Questions and answers on variations VMP

The most important information can be found in the guidance document Variations VMP HMV4, guidance document Formal requirements HMV4 (particularly section 3.12), and the form Variations VMP HMV4 on the Swissmedic website.

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.

In such cases, an interim official decision is issued and the notification will have to be submitted as a variation with assessment (“shortened” time limit). If the applicant notices that the time limit has passed before submitting the corresponding variation without assessment, the application should be submitted as a variation with assessment (“shortened” time limit) from the outset. Both the time limit and fee requirements for variations with assessment (“shortened” time limit) will be applied.

Yes. According to Art. 25a TPO, variations without assessment have to be reported to Swissmedic in writing after they have been implemented. The implementation date must therefore be in the past and must be stated on the Variations VMP HMV4 form.

An exception exists if the variations without assessment are part of a multiple application that includes variations with assessment. 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 variation without assessment has already been implemented as part of the multiple application, Swissmedic also requires an implementation date.

Any deviations from the requirement to state the implementation date on the Variations VMP HMV4 form will be specified on the form.

Swissmedic follows the definition stated by the EMA in its Q&A.

Implementation of a quality change without assessment: 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 variation without assessment 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 submitting a multiple application. Swissmedic therefore recommends that such applications be submitted together as a multiple application only if their subject matter is related.

For variations without assessment that involve a change in the product information texts, the date of revision should be modified to match the implementation date (see explanations in the Information for healthcare professionals and Veterinary medicinal product package leaflet documents).

For variations with assessment, “shortened” time limit, that involve a change in the product information texts, the date of revision should match the date the application was submitted (see explanations in the Information for healthcare professionals and Veterinary medicinal product package leaflet templates).

No extension of the time limit for corrective actions is granted for companies, either for variations without assessment or variations with assessment, “shortened” time limit. For both variation types, a maximum of 30 calendar days is granted for corrective actions.

A form consisting of the administrative part (sections 1–7) plus the proposed variation (e.g. F.I.a.1.a) "new active substance manufacturer with DMF"). 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.

Swissmedic does not require covering letters for applications for variations without assessment and variations with assessment, “shortened” time limit, provided no further information or explanations in addition to those in the form Variations VMP 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.

No. For a multiple application, all the information and proposed variations should be submitted 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. E.106 cannot be submitted as collective or collective-multiple applications because they do not meet the requirements of Art. 22b TPLRO.

Applications for variations that are submitted as part of ongoing new authorisation applications are not recorded as separate applications, but are included in the ongoing review of the new authorisation. Submitting additional documentation while an application is being processed or submitting a variation for an ongoing new authorisation procedure may result in Swissmedic taking additional time or charging additional fees (see Chapter 1.1 “Additional time” of guidance document Time limits for authorisation applications HMV4)

All variations in a multiple application will be completed together. This means that if an individual variation within a multiple application has to be improved, the total processing time for all the variations will increase.

For this application type, the Manufacturer information HMV4 form only needs to be submitted if the secondary packer has changed.

The form Variations VMP HMV4 does not include changes in the name and/or address of the authorisation holder because these do not require a separate application. The variation is initiated by Swissmedic when the application for a change in establishment licence is received (see guidance document Change name or domicile of the authorisation holder link).

No. E.106 only applies to the implementation of new requirements according to the revised TPLRO. In connection with a multiple application, in addition to E.106 you can also submit other pooled variations for the specific medicinal product. However, safety-related variations cannot form part of multiple applications.

The full declaration for co-marketing medicinal products should be implemented with A.101, not separately.

There is no need to submit an A.100. A.1 is sufficient.

A variation without assessment C.3.

Yes, provided these specific variations are processed in an Assessment Report (AR) by the reference authority. For multiple applications, all variations within the same multiple application must be processed in the same Assessment Report.

As a variation without assessment C.9 if the changes cannot be submitted as part of another application.

The decision to omit the package leaflet should be submitted with an A.z administrative variation that does not require assessment or as part of another upcoming application for a change to the medicinal product information.

