Pharma companies must comply with the latest Saudi Food and Drug Authority (SFDA) variation guidelines to ensure compliance with the drug life cycle management regulations in Saudi Arabia. Since the SFDA regularly updates its procedures for accepting and evaluating drug variation submissions, regulatory professionals must apply the latest version of the SFDA Variation Guideline.
The variation application is a request from the Marketing Authorization Holder (MAH) to the SFDA to change or update the registered drug information. It is a post-approval procedure that frequently takes place after the SFDA approval to ensure that amendments to the registered drug file are approved for marketing.
Table of contents
What is this article about?
This article provides a comprehensive overview of the variation requirements issued by SFDA. It is intended to assist applicants in understanding the different types of variations, applicable timelines, submission procedures, change classifications including administrative, quality, safety and efficacy-related changes, as well as the required file formats and applicable fees in accordance with SFDA guidelines.
What are the procedures for variation application?
The potential impact of changes on product quality may range from low to high risk. Therefore, manufacturers are encouraged to adopt a risk-based regulatory approach when managing post-approval changes.
- Obtain prior approval from the SFDA for major changes before implementation.
- Notify the SFDA of minor changes in accordance with the applicable reporting requirements
To facilitate the management of post-approval changes, the SFDA has established different variation categories based on the nature and potential impact of the proposed change. These categories define the appropriate regulatory communication requirements and specify whether a change requires prior approval, immediate notification or reporting within a specified timeframe after implementation.
Notification Only
These variations do not require prior approval. They are moderate to low-risk changes that have no 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 within a defined period before or after implementation.
Requires Pre-Approval
On the other hand, major changes require approval before implementation. They heavily impact the product’s quality, safety, and efficacy. Therefore, the MAH has to submit all the relevant documents to SFDA to describe and justify the variation. The approval might require an SFDA Good Manufacturing Practices (GMP) inspection for some variation types, such as resourcing from a new manufacturing site.
Variation Types
Starting in version 6.1 of the SFDA variation guidelines, the SFDA introduced a new type called IAIN, a new level that SFDA placed between the already known two types, type IA and IB, and is considered a minor variation.
When one or more conditions established in the SFDA guideline for minor change of Type IA are not met, the concerned change may be submitted as Type IB variation, unless the change is specifically classified as a major change variation of Type II.
A detailed description of each variation type is provided below.
Type IA Variation
Such minor variations do not require prior approval before implementation; this is referred to as 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 the following:
- All IA variations have been implemented during the previous year.
- Date of implementation of each variation.
Type IAIN Variation
It should be submitted within 14 days after implementation. Note that it is possible to group IA with IAIN variations as follows:
- Type IA or IAIN variation can be grouped for one medicinal product or affect several medicinal products from the same MAH.
- Type IA/IAIN can also be grouped with Type IB and Type II variations. Such grouped submissions will follow the review timeline of the highest variation in the group.
Type IB
Under this type of variation fall 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 Type II major changes.
Type IB variations must be submitted to the authority by MAH before implementation, but they do not require formal approval. However, the MAH must wait 60 working days to ensure the application is deemed acceptable before implementing the change (“Tell, Wait, and Do” procedure).
It is also possible for an 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, the application must contain all the relevant supporting information and documentation.
Variation Timelines
| Variation Type | Timeline |
| Submission Validation Notes | 30 working days. |
| Evaluation/Inspection | 60 working days. |
| Pricing | 60 working days |
| Type IA | 30 working days |
| Type IAIN | Within 14 working days. |
| Type IB | 60 working days |
| Type II | 100 working days |
The application that includes more than one type of variation such as Type IB & Type II, the total performance target for the application is 100 working days.
