Type-IA variations: questions and answers
Once a veterinary product has received approval from the Commission (the “Commission Decision”) all further procedures connected with the product will fall under “Post-Authorisation Procedures”.
The guidance published under Post-authorisation procedural Q&A provides an overview for different types of post-authorisation procedures that occur frequently and, in each case, addresses a number of questions which Marketing Authorisation Holders (MAHs) may have.
Applicants should use the eSubmission Gateway / Web Client for all veterinary procedural submissions to the Agency. For more information, including links to guidance on registration with the system, see the Veterinary eSubmission website.
- The Rules governing Medicinal Products in the European Union, Volume 6, Notice to Applicants
- Community Legislation
- Commission Regulation (EC) No 1234/2008 - referred to as the ‘Variations Regulation’
- Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
- Commission guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 and on the documentation to be submitted pursuant to those procedures (2013/C 223/01) - referred to as the ‘Variations Guidelines’, and also as the ‘Classification Guideline’ or the ‘Procedural Guideline’
The Variations Regulation and the Variations Guidelines set out a list of changes to be considered as Type IA variations. Such minor variations have only a minimal impact, or no impact at all, on the quality, safety or efficacy of the veterinary medicinal product, and do not require prior approval before implementation (“Do and Tell” procedure). The Variations Guidelines clarify the conditions which must be met in order for a change to be considered a Type IA variation.
Such minor variations are classified in two subcategories, which impact on their submission:
Type IA variations requiring immediate notification (‘IAIN’)
The Variations Guidelines specify which Type IA variations must be notified (submitted) immediately to the National Competent Authorities/European Medicines Agency (‘the Agency’) following implementation, in order to ensure the continuous supervision of the veterinary medicinal product.
Type IA variations NOT requiring immediate notification (‘IA’)
Variations which do not require immediate notification may be submitted by the MAH within 12 months after implementation, or may be submitted earlier, should this facilitate dossier life-cycle maintenance or when necessary e.g. to ensure that the latest product information is reflected in certificates of medicinal products.
The 12-month deadline to notify minor variations of Type IA allows for an ‘annual reporting’ for these variations, where a MAH submits several minor variations of Type IA which have been implemented during the previous twelve months.
Most of these Type IA variations do not impact on the product information. However, in case of an upcoming submission of a variation, extension or other regulatory procedure which will affect the product information, the MAH should also include any Type IA change(s) affecting the product information, in order to keep the product information up-to-date and to facilitate document management.
There are no recommended submission dates for Type IA variations. However, MAHs are encouraged to avoid submitting Type IA notifications shortly before or during the Agency holiday periods (e.g. end of July and Christmas).
Meaning of “implementation” for Type IA variations
For quality changes, implementation is when the company makes the change in its own Quality System.
This interpretation allows companies to manufacture conformance batches and generate any needed stability studies to support a Type IAINvariation before making an immediate notification1 because the change will not be made in their own Quality System until these data are available.
For changes to the pharmacovigilance system (DDPS), ‘implementation’ is when the company makes the change in its DDPS (i.e. when it internally approves the DDPS incorporating the changes).
For product information, ‘implementation’ is when the company internally approves the revised product information. The revised product information will then be used as a basis for the next packaging run.
1. For example the type IAIN for addition, deletion or replacement of components in the flavouring or colouring system requires stability data on at least two pilot scale or industrial scale batches.
Article 7(2)(a) of the Variations Regulation sets out the possibility for a MAH to group several Type IA/ IAINvariations under a single application to the same relevant authority, or to group them with other types of variations.
Possible grouping of Type IA/IAIN changes only:
- Several Type IA or IAIN affecting one medicinal product
- This means for instance that a Type IA variation, which is normally not subject to immediate notification, can be included in the submission of a Type IAINvariation.
- One Type IA or IAIN affecting several medicinal products from the same MAH.
- Several Type IA and/or IAIN affecting several medicinal products from the same MAH provided that those variations are the same for all medicinal products and are submitted to the same relevant authority.
- Type IA/IAIN can also be grouped with other variations (e.g. Type IB, Type II, extension).
- Such grouped submissions will follow the timetable and review procedure of the highest variation in the group. Please also refer to “What type of variations can be grouped?”
It must be noted however, that when submitting Type IA/IAINvariations as part of a group, the legal deadlines for submission of each variation should be respected i.e. a Type IAIN should always be submitted immediately, whether or not it is grouped with other variations, and any Type IA variation should always be submitted within 12 months following its implementation.