Yes. You can submit the deletion of a manufacturer that involves several sections of the Manufacturer information HMV4 form as a variation without assessment B.3 a).

Apart from that, the wording (singular or plural) of the variation in the form Variations VMP HMV4 should be followed.

Yes. Apart from that, the wording (singular or plural) of the variation in the form Variations VMP HMV4 should be followed.

One variation per CEP has to be submitted when presenting new or updated Ph. Eur. certificates of suitability.

An additional manufacturing site for the primary and secondary packaging has to be submitted as two variations: B.20 (for non-sterile finished products) or F.II.B.1 d) (for sterile medicinal products) and B.21).

Yes. As a variation with assessment, “standard” time limit F.I.f.1. All changes have to be set out in detail in the “Previously approved” / "Applied for” list.

Swissmedic will also accept the submission of several variations involving the same variation template for section F. Quality variations with assessment as one variation on template F.z b) “standard” time limit. In this case, the scope / justification section must list the number of the variation template to which the variations refer and all change parameters must be set out in detail in the “Previously approved” / "Applied for” list. (See section 3.12 of guidance document Formal requirements HMV4).

Example:

F.z Other quality change that requires assessment

Scope / justification for the change

F.II.b.3. Change in the manufacturing process for the finished product, including an intermediate used in the manufacture of the finished product

a) 1x minor change in the manufacturing process
b) 1x introduction of active substance overage
c) 1x change in bulk hold time

Editorial changes to part 2 can be submitted as a variation without assessment B.43. “Editorial changes to part 2 of the dossier if it is not possible to incorporate them into part 2 of a pending procedure” (see also section 3.12 of guidance document Formal requirements HMV4).

In the case of rubber closures for parenterals, the manufacturer and/or the precise, manufacturer-specific designation for the closure as well as the specifications for the closure must be stated in section II.C.3 of the quality documentation. Closures may exhibit the following differences, which can influence the finished product quality:

• surface treatment (e.g. silicon or Teflon coating);
• type of rubber closure (e.g. halobutyl type), i.e. exhibiting a different qualitative and quantitative composition;
• dimensions (even minor deviations can impair the impermeability of the closed vial).

Moreover, Ph. Eur. section 3.2.9, “Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders”, states the following: “The manufacturer of the preparation must obtain from the supplier an assurance that the composition of the closure does not vary and that it is identical to that of the closure used during compatibility testing.”

Thus, the manufacturers of rubber closures for a parenteral dosage form may only be deleted from section II.C.3 by way of an application for a variation without assessment B.3.s) if it is explicitly stated in this section that only alternative closures with the same quantitative and qualitative composition and identical specifications may be used.

No. A variation without assessment is a simple and fast procedure intended for minor variations with no data assessment. It is therefore a condition of B.45 variations that no further data is required. In the case described, however, the stability data have to be assessed. This means that a variation without assessment B.45 and a variation with assessment F.I.d.1.c are required. In its F.I.d.1 variation, the applicant should confirm that the stability studies of the active substance were conducted in the packaging material specified in the CEP dossier submitted to the EDQM. Where CEPs were issued before 1 September 2011 and do not specify packaging material, the applicant should also submit details of the packaging materials used in the stability studies.

Terminal sterilisation of primary packaging components that are subsequently used in the aseptic manufacture of medicinal products is a critical process and the sterility of the primary container is a crucial quality factor in guaranteeing medicinal product sterility. For this reason, a variation with assessment F.II.b.1.e should be submitted for pre-filled syringes and other types of sterilised primary container that are filled in an aseptic process (e.g. ophthalmic preparations) and which do not undergo any further sterilisation process after they have been filled and their primary packaging has been closed. The application should contain documents on the site’s GMP conformity and information on the sterilisation method. If a Ph. Eur. method is not used for sterilisation, validation data should be submitted too (see also EMA/CHMP/CVMP/QWP/850374/2015).    

