Pharma companies must always refer to the latest sfda variation guidelines to ensure compliance with the regulations in Saudi Arabia. The SFDA is continuously updating its way of accepting and evaluating the variation submissions, so the GCC variation guidelines or SFDA Variation Guidelines are the references for the industry to follow.
As most know, the variation file is the request from the MAH to the SFDA to change or update the registered drug information. It is a post-approval regulatory procedure that is frequently taking place after the SFDA drug registration to ensure that the amendments on the registered drug file are approved for marketing.
We will in this post discuss the latest version (Guidelines for Variation Requirements v 6.1).
SFDA Variation Guidelines
The sfda variation guidelines describe the types of variations and the requirements for their submission to update the registered drug file. It covers the administrative and CMC changes for manufacturers, MAH, API, and drug products.
The changes vary from low to the high potential risk concerning product quality. The manufacturer is encouraged to utilize a risk-based regulatory processes system for;
(a) requesting approval for any major changes from the regulatory authority before implementation.
(b) notifying the regulatory authority for minor changes after implementing.
The above system includes the following categories for regulatory communications with one or more levels in each category according to when we need to notify SFDA for any post-approval changes.
In the sfda variation guidelines, there are types of variations that do not require prior approval. They are moderate to low-risk changes without a high impact on the product’s quality, safety, and efficacy. According to the guidelines, these changes are communicated to the regulatory authority as a formal notification that takes place within a defined period of time before or after implementation.
On the other hand, the SFDA variation guidelines clearly identified major changes that require approval before implementation. They are with heavy impact on the quality, safety, and efficacy of the product. Therefore, the MAH should submit a detailed eCTD dossier to describe and justify the variation. Note that the approval might require an SFDA GMP inspection for some variation types, such as when resourcing from a new manufacturing site.
Types of SFDA Drug Variations
We can notice in the SFDA variation guidelines version 6.1 that the SFDA had introduced a new type called IAIN. It becomes between type IA and IB, and it is too considered a minor variation.
In below post section, we will detail all the variation types:
Type IA Variation
Such minor variations do not require prior approval before implementation (“Do and Tell” procedure). Type IA variations, however, can be compiled in a single variation application to be submitted to the SFDA no later than January 31st of each year. The variation application for every product should clearly indicate:
- All IA variations have been implemented during the previous year.
- Date of implementation of each variation.
Type IAIN Variation
Should be submitted immediately, within a maximum of 14 days after implementation. Note that it is possible to group IA with IAIN variations as follows:
Grouping Type IA/IAIN changes
Type IA or IAIN variation can be grouped for one medicinal product or affecting several medicinal products from the same MAH.
Grouping Type IA/IAIN with other types of variations
Type IA/IAIN can also be grouped with other variations like Type IB and Type II. Such grouped submissions will follow the review timeline of the highest variation in the group.
Under this variation type falls the changes that are neither Type IA nor Type II. Meaning, the change can be considered Type IB when Type IA conditions are not met and the change is not listed as one of the Typed II major changes.
Type IB variations must be submitted to the authority by MAH before implementation, but it does not require formal approval. However, the MAH must wait a period of 60 working days to ensure that the application is deemed acceptable before implementing the change (“Tell, Wait and Do” procedure).
Grouping Minor (IB) Variations
It is also possible for a MAH to group a Type IB variation with other variation(s) for the same product, like Type IA and Type II. Such grouped submissions will follow the review timeline of the highest variation in the group.
These are the major variations that may significantly impact the Quality, Safety, or Efficacy of a medicinal product and require prior approval before implementation. For this major type, there are no specific documents or requirements by SFDA. For example, if the change is in a manufacturing site, a whole module 3 needs to be resubmitted with the variation.