The same principle applies whether a single or a group of Type IA/IAINvariations is being submitted.
However, if the Type IA/IAINvariations are grouped with other variations (Type IB, Type II, extension), the grouped submission will follow the review procedure and timelines of the highest variation in the group and the rapporteur will provide an assessment report for the group. Although the Rapporteur is not expected to assess the Type IA/IAINvariations in the group, the Rapporteur will confirm in the assessment report whether non-acceptance of (part of) the change(s) in the group leads to non-acceptance of the Type IA/ IAIN changes in the group.
A Type IA/IAINvariation application should contain the elements listed in Annex IV of the Variations Regulation and should be presented in accordance with the appropriate headings and numbering of the NTA format.
- Cover letter (for groupings, include a short overview of the nature of the changes). If a variation is submitted because it has been requested as an outcome arising from another pre-/post-authorisation procedure (including as a result of a PSUR or post-authorisation measure (PAM) e.g. condition, specific obligation, recommendation), then this should be clearly mentioned in the cover letter for the resulting variation, identifying the related EMA procedure number from which the variation arose. In case the reference number for the PAM has not been confirmed by the Agency, a description of the commitment/measure is sufficient at time of submission (or contact firstname.lastname@example.org to check for the PAM reference number).
- The completed EU variation application form (as published on the eAF eSubmission website), including the details of the marketing authorisation(s) concerned, as well as a description of all variations submitted together with their date of implementation. Information on the electronic application form for variations can be found on the eAF eSubmission website. Where a variation leads to or is the consequence of other variations, a description of the relation between these variations should be provided in the appropriate section of the application form. MAHs are reminded that the variation application form should be signed by the official contact person. Should the official contact person not be available, an official letter of authorisation confirming the delegation of signature to a different person should be enclosed. For a grouping affecting several veterinary medicinal products, MAHs are reminded to confirm in the application form under “Declaration of the applicant” that the MAs concerned belong to the same MAH and that the main signatory confirms authorisation to sign on behalf of the designated contacts. In order to facilitate the completion of the application form, MAHs are advised to consult the European Medicines Agency practical guidance on the application form for centralised type IA and IB variations .
- Reference to the respective part of the variations guidelines or reference to the published Article 5 procedure: Regulatory and procedural guidance used for the relevant application, if applicable. Applicable conditions and documentation should be clearly ticked on the extract provided, or marked as not applicable, if that is the case. If a condition or documentation is not applicable,this should be explained and a justification for its absence should be provided. The extract(s) can be submitted as a separate annex in module 1.2.
- Relevant documentation in support of the proposed variation including all documentation as specified in the Variations Guidelines.
- If applicable, the revised summary of product characteristics, labelling and/or package leaflet as a full set of annexes. (See also “When do I have to submit revised product information? In all languages?”)
- The EMA has also published a pre-notification checklist to assist applicants with their submissions.
Grouped Type IA/IAIN variations
For grouped Type IA/IAINvariations concerning one marketing authorisation, all Type IA variations must be declared in the variation application form. The supportive documentation for all variations concerned should be submitted as one integrated package (i.e. there is no need to submit a separate documentation package for each variation). However, the present-proposed section of the application form should clearly identify the relevant dossier sections in support of each variation.
For a (group of) Type IA/IAINvariation(s) concerning several marketing authorisations, a common cover letter and common application form referring to all veterinary medicinal products and variations concerned should be submitted. In addition, for each veterinary medicinal product the relevant supportive documentation and revised product information (if applicable) should be provided, in order to allow the Agency to update the dossier of each marketing authorisation with the relevant updated/new information. Cross-references to any documentation submitted for another veterinary medicinal product can therefore not be accepted. For further details, please refer to “How shall I present a grouped variations application?”
It should be noted that the responsibility for the quality of the submitted documentation lies with the MAH and is crucial to the overall process. The MAH is responsible for ensuring that the Type IA variation complies fully with the conditions and documentation requirements as specified in the Variations Guidelines.
Type IA variations are intended to provide for a simple, rapid and efficient procedure for minor changes. The MAH should be aware that the submission of redundant information or a confusing dossier presentation will not facilitate rapid procedures. Similarly, deficient and missing documentation can lead to rejection of the variation. The MAH can be requested to provide missing documentation during the review of the application. Not providing the requested information immediately on request of the Agency can lead to rejection of the variation.
