4, 5, 7	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a type II variation procedure).
2. The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits.
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The test method is not a biological/immunological/immunochemical method or a method using a biological reagent for a biological active substance (does not include standard pharmacopoeia microbiological methods).
7. For any material, the change does not concern a genotoxic impurity. If it involves the final active substance, other than for residual solvents which must be in line with ICH/VICH limits, any new impurity control should be in line with the Ph. Eur. or National Pharmacopoeia of a Member State.
8. The specification parameter does not concern a critical parameter, for example any of the following: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the active substance), any critical physical characteristics e.g. particle size, bulk or tapped density, identity test, water, any request for skip testing.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. Comparative table of current and proposed specifications.
3. Details of any new analytical method and validation data, where relevant.
4. Batch analysis data on two production batches (3 production batches for biologicals, unless otherwise justified) of the relevant substance for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch containing the active substance complying with the current and proposed specification. For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification/risk assessment from the marketing authorisation holder or the ASMF Holder, as appropriate, that the in-process parameter is non-significant, or that the in-process parameter is obsolete.
7. Justification from the MAH or ASMF Holder as appropriate of the new specification parameter and the limits.

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B.I.b.2 Change in test procedure for active substance or starting material/reagent/intermediate used in the manufacturing process of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor changes to an approved test procedure	1, 2, 3, 4	1, 2	IA
b) Deletion of a test procedure for the active substance or a starting material/reagent/ intermediate, if an alternative test procedure is already authorised.	7	1	IA
c) Other changes to a test procedure (including replacement or addition) for a reagent, which does not have a significant effect on the overall quality of the active substance	1, 2, 3, 5, 6	1, 2	IA
d) Substantial change to or replacement of a biological/ immunological/ immunochemical test method or a method using a biological reagent for a biological active substance			II
e) Other changes to a test procedure (including replacement or addition) for the active substance or a starting material/intermediate		1, 2	IB
Conditions
1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.
2. There have been no changes of the total impurity limits; no new unqualified impurities are detected.
3. The method of analysis should remain the same (e.g. a change in column length or temperature, but not a different type of column or method).
4. The test method is not a biological/immunological/immunochemical method, or a method using a biological reagent for a biological active substance. (does not include standard pharmacopoeial microbiological methods).
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The active substance is not biological/immunological.
7. An alternative test procedure is already authorised for the specification parameter and this procedure has not been added through IA/IA(IN) notification.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), including a description of the analytical methodology, a summary of validation data, revised specifications for impurities (if applicable).
2. Comparative validation results, or if justified comparative analysis results showing that the current test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.