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    Variation – how to successfully update your dossier

    Have you been granted the Marketing Authorisation (MA) for your medicinal product? Are you about to release it into the market? That is for sure very positive information! Do you think it is over and from now on, nothing more has to be done? Unfortunately not. During your product’s life cycle you will surely deal with many improvements and face multiple post-approval variations to the quality dossier of your product. To assure the highest quality of your product you have to keep up with scientific progress and technical development, which may often lead to quality-related changes. Finally, you may realise that a process you use should be more cost-effective and therefore optimized. All these are examples that lead to something inevitable: updates to the initially registered dossier. 

    As you are or may soon be aware, there are a plethora of reasons to revise the already registered dossier. How to actually make them, is a separate story. In this article, you are going to find out about the necessary steps to implement, submit and successfully process your planned updates, regardless of whether they relate to the quality or safety of your medicinal product, pharmacovigilance system, or are purely of administrative nature.

    What do we call a variation?

    Formally [1], for the MA, a variation is any change to:

    a) medicinal product’s registered dossier;

    b) decision granting MA, corresponding Summary of Product Characteristics, Package Leaflet, and labelling;

    c) as b, but for veterinary products.

    But what does this actually mean?

    Generally speaking, variations are changes or updates to any currently approved aspect of a pharmaceutical product and the content of its MA. These aspects include, but are not restricted to:

    • a change to product formulation;
    • manufacturing process;
    • site of manufacture;
    • specifications for active substances (API) or/and finished product (FP);
    • type of used container and its materials;
    • product information including changes to artwork designs of outer and immediate packaging as well as updates to the package leaflet.

    The most common changes during a life-cycle of a product are variations concerning quality aspects of the dossier and, in a broad sense, relevant to product information. All quality-related changes should be managed through a Marketing Authorisation Holder (MAH)’s Pharmaceutical Quality System. However, it may not be enough to manage them internally only. There is a range of quality changes that must also be reported to the regulatory authority.

    Knowing your product’s registration dossier and understanding the manufacturing process and respective controls are crucial for deciding which post-approval changes require regulatory activities at all and, whether they should be reported prior to or after their implementation. The technical dossier should consist of data considered as an Established Conditions which allow understanding (for MAH and regulatory authorities as well) of what is crucial to assure the appropriate quality of the product, and what can be ’only’ considered as supportive, where the impact on quality can be reasonably excluded. It needs to be clearly distinguished. It is the post-approval change of the former one that triggers a regulatory submission. Any amendment to the registration dossier, whether it is a deletion, addition, or changing of the data included in the original documentation, will lead to a variation procedure. You can learn more about what quality data can be considered suitable for registration in our article here.

    Avoiding unnecessary variations

    As a general rule, as briefly pointed out earlier, over-detailed descriptions in the quality dossier may pose a challenge during a product’s lifecycle. They can limit the flexibility of those changes, which would not typically require any variation submission. Providing an over-detailed description in the dossier leads to a situation, where any upcoming updates or proposed changes require additional time and costs, which could have been avoided. Usually, data not required for approval should not be included in the dossier. Nevertheless, it is still required to provide precise data which allows for a good understanding of processes described in the regulatory dossier.

    For example, including a too specific description in the registration dossier about the details of the manufacturing process, such as serial numbers of used equipment should trigger a variation procedure in case of replacing this equipment even for the same model. In order to minimize future regulatory activities, a description of the manufacturing process should only consist of data that are considered crucial for the registration procedure.

    In another instance, there is a way to avoid variation procedures affecting the FP when it is possible to make a reference to the European Pharmacopoeia. In such cases, a statement in the dossier that says that the ‘current edition’ of Ph. Eur. monograph is followed, usually suffices. It assures that any upcoming changes are introduced at the time of the implementation of the respective Ph. Eur. monograph. This approach ensures that there is no need to notify competent authorities when such quality updates are made. 

    If you use an API for which there is a Certificate of Suitability (CEP), a variation should be submitted in case a new or revised CEP is placed. It does not matter whether the CEP was issued for an API, excipient, or starting material/reagent/intermediate used in the manufacturing process of the API. What does matter, however, is the relation between the CEP version and the material used. If one or more revisions of the CEP were omitted but the material of the omitted CEP was not used in the manufacturing process of the FP or API, a single variation can be submitted in order to fulfill MAH’s obligation to keep the dossier up to date. Please note, that an API from omitted CEP can’t be used for the manufacturing of a commercial product. 