Submission of Type IA/IAIN variation applications
The variation application presented in the correct format should be submitted to the Agency.
Applicants should use the eSubmission Gateway / Web Client for all veterinary procedural submissions to the Agency. For more information, including links to guidance on registration with the system, see the Veterinary eSubmission website.
All submissions should be made in accordance with the guideline on e-submissions.
- Commission Regulation (EC) No 1234/2008
- Commission Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008
- Variations Guidelines (2013/C 223/01)
- Electronic application forms website
- European Medicines Agency practical guidance on the application form for centralised type IA and IB variations
- Pre-notification check for type IA variations: ensuring the quality of veterinary type IA variation submissions
- Dossier requirements for post-authorisation submissions in the centralised procedure
- Veterinary eSubmission website
- eSubmission Gateway and Web Client information website
- Article 5 procedure: Regulatory and procedural guidance
The Agency will review the (grouped) Type IA/IAINvariation(s) within 30 calendar days following receipt. The Agency will check the correctness of the application form, the presence of the required documentation and compliance with the required conditions, in accordance with the variations guidelines.
- Receipt of Type IA/IAINvariation application Day 0
- Start of Agency check Day 1
- Favourable/Unfavourable review outcome by Day 30
By day 30, the Agency will inform the MAH by EudraLink.
Where the outcome of the procedure is favourable and the Commission Decision granting the marketing authorisation requires amendment, the Agency will inform the Commission accordingly.
Type IA/IAIN changes can be implemented prior to submission of the application. However, in case of an unfavourable outcome, the Variations Regulation requires the MAH to immediately cease applying the rejected variation(s). Please refer to “What should I do in case of an unfavourable review outcome for my type IA/IAIN variation?” for further details.
It is still possible for MAHs to submit Type IA application prior to its implementation, particularly when the proposed changes are related to other notifications/variations requiring prior approval.
However, the submission of one or several Type IA/IAINvariations affecting more than one marketing authorisation of the same MAH, in one application to the same relevant authority (similar to worksharing) is possible under Article 7(2) of the Variations Regulation – see also “Can I group the submission of Type IA/IAIN variations? Can they be grouped with other types of variations?”
This type of grouping is referred to as ’IG’ by the Agency.
In addition, it is also possible to group a Type IA/IAINvariation(s) with a Type IB or Type II variation which is submitted for a worksharing procedure. In such case, the review of the Type IA/IAINvariation will be performed as part of the worksharing procedure.
A Type IA/IAINvariation will be rejected when not all of the conditions for the Type IA/IAINvariation are met, or when the submitted documentation as required by the Variations Guidelines is deficient. In such case, the MAH shall immediately cease to apply the rejected changes.
In the case of a negative outcome of a Type IA application because the conditions for Type IA variation(s) are not met and consequently a resubmission (as a Type IB, Type II variation or extension) is needed or because documentation is deficient, it is the MAH’s responsibility to judge whether the rejected Type IA variation has an impact on the quality, safety or efficacy of the veterinary medicinal product. If this is the case, the MAH has to take appropriate action.
The Agency may ask the MAH to complete a suspected quality defect notification form and provide a Risk Assessment report on the impact of the product on the market via e-mail to email@example.com within 7 calendar days from the date of the rejection letter. Such requests are expected to be very exceptional. The MAH should follow the instructions under Quality Defects.
For information on the fees applicable for Type IA and IAINvariations, please refer to fees payable to the European Medicines Agency. Such fees cover all authorised strengths, pharmaceutical forms and presentations of a given veterinary medicinal product.
For variations introducing additional presentations or pack sizes, each additional presentation or pack size attracts separate fees (x additional presentations = x separate fees). Each presentation or pack size should therefore be declared as a separate variation on the variation application form under the section ‘variations included in this application’.
Grouped Type IA or IAINvariations, whether consequential or not, will each attract a separate type IA fee.
The fee will become due on the date of receipt of the Type IA or IAINvariation notification and fees will be payable within 45 calendar days of the date of the said notification. After approximately 15 days, an invoice will be sent to the applicant’s billing address held on the Agency’s file.
The invoice will contain details of the product and type of procedure involved, the fee amount, the customer purchase order number associated with the procedures invoiced and financial information.
