B. QUALITY CHANGES – B.II FINISHED PRODUCT – B.II.a) Description and composition (obsolete version)

This is an archived version. Please see the current version here: Q. QUALITY CHANGES – Q.II. FINISHED PRODUCT – Q.II.a) Description and composition

B.II.a.1 Change or addition of imprints, bossing or other markings including replacement, or addition of inks used for product marking.

B.II.a.2 Change in the shape or dimensions of the pharmaceutical form

B.II.a.3 Changes in the composition (excipients) of the finished product

B.II.a.4 Change in coating weight of oral dosage forms or change in weight of capsule shells

B.II.a.5 Change in concentration of a single-dose, total use parenteral product, where the amount of active substance per unit dose (i.e. the strength) remains the same

B.II.a.6 Deletion of the solvent / diluent container from the pack

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B.II.a.1 Change or addition of imprints, bossing or other markings including replacement, or addition of inks used for product marking.	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Changes in imprints, bossing or other markings	1, 2, 3, 4	1, 2	IA_IN
b) Changes in scoring/break lines intended to divide into equal doses		1, 2, 3	IB
Conditions
1. Finished product release and end of shelf life specifications have not been changed (except for appearance).
2. Any ink must comply with the relevant pharmaceutical legislation.
3. The scoring/break lines are not intended to divide into equal doses.
4. Any product markings used to differentiate strengths should not be completely deleted.
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 detailed drawing or written description of the current and new appearance, and including revised product information as appropriate.
2. Samples of the finished product where applicable (see NTA, Requirements for samples in the Member States).
3 Results of the appropriate Ph. Eur tests demonstrating equivalence in characteristics/correct dosing.

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B.II.a.2 Change in the shape or dimensions of the pharmaceutical form	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Immediate release tablets, capsules, suppositories and pessaries	1, 2, 3, 4	1, 4	IA_IN
b) Gastro-resistant, modified or prolonged release pharmaceutical forms and scored tablets intended to be divided into equal doses		1, 2, 3, 4, 5	IB
c) Addition of a new kit for a radiopharmaceutical preparation with another fill volume			II
Conditions
1. If appropriate, the dissolution profile of the reformulated product is comparable to the old one. For herbal medicinal products, where dissolution testing may not be feasible, the disintegration time of the new product compared to the old one.
2. Release and end of shelf-life specifications of the product have not been changed (except for dimensions).
3. The qualitative or quantitative composition and mean mass remain unchanged.
4. The change does not relate to a scored tablet that is intended to be divided into equal doses.
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 detailed drawing of the current and proposed situation, and including revised product information as appropriate.
2. Comparative dissolution data on at least one pilot batch of the current and proposed dimensions (no significant differences regarding comparability see the relevant (Human or Veterinary) guidance on Bioavailability). For herbal medicinal product comparative disintegration data may be acceptable.
3. Justification for not submitting a new bioequivalence study according to the relevant (Human or Veterinary) guidance on Bioavailability.
4. Samples of the finished product where applicable (see NTA, Requirements for samples in the Member States).
5. Results of the appropriate Ph. Eur tests demonstrating equivalence in characteristics/correct dosing.
Note: For B.II.a.2.c Applicants are reminded that any change to the “strength” of the medicinal product requires the submission of an Extension application.