SFDA Variation Timelines
|SFDA Dept||No. of waves & Response timeline|
|Submission Validation Notes||30 working days.|
|Evaluation & Inspection||60 working days.|
|Appeal against the rejected variation||60 calendar days|
|Type IA||To be submitted no later than January 31st covering last year’s variations.|
|Type IAIN||To be submitted immediately, within 14 days after implementation.|
|Type IB||60 working days|
|Type II||100 working days|
Examples from the SFDA Variation Guidelines
|Type of Change||Subset of change||Type of Variation|
|Change in the Marketing Authorization Holder||Change in the name and/or address of the marketing authorization holder||IAIN|
|=||Transfer the product to new marketing authorization holder (different legal entity)||IB|
|Remove agent name from the artwork (Mock-up)||NA||IA|
|Change in the (invented) name of the medicinal product||NA||IB|
|Change in the name and/or address of a manufacturer or supplier of the active substance, starting material, reagent, or intermediate used in the manufacture of the active substance (where specified in the product dossier) where no Certificate of Suitability is available||NA||IA|
|Change in the name and/or address of a manufacturer of the finished product, including quality control sites||Manufacturer responsible for batch release||IAIN|
|=||All other site types||IA|
Active Substance Changes (API)
|Type of Change||Subset of change||Type of Variation|
|Change in the manufacturer of a starting material/reagent/intermediate used in the manufacturing process of the active substance or change in the manufacturer of the active substance, where no Certificate of Suitability is available||The proposed manufacturer is part of the same organization as the currently approved manufacturer.||IB|
|=||The proposed manufacturer uses a substantially different route of synthesis or manufacturing conditions, which may potentially change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification or physiochemical properties impacting bioavailability.||II|
|Changes in the manufacturing process of the active substance||Minor change in the manufacturing process of the active substance.||IA|
|=||Substantial change to the manufacturing process of the active substance which may have a significant impact on the quality, safety, or efficacy of the medicinal product.||II|
|Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance||Up to 10-fold increase compared to the currently approved batch size||IA|
|=||Downscaling down to 10-fold||IA|
|Change in the specification parameters and/or limits of an active substance, starting material/intermediate/reagent used in the manufacturing process of the active substance||Tightening of specification limits||IAIN|
|=||Addition of a new specification parameter to the specification with its corresponding test method||IA|
|=||Change outside the limits of the approved specifications range for the active substance||II|
|Change in test procedure for the active substance or starting material/reagent/intermediate used in the manufacturing process of the active substance||Minor changes to an approved test procedure||IA|
|=||Other changes to a test procedure (including replacement or addition) for the active substance or a starting material/intermediate||IB|
|Change in the re-test period/storage period or storage conditions of the active substance||Change in storage conditions of the active Substance||IB|
|Certificate of Suitability||The new certificate from a new manufacturer (replacement or addition).||IAIN|
Finished Product Changes
|Type of Change||Subset of change||Type of Variation|
|Changes in the composition (excipients) of the finished product||Qualitative or quantitative changes in one or more excipients that may have a significant impact on the safety, quality, or efficacy of the medicinal product.||II|
|=||Replacement of a single excipient with a comparable excipient with the same functional characteristics and at a similar level||IB|
|Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product||The site, which requires an inspection by SFDA.||II|
|Change in the manufacturing process of the finished product||Substantial changes to a manufacturing process that may significantly impact the quality, safety, and efficacy of the medicinal product.||II|
|=||Minor change in the manufacturing process||IA|
|Change in the batch size (including batch size ranges) of the finished product||Up to 10-fold compared to the currently approved batch size.||IAIN|
|=||Downscaling down to 10-fold.||IA|
|Change in the specification parameters and/or limits of the finished product||Tightening of specification limits||IA|
|=||Change outside the approved specifications limits range.||II|
|=||Deletion of a specification parameter which may have a significant effect on the overall quality of the finished product||II|
|Change in test procedure for the finished product||Minor changes to an approved test procedure.||IA|
|=||Other changes to a test procedure (including replacement or addition).||IB|
|Change in immediate packaging of the finished product||Change in the container type or addition of a new container||IB for Solid and semisolid II for Sterile product|
|Change in a pack size of the finished product||Change in the number of units (e.g., tablets, ampoules, etc.) in a pack||IB|
|Change in supplier of packaging components or devices (when mentioned in the dossier)||Replacement or addition of a supplier||IA|
|Change in the shelf-life or storage conditions of the finished product||Extension of the shelf-life of the finished product||IB|
|Pharmacovigilance||QPPV registration or information update||No longer submitted as variation. Since May 2021|
Unaccepted Variations (Requires New Application)
Some major changes are obviously too essential to be considered as variations.
The SFDA does not accept some changes on the registered file as a variation since they are too substantial to review as an update on a registered file. Therefore, they are required to be filed in a new registration submission for an independent review. Examples of those changes are:
- Changing the API with a different API.
- Addition of an API in a multi-component product.
- Removal of an API from a multi-component product.
- Change in the dose of an APIs.
- Change in the dosage form, e.g., changing the dosage form from an immediate-release product to a slow- or delayed-release dosage form and vice versa.
- Change in the pharmaceutical form, e.g., changing from a liquid to a powder for reconstitution, or vice versa.
- A change from multi-dose to single-dose or vice-versa (both for addition or replacement).
- Change in the strength of the finished product.
- Change in the route of administration or addition of route of administration.
SFDA Variation File Format
The variation submission must be in eCTD format and including all the affected files by the new change. Companies do not have to include the full copy of the dossier. Only the must include in addition to the affected sections of the dossier.
The SFDA started charging for variation submission in 2021 through their system (eSDR). Companies must settle an invoice of SAR 4000 for every variation application.
Download SFDA Variation Guidelines (GCC) version 6.1
The latest version (6.1) published in October 2020.