Applicants requiring a purchase order number or similar references on the invoice are requested to clearly indicate it on the cover letter or application form accompanying the dossier, as well as in the “Customer reference” box of the delivery file to be generated for submission via the EMA Gateway. The Agency does not accept standalone notifications of purchase order numbers that are not associated with a dossier. The Agency will charge the fee for Type IA variations or grouped Type IA variations at the start of the procedure, irrespective of its outcome (positive, negative, or partial or full withdrawal).
Type IA variations that are grouped with other type of variations or extensions or which are part of a worksharing procedure will continue to be charged on conclusion of the validation of the application.
Please refer to the Q&A: Mock-ups.
Differentiation should be made between the addition of a presentation where the two presentations will co-exist on the market on a long-term basis versus a replacement of a presentation where the new presentation will replace the previous one (it is expected that for a certain period of time, the two presentations will co-exist on the market until the stock of the previous presentation runs out).
In principle, a replacement of one presentation by another presentation does not trigger a new EU number, unless the number of units of veterinary medicinal product being an integral part of the medicinal product (e.g. prefilled syringes) is changed.
Examples of changes in presentations for replacement, not triggering a new EU number (this is not an exhaustive list):
- Replacement of the primary or secondary packaging,
- Change in composition (e.g. change in excipients),
- Change in units per blisters (without change to the total number of units per pack).
Examples of changes in presentations for replacement, triggering a new EU number (this is not an exhaustive list):
- 30 to 60 tablets,
- 2 prefilled syringes containing the veterinary medicinal product instead of one prefilled syringe.
In case of addition, as the presentations will co-exist on the market, two packs with different contents cannot be covered by the same EU number and will be considered as different presentations.
Changes in the number of any unit (not restricted to the veterinary medicinal product) or changes in the specifications of any unit (not restricted to the medicinal product) contained in the pack will trigger a new EU number.
Examples of changes that will trigger new EU numbers (this is not an exhaustive list):
- Introduction of an alternative syringe of different volume or an alternative syringe,
- Introduction of an alternative immediate (primary) packaging made from a different material,
- Introduction of an alternative shape/dimension of a pharmaceutical form.
If you have any questions on any upcoming submission, please contact firstname.lastname@example.org.
The request should be sent together with a draft Annex A (in English only) to email@example.com with a copy to the product shared mailbox, and should be made at least 5 working days in advance of the intended submission of the variation. Once a number has been allocated, this number should subsequently be included in the Annex A and product information annexes submitted together with the variation notification.
- The complete set of Annexes in all EEA languages should be provided as part of the variation application, in Word format (highlighted) and in PDF (clean).
- The ‘complete set of Annexes’ includes Annex A (if applicable), I, II, IIIA and IIIB i.e. all authorised presentations (if applicable), SPC, labelling and PL texts for all strengths and pharmaceutical forms of the product concerned, as well as Annex II. The complete set of Annexes must be presented sequentially (i.e. Annex I, II, IIIA, IIIB) as one document for each official EU language. Page numbering should start with "1" (bottom, centre) on the title page of Annex I. All Annexes should be in compliance with the 'QRD convention' published on the Agency website. When submitting the full set of Annexes in PDF format, the formatting checklist and the user guide on how to generate PDF versions of the product information should be followed.
- Highlighted changes should be indicated via ‘Tools – Track Changes’. Clean versions should have all changes ‘accepted’.
- Icelandic and Norwegian language versions must always be included.
- The Annexes provided should only reflect the changes introduced by the variation(s) concerned. However, in exceptional cases where MAHs take the opportunity to introduce minor linguistic amendments in the texts or to align the product information with the latest QRD template, this should be clearly mentioned in the cover letter and in the precise scope section of the application form.
In addition, the section “present/proposed” in the application form should clearly list the minor linguistic amendments introduced for each language. Alternatively, such listing may be provided as a separate annex attached to the application form. Any changes not listed will not be considered as part of the variation application. In such cases, and in cases where any other ongoing procedures may affect the product information Annexes, the MAH is advised to contact the Agency in advance of submission or finalisation of the procedure(s) concerned.
- When the Type IA/IAINvariation concerns several veterinary medicinal products, the relevant complete set of product information Annexes should be included for each product concerned.
