The most important information can be found in the guidance document Variations and extensions HMV4, guidance document Formal requirements HMV4 (particularly section 3.11), and the form Variations and extensions HMV4 on the Swissmedic website.
1. Formal requirements
If an applicant has submitted the incorrect variation type, it will be notified in the interim decision. It will then have to revise its notification of variation so that the correct type is submitted. If a variation cannot be accepted or approved, it may be necessary to demand cancellation of the implemented variation. This rarely happens, however.
Type IAIN variations must be notified to Swissmedic no later than one month after implementation.
In these cases an interim decision will be issued and the notification will then have to be submitted as a type IB variation. If the applicant notices that the deadline has passed before submitting the corresponding type IA or type IAIN variation, the application should be submitted as a type IB variation from the outset.
Yes. The definition for type IA/IAIN is "Minor variation to be reported subsequently" (TPO Art. 21). These variations must already have been implemented at the time of submission; the implementation date must be in the past and must be stated on the form Variations and extensions HMV4.
An exception applies if the type IA or IAIN variations form part of a multiple application that also contains other types of variations (type IB, type II or extensions). In these cases, the variations can be implemented after the variations in the multiple application have been approved, and an implementation date does not need to be stated. However, if the type IA-/IAIN variation has already been implemented as part of the multiple application, we would then also require an implementation date.
Any deviations from the requirement to state the implementation date (e.g. not necessary for A.101, PMF) are mentioned in the Variations and extensions HMV4 form.
Swissmedic follows the definition stated by the EMA in its Q&A.
Implementation of an IA/IAIN quality change: Date on which the company makes the change in its own quality system. For Switzerland, the Switzerland-specific quality system is relevant in this context.
Implementation of a IA/IAIN variation for product information and/or packaging texts: Date of internal release by the company / approval of the revised product information and/or packaging texts. Here too, the Switzerland-specific release is relevant for Switzerland.
The implementation date should be stated in the format "DD.MM.YYYY".
Although this type of submission for a multiple application is possible in principle, it does raise the question of the usefulness of a multiple application. Swissmedic therefore recommends that such applications be submitted together as a multiple application only if their subject matter is related.
Yes, it is possible to collect type IA variations for a product and submit them as a multiple application provided the conditions are fulfilled.
However, Swissmedic would advise the authorisation holder to consider a staggered submission in order to preserve an ideal overview of type IA variations for a medicinal product.
For variations of type IA, IAIN involving a change to the product information texts, the date of revision (month/year) should, if applicable, be adjusted to match the implementation date, taking account of the requirements stated in section 2.20 and Annex 1 of the guidance document Product information for human medicinal products HMV4.
It is important to note that any requirements in the guidance document Product information for human medicinal products HMV4 (section 2.20 and Annex 1) may override this requirement (e.g. the requirement that the date of revision should not be adjusted).
For variations of type IB involving a change to the product information texts, the date of revision in the form month/year should, if applicable, be adjusted to match the date of application submission, taking account of the requirements stated in section 2.20 and Annex 1 of the guidance document Product information for human medicinal products HMV4.
It is important to note that any requirements in the guidance document (section 2.20 and Annex 1) may override this requirement (e.g. the requirement that the date of revision should not be adjusted).
No extension of the time limit for corrective actions is granted for companies, either for type IA/IAIN or type IB variations. For both variation types, a maximum of 30 calendar days is granted for corrective actions.
While Switzerland does not recognise "Annual Report" as a concept, the authorisation holder can collect all type IA variations for a medicinal product and submit these once a year. It is important that the implementation date for the "oldest" type IA variation should not be more than 12 months before the reporting date (see also Q&A 1.8).
A form consisting of the administrative part (sections 1-7) plus the requested variation (e.g. B.II.b.1.a "Secondary packaging site"). In the administrative part, the table under section 1 (Basic information) must be reproduced and completed according to the number of authorisation numbers/medicinal products concerned.
When categorising an "Other change", Swissmedic takes account of the published list "CMDh Recommendations for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) No 1234/2008".
Swissmedic does not require covering letters for applications for variations of types IA, IAIN and IB, provided no further information or explanations in addition to those in the form Variations and extensions HMV4 are required.
Yes, co-marketing products must make the adaptations to the revised TPLRO (Full declaration) only after these have been implemented for the basic product.
Both for the form Variations and extensions HMV4 and the form New authorisations of human medicinal products HMV4 the eCTD file name starts with 1.2.1 ch-foapplvar-. In the variable part it is then up to the applicant to generate an appropriate file name, provided it is not too long.
