B. QUALITY CHANGES – B.II FINISHED PRODUCT – B.II.d) Control of finished product (obsolete version)

B.II.d.1 Change in the specification parameters and/or limits of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Tightening of specification limits	1, 2, 3, 4	1, 2	IA
b) Tightening of specification limits for medicinal products subject to Official Control Authority Batch Release	1, 2, 3, 4	1, 2	IA_IN
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 such as odour and taste or identification test for a colouring or flavouring material)	1, 2, 9	1, 2, 6	IA
e) Change outside the approved specifications limits range			II
f) Deletion of a specification parameter which may have a significant effect on the overall quality of the finished product			II
g) 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, 7	IB
h) Update of the dossier to comply with the provisions of an updated general monograph of the Ph. Eur for the finished product*	1, 2, 3, 4, 7, 8	1, 2	IA_IN
i) Ph. Eur. 2.9.40 Uniformity of dosage units is introduced to replace the currently registered method, either Ph. Eur. 2.9.5 (Uniformity of mass). or Ph. Eur. 2.9.6 (Uniformity of content)	1, 2,10	1, 2, 4	IA
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), unless the supporting documentation has been already assessed and approved within another 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.
7. The change does not concern any impurities (including genotoxic) or dissolution.
8. The change concerns the updating of the microbial control limits to be in line with the current Pharmacopoeia, and the currently registered microbial control limits (present situation) are in line with the pre January 2008 (non harmonised) situation and does not include any additional specified controls over the Pharmacopoeia requirements for the particular dosage form and the proposed controls are in line with the harmonised monograph.
9. The specification parameter or proposal for the specific dosage form does not concern a critical parameter for example: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the finished product) any critical physical characteristics (hardness or friability for uncoated tablets, dimensions, etc.) a test that is required for the particular dosage form in accordance with the general notices of the Ph. Eur.; any request for skip testing.
10. The proposed control is fully in line with the Table 2.9.40.-1 of Ph. Eur. 2.9.40 monograph, and does not include the alternative proposal for testing uniformity of dosage units by Mass Variation instead of Content Uniformity when the latter is specified in Table 2.9.40.-1.
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 finished product for all specification parameters
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch complying with the current and proposed specification. For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification/risk assessment showing that the parameter is non-significant or that it is obsolete.
7. Justification of the new specification parameter and the limits
* Note: There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia or a national pharmacopoeia of a Member State in the case that reference is made to the ‘current edition’ in the dossier of an authorised medicinal product. This variation therefore applies to cases where no reference to the updated monograph of the pharmacopoeia was contained in the technical dossier and the variation is made to make reference to the updated version.

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B.II.d.2 Change in test procedure for the finished product	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 method is already authorised	4	1	IA
c) Substantial change to, or replacement of, a biological/ immunological/ immunochemical test method or a method using a biological reagent or replacement of a biological reference preparation not covered by an approved protocol			II
d) Other changes to a test procedure (including replacement or addition)		1, 2	IB
e) Update of the test procedure to comply with the updated general monograph in the Ph. Eur.	2, 3, 4, 5	1	IA
f) To reflect compliance with the Ph.Eur. and remove reference to the outdated internal test method and test method number*	2, 3, 4, 5	1	IA
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. The registered test procedure already refers to the general monograph of the Ph. Eur. and any changes are minor in nature and require update of the technical dossier.
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.
* Note: There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia in the case that reference is made to the ‘current edition’ in the dossier of an authorised medicinal product.

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B.II.d.3 Variations related to the introduction of real-time release or parametric release in the manufacture of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II