SFDA Variation Guidelines Overview

Pharma companies need to be always updated with the latest sfda variation guidelines to ensure compliance with the drug life cycle management regulations in Saudi Arabia. The SFDA is continuously updating its way of accepting and evaluating drug variation submissions. To keep up with that, regulatory professionals have to follow the latest versions of the SFDA Variation Guidelines ( also published as GCC variation guidelines).

As known, the variation file is a 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 takes 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 high potential risks 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 of minor changes after implementation.

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 of any post-approval changes.

Notification Only

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 before or after implementation.

Requires Pre-Approval

On the other hand, the SFDA variation guidelines 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 the below section, we will detail all the variation types:

Type IA Variation

Such minor variations do not require prior approval before implementation, it is called the “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 indicate:

• All IA variations have been implemented during the previous year.
• Date of implementation of each variation.

Type IA_IN Variation

Should be submitted immediately, within a maximum of 14 days after implementation. Note that it is possible to group IA with IA_IN variations as follows:

Grouping Type IA/IA_IN changes

Type IA or IA_IN variation can be grouped for one medicinal product or affect several medicinal products from the same MAH.

Grouping Type IA/IA_IN with other types of variations

Type IA/IA_IN 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.

Type IB

Under this type of variation falls the changes that are neither Type IA nor Type II. This means that 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 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.

Type II

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

Administrative Changes

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
Change in the Marketing Authorization Holder	Transfer the product to a 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 might 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 a 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 the 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 a variation. Since May 2021

Unaccepted Variations (Requires New Application)

Some major changes are 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 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 include 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.

Variation Fees

The SFDA started charging for variation submission in 2021. Companies must settle a governmental invoice through the SADAD system for every variation application. SFDA collects the fees per registered pack. For the variation fee amount, refer to our article SFDA Fees.

Download SFDA Variation Guidelines (GCC) version 6.1

The latest version (6.1) was published in October 2020.