If you receive an interim decision as a result of shortcomings in form or content and these have been answered within 30 days, you must wait for 60 days from the date of confirmation of receipt / Acceptance of delivery (for Portal users) of the replies before you can assume that the variation has been accepted/approved.
The curriculum vitae of experts is not necessary for type IA/IAIN variations.
If the content of the existing Module 2 does not change as a result of the type IB variation, then Module 2 and Module 1.4.1 do not need to be submitted.
No, for a multiple application all the information and proposed variations should be requested in one pdf file.
As before – and as also applies with other applications (e.g. renewal) – you submit one form for each medicinal product/authorisation number, not one form for each medicinal product dosage strength.
No. A.109 cannot be submitted as collective or collective-multiple applications because they do not meet the requirements of Art. 22b TPLRO.
2. Regulatory changes
No, application A.109 should be submitted separately.
No, A.109 only applies to the implementation of new requirements according to the revised TPLRO. In connection with a multiple application, in addition to A.109 you can also submit other pooled variations for the specific medicinal product. However, safety-related variations cannot form part of multiple applications.
No, a modified pack design corresponds to an A.100 variation (Change in the product information and/or packaging texts without the submission of scientific data) and cannot be processed under A.102 since A.102 is only intended for the additional pack size. A multiple application should therefore be submitted (A.100 and A.102).
The full declaration for co-marketing medicinal products should be implemented with A.101, not separately.
The scenario described above involves a regulatory change A.5: Change in the name and/or address of a manufacturer of the finished product (including batch release and quality control sites) (type IAIN, or IA, depending whether the corresponding manufacturer is responsible or not for batch releases).
If the product information and/or packaging texts are now modified in connection with this change, a separate A.100 variation is not necessary. A.5 changes must be notified for each medicinal product concerned.
In this case we consider the submission of an A.100 to be unnecessary. A.5 is sufficient.
Yes, you can submit the deletion of a manufacturer that involves several sections of the Manufacturer information HMV4 form as an A.7 variation (type IA).
The wording (singular or plural) of a variation in the Variations and extensions HMV4 form should be followed in all cases. In this case, the variation reads: "Deletion of sites..." (Plural).
The adaptations of a co-marketing medicinal product to its basic product should be notified to Swissmedic via the regulatory change A.101.
If this involves a change in the packaging code, or if not all the conditions are fulfilled, this would be a type IB variation, otherwise a type IAIN variation. In both cases, the changes to the co-marketing medicinal product must be notified to Swissmedic within 30 days of approval of the corresponding changes to the basic product.
Since the implementation of the change(s) to the co-marketing medicinal product must be made at the same time as that for the basic product, and since this rarely occurs within the 30 days described above, Swissmedic does not require an implementation date for A.101 b) (type IAIN).
Sample packs should be notified to Swissmedic on the Variations and extensions HMV4 form (regulatory change: A.102).
The promotional section of sample packs is checked only if an advertising permit needs to be obtained (sensitive groups: laxatives, anorectics, analgesics, sedatives and sleeping aids, with the potential for dependence or abuse). Authorisation of the sample pack must be applied for in the normal manner, and the promotional section must satisfy the legal provisions applicable to therapeutic products.
Since Swissmedic does not check the promotional section (apart from the exceptions mentioned above), a variation does not need to be submitted to us unless a product subject to compulsory prior control is involved. The legal provisions applicable to therapeutic products must be satisfied (direct responsibility of the authorisation holder).
Variation A.1 is included in Annex 7 to TPLRO. However, since authorisation holders do not need to notify A.1 separately, but this variation is rather initiated by Swissmedic in connection with a corresponding variation application for the establishment licence (change of name/domicile), A.1 is not included in the Variations and extensions HMV4 form.
No, the above-mentioned change should be submitted as a C.I.2 a) variation. Regardless of whether the conditions stated in the form can be satisfied or not, the application should be classified as type IAIN or type IB.
C.I.2 a) (type IAIN or IB).
3. Changes in quality
The wording (singular or plural) of a variation in the Variations and extensions HMV4 form should be followed in all cases. It is necessary to submit one variation per CEP when presenting a new or updated Ph. Eur. certificate of suitability. If deleting Ph. Eur. certificates of suitability, several deletions can be combined in one application.
No, each individual PACMP must be submitted with a B.II.g.2 variation, and the variation template for B.II.g.2 must be copied accordingly.