Examples
Administrative Changes
Some examples of the administrative changes include the following:
| Type of Change | Subset of change | Type of Variation |
| Change in the Marketing Authorization Holder | Transfer the product to new marketing authorization holder (different legal entity) | IB |
| Change in the (invented) name of the medicinal product | NA | IB |
| Change in name of the active substance | NA | IAIN |
| 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 |
| Change in ATC Code /ATC Vet Code | NA | IA |
Quality Changes
It includes the quality changes related to Active substances, finished product, CEP/TSE/Monographs/PMF/VAMF, drug containing medical device
Some examples of the qualitative changes:
Active Substance:
| 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. | Introduction of a manufacturer of the active substance supported by a DMF | II |
| Changes in the manufacturing process of the active substance. | Minor change in the manufacturing process of the active substance | IA |
| 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 |
| Change to in-process tests or limits applied during the manufacture of the active substance | Tightening of in-process limits | IA |
| Change in immediate packaging of the active substance | Change in the qualitative and quantitative composition | IA |
| Change in the re-test period/storage period or storage conditions of the active substance | Extension or introduction of a re-test period/storage period supported by real time data | IB |
Finished Product Changes
| Type of Change | Subset of change | Type of Variation |
| Change or addition of imprints, bossing or other markings including replacement or addition of inks used for product marking. | Changes in scoring/break lines intended to divide into equal doses | IB |
| Changes in the composition (excipients) of the finished product | Increase or reduction in components of the flavoring or coloring system | IAIN |
| Deletion of the solvent/diluent container from the pack | NA | IB |
| 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 |
| Change in the specification parameters and/or limits of an excipient | Tightening of specification limits | IA |
| Change in the specification parameters and/or limits of the finished product | Tightening of specification limits | IA |
| Variations related to the introduction of real-time release or parametric release in the manufacture of the finished product | NA | II |
| Change in the specification parameters and/or limits of the finished product | Tightening of specification limits | IA |
| Change in the shelf-life or storage conditions of the finished product | Change in storage conditions of the finished product or the diluted/reconstituted product | IB |
| Change in the pack size of the finished product outside the range of the currently approved pack sizes | 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 coating weight of oral dosage forms or change in weight of capsule shells | Gastro-resistant, modified or prolonged release pharmaceutical forms where the coating is a critical factor for the release mechanism | II |
Certificate of Suitability (CEP) / Transmissible Spongiform Encephalopathy (TSE)/Monographs
| Type of Change | Subset of change | Type of Variation |
| Change to comply with reference pharmacopeia | Change in specifications from a reference pharmacopeia to another reference pharmacopeia | IA |
| Submission of new or updated certificate of suitability or deletion of certificate of suitability for active substance, excipient or starting material/reagent/intermediate used in the manufacturing process of the active substance. | Deletion of TSE Certificate of suitability for an active substance/starting material/reagent/intermediate/or excipient (in case multiple certificates exist per material) | IA |
Plasma Master File (PMF) / Vaccine Antigen Master File (VAMF)
| Type of Change | Subset of change | Type of Variation |
| Inclusion of a new, updated or amended Plasma Master File in the marketing authorization dossier of a medicinal product | First-time inclusion of a new Plasma Master File not affecting the properties of the finished product | IB |
| Addition of MDMA test kit to test individual donations as a new test kit or as a replacement of an existing test kit | NA | IA |
Drug containing medical device
| Type of Change | Subset of change | Type of Variation |
| Change of a measuring or administration device | Deletion of a device | IAIN |
Safety, Efficacy, Pharmacovigilance Changes
| Type of Change | Subset of change | Type of Variation |
| Change in the summary of product characteristics, labelling and patient information leaflet of a generic/hybrid/biosimilar medicinal product following assessment of the same change for the reference product | Implementation of change(s) for which no new additional data are submitted by the MAH | IB |
| Change in legal status of a medicinal product or distribution site | Change the distribution site of the reference medicinal product | IB |
Variations that require submission of New Application
In certain major cases, when the conditions are not met then the SFDA mandates the applicants to submit a new application instead of submitting the variation applications. Examples of those changes in which a new application is necessary includes:
- Changing the API to a different API.
- Addition of an API in a multi-component product.
- Removal of an API from a multi-component product.
- Change in the strength of the APIs.
- Change in the pharmaceutical form, e.g., from an immediate-release product to a slow-release or delayed-release dosage form, and 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 a route of administration.
- Addition or replacement of a measuring or administration device.
File Format
The variation application is submitted in the electronic Common Technical Document (eCTD) format and includes replacement of the parts affected by the variations, rather than the complete submission of the dossiers.
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.
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About the Author
Published by regulatory affairs team in PharmaKnowl, Riyadh office.
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