Q.II.a.2 Change in the shape or dimensions of the pharmaceutical form
Q.II.a.3 Change in the composition (excipients) of the finished product
Q.II.a.4 Change in coating weight of oral dosage forms or change in weight of capsule shells
Q.II.a.6 Deletion of the solvent/diluent container from the pack
#qiia1
| Q.II.a.1 Change or addition of imprints, bossing (embossing/debossing) 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 (embossing/debossing) or other markings | 1, 2, 3, 4 | 1 | IAIN |
| (b) Changes in scoring/break lines intended to divide into equal doses | 1, 2 | 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), including a detailed drawing or written description of the current and new appearance, and including revised product information as appropriate. | |||
| 2. Results of the appropriate Ph. Eur tests demonstrating equivalence in characteristics/correct dosing. | |||
#qiia2
| Q.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 | IAIN |
| (b) Gastro-resistant, modified or prolonged release pharmaceutical forms and scored tablets intended to be divided into equal doses | 1, 2, 3, 4 | 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 shape or 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), 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 guideline on Investigation of Bioequivalence). For herbal medicinal product comparative disintegration data may be acceptable. | |||
| 3 Justification for not submitting a new bioequivalence study according to the relevant guideline on Investigation of Bioequivalence. | |||
| 4. Results of the appropriate Ph. Eur tests demonstrating equivalence in characteristics/correct dosing. | |||
| Note: For Q.II.a.2.c Applicants are reminded that any change to the ‘strength’ of the finished product requires the submission of an Extension application. | |||
#qiia3
| Q.II.a.3 Change in the composition (excipients) of the finished product | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Change in components of the flavouring or colouring system | |||
| 1. Addition, deletion or replacement | 1, 2, 3, 4, 5, 6, 7, 9 | 1, 2, 4, 5 | IAIN |
| 2. Increase or reduction | 1, 2, 3, 4, | 1, 2 | IA |
| (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, 6 | 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 finished product (for example, biological excipients or a 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 | ||
| 3. Change that is supported by a bioequivalence study | II | ||
| 4. Replacement of excipient(s) with comparable excipient(s) with the same functional characteristics | 1, 3, 4, 5, 6, 7, 8 | 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 one or more excipient(s) which currently make(s) 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 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 Union legislation (e.g. Regulation (EC) No 1333/2008 of the European Parliament and of the Council (3), Commission Regulation (EU) No 231/2012 (4) on food additives and Regulation (EC) No 1334/2008 of the European Parliament and of the Council (5) 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 guideline on Investigation of Bioequivalence). 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 finished product. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), and revised product information as appropriate. | |||
| 2. A declaration that the required stability studies have been started under ICH 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 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. 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). | |||
| 5. Data to demonstrate that the new excipient does not interfere with the finished product specification analytical procedures, if appropriate. | |||
| 6. Justification for the change/choice of excipients etc. must be given by appropriate development pharmaceutics (including stability aspects and antimicrobial preservation where appropriate). | |||
| 7. 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. | |||
| 8. Justification for not submitting a new bioequivalence study according to the current guideline on Investigation of Bioequivalence. | |||
| Notes: (3) Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008 on food additives (OJ L 354, 31.12.2008, p. 16, ELI: http://data.europa.eu/eli/reg/2008/1333/oj). (4) Commission Regulation (EU) No 231/2012 of 9 March 2012 laying down specifications for food additives listed in Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and of the Council (OJ L 83, 22.3.2012, p. 1, ELI: http://data.europa.eu/eli/reg/2012/231/oj). (5) Regulation (EC) No 1334/2008 of the European Parliament and of the Council of 16 December 2008 on flavourings and certain food ingredients with flavouring properties for use in and on foods and amending Council Regulation (EEC) No 1601/91, Regulations (EC) No 2232/96 and (EC) No 110/2008 and Directive 2000/13/EC (OJ L 354, 31.12.2008, p. 34, ELI: http://data.europa.eu/eli/reg/2008/1334/oj). | |||
#qiia4
| Q.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 pharmaceutical forms where the coating or capsule shell is a critical factor for the release mechanism | 1, 3, 4, 5, 6 | IB | |
| (c) Modified or prolonged release pharmaceutical forms where the coating or capsule shell 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 or for the control of other quality attribute(s). | |||
| 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). | |||
| 2. A declaration that the required stability studies have been started under ICH 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. | |||
| 3. The results of stability studies that have been carried out under ICH 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. Comparative batch analysis data and comparative dissolution profile data of at least two pilot scale batches of the finished product in the current and proposed formulation. For herbal medicinal products where dissolution testing may not be feasible, comparative disintegration data should be provided. | |||
| 5. Justification for not submitting a new bioequivalence study according to the current guideline on the Investigation of Bioequivalence. | |||
| 6. Declaration that the finished product specification has only been updated in respect of weight and dimensions. | |||
#qiia5
| Q.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 |
#qiia6
| Q.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 finished product. | |||
| 2. Revised product information. | |||
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