    That being said, defining which elements in a registration dossier are fundamental to guarantee the product’s quality is crucial as they consequently require a regulatory submission if changed during the product’s life cycle. Properly determining these parts can contribute to a more precise and accurate understanding of which post-approval changes require the involvement of the regulatory assessment including the appropriate classification of variation submission. Doing so is not only purely time and cost-efficient, but also excludes or minimizes the associated regulatory burden both for MAH and various regulatory Agencies.

    How about a variation in practice?

    Let’s say that you completed the arrangements for the prospective assessment of the planned changes, and you know what changes should be introduced and reported via variation procedures. You also know what can be addressed and managed through a company’s Pharmaceutical Quality System, that may be verified during an inspection. What you may not know, is what to do next?

    Here, we will explain what are the necessary steps for each regulatory submission, depending on the nature of the proposed changes.

    MAH is legally obliged to ensure that the medicinal product’s dossier is up to date. MAH assures that by evaluating and managing any occurring variations and determining the need for reporting them to the regulatory authority. On the other hand, if you are an Active Substance Master File Holder and in agreement with MAH, your submission is referenced during the initial Marketing Authorisation Application or post-approval variation procedure, you are also committed to any subsequent communication with MAH in case of changes to data that require regulatory involvement. That way, by assuring proper and quick contact, the MAH can properly assess the estimated impact of the change on the intended performance of the product, and, in relevant cases, report related changes to the competent authority.

    Based on the level of risk to public or animal health, and the impact on quality, safety, and efficacy, in the EU, variations in medicinal products can be classified into different variations categories [1]. Commission Regulation 1234/2008 defines the classification of variations which shall be considered as:

    • extensions of MA
    • minor variations of Type IA or Type IB
    • or major variations of Type II.

    There are approximately 350 different types of variation codes and classification sub-categories plus around 50 additional CMDh recommendations [2]. Substantially, after the end of the initial MA registration procedure, if no renewals or subsequent recognition of a MA by other Member States are planned, MAH can submit variations at any time.

    Type IA: ‘Do and Tell’

    The particular moderate- to low-risk changes that do not require prior approval are minor variations of Type IA. This kind of variation generally requires less detailed justification and can be implemented beforehand (commonly known as the ‘Do and Tell’ procedures).

    Such minor variations are additionally classified into two subcategories:

    • Type IA variations requiring immediate notification (‘IAIN’)

    The Classification Guideline specifies which Type IA variations must be submitted immediately after implementation, as a part of continuous supervision of the medicinal product. It is a frequently asked question, what does the ‘immediately’ even mean? A common practice is to assume, depending on the kind of variation, that immediately means no later than 14 days from the implementation date. However, the exact term is not defined in the European Regulation. To learn more on implementation see our article here.

    • Type IA variations which do not require immediate notification (‘IA’)

    These types of variations can be submitted within 12 months after the implementation date. When it comes to Type IA variations, it is up to MAH to decide whether each variation will be submitted separately or in an annual report for variations that were implemented during the previous 12 months.

    The Classification Guideline established the pre-defined list of precise conditions which must be met in order to consider a change as a minor Type IA variation.

    Type IB and type II: ‘Tell, Wait and Do’

    By default, every IA/IAIN variation can be considered as Type IB, when one or more conditions mentioned in the guideline are not met. However, some of the changes specified in the Classification Guideline are considered as the ones that have a higher or sometimes even a significant impact on quality, safety or efficacy. Therefore, apart from mentioned earlier ‘Do and Tell’ procedures, the guideline specifies a comprehensive list of predefined variations that can be classified as ‘Tell, Wait and Do’ variations: Type IB or Type II, due to their potentially greater impact on the quality of the product.
    In the case of ‘Tell, Wait and Do’ variations, the MAH must gather all required supporting data in order to perform submission, obtain approval, and then implement the change after the positive evaluation. During these types of variations, data provided by the MAH require regulatory assessment. Type IB variations are considered to potentially have an impact on the safety or efficacy of the medicinal product, whereas when it comes to variations that are classified as Type II, they encompass major variations which are generally expected to significantly affect the safety, and efficacy of the medicinal product. In case of these types of variations careful data assessment is performed, sometimes followed by a request of providing supplementary information in case of insufficiencies before issuing an approval.

