B. QUALITY CHANGES – B.II FINISHED PRODUCT – B.II.c) Control of excipients (obsolete version)

This is an archived version. Please see the current version here: Q. QUALITY CHANGES – Q.II. FINISHED PRODUCT – Q.II.c) Control of excipients

B.II.c.1 Change in the specification parameters and/or limits of an excipient

B.II.c.2 Change in test procedure for an excipient

B.II.c.3 Change in source of an excipient or reagent with TSE risk

B.II.c.4 Change in synthesis or recovery of a non- pharmacopoeial excipient (when described in the dossier) or a novel excipient

#biic1

B.II.c.1 Change in the specification parameters and/or limits of an excipient	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Tightening of specification limits	1, 2, 3, 4	1, 2	IA
b) Addition of a new specification parameter to the specification with its corresponding test method	1, 2, 5, 6, 7	1, 2, 3, 4, 6, 8	IA
c) Deletion of a non-significant specification parameter (e.g. deletion of an obsolete parameter)	1, 2, 8	1, 2, 7	IA
d) Change outside the approved specifications limits range			II
e) Deletion of a specification parameter which may have a significant effect on the overall quality of the finished product			II
f) Addition or replacement (excluding biological or immunological product) of a specification parameter with its corresponding test method, as a result of a safety or quality issue		1, 2, 3, 4, 5, 6, 8	IB
g) Where there is no monograph in the European Pharmacopoeia or the national pharmacopoeia of a Member State for the excipient, a change in specification from in-house to a non-official Pharmacopoeia or a Pharmacopoeia of a third country		1, 2, 3, 4, 5, 6, 8	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 (does not include standard pharmacopoeial microbiological methods)
7. The change does not concern a genotoxic impurity.
8. The specification parameter does not concern the control of a critical parameter. e.g.: impurities (unless a particular solvent is definitely not used in the manufacture of the excipient) any critical physical characteristics (particle size, bulk, tapped density, etc.) identity test (unless there is a suitable alternative control already present) microbiological control (unless not required for the particular dosage form)
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 biological excipients,) of the excipient for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch containing the excipient complying with the current and proposed specification. For herbal medicinal products comparative disintegration data may be acceptable.
6. Justification for not submitting a new bioequivalence study according to the relevant (Human, Veterinary) Guideline on Bioavailability, if appropriate.
7. Justification/risk assessment showing that the parameter is non-significant or that it is obsolete.
8. Justification of the new specification parameter and the limits.

#biic2

B.II.c.2 Change in test procedure for an excipient	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 if an alternative test procedure is already authorised	5	1	IA
c) Substantial change to or replacement of a biological/ immunological/ immunochemical test method or a method using a biological reagent			II
d) Other changes to a test procedure (including replacement or addition)		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 (does not include standard pharmacopoeial microbiological methods).
5. 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.

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B.II.c.3 Change in source of an excipient or reagent with TSE risk	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) From TSE risk material to vegetable or synthetic origin
1. For excipients or reagents not used in the manufacture of a biological / immunological active substance or in a biological / immunological medicinal product	1	1	IA
2. For excipients or reagents used in the manufacture of a biological / immunological active substance or in a biological / immunological medicinal product		1, 2	IB
b) Change or introduction of a TSE risk material or replacement of a TSE risk material from a different TSE risk material, not covered by a TSE certificate of suitability			II
Conditions
1. Excipient and finished product release and end of shelf life specifications remain the same.
Documentation
1. Declaration from the manufacturer or the marketing authorisation holder of the material that it is purely of vegetable or synthetic origin.
2. Study of equivalence of the materials and the impact on production of the final material and impact on behaviour (e.g. Dissolution characteristics) of the finished product.

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B.II.c.4 Change in synthesis or recovery of a non- pharmacopoeial excipient (when described in the dossier) or a novel excipient	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor change in synthesis or recovery of a non- pharmacopoeial excipient or a novel excipient	1, 2	1, 2, 3, 4	IA
b) The specifications are affected or there is a change in physico-chemical properties of the excipient which may affect the quality of the finished product.			II
c) The excipient is a biological/immunological substance			II
Conditions
1. The synthetic route and specifications are identical and there is no change in qualitative and quantitative impurity profile (excluding residual solvents, provided they are controlled in accordance with ICH/VICH limits), or in physico-chemical properties.
2. Adjuvants are excluded.
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. Batch analysis data (in a comparative tabulated format) of at least two batches (minimum pilot scale) of the excipient manufactured according to the old and the new process.
3. Where appropriate, comparative dissolution profile data for the finished product of at least two batches (minimum pilot scale). For herbal medicinal products, comparative disintegration data may be acceptable.
4. Copy of approved and new (if applicable) specifications of the excipient.