API (active pharmaceutical ingredients) registration in the Russian Federation

General notes for the API regulations in Russia

In order to market commercial active pharmaceutical ingredient (API or “pharmaceutical substance not for production” - national term), manufacturer or API rights holder should officially register that API in Russia.

In contrary to finished drug products, where Eurasian Economic Union (EAEU) registration Rules apply, API registration (officially named "Enrollment to the State Register of the Russian Federation") undergo National registration only, and in this review we will focus on the API registration in Russia.

Understanding the Regulations

First, not all APIs are needed to be registered, but only the commercial APIs. For understanding of that principle, API classification in Russia should be considered.

As per legislation of the Russian Federation and applicable National regulations, all APIs in Russia can be classified into three categories:

1) Registered commercial APIs

Once registered, APIs of this type can be legally imported and marketed, their circulation is regulated by the Federal Law 61-FZ “On circulation of medicinal drugs”.

Manufacturer of registered API can contract any number of local FDP manufacturers for use of the registered API in their production.

2) APIs, whose dossiers (ADMF) were approved in frames of state registration of a finished drug product (FDP)

For API of that category, strict limitations apply:

• Such APIs are “linked” only to the registered FDP, being limited only to manufacturing purpose stated in the registration dossier of that particular FDP.
• Any ways of circulation and/or commercial use of such APIs that come outside the quality agreement(s) of the API manufacturer and the MAH (defined in Russia under term “Registration Certificate Holder”) of particular registered FDP are not allowed in Russia.
• In case of contract API manufacturers, while having absence of “exclusive” production and commercial limitations in such quality agreement(s) with the MAH(s) of FDP(s), such APIs cannot be legally marketed in Russia out of the “manufacturing only” limitations presented in that registration dossiers of corresponding registered FDPs.
• In cases of local FDP manufacturing such APIs are expected to be listed in the Russian registration certificates of corresponding registered FDP(s) - in order to be permitted for import only for the purpose of local manufacturing of corresponding bulk drug product(s).

3) Non-registered APIs

Commercial importation and marketing of such APIs is directly prohibited in the Russian Federation.

 © Pharegis LLC, 2023

API registration procedure and timeline

The procedure of API enrollment to the State Register of Medicines comprises the following stages:

Total expected term is 4-8 months while having only single official MoH request (that is what we focus on at preparatory stages 1-3 and it is the best option available) as well as submission of RP DMF by Pharegis together with AP DMF within single initial submission.

This timeline range is practically attainable in case of full cooperation from the customer side – in terms of shipment of the samples and addressing specific points of the official request (e.g. provision of additionally requested documents). 

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EAEU GMP certification

Overview

For the registration (“inclusion to state register of medicines”) of a commercial API in Russia, it is also required to present EAEU GMP certificate for the API manufacturing site. Before 2021, Russian GMP conclusions (certificates) were required for the API registration, now the national API registration procedure in Russia requires EAEU GMP certificate.

EAEU GMP certification is governed by the Resolution № 77 dd. Nov 03, 2016 of the Council of the Eurasian Economic Commission "On Adoption of the Rules of Good Manufacturing Practice of the Eurasian Economic Union".

The federal authorized body, Ministry of Industry and Trade (MIT) of the Russian Federation had officially empowered Federal State Institution “State Institute of Drugs and Good Practices” ("FSI SID&GP")  as the only dedicated institution that performs EAEU GMP inspections and GMP certification expertise.

Historically, Pharegis LLC obtained first-ever Russian GMP conclusion for Chinese APIs manufacturer back in 2016, it was the second ever Russian GMP certificate among all Chinese pharmaceutical manufacturers.

EAEU GMP inspection: scope and procedure

The inspections of API manufacturing site are performed by team of 2 (rarely 3) duly authorized inspectors of FSI SID &GP, taking 3-4 full business days (usually 9 am – 5 pm) for each manufacturing site, having 45 minutes lunch break as well as 2 coffee breaks.

As for the typical scope of EAEU GMP inspection, here is a sample of real anonymized EAEU inspection plan with areas that it covers and documents to be evaluated.

EAEU GMP inspection: interpreters team

The regulations require availability of the interpreters provided by the site or applicant, each interpreter is dedicated to its own inspector since the inspectors work in parallel. Having managed dozens of Russian and EAEU GMP inspections, Pharegis usually provides team of professional interpreters experienced in pharmaceutical manufacturing, QMS and GMP regulations, and we have outstanding feedback from all inspectors (including the Head of FSI SID &GP himself) concerning the interpreting performance.

EAEU GMP: expected challenge, statistics and options proposed by Pharegis

EAEU GMP inspections are more challenging than EU ones, most manufacturers compare overall challenge of EAEU inspections to Brazil (Anvisa) ones. As per the statistical data since 2016, 1/3 of overall GMP applications resulted in GMP certification refusal due to sum of GMP non-compliance observations and/or follow-up CAPA inadequacy.

Pharegis can minimize the risk of GMP certification refusal to zero by adding our procedure of thorough pre-inspection GMP audit that is second to none in Russia and EAEU. Contact us to get the details, we also offer that service as a standalone one.

EAEU GMP certification timeline

Overall duration of EAEU GMP certification is 6-12 months, depending on the queue of applicants, complexity of APIs manufactured by the site (sterile/biotech etc), as well as chosen services options.

To optimize the registration timeline as much as possible, we perform both GMP certification and API  registration in parallel, where the EAEU GMP certificate will be required only at the finishing stage of the API registration.

So EAEU GMP certification will NOT prolong the overall timeline of the registration of you API(s).

We can focus on a chosen part of the whole project – either GMP part or API registration part if you would like to divide the project with any 3^rd party for some reason (as per our experience that is more complex in terms of logistics, data integrity, overall timeline optimization and costs).

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API dossier requirements

The requirements to an API registration dossier are regulated by the Federal Law 61-FZ “On circulation of medicinal drugs”, the contents of  technical parts of the dossier are similar to European Medicines Agency (EMA) EDMF as regulated by EMA Guideline on Active Substance Master File Procedure.

There are national specifics for the administrative part and the ND (see below)

Our API registration inquiry form contains all required dossier parts of an API from your side.

Moreover, the inquiry form also reflects all key parameters of your potential API(s) registration process in detail – those choices are very flexible with Pharegis and they are completely yours, as we never urge using our services like big «as is» package.

However, in case of several registration projects we could gladly propose you an exclusive offer that will fully satisfy your needs and the budget.

We will check your inquiry for API registration and reply with the specific commercial offer shortly. In our commercial offer we will also provide you information on services options that you can choose from.

Understanding of “ND”

The key reference for a registered API

Normative document (ND) of registered API is part of that API registration dossier, and it is the main reference document of the registration dossier for the commercially registered API.

The ND is to be approved and issued by MoH together with the official registration letter (MoH letter for inclusion of the API to the State Register of Medicines of the Russian Federation) to the applicant of the API registration.

Contents and confidential nature of ND

Any ND is written in Russian language and is the reference for corresponding API’s nomenclature, QC specification, detailed description of QC methods, packaging, labelling, storage and transportation conditions, as well as for the shelf life.

 Apart the applicant and the API manufacturer, only MoH, MIT, Roszdravnadzor (being the federal executive bodies); authorized expertise institutions (specifically - FSI SCEEMP and FSI SID &GP) and accredited certification institutions have access to the ND - it is not a document for public use. ND is also used as the reference by customs authorities during API importation procedures.

However, an ND in most cases does not contain sections of Restricted Part of corresponding API dossier and does not reflect any parts of the manufacturing process and parameters details, as well as the validation data.

Potential adjustments to initial API dossier

The main difference between initial API dossier sections and the ND is that the ND should comply to Russian national regulations.

In terms of the QC sections of the dossier, in order to be registered in Russia, API should correspond to requirements of Russian State Pharmacopeia. That applies to both specification limits and additional QC tests. So initial API dossier sections should be checked (and adjusted if needed) before the submission for API registration in order to correspond to the API ND.

Any specification and QC tests in ND can contain references to USP, Eu.Ph., BP or other compendial monographs, as well as in-house validated QC methods. So there is absolutely no need to adjust all QC to monographs of the Russian Pharmacopeia.

Nevertheless, there are cases where methods stated in Russian State Pharmacopeia (RSP) have more strict limits. In that case RSP limits should apply in the API dossier submitted for the registration.

Also, additional QC tests can be required as per RSP for particular formulations. For example, QC tests like “Abnormal toxicity” and “Depressive substances” as well as “Bacterial endotoxins” are frequently requested by MoH to be added to ND as per RSP requirements.

Sterile API, APIs intended for production of sterile formulations, API derived from human or animal blood, organs, tissues, plant materials, microorganisms/produced by microorganisms often have such additional QC tests in the API specifications for export to Russia and the corresponding API NDs.

What we do with ND and API registration dossier

There is no need to know all subtleties about the ND since it is part our daily work we do during gap analysis and API dossiers preparation.

We prepare all NDs from scratch, strictly considering all adjustments with the manufacturer in advance, under strict local regulations (including e.g. used fonts’ sizes) for its format and contents. Considering all dossier adjustments with the manufacturer and preparation of the ND are our routine, yet very important activity we thoroughly perform for each API registration application.

 © Pharegis LLC, 2023