    The Classification Guideline also specifies the required list of documentation that needs to be provided in every IA or IB submission, whereas Type II variations require appropriate supporting Module 2 documentation that needs to be assessed and signed off by an appropriately qualified Expert before each submission.

    Line Extension

    Lastly, apart from described types of variations above, there may be cases when a variation is so major that it is considered as Line Extensions instead of variation Type II. This is the case when changes are considered to have a fundamental impact on the terms of the initial MA and where significant alterations occur. As an example, let’s theoretically consider a sterile product in a form of a pre-filled syringe, whose process is biotechnologically based and which is registered for the treatment of diabetes. If a manufacturer wants to change the pre-filled syringe into a chewable gum, respective changes would surely be beyond typical Type II changes, and a Line Extension application should be submitted. Nevertheless, each Line Extension should be a subject of discussion with the respective Agency as it can sometimes be case-dependent.

    Practical examples

    As a practical example of what to do in the case of variations to the manufacturing process of a FP, imagine that you plan to implement a minor change in the composition of the FP – let’s say, for example, you intend to change the components in the flavouring or colouring system. Since this should not majorly affect your product’s quality, you quickly find out that the default variation is a Type IAIN no. B.II.a.3.a.1. As mentioned in the guideline, there is a list of certain conditions to be fulfilled (here, such as no change in functional characteristics of the pharmaceutical form), as well as a precise list of documents that need to be submitted (e.g. submitting results for at least two pilot-scale or industrial-scale batches) and only meeting those allows you to continue with processing the variation according to the pre-defined classification. 

    In another example, let’s say you plan to extend the re-test period of your chemical active substance. Let’s assume you have relevant stability data in hand. You may find that it is enough since your data supports an extended re-test period. However, by looking through the respective classification you will soon learn, that such change requires a straight submission of type IB variation. It is only after the Authority evaluates the documentation and then hopefully issues corresponding approval that the change can be implemented.

    There are also cases when you can submit some changes under a single scope of Type II variation, for instance, when introducing a new manufacturing site for the FP via the B.II.b.1 classification category. When MAH wishes to introduce directly related changes to the manufacturing process, batch size, and in-process controls to adapt to the new manufacturing site settings, submission under the single scope of a Type II variation mentioned above is possible. However, it is not always as easy. When MAH plans to submit a variation aiming to add a new manufacturing site, but this time for API, under classification category B.I.a.1, and in cases where the introduction of this new API manufacturer has an impact on the FP (e.g. changes to the API specifications or connected analytical methods) individual variations have to be submitted under the appropriate B.I.b. categories. Variations can be also grouped, based on the relevant cases for grouping variations [1].

    In any case, a classification of a variation is a very important step and it should be performed in advance, taking into account all the quality and regulatory information available with elevated attention to details. The wrong classification may lead to rejection of change by the Agency, time delays in implementation of such change, and increased costs.

    Variations in product’s lifecycle

    Since MAH is legally obliged to guarantee that the medicinal product’s dossier is up to date, changes to any currently authorised elements of the pharmaceutical product’s dossier and the content of its MA are unavoidable. Depending on the nature of the proposed changes, whether they are of administrative, quality or safety, efficacy, and pharmacovigilance-related nature, changes to the dossier should be appropriately classified and introduced. They all should be done in order to continually improve the medicinal product across its entire lifecycle. The Classification Guideline contains the pre-defined list of precise conditions which must be fulfilled in order to consider a change as a minor ‘Do and Tell’ variation that can be implemented prior to submission. It also specifies the required documents that are needed for every IA or IB submission, and points out which types of changes are considered Type II by default.

    Chemistry, Manufacturing, and Control changes encompass a various range of variations, which vary from low to the high potential risk concerning product quality, safety, and efficacy. Proper understanding of the need for notifying variations and knowing when to avoid unnecessary submissions is the core to regulatory management of your product’s lifecycle.

    Shall you find yourself in the need for proper assessment of a variation including its classification, estimated impact on the quality of the product, help with the dossier’s preparation and finally the submission to the Authority in national, Centralised or European procedures (Decetralised and Mutual Recognition), get in touch with us! We are pretty sure we can help you!


    [1] 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;

    [2] CMDh Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) 1234/2008.