- For Type IA/IAINvariations affecting Annex A (e.g. introduction of a new presentation), translations of the revised Annex A in all EU languages should be provided as separate documents in clean Word and PDF format, together with the variation application. Where the variation introduces a new EU sub-number, the new sub-number should be included in the Annex A and in the product information texts as part of the variation application (see also “How to obtain new EU sub-numbers for a Type IAINvariation concerning an additional presentation (e.g. new pack-size)”?). Similarly, in case of a deletion of a pharmaceutical form/strength/pack-size(s), the amended Annex A and product information Annexes should be provided as part of the variation application.
- Product information: Reference documents and guidelines
- QRD convention to be followed for the EMA-QRD templates
- Checklist for the submission of Type IA and Type IB (without linguistic review) product information annexes and Annex A (if applicable) – veterinary
- User guide on how to generate PDF versions of the product information - veterinary
By the end of this period, the Agency will send the complete set of Annexes, based on the latest (previously) approved Annexes and reflecting the Type IA/IAIN change(s) agreed, together with a line-listing of those Type IA/IAIN application(s). The Commission will subsequently issue a Commission Decision on the Type IA/IAIN application(s) concerned.
However, where any Opinion affecting the Annexes is transmitted to the Commission within these 12 months, the changes of the Type IA/IAIN application(s) concerned will already be included in the Annexes to that Opinion and will consequently be reflected in the resulting Commission Decision. This Commission Decision will therefore replace the 12-monthly updating of the MA for the Type IA/IAIN application(s) concerned.
On the occasion of the next Type IA/IAINvariation affecting the Annexes, the procedure outlined above will be repeated based on the new ‘Reference point’ of the next Type IA/IAIN concerned (see also diagram below, which illustrates the 12-monthly updating process.
In addition, it is important that in case of an upcoming submission of a variation, extension or other regulatory procedure which will affect the product information, the MAH should also include any Type IA change(s) affecting the product information that have not been previously notified, in order to keep the product information up-to-date and to facilitate document management.
Type IA/IAINvariations do not require prior approval before implementation (“Do and Tell” procedure), i.e. they can be implemented and notified to the Agency either immediately for Type IA variations requiring immediate notification (‘IAIN’) or within 12 months for Type IA variations not requiring immediate notification (‘IA’).
For Type IA variations affecting the product information, the date of revision of the text to be included in section 10 of the summary of product characteristics and in the corresponding section of the package leaflet at the time of printing1 should be the date of implementation of the change by the MAH. For the meaning of “implementation” see “When shall I submit my Type IA/IAIN variation(s)?”.
1The date of revision of the text in both section 10 of the summary of product characteristics and in the corresponding section of the package leaflet should be left blank in the full set of Annexes submitted to the Agency.
The European Commission Variations Guidelines specify that “If amendments to the dossier only concern editorial changes, such changes should generally not be submitted as a separate variation, but they can be included in a variation concerning that part of the dossier. In such cases the changes should be clearly identified in the application form as editorial changes and a declaration that the content of the concerned part of the dossier has not been changed by the editorial changes beyond the scope of the variation submitted should be provided”. Changes that can be classified as a variation according to the Variations Guidelines are not considered editorial changes and should be submitted under the appropriate variation category.
The Agency strongly recommends the submission of editorial changes within procedures that have an administrative validation phase (e.g. type IB or type II variations. This allows the appropriate review of proposed editorial changes during validation and the consequential amendment of the submission prior to assessment, if needed. The editorial changes proposed should affect the same part of the dossier concerned by the variation procedure. For example, if a variation affects Part 2.C, editorial changes can be submitted in Part 2.C.
Exceptionally, the Agency may accept minor editorial changes as part of IA variations, if affecting the same dossier sub-section impacted by the variation submitted. This is due to the fact that IA notifications are administrative in nature and do not have a validation phase. The Agency expects MAHs to keep proportionality between the submissions of editorial changes versus the real change of the variation. In case of doubt about the acceptability of editorial changes in future type IA applications, MAHs are advised to contact firstname.lastname@example.org in advance of the submission.
MAHs are reminded to follow this guidance and to ensure the high quality of variation applications in support of a timely processing of these submissions.
Editorial changes should generally not be submitted as a separate variation and therefore no reference to a variation category is required when they are encompassed within another variation procedure.