A single F.II.b.1 variation for a new manufacturing site of a finished product may include the following changes that are directly related to the change in the manufacturing site: changes in the manufacturing process, batch size and in-process controls to adapt to the conditions at the new manufacturing site.

All changes directly related to the change in the manufacturing site that are applied for as part of a single F.II.b.1 variation must be listed in the Variations VMP form and compared in the “Present / Proposed” table.

Changes that affect the finished product and are not directly related to the new manufacturing site applied for, such as changes to the excipients, the specification parameters/limit values for the finished product or the container closure system, including the suppliers, must be submitted as additional variations.

As changes under F.V.b.1 are EU-specific changes that are not listed in the Swiss form, these can be submitted in Switzerland (including as part of a multiple application) as a type F.z b) change (Other quality change that requires assessment, “standard” time limit). It should be noted under “Scope / justification” that the application has been submitted in the EU as a type F.V.b.1 a), b) or c) change, and all changes must be listed in the table “Present / Proposed”.

No, an application for implementation following the expiry of document protection for the reference medicinal product may only be submitted once the document protection has expired.

Additional editorial changes may be made as part of a variation with assessment G.I.4. It is not necessary to apply for an additional variation without assessment C.9 for this purpose.

If the reference product is no longer authorised, it is basically the responsibility of every holder of authorisation for a KAS without innovation that is still authorised to keep its product information texts up to date and in line with the state of the art. However, it is also possible to adapt the product information texts to another KAS without innovation if more recent texts are available for the latter.

This first-time implementation should be submitted as a variation with “shortened” time limit G.I.2 z).

If the text should then be consistently adapted to the same KAS without innovation, the following applications can be submitted as a variation without assessment C.3, provided that the conditions according to the Variations VMP HMV4 form are met.

a) Yes, that is correct. An additional (higher) dosage strength corresponds to a variation I.II.1 c) and may be marketed under the same trade name with the addition of the dosage strength (generally in mg / mL).

b) A new dosage strength number will be issued for the new dosage strength, with corresponding new packaging codes for the new packs (see section 9.2 of guidance document Variations VMP HMV4).

c) As a general rule, a new authorisation number will only be issued if the variation has substantial implications for quality, safety or efficacy (see section 9.2 of guidance document Variations VMP HMV4). In individual cases, Swissmedic will consider the submitted documentation when making its decision.

Any application that would normally entail a new authorisation number, such as a new dosage form, can be submitted at any time.

Variations that do not require a new authorisation number (normally a new dosage strength for solid and semi-solid forms) can be submitted as part of 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.

No. When categorising variations and considering the modalities of their submission, Swissmedic is guided by the relevant directives, specifically Regulation (EC) no. 2019/6 and Implementing Regulation (EU) 2021/17 (variations not requiring assessment) issued under this Regulation, and guidance document EMA/CMDv/7381/2021 (variations requiring assessment) (cf. Art. 25c para. 1 of the Therapeutic Products Ordinance [TPO; SR 812.212.21]).

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.

In this example, one variation I.II.1.d) “Change or addition of a pharmaceutical form” should be submitted. The new dosage strengths and administration route are subsumed into the new pharmaceutical form 2.d).

Yes, a cost cap does apply and the maximum amount is CHF 5,000.

In addition to the discontinuation, a variation without assessment B.3 v) “Deletion of a pharmaceutical form or dosage strength” has to be submitted for the remaining medicinal products so that the collective medicinal product information can be updated.

Please note that “Discontinue preparation” applications are not variations in accordance with the Variations VMP HMV4 form and cannot therefore be submitted in a multiple application.

Regardless of whether or not a collective medicinal product information text that includes additional medicinal products exists, discontinuation of a dosage strength must be submitted as a variation without assessment B.3 v “Deletion of a pharmaceutical form or dosage strength.

A variation G.I.7 a) “Addition of a new, or a variation to, an approved therapeutic indication” should be submitted in addition to an application I.II.1.c) “Modification or addition of a dosage strength”.

You can use the “new application / variation” submission type for variations with and without assessment.