Following the recommendation pursuant to Article 5 of the Variation Regulation, the adaption to the model texts should be classified as variation C.I z.

If an appropriate model text regarding strength and dosage form exists, a minor variation Type IA is acceptable together with a declaration that the text has been adapted word by word.
If the model text is different in strength or dosage form or if deviations from the model texts are intended, a variation Type IB should be submitted. All deviations should be marked and justified.

Adaptions of texts to conform with the excipient guidelines (changes in the SmPC and corresponding PIL/labelling) are to be submitted as variations Type IB classification category C.I.z.

According to the general grouping rules, a text adaptation to excipient guidelines submitted as a variation of Type IB classification category C.I.z, can be submitted together with variations of Type IA or IA (IN) classification categories A or C.

If an additional variation Type lB category C or a variation Type ll category C is submitted, a text adaptation to excipient guidelines can be included in the course of this variation.
No separate variation submission is necessary nor is reference to a variation code required. It is sufficient to describe this change in the texts in the application form under "Precise scope and background for change". In this constellation, the adaptation to excipient guidelines is free of charge. For further information please also refer to the Questions & Answers of the CMDh, Variations, Question 3.16.

Adaptions of texts to conform with the MedDRA terminology (changes in the SmPC and corresponding PIL/labelling) are to be submitted as a variations Type IB classification category C.I.z.

According to the general grouping rules, a text adaptation to MedDRA terminology submitted as a variation of Type IB classification category C.I.z, can be submitted together with variations of Type IA or IA (IN) classification categories A or C.

If an additional variation Type lB category C or a variation Type ll category C is submitted, a text adaptation to MedDRA terminology can be included in the course of this variation.
No separate variation submission is necessary nor is reference to a variation code required. It is sufficient to describe this change in the texts in the application form under "Precise scope and background for change". In this constellation, the adaptation to MedDRA terminology is free of charge. For further information please also refer to the Questions & Answers of the CMDh, Variations, Question 3.16.

When adapting product informations to updated CCDS, each change aspect which triggers an update in the CCDS should be mentioned in the scope of the application form and should be classified according to the variation guideline.
The identified change aspects can be combined in a grouped variation application.
The term “change aspect” includes the following items: e.g. literature investigations, database investigations, adaption to the Core Safety Profile, adaption to reference texts etc.

The reference medicinal product is defined in Art. 10(2)(a) of Dir. 2001/83/EC. This is the medicinal product, to which a marketing authorisation application according to 10(1) or 10(3), resp., Dir. 2001/83/EC refers to.

If there are changes in the product texts of the reference medicinal product, this variation category can be used for the referring marketing authorisations to adapt their product texts.

The reference medicinal product should be clearly specified within the scope of the application form –stating the medicinal product name, marketing authorisation holder and marketing authorisation number and the confirmation that the reference product is the reference product from the original application.

The relevant excerpt from the marketing authorisation application form should be appended as proof. Furthermore, the concerned product texts of the reference medicinal product should be appended to the application.

We refer to the following Q/A of the CMDh :

Question 4.14
How can a generic MA be adapted to the most current version of the SmPC, if the results of several procedures, e.g. PRAC/ PhVWP recommendations and PSUR worksharing, have to be considered?
Answer:
The applicant has to submit one variation application according to C.I.3.a, b or z for each single change applied for. The single change is defined by one data package triggering the variation. All these single changes may be combined in one grouped application, see also Examples for acceptable and not acceptable groupings for MRP / DCP products, http://www.hma.eu/96.html.
It is not acceptable to wait for the originator to have implemented all these changes and subsequently submit a single variation C.I.2.a in order to adapt to the originator,nor is it possible to include all the changes in a Company Core Data Sheet (CCDS) and to submit a single variation of type II under category C.I.4.

The change in the package leaflet can be applied for together with the change in the SmPC in one variation application.
The following Art. 5 recommendation is applicable, that a type IB variation is required for these cases:

The classification for dispensing of medicinal products is regulated by the Ordinance on the Prescription Requirement for Medicinal Products ("Arzneimittelverschreibungs-Verordnung", AMVV) as well as the Ordinance on Pharmacy-only Medicinal Products and Medicinal Products Sold outside Pharmacies ("Verordnung über apothekenpflichtige und freiverkäufliche Arzneimittel", AMVerkRV). If the dispensing classification of a substance is altered by way of an ordinance without requiring changes other than the dispensing classification itself in the informative texts, this is to be notified by way of a national variation in accordance with Section 29 sub-section 1 of the Medicinal Products Act (Arzneimittelgesetz, AMG). Any adjustments to the QRD template that are necessary as a result of the altered dispensing classification can also be indicated. The corresponding updated texts are to be submitted. Should further changes become necessary at the same time, the adaptation to the ordinance can be notified exceptionally within the next national Type IB variation or Type II variation category C.