Within the section of the variation application form under the section on ‘Precise scope and background…’, the MAH should provide:
- a brief description of the proposed editorial changes and a justification as to why they are considered ‘editorial’ (i.e. why they should not trigger a specific variation);
- a declaration confirming that the changes proposed as editorial do not change the content of the concerned part(s) of the dossier beyond the scope of the variation within which the editorial changes are being submitted;
- confirmation that all relevant parts of the dossier have been updated accordingly and are included within the variation package.
Additionally, all the editorial changes should be listed in the present/proposed table (or provided as a separate annex that is cross-referred to from this table), identifying each related change in the dossier down the lowest section heading and page numbers where possible.
Any changes proposed by the applicants as editorial will be carefully considered by the Agency at time of submission and may be subject to further assessment at the same time as the overarching variation. Proposed editorial changes that cannot be accepted as such will be rejected. In case of doubt, applicants can contact email@example.com in advance of the planned submission.
Editorial changes in Part 2 (quality)
.The following may be considered as examples of editorial changes to Part 2: adding headers for ease of use, reordering of existing information without changing the meaning, alignment of information among/within the sections provided the correct reference that had been previously agreed can be demonstrated (e.g. alignment of information in flow charts to process description), punctuation changes and grammar/orthographic corrections that do not alter the meaning of the text.
Examples of changes that cannot be considered editorial: removal of specification parameters or manufacturing description, update of information to bring the dossier content in line with the current manufacturing process, etc.
Proposed changes that require confirmation by the rapporteur may only be accepted when submitted within the scope of an upcoming variation Type IB or Type II which impacts upon the corresponding section of Part 2.
If editorial changes are required and there is no upcoming procedure, the MAH may consider submitting these changes as a separate, default Type IB variation (B.I.z or B.II.z, as appropriate).
Editorial changes in Parts 3 (safety & residues) and 4 (pre clinical & clinical)
Editorial changes in Parts 3 and 4 are not foreseen. Please contact firstname.lastname@example.org in advance of an upcoming submission.
Formatting changes, correction of typographical errors and/or mistakes to the English product information or other linguistic versions of the product information are considered editorial changes provided that the meaning of the text is not altered. These changes can be included within the scope of any upcoming procedure impacting on the product information.
Changes in the scientific content or meaning cannot be accepted as an editorial change. These changes should be classified under the scope of the relevant category as per the Variations Guidelines (e.g. Type II, C.I.4). If no relevant scope is available, a variation Type IB C.I.z may be appropriate.
Proposed changes that may require confirmation by the Rapporteur or linguistic review will only be accepted when submitted within the scope of an upcoming variation Type IB or Type II under chapter C (of the Variations Guidelines) which impacts upon the product information and where linguistic review is foreseen, if applicable.
Should there be no upcoming regulatory procedure in which to include the editorial changes, these could also be submitted as a stand-alone, default Type IB variation e.g. under C.I.z if they affect the English product information. If other languages are affected and in case no procedure affecting the product information is upcoming, holders are advised to contact email@example.com to discuss how to handle these necessary changes.
The MAH should liaise with the Agency without delay if the mistake concerns an incorrect or missing important information (e.g. contra-indication or adverse event), in the English or any of the other language versions, that could affect the safe and effective use of the veterinary medicinal product and/or lead to a potential medication errors (e.g. wrong strength, wrong posology, wrong route of administration).
Variation scopes B.I.a.4.c, B.I.b.1.d, B.I.c.2.c, B.II.b.5.c, B.II.c.1.c, B.II.d.1.d, B.II.e.2.c and B.IV.2.f of the Variations Guidelines deal with the deletion of a non-significant in-process control (IPC) test or specification parameter. Provided all relevant conditions and documentation requirements are met, all these variations fall under the Type IA category (“Do and tell”).
For the categories listed above and other variations related to specifications of active ingredients, excipients, finished product, packaging material or measuring or administration device, the deletion of an obsolete parameter is given as an example. For finished products, this is further exemplified by mentioning of odour and taste. Although it is not possible to give similar examples for all of the categories mentioned above, these examples serve as an indication of the types of changes considered to fall under this variation category, regardless if this is related to in-process controls or specifications. This is therefore intended to be used for truly obsolete tests that are no longer part of normal specifications for newer products, but have remained for historical reasons in older products.
This variation category is not intended to include changes in relation to revisions of the control strategy with an intention to minimise redundant testing of parameters and attributes (critical or non-critical) that are tested at different stages during the production, or cases where process/ product characterisation performed after authorisation has shown that the attribute/ parameter is non-critical. Such changes require regulatory assessment and are to be handled as Type IB or II variations as appropriate.