Any applicant who wants a new packaging code for any of the cases outlined above can apply for a type IB variation. The wish to obtain a new packaging code should be mentioned in the covering letter or on the form.
No. A separate template B.II.b.1 must be completed for each change (3 copies of template B.II.b.1). The three changes (secondary packaging site (B.II.b.1.a), primary packaging site (B.II.b.1.b), and new manufacturing site for non-sterile medicinal products (B.II.b.1.e)) may not be checked on one template.
We expect the copy of the approved release and end-of-shelf-life specifications to be inserted in Module 1 under "additional data".
Please submit your described variation as B.IV.1.z. Other variation (type IB).
A name change for suppliers of primary packaging should be submitted as B.II.e.7.z (type IB).
For the change in batch release c) provides subitems 1, 2 or 3, each of which starts with "Replacement or addition of a manufacturer responsible for batch release…". "Replacement" means that a deletion and new notification can be implemented in the same step.
An additional manufacturing site for the primary and secondary packaging involves two changes: B.II.b.1.a) and B.II.b.1.b).
A distinction should be made between the establishment of a new MCB or a new WCB.
a) Establishment of a new MCB: type II, B.I.a.2.c)
b) Establishment of a new WCB (provided that an approved protocol is followed): type IB, B.I.a.2.a)
A variation can be submitted as "Other change" if it is not listed in Annex 7 TPLRO (List of variations according to articles 21-24 TPO). An "Other change" is by default a minor variation of type IB. If a more extensive variation is involved, both Swissmedic and the marketing authorisation holder can upgrade this to a variation of type II.
When categorising an “Other change”, Swissmedic also takes account of the published list “CMDh Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) No 1234/2008”. An "Other change" can then be submitted as type IA or type IAIN only if it was also classified as such in the published CMDh list. The submission must reference the list "CMDh Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) No 1234/2008", the corresponding EU variation number and the "Date issued".
The use of a new working virus stock that has been qualified according to an approved protocol does not need to be reported to Swissmedic.
The Annual Update for an authorised seasonal influenza vaccine must be submitted as a B.I.a.5 change: Changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against influenza (type II). The corresponding documents should be made available to Swissmedic as soon as possible. The procedure is identical to the former procedure. If possible, the application is processed as a matter of priority.
N.B.: This change may not be part of a multiple application. The Annual Update may only include changes connected with the new strains.
No. A single type II variation for all changes in Module 3.2.S does not cover the workload that Swissmedic has. For this reason, the Agency does not accept this type of classification. The specifications should continue to be listed in the appropriate templates for variations (B.I.a.1 (active substance manufacturer); B.I.a.2 (active substance manufacturing process); B.I.a.3 (active substance batch size); B.I.a.4 (active substance in-process controls); B.I.b.1 (active substance specifications); etc.) and submitted as a multiple application.
4. Safety, efficacy and pharmacovigilance changes
The company requests the following variations in connection with a multiple application:
C.I.6.a): Addition of a new, or a variation to, an approved therapeutic indication for bacterium D (type II) and
C.I.6.b): Deletion of a therapeutic indication for bacterium A (type IB)
The maximum amount levied will be that for the new authorisation of a medicinal product.
No. Submit a C.I.4 variation (type II) in this case. The PRAC recommendations and corresponding PRAC minutes are adequate documentation. The PRAC assessment report should also be submitted if available.
For changes to product information texts, Swissmedic expects the following under “currently approved – proposed”:
- A.100: List of sections that have been changed
- C.I.2: Status of “old” information compared with status of “new” information.
- C.I.4: List of sections that have been changed
The Variations and extensions HMV4 form now specifies what information has to be provided for a variation to medicinal product information texts for the relevant applications.
5. Changes to Plasma Master File (section X)
Annual updates to PMFs for authorised medicinal products should be submitted to Swissmedic in a cover letter (no additional form needed) once a year as conditions of authorisation. Changes to PMFs must be notified to Swissmedic using the form Variations and extensions HMV4 or as an application for approval. Annual PMF updates (to fulfil conditions of authorisation) and variations to this PMF can be submitted simultaneously (and will be treated as a multiple application in this case).
To ensure a clear distinction between “simple PMF annual updates” and a combination of “PMF annual update and variation(s) to a PMF”, we would ask companies to specify in their cover letter that:
- The annual update is not combined with variations or
- The annual update is combined with variations to the PMF*
Where a PMF annual update is combined with variation(s) to a PMF, Swissmedic will therefore expect to receive a cover letter containing the appropriate indication (see above), an appropriately completed Variations and extensions HMV4 form and the PMF annual update.