If the dispensing classification for a substance is only altered with regard to individual aspects (e.g. indications, pack sizes) and this also entails alterations of these aspects themselves, a variation stating the appropriate category/categories in accordance with the European Commission's guidelines is to be submitted. It should be borne in mind that only one dispensing classification per medicinal product is permissible. Submission of the variation is only permissible after the ordinance for changing the dispensing classification has entered into force. This applies regardless of whether the medicinal product is marketed/placed on the market at this time.

In the case of medicinal products that are declassified by ordinance for distribution outside of pharmacies, this fact is to be notified in accordance with Section 29 sub-section 1 AMG and the updated texts are to be submitted. If this is not (or no longer) a medicinal product that is only allowed to be dispensed to the consumer by pharmacies, the specification "apothekenpflichtig" (pharmacy-only drug) is to be deleted from the informative texts.

If the smallest pack size on the market is used as a sample, the competent authority does not need to be notified of this. However, compliance with the requirements of Section 47 sub-section 3 of the German Medicinal Products Act ("Arzneimittelgesetz", AMG) remains unaffected by this.

Using a smaller pack size as a sample than that authorised is also possible. However, such variations in pack size have to be submitted in accordance with the rules of the variation regulation. Should you subsequently wish to change back to the former arrangement, this shall also be notified appropriately.

The inclusion of information on already authorised indications protected by a patent due to expiration of this patent should be applied for as a type IB variation C.I.z since this implies a change of the product texts.

As variations in the marketing status (distribution or non-distribution in Germany) of licensed pack-sizes are variations to the informative texts, they are to be classified as type IB variation category C.I.z.

The BfArM recommends including the following sentence in the informative texts of all licensed pack-sizes:

„Es werden möglicherweise nicht alle Packungsgrößen in den Verkehr gebracht.“
("It is possible that not all pack-sizes are placed on the market.")

Should this information not yet be included in the texts, it can be added by way of a type IB variation category C.I.z.

For editorial changes as well as adjustments to the current QRD template and the special features list (Besonderheitenliste)/Excipients Guideline, please refer to the CMDh Q&A for Variations #3.16.

The procedure described above is also explicitly applicable to variations of purely national marketing authorisations.

The answer is given under topic Purely National Variation Procedures

No. The assessment within a variation procedure is restricted to the documentation which is required in accordance with the Guideline on the details of the various categories of variations and further relevant guidance.

Consequently, only documentation in connection with the variation should be submitted by the applicant. Moreover, only such documents which support the applied variation will be assessed by the competent authority.

In view of this, please note that only those changes are deemed to have been notified properly that are listed under section 3 "Types of Changes“ in the application form and are thus subject to the decision of the variation application.

The present/proposed section in the application form should list the complete information on the present as well as the proposed manufacturer of an active substance and/or finished product including their manufacturing sites with full addresses and their respective functions. Should there have been no changes with regard to manufacturer, manufacturing sites including full addresses, and respective functions they should nevertheless be listed again in the “proposed” section.

Correct implementation and corresponding processing in the competent regulatory authority’s medicinal product database can only be ensured if the information provided is complete and comprehensible.

According to the CMDh Q&A to Variations #3.16, the EMA Post-authorisation Guidance Q&A on Editorial Changes has to be considered.

This guidance is also explicitly applicable to variations of purely national marketing authorisations.

1. The following are feasible as editorial changes:

• the addition of headings.
• the rearrangement of existing content without changing its content.
• the adaptation of information, provided that proof can be given that the correct data has already been registered and approved.
• orthographic and grammatical corrections.

Please note that editorial changes can only be made up to the fourth segment of the dossier part affected by the change.
Example: If the indicated change affects module 3.2.S.2.1, only editorial changes from modules 3.2.S.2.1 to 3.2.S.2.7 can be submitted.

The application form should also contain the justification of the editorial changes required in the EMA Post-Authorisation Guidance as well as a tabular comparison of the changes. It must also be confirmed in the application form that the editorial changes do not alter the content of the dossier beyond those changes notified.