Range is defined from the smallest to the biggest approved pack size (not from ‘0’) for the same pharmaceutical form and strength. The pack size equals the number of units of the pharmaceutical form (e.g. tablets, sachets, ampoules, etc.) contained per outer packaging. Pack sizes not included within this range are considered to be outside of the range.
For the addition of a new pack size where the number of units of the pack is within the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a variation B.II.e.5.a.1 (IAIN).
For the addition of a new pack size where the number of units of the pack is outside the range of the currently approved pack sizes for the strength and pharmaceutical form, applicants should submit a variation B.II.e.5.a.2 (IB).
In support of a timely introduction of new pack sizes to the market, the EMA accepts the following approach for the introduction of various pack sizes falling outside the range within a single grouped submission. The biggest or the smallest pack size per strength outside the range should be classified as B.II.e.5.a.2 (IB). This presentation defines the new limits of the range so that any intermediate pack size for the strength and pharmaceutical form can be classified as B.II.e.5.a.1 (IAIN).
Some examples are provided below to illustrate the principles explained above.
The 20 mg strength of ‘Veterinary Medicinal Product A’ currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form ‘film-coated tablets’ and the MAH intends to apply for a new pack size of 45 tablets. The introduction of a new pack size of 45 tablets for the 20 mg strength is considered within the range of approved packs (30-60 tablets) and should be classified as variation B.II.e.5.a.1 (IAIN).
The 20 mg strength of ‘Veterinary Medicinal Product A’ currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form ‘film-coated tablets’ and the MAH intends to apply for a new pack size of 90 tablets. The introduction of a new pack size of 90 tablets for the 20 mg strength is considered outside the range of approved packs (30-60 tablets) and should be classified as variation B.II.e.5.a.2 (IB).
The 20 mg strength of ‘Veterinary Medicinal Product A’ currently has two approved pack sizes of 30 and 60 tablets for the pharmaceutical form ‘film-coated tablets’ and the MAH intends to apply for two new pack sizes of 90 and 120 tablets at the same time. The introduction of a new pack size of 120 tablets for the 20 mg strength is considered outside the range of packs and should be classified as variation B.II.e.5.a.2 (IB). This pack size defines a new limit for the range (30-120), so that the introduction of a pack size of 90 tablets can be classified as a variation B.II.e.5.a.1 (IAIN). The MAH should therefore apply for a grouped variation of 1 x type IB - B.II.e.5.a.2 and 1 x type IAIN - B.II.e.5.a.1.
The 20 mg and 40 mg strengths of ‘Veterinary Medicinal Product B’ currently each have two approved pack sizes of 2 and 10 pre-filled syringes for the pharmaceutical form ‘solution for injection’. The MAH intends to apply for four new pack sizes:
- 5 and 30 pre-filled syringes for the 20 mg strength;
- 5 and 30 pre-filled syringes for the 40 mg strength
For the 20 mg strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10) and should be classified as variation B.II.e.5.a.1 (IAIN) and the introduction of a new pack size of 30 pre-filled syringes is considered outside the range of approved packs (2-10) and should be classified as variation B.II.e.5.a.2 (IB).
For the 40 mg strength, the introduction of a new pack size of 5 pre-filled syringes strength is considered within the range of approved packs (2-10) and should be classified as variation B.II.e.5.a.1 (IAIN) and the introduction of a new pack size of 30 pre-filled syringes is considered outside the range of approved packs (2-10) and should be classified as variation B.II.e.5.a.2 (IB).
The MAH should therefore apply to the EMA for a grouped variation for the abovementioned scopes.
The 50 mg strength of ‘Veterinary Medicinal Product C’ currently has two approved pack sizes of 10 and 30 tablets for the pharmaceutical form ‘film coated tablets’ and the MAH intends to apply for a multipack of 30 (3x10) tablets. The introduction of a multipack 30 (3x10) tablets for the 50 mg strength is considered within the range of approved packs (10-30) and should be classified as variation B.II.e.5.a.1 (IAIN).
For variations introducing additional presentations or pack sizes, each additional presentation or pack size attracts separate fees (x additional presentations = x separate fees). Each presentation and pack size should therefore be declared as a separate variation on the variation application form under the section ‘variations included in this application’.