Gene and Cell Therapy Registration in the EAEU. What Chapters 31–32 of Decision No. 89 Require
Two developers working with cellular products, and both plan to enter the Russian market. The first submits documents under Federal Law No. 180-FZ «On Biomedical Cell Products»; the second follows the Eurasian Economic Union (EAEU) procedure. A year later, the first receives a rejection — his product does not fall under Federal Law No. 180. The regulator explains: genetically modified cells must be registered under EAEU law. A year of work is lost.
Such situations became a pattern by 2024–2025. The market for advanced therapy medicinal products (ATMPs) in the EAEU received its own regulatory framework back in 2016, but the distinction between the national Russian track and the Union track still causes practical errors. Let us examine how Chapters 31 and 32 of Decision No. 89 function, how they differ from one another, and why correct product classification matters more than any other step in a regulatory strategy.
Two Tracks, One Technology
Russian law contains two parallel instruments for products based on cells and genetic material. The first is Federal Law of the Russian Federation dated June 23, 2016, No. 180-FZ «On Biomedical Cell Products» (FZ-180). It governs biomedical cell products (BCPs): complexes of cell lines with excipients that do not fall under EAEU jurisdiction. The second instrument consists of EEC Council decisions, namely Decision dated November 3, 2016, No. 89 (Rules for Conducting Studies of Biological Medicinal Products, hereinafter Decision No. 89) and Decision dated November 3, 2016, No. 78 (Rules for Registration, hereinafter Decision No. 78).
The boundary between them is established within FZ-180 itself. Since 2023, its amended version explicitly states that BCPs do not include «high-tech medicinal products, including gene therapy products, subject to registration in accordance with EAEU law.» In practical terms: if a product contains a recombinant nucleic acid or genetically modified cells for a therapeutic purpose, it is an ATMP governed by Decision No. 89.
In practice, the boundary is blurred. Cells that have undergone «substantial manipulation» — cultivation with a change in biological properties — can be classified under either track depending on their mechanism of action. The first step in any ATMP development strategy is therefore to obtain written confirmation from the Ministry of Health of Russia or the EEC on the product’s regulatory category. Without it, dossier work proceeds without a foundation.
The Situation Before Decision No. 89
Until November 2016, EAEU member states regulated biological preparations and cellular products under national rules. In Russia, Federal Law No. 180 «On Biomedical Cell Products» had been in effect since June 2016 — adopted in the same year as the Union package but several months earlier. Kazakhstan and Belarus operated under their own national procedures. There were no unified requirements for the volume of preclinical data, the characterization of viral vectors, or manufacturing facility standards.
This created several practical problems. Data generated in Russia were not automatically recognized in Kazakhstan. A manufacturer that had passed a Russian GMP inspection could not rely on those results when registering in Belarus. For rare disease products, where the patient pool is inherently small, the requirement to duplicate studies in every country made development economically unviable.
Decision No. 89, adopted as a package with Decision No. 78 and Decision No. 77 (GMP), was designed to close these gaps through harmonization.
What Chapters 31 and 32 Changed
Decision No. 89 establishes specific study requirements for the main ATMP categories.
Chapter 31 covers gene therapy medicinal products (GTMPs) — ATMPs whose active substance contains a recombinant nucleic acid. This includes products based on viral vectors (adeno-associated virus, AAV; lentiviruses), plasmid constructs, and genome editing systems.
Chapter 32 governs somatic cell therapy medicinal products (SCTMPs) — cells that have undergone «substantial manipulation» or are used for a purpose other than their original functional role. Chimeric antigen receptor T-cells (CAR-T), dendritic cell vaccines, and cells with a modified phenotype fall into this category.
Separately, tissue-engineered medicinal products (TEMPs) form a third independent ATMP category under Decision No. 78. TEMPs contain engineered cells or tissues intended to regenerate, repair, or replace human tissue. Examples include autologous chondrocytes on a biocompatible scaffold for cartilage restoration, or skin cells on a matrix for wound healing. If a product additionally incorporates a registered medical device as an integral component, it qualifies as a combined ATMP and undergoes assessment under stricter requirements.
The key requirements of Chapters 31 and 32 are summarized below.
| Parameter | Chapter 31 (GTMPs) | Chapter 32 (SCTMPs) |
|---|---|---|
| Starting materials | Plasmids, packaging cell banks, viral seed cultures | Donor cells, culture media, cryoprotectants |
| Specific risks | Gonadal biodistribution, vector shedding, insertional mutagenesis (VCN) | Tumorigenicity, cross-contamination of autologous batches |