2. The following are not feasible as editorial amendments:

• the deletion of specification parameters or manufacturing descriptions, etc.
• updates to adapt the dossier to current manufacturing processes, etc.
• the correction of incorrect descriptions, e.g. the change from 'solution' to 'suspension'
• adaptation of former 'in-house' methods to Ph. Eur.
  (list not conclusive)

Please note that the examples under 2. should only be regarded as examples.

Should an editorial change be observed during the processing of a variation application that cannot be implemented as such according to the applicable criteria, you may be asked at any time to classify and notify the change in accordance with the Classification Guideline.

In this context, it should be noted that requests for corrections always lead to a delay in the validation phase, as the request cannot be forwarded immediately to the relevant department. Therefore, in your own interest, please carefully check each editorial change in advance for plausibility on the basis of the above criteria.

A change of the reference medicinal product of the initial marketing authorisation is generally not possible. Please refer to the CMDh Questions & Answers on Variations No. 3.13 (cf. https://www.hma.eu/20.html).

However, in order to update the product information, reference can be made to the authorisation of another EU/EEA reference medicinal product within the same global marketing authorisation (GMA), if this update is made in order to ensure the safety of the medicinal product.

In cases where the texts of this marketing authorisation have not been harmonised with the initial marketing authorisation, a Type II variation C.I.2.b is required to adapt the product information.

If the texts are harmonised, adaptation is possible via a Type IB variation C.I.2.a.

According to Section 11 (1) sentence 9 AMG, the marketing authorisation holder is further obliged to keep the texts up-to-date with the current state of scientific knowledge. For this purpose, the results of all procedures concerning the marketing authorisation, in particular PRAC recommendations, conclusions from PSUR worksharing procedures or from PSUR Single Assessments (PSUSA) must be implemented and the individual amendments must be applied for in accordance with the respective applicable amendment category pursuant to the Variation Guideline.
Further changes are to be applied for as Type II Variations C.I.4 (cf. the above-mentioned CMDh Questions & Answers on Variations 4.14 and 4.19).

Data on the resistance situation of systemically available antibiotics in Germany is regularly reassessed in the Z.A.R.S. project and is considered in the resistance table for Section 5.1 of the SmPC. In addition, the annually updated data from EUCAST (European Committee on Antimicrobial Susceptibility Testing) are processed and the relevant limits in relation to the respective approved indications of an antibiotic are presented in the EUCAST table.

Information on marketing authorisations from national procedures:

Adaptations to the current resistance data in section 5.1 of the Summary of Product Characteristics have to be submitted as a Type IB variation category C.I.z, unless the marketing authorisation holder is a participant in the Z.A.R.S. project. The update of the EUCAST table is included in the variation. In cases of adjustments to the reference product, the adaption to the resistance data has to be submitted as a separate variation category.

Participants in the Z.A.R.S. project update the resistance data with a Type IA variation with the variation category C.I.z. With each variation, relevant proof of participation in the project must be submitted. The variation is free of charge. Therefore, variations from Z.A.R.S. participants for updating the resistance data should be submitted separately. In cases of adaptations to the reference product, the Z.A.R.S. data can be updated without a separate variation category, but this should be mentioned in the scope.

Information on marketing authorisations from MRP and DCP:

Adaptations to the current resistance data in section 5.1 of the Summary of Product Characteristics have to be submitted as a Type IB variation category C.I.z.
For participants of the Z.A.R.S. project with submission of the relevant evidence, this change is free of charge in DE.
If participants of the Z.A.R.S. project add Z.A.R.S. data exclusively to the non-official part of the DE Summary of Product Characteristics, a national IA variation category C.I.z is to be submitted.

In the case of a mixed EMA worksharing procedure, national marketing authorizations (from MRP/DCP/NAT) are incorporated in addition to one or more centralised marketing authorizations. In these cases, the review of the translated text changes will only be performed in the context of the EMA Post-Opinion Linguistic Review, i.e. exclusively for the centralised marketing authorizations concerned.
The result of this review, which is approved by the European Commission, is then transferred in the same wording to the national marketing authorizations, i.e. DCP, MRP and purely national marketing authorizations. The transfer is done under the responsibility of the marketing authorization holder and there is no separate submission of a draft version required.
However, a confirmation is requested to the procedure management, that the amended text passages in the national marketing authorizations correspond to the opinion of the worksharing procedure and the translations adopted by the European Commission. For the national marketing authorizations involved in the procedure, a request to submit the amended product information to the "PIT" portal will be sent via PharmNet.Bund after the positive adoption of national translations in the EMA worksharing procedure.