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B.II.a.3 Changes in the composition (excipients) of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Changes in components of the flavouring or colouring system
1. Addition, deletion or replacement	1, 2, 3, 4, 5, 6, 7, 9, 11	1, 2, 4, 5, 6	IA_IN
2. Increase or reduction	1, 2, 3, 4, 11	1, 2, 4	IA
3. Biological veterinary medicinal products for oral use for which the colouring or flavouring agent is important for the uptake by target animal species			II
b) Other excipients
1. Any minor adjustment of the quantitative composition of the finished product with respect to excipients	1, 2, 4, 8, 9, 10	1, 2, 7	IA
2. Qualitative or quantitative changes in one or more excipients that may have a significant impact on the safety, quality or efficacy of the medicinal product			II
3. Change that relates to a biological/immunological product			II
4. Any new excipient that includes the use of materials of human or animal origin for which assessment is required of viral safety data or TSE risk			II
5. Change that is supported by a bioequivalence study			II
6. Replacement of a single excipient with a comparable excipient with the same functional characteristics and at a similar level		1, 3, 4, 5, 6, 7, 8, 9, 10	IB
Conditions
1. No change in functional characteristics of the pharmaceutical form e.g. disintegration time, dissolution profile.
2. Any minor adjustment to the formulation to maintain the total weight should be made by an excipient which currently makes up a major part of the finished product formulation.
3. The finished product specification has only been updated in respect of appearance/odour/taste and if relevant, deletion of an identification test.
4. Stability studies have been started under ICH/VICH conditions (with indication of batch numbers) and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant (at time of implementation for Type IAs and at time of notification for Type IBs) and that the stability profile is similar to the currently registered situation. Assurance is given that these studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specification at the end of the approved shelf life (with proposed action). In addition, where relevant, photo-stability testing should be performed.
5. Any new proposed components must comply with the relevant Directives (e.g. Directive 94/36/EC of the European Parliament and of the Council and Comission Directive 2008/128/EC for colours for use in foodstuffs and Directive 88/388/EEC for flavours).
6. Any new component does not include the use of materials of human or animal origin for which assessment is required of viral safety data or compliance with the current Note For Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products.
7. Where applicable, the change does not affect the differentiation between strengths and does not have a negative impact on taste acceptability for paediatric formulations.
8. The dissolution profile of the new product determined on a minimum of two pilot scale batches is comparable to the old one (no significant differences regarding comparability, see the relevant (Human or Veterinary) guidance on Bioavailability). For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.
9. The change is not the result of stability issues and/or should not result in potential safety concerns i.e. differentiation between strengths.
10. The product concerned is not a biological/immunological medicinal product.
11. For veterinary medicinal products for oral use, the change does not affect the uptake by target animal species.
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 identification method for any new colorant, where relevant, and including revised product information as appropriate.
2. A declaration that the required stability studies have been started under ICH/VICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
3. The results of stability studies that have been carried out under ICH/VICH conditions, on the relevant stability parameters, on at least two pilot or industrial scale batches, covering a minimum period of 3 months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
4. Sample of the new product, where applicable (see Notice to Applicants Requirements for samples in the Member States).
5. Either a Ph. Eur. Certificate of Suitability for any new component of animal susceptible to TSE risk or where applicable, documentary evidence that the specific source of the TSE risk material has been previously assessed by the competent authority and shown to comply with the scope of the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathies via Human and Veterinary Medicinal Products. The following information should be included for each such material: Name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals and its use. For the Centralised Procedure, this information should be included in an updated TSE table A (and B, if relevant).
6. Data to demonstrate that the new excipient does not interfere with the finished product specification test methods, if appropriate.
7. Justification for the change/choice of excipients etc. must be given by appropriate development pharmaceutics (including stability aspects and antimicrobial preservation where appropriate).
8. For solid dosage forms, comparative dissolution profile data of at least two pilot scale batches of the finished product in the new and old composition. For herbal medicinal products, comparative disintegration data may be acceptable.
9. Justification for not submitting a new bioequivalence study according to the current Note for Guidance on The Investigation of Bioavailability and Bioequivalence.
10. For veterinary medicines intended for use in food producing animal species, proof that the excipient is classified according to Article 14(2)(c) or, if not, justification that the excipient does not have pharmacological activity at the dose at which it is administered to the target animal.

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B.II.a.4 Change in coating weight of oral dosage forms or change in weight of capsule shells	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Solid oral pharmaceutical forms	1, 2, 3, 4	1, 2	IA
b) Gastro-resistant, modified or prolonged release pharmaceutical forms where the coating is a critical factor for the release mechanism			II
Conditions
1. The dissolution profile of the new product determined on a minimum of two pilot scale batches is comparable to the old one. For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.
2. The coating is not a critical factor for the release mechanism.
3. The finished product specification has only been updated in respect of weight and dimensions, if applicable.
4. Stability studies in accordance with the relevant guidelines have been started with at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant at the time of implementation and assurance that these studies will be finalised. Data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
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. A declaration that the required stability studies have been started under ICH/VICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action). In addition, where relevant, photo-stability testing should be performed.

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B.II.a.5 Change in concentration of a single-dose, total use parenteral product, where the amount of active substance per unit dose (i.e. the strength) remains the same	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II

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B.II.a.6 Deletion of the solvent / diluent container from the pack	Conditions to be fulfilled	Documentation to be supplied	Procedure type
		1, 2	IB
Documentation
1. Justification for the deletion, including a statement regarding alternative means to obtain the solvent / diluent as required for the safe and effective use of the medicinal product.
2. Revised product information.