A corresponding publication can be found in the Swissmedic Journal 09/2018 (page 826).
* Marked accordingly in the Variations and extensions HMV4 form
Swissmedic is not intending to harmonise its practice with European requirements.
Indirectly yes, because there will be "grouping" by the highest category taking account of the PMF classifications according to D2-D23 (see Annex 7 TPLRO, section X. Variations to PMFs).
For each PMF, applications for one or more PMF variations are submitted according to the highest category (type II, IB, IA/IAIN) as classified in the EU Guideline (Guideline 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 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures) under "B.V.a.1 PMF / VAMF" or "D. PMF / VAMF".
Example 1: The applicant plans to submit two type IA variations and one type II variation together: All three variations are to be submitted as a type II application.
Example 2: The applicant plans to submit four type IB variations together: All four variations are to be submitted as a type II application.
No, Swissmedic is not involved in the EU’s PMF certification process.
Not at all. Swissmedic has no access to the PMF registered centrally in the EU.
a) Yes, that is correct. An additional (higher) dosage strength corresponds to an extension 2.c) and may be marketed under the same trade name with the addition of the dosage strength in mg / mL.
b) A new dosage strength (formerly sequence) will be issued for the new dosage strength, with corresponding new packaging codes for the new packs (see guidance document Variations and extensions HMV4, sections 9.2).
c) Generally speaking, it can be stated that a new dosage strength(number) is issued within the same authorisation number, provided no effects on efficacy, interactions, absorption etc. are expected. In conclusion however, your question cannot be answered since not enough information is provided.
An extension that requires a new authorisation number (according to the guidance document: Variations and extensions HMV4, section 9, e.g. new pharmaceutical form) can be submitted at any time.
Extensions that do not require a new authorisation number (e.g. new dosage strength for solid and semi-solid forms) can be submitted in connection with the ongoing first authorisation procedure (submission of additional documents with possible delay in the first authorisation). Alternatively, the application can be submitted after the conclusion of the first authorisation procedure.
A seq. 0000 may be submitted only if a new eCTD lifecycle is started. This is the case if an existing product is switched from eDok/paper (with/without baseline) to eCTD or in the event of new notifications. For extensions, Swissmedic recommends working with the existing lifecycle and e.g. integrating the new pharmaceutical form in the existing lifecycle. If a new lifecycle is to be started for an extension, Case Management or Operational Support Services must always be consulted beforehand.
Yes, this is possible provided that the medicinal product with the new active substance has Orphan Drug Status.
7. Other questions
No. When categorising variations and considering the modalities of their submission, Swissmedic is guided by the relevant directives, specifically Regulation (EC) no. 1234/2008 and the European Commission Guidelines based on this Regulation (cf. Art. 25 para. 1 of the Therapeutic Products Ordinance [TPO; SR 812.212.21]).
Yes, medicinal products may continue to be supplied to druggists with those old packaging elements (C vignette) during the published transitional periods. This does not apply to medicinal products that must incorporate a warning on the packaging.
The automated notification via e-mail will still happen.
As in the EU, the transfers of authorisations are also not classified as variations in Switzerland, but as "Übrige/Other" applications. These applications will continue to be requested by the future authorisation holder. The application must be submitted to Swissmedic at least three months before the planned transfer date. Further details can be found in the guidance document Transferring an authorisation HMV4.
Your proposed sentence may not be included in package leaflets. The reasons for this include the transfer of responsibility for publication from Swissmedic to the "institution in the form of a foundation" (refdata) and the fact that the wording of section 16 of the Patient Information is fixed according to the annex to the TPLRO and that no addition is possible.
Yes, it is true that "only" the process-controlling variation application is currently displayed in the Swissmedic portal for multiple applications without any mention of that fact that a multiple application is involved.
Swissmedic is currently checking whether an upgrade is possible to enable multiple applications to be displayed in the portal.
When categorising variations and considering the modalities of their submission, Swissmedic is guided by the relevant generally accessible directives, specifically Regulation (EC) no. 1234/2008 and the European Commission Guidelines based on this Regulation (cf. Art. 25 para. 1 of the Therapeutic Products Ordinance [TPO; SR 812.212.21]). However, individual agreements that the EMA or a national authority has concluded bilaterally with individual authorisation holders cannot be considered in applications submitted to Swissmedic.
Last modification 09.07.2019