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Back to Basics – Biological Medicines

8th April 2026

Let’s get Back to Basics – Biological Medicines

According to Part I of Annex I of Directive 2001/83/EC, a biological medicinal product is a product that contains a biological substance.

A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing, together with information about the production process and its control.

For example: recombinant proteins, monoclonal antibodies, medicinal products derived from human blood and human plasma, immunological medicinal products and advanced therapy medicinal products (ATMP) should be considered biological medicinal products.

Such biological sources can be bacteria, yeast, plant/animal cells, blood products, plasma-derived products, allergens and products manufactured using recombinant technology.

Biological medicinal products were previously developed mainly for rare diseases, but these days more of them are directed towards treatment of common diseases like diabetes, arthritis, inflammatory bowel diseases, asthma and cancer.

Unlike traditional small-molecule drugs manufactured by chemical synthesis, biological medicinal products are typically administered via injection or infusion requiring strict aseptic conditions and are manufactured through a highly complex, intricate & sensitive biotechnology process known as biomanufacturing.

RA professionals must navigate complex regulatory frameworks when submitting dossiers to seek product approval and to manage post-market compliance for these biological medicinal products.

Many of these products as well as ATMP medicinal products will require approval via the centralised procedure. Others (e.g. naturally derived biologicals) may be nationally authorised in individual Member States.

European Regulatory Affairs Limited specialise in the navigation of regulatory frameworks, gap analysis, communication with regulatory authorities & the planning & submission of dossiers to obtain product approval and manage post-market maintenance via the Centralised, National & MRP/DCP procedures.

Biologicals encompass a huge & diverse area and this article strives to provide a basic overview of some of the basic elements, approval pathways, and highlight some check-lists from the EMA & MHRA to follow before submission to avoid some common validation errors during review.

ATMP (Advanced Therapy Medicinal Products): are products for human use, including gene therapy, somatic cell therapy and tissue engineered products. ATMPs may also incorporate, as an integral part of the product, one or more medical devices in which case they are referred to as “Combined ATMPs”.

ATMPs can be classified into three main types:

Gene therapy medicines: these contain genes that lead to a therapeutic, prophylactic or diagnostic effect. They work by inserting ‘recombinant’ genes into the body, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases. A recombinant gene is a stretch of DNA that is created in the laboratory, bringing together DNA from different sources
Somatic-cell therapy medicines: these contain cells or tissues that have been manipulated to change their biological characteristics, or cells or tissues not intended to be used for the same essential functions in the body. They can be used to cure, diagnose or prevent diseases
Tissue-engineered medicines: these contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue

Approval Pathways: ATMPs, biologicals and biosimilars can be submitted using the following pathways depending on the biotechnological process to be used, whether the active is new and for which indications & Member States the MAA applications are being sought

National – Great Britain (England, Scotland & Wales): All ATMP, biologicals & biosimilar products must be submitted according to MHRA guidance through the MHRA portal. For applications for Northern Ireland the EU guidance must be followed.
Mutual recognition procedure/Decentralised procedure: Biological medicines can be registered through the mutual recognition or decentralised procedures, provided that they do not fall within the Annex to Regulation (EC) No 726/2004; in which case the centralised procedure has to be followed. Some biosimilars may be approved at national level, such as some low-molecular weight heparins.
Centralised Procedure: All ATMP, biologicals & many biosimilar products must be submitted through the Centralised Procedure. All medicines produced using biotechnology and those for specific indications (e.g. for cancer, neurodegeneration and auto-immune diseases) must be approved in the EU via the centralised procedure. Nearly all biosimilars approved for use in the EU have been approved centrally, as they use biotechnology for their production.

Early Engagement with the relevant Regulatory Authorities is strongly recommended. The guidance should be thoroughly reviewed during development of a biological medicinal product & well in advance before the preparation of a MAA to understand what requirements are to be fulfilled.

Biosimilars: A biosimilar is a biological medicine highly similar to another biological medicine already approved in the EU (called “reference medicinal product”) in terms of structure, biological activity and efficacy, safety and immunogenicity profile (the intrinsic ability of proteins and other biological medicines to cause an immune response).

Developers of biosimilars are required to demonstrate through comprehensive comparability studies with the ”reference medicinal product” that:

their biological medicine is highly similar to the reference medicine, notwithstanding natural variability inherent to all biological medicines
there are no clinically meaningful differences between the biosimilar and the reference medicine in terms of safety, quality and efficacy

Biosimilar development relies heavily on comparability studies to establish similarity to the reference product. This involves a comprehensive head-to-head comparison of the biosimilar and the reference medicine.

Guidelines on Biologicals are outlined on the EMA & MHRA websites to facilitate the preparation of these Marketing Authorisation Applications (MAA). The guidelines on the EMA website for the active substance and the finished product are important sources of information when preparing MAA applications for these products.

The ICH guidance M4 (R4) on common technical document (CTD) for the registration of pharmaceuticals for human use, needs to be followed for the preparation of a well-structured Common Technical Document for applications that will be submitted to regulatory authorities.

Bio-processing:

This typically involves 2 stages

Upstream

This is the stage where cells or microorganisms are prepared, cultivated and controlled so they can produce the desired biological output. It includes the preparation of a Master Cell Bank & from it a Working Cell Bank.

Downstream

Downstream processing aims to isolate, purify, and concentrate the previously synthesized drug substance (DS).

Other critical steps in bio-processing are as follows:

Formulation & Fill-Finish: Final formulation to ensure stability, followed by sterile filling into vials or syringes in aseptic conditions to which regulatory authorities focus strongly on.

Quality Control (QC) & GMP Compliance:

- Process Validation: Documenting that the process consistently produces the intended result.
- Strict Documentation: Compliance with GMP, including detailed, auditable records for batch release.
- Environmental Monitoring: Ensuring sterile environments & conditions

Typical Biotech Manufacturing process with relevant ICH guidance’s:

Figure 1 – source : ICH – Manufacturing Process for Biologicals

Check the EMA questions & answers guidance for biological medicinal products to ensure that all the required supporting documentation & reports are present so that CTD sections are complete, to pre-empt validation issues arising.

It is advised to review the EMA validation checklist before submission of the dossier and the MHRA Marketing Authorisation pre-submission checklist to keep validation issues to a minimum to help speed up review time.

If you would like to discuss any of the above and if you need support for any of your Biosimilar applications, we are ready to assist you and your team.

Feel free to contact us and we will be happy to help.

Written by European Regulatory Affairs Limited

Some useful definitions for you:

Biotechnology: Technology that relies on biological systems, living organisms or components from living organisms (such as genes or enzymes) to make a specific product. A medicine obtained by biotechnology often has been produced by inserting a gene into cells so that they can produce the desired protein.

Comparability: Head-to-head comparison of a biosimilar with its reference medicine to rule out any significant differences between them in terms of structure and function. This scientific principle is routinely used when a change is introduced to the manufacturing process of medicines made by biotechnology, to ensure that the change does not alter safety and efficacy.

Immunogenicity: as defined by the European Medicines Agency (EMA), refers to a biological medicine’s ability to trigger an unwanted immune response, leading to the development of anti-drug antibodies (ADAs). These antibodies can cause adverse reactions, reduce drug effectiveness, or neutralize the drug’s therapeutic function.

MCB (Master Cell Bank): An aliquot of a single pool of cells which generally has been prepared from the selected cell clone under defined conditions, dispensed into multiple containers and stored under defined conditions.

Monoclonal Antibodies: Monoclonal antibodies are immunoglobulins (Ig) with a defined specificity derived from a monoclonal cell line. Monoclonal antibodies may be generated by recombinant DNA (rDNA) technology, hybridoma technology, B lymphocyte immortalisation or other technologies (e.g. display technology, genetically engineered animals).

WCB (Working Cell Bank): The Working Cell Bank is prepared from aliquots of a homogeneous suspension of cells obtained from culturing the MCB under defined culture conditions.

Back to Basics – Mutual recognition procedure (MRP)

31st May 2024

With our new logo and new website we expect some new visitors, so, we are continuing our back to basics post for those who may be new to Regulatory Affairs. (If you need help with the jargon visit our A-Z Glossary of Regulatory abbreviations).

MRP

When an Applicant has a single marketing authorisation (MA) in one Member State and wishes to market the same medicinal product in other Member States in EU/EEA, a Mutual Recognition Procedure (MRP) can be used.

The Competent Authority where you hold the single MA acts as the Reference Member State (RMS) and the new Member States you chose are referred to as Concerned Member States (CMSs).

The RMS prepares the Assessment Report on the medicinal product and runs the procedure. The CMSs will raise questions during the procedure.

However, before you submit your MRP application, there are a number of things to consider;

You must ensure that the current dossier complies with the current legislation and EU guidelines. If your current dossier is not in line with the current legislation and EU guidelines it must be updated by variation prior to submitting the MRP application.
There must be no ongoing variations.
You must agree an appropriate time slot and request an updated Assessment Report (AR) from the RMS prior to submitting the application.
Each Member State will have a slightly different working procedure, but most require that discussions/requests start at least three months before your preferred starting time.
The RMS must allocate procedure number (e.g. IE/H/123/001/MR).
You must choose your CMSs carefully. Where applicable, review the approved legal supply status and local requirements (e.g. need for a local representative, local person for pharmacovigilance etc.) and reimbursement procedures etc. of each Member State.

If applicable compare the SmPCs of reference product across the interested territories, identify any differences paying particular attention to the indication(s) and posology.

The MRP follows by a 90-day period followed by a 30-day national phase.

To ensure that your MRP starts on time, it is advised to review the ‘additional data’ requirements of each Member State (e.g. do the cover letters, letter of authorisation need wet/original/notarised signatures etc?) and ensure the correct payment amount has been paid.

The CMSs can raise questions that relate to any aspect of the dossier from Module 1 to Module 5 such as issues with specifications, analytical validation, breakability data on scored tablets, process validation, biostudies including statistics applied to the studies, etc., all have to be addressed as “serious risk to public health”.

The CMSs are not allowed to ask for, and the Applicant is not allowed to supply, new data during an MRP.

Seven calendar days after close/end of procedure the Applicant should send high quality national translations of SmPC, PL and labelling and mock-ups to CMSs. It is critical that the translation service used is reliable and technically competent to translate medical text.

It is also important that the correct dialect or form of language is used. Due to this tight turnaround time, it is advised that discussions with your translator be performed in well in advance of the predicted Day 90.

The CMS should issue a marketing authorisation within 30 days after closure of the procedure, however in most cases depending on the Member State, this 30-day period is frequently missed.

Day Zero MRPs

A Zero Day MRP is an administrative RUP or MRP with a shortened timetable. A Day zero MRP is used in exceptional cases to mitigate shortages or issues with access to critical medicines in the new Member State.

In most cases the new CMS will not raise any quality or clinical question but will have specific criteria that need to be met prior to accepting a Day Zero MRP. The main prerequisite approval for a Day Zero MRP is that the medicinal product will be marketed in Member State as a result. Even though the procedure is administrative, the applicant should contact the RMS to agree on a submission date.

Countries like Iceland and Malta rely on such procedures due to the small size of the markets there.

Feel free to contact us here at ERA to assist you with all things regulatory in Ireland, UK and across the EU.

We take the pain out of regulatory so that you can take your medicine to the next level.

Written by

Fiona Downey

Fiona Downey 1

Back to Basics – The Decentralised Procedure (DCP)

17th June 2024

We continue our back to basics series for those who may be new to Regulatory Affairs (If you need help with the jargon visit our A-Z Glossary of Regulatory abbreviations).

In the EU, there are two different procedures available to apply for a marketing authorisation application (MAA) for the same medicinal product in more than one Member State at a time:

the Decentralised Procedure (DCP)
the Mutual Recognition Procedure (MRP).

This Article focuses the Decentralised Procedure (DCP).

The DCP is only applicable if no marketing authorisation has previously existed in the EU/EEA, as per Directive 2004/27/EC and if an identical dossier is submitted simultaneously in all selected Member States.

To prepare for a DCP submission:

Establish a Reference Member State (RMS).
- One Member State called the RMS will be selected by the Applicant to lead the assessment of the MAA.
- To do this, complete a “Request for RMS in a Decentralised Procedure” Form and send it to your preferred RMS at least 2 months before the planned date of submission of the marketing authorisation application.
- Only one RMS request can be submitted at a time. It is advisable to establish an RMS as soon as possible as DCP slots get booked up very quickly.
- The guidance, Decentralised Procedure – Requests to act as RMS, provides an overview of the booking system & links to the various National Competent Authorities who act as RMS
Prepare a dossier in accordance with the current legislation and EU guidelines.
Check that the requirements for submissions for new Marketing Authorisations are met for the various Member States to avoid validation comments (at Day -14) and also for any additional requirements to determine if any wet/original/notarised signatures are required
Ensure the correct fee amount has been paid.
Check the dossier for common validation issues raised by the RMS and the CMSs in DCP procedures to prevent them being requested during the validation of your application.
The applicant then simultaneously submits an identical dossier to the RMS and all CMS by the agreed submission date booked with RMS.
The application will be submitted via CESP portal, according to eCTD Guidelines, & then applicant will send any hard copies/original documents required by various Member States as per national requirements.

Assessment Reports (Day 70, D120, Day160, D210):
- The RMS is responsible for preparing an Assessment Report (AR) which summarises the dossier presented by the applicant. The AR characterises and critically evaluates the medicinal product concerned with regard to its quality, safety and efficacy.
- This AR will be made available to all Concerned Member States (CMS) together with SmPC, PL and labelling by the RMS and forms the basis for the evaluation by CMS.
- In the case a Member State concerned by the procedure is unable to accept the AR or draft AR on the basis of a “potential serious risk to public health”, the application will be sent to the CHMP for arbitration.
End of Procedure can be in 90-210 days after validation phase is closed.
It is advisable to plan the national translations in time. It is critical that the translation service used is reliable and technically competent to translate medical text.
Seven calendar days after end of procedure the Applicant should send high quality national translations of SmPC, PL and labelling and mock-ups to individual CMSs.
There is usually a 30-day National assessment before of the granting of the MA, however the timelines differ in each MS.
If consensus is not reached at the end of the procedure, a pre-arbitration (CMDH) and arbitration (CHMP) phase may take place.

We can help you to do all of the above or even better we can do it for you – to save you time and money let our experienced team take the pain out of it for you.

Written by

Marian Winder

Back to Basics – Variations – Types & Timelines

9th May 2024

Here is the second installment of our Back to Basics series: VARIATIONS

So, let’s start with a summary of the different types of variations & their timelines.

Variations are

changes made to the dossier of an authorised medicinal product after its initial registration
They may concern administrative changes, Quality changes, Safety/Efficacy changes or Vigilance changes
Variations can be categorised as Type IA_IN, Type IA, Type IB (foreseen or unforeseen) or Type II whether they are within a Centralised, Mutual Recongition/Decentralised (MRP/DCP) or National Procedure (NP)
Variations can either be a single or grouped together.
There is also a mechanism to submit variations by a work sharing procedure.

Procedures around variations are currently governed and harmonised throughout the EU by Commission Regulation (EC) No 1234/2008 of 24 of November 2008 (“the Variations Regulation”) which has subsequently been amended by Regulation (EU) 712/2012*.

[*Update added on 13th Jan 2025: Regulation (EU) 2024/1701 of 11 March 2024 amending Regulation (EC) No 1234/2008 entered into force on 7 July 2024. It became applicable on 1 January 2025]

Variation Types

Definition

Timelines

Human Medicines Regulations

Type IA_IN

A minor variation which has only minimal/or no impact on the quality, safety or efficacy of the medicinal product. The competent authority should be notified immediately after implementation.

‘Immediately’ is not defined in EU guidance but is generally considered to be within 2 or so weeks of implementation* of the change.

*For quality changes, ‘implementation’ is when the company makes the change in its own quality system. For product information, it is when the company internally approves the revised product information. The revised product information will then be used in the next packaging run.

e.g. to introduce a PSMF or change company address

Do & Tell (close to implementation date)
30 day timetable once validated
No clock stop
No timetable is issued
Rejection is possible if documentation requirements are not met
Approval received from the RMS (and maybe from the CMS)

Type IA

A minor variation which has only minimal/or no impact on the quality, safety or efficacy of the medicinal product.

Where all required data

conditions are met such variations do not require any prior approval, but must be notified by the MAH within 12 months following implementation in so called ‘annual reports’ or may be submitted earlier should this facilitate dossier life-cycle maintenance or when necessary. This is known as the ‘Do and tell’ procedure.

e.g. updated CEP from an already approved manufacturer

Do & Tell (Annual basis)
30 day timetable once validated
No clock stop
Rejection is possible if documentation requirements are not met
Approval received from the RMS (and maybe from the CMS)
Competent authorities should implement the decision nationally within six months.

Type IB

Variations which are neither a minor variation of Type IA nor a major variation of Type II nor an extension are classified as Type IB variation by default.

They are further classified as being either foreseen or unforeseen (consult variation guidance documents referenced in section 4, below, for further information) e.g. change of product name for nationally authorised products

Tell and Do (await approval before implementation)
30-60 day timetable, once validated
clock stop period is possible
A timetable is issued
Responses to MS comments can be submitted
A National Phase is possible

Type II

Type II variations are classified as major variations. They arise from a change that does not meet the requirements of a Type I variation, but is not so complex as to lead to a new Marketing Authorisation application. There are two classifications of Type II variations:

(1) Type II Complex

(2) Type II Urgent Safety

Type II variations require a formal approval e.g. addition of a new therapeutic indication

Tell and Do (await approval before implementation)
30/60/90 day timetable, excluding clock stop
A timetable is issued
Responses to MS comments can be submitted
A National Phase is common

Grouping:

Where the same variation(s) affect one or more marketing authorisation(s) from the same holder, the marketing authorisation holder may choose to submit these variations as one application.

In most instances it is possible to group type IA variations regardless of content.

Some competent authorities may not allow grouping for national variations.

In specified cases it is possible to group type IA and type IB/type II variations (consult acceptable and non-acceptable grouping guidance document referenced below, for further information. In these cases the changes will tend to be consequential and the procedure type defaults to the highest recorded procedure.

The website of the relevant competent authority should be referred to, to confirm the possibility of grouping.

For grouping that includes type IB and type II procedures and falls outside the scope of acceptable and non-acceptable grouping guidance documents, consent for the grouping should be sought in advance from the competent authority to avoid rejection.

Worksharing:

Article 20 of the Commission Regulation (EC) No 1234/2008 allows for the possibility for the Marketing Authorisation Holder to submit the same type IB or type II variation or the same group of variations affecting more than one marketing authorisation from the same Marketing Authorisation Holder in one application.

A worksharing procedure allows for one authority to be chosen amongst the competent authorities of the member states to examine the variation on behalf of the other concerned authorities. In case a grouped application is applied this may also contain consequential IA changes.

Line extensions are excluded from worksharing.

Further to above, Applicants may wish to pay particular attention to the following CMDh documents:

Feel free to contact us here at ERA to assist you with all things regulatory in Ireland, UK and across the EU.

We take the pain out of regulatory so that you can take your medicine to the next level.

Written by

Marian Winder

Marian Winder 1

Tag Archive for: Back to Basics

Back to Basics – Biological Medicines

Back to Basics – Mutual recognition procedure (MRP)

MRP

Day Zero MRPs

Back to Basics – The Decentralised Procedure (DCP)

Back to Basics – Variations – Types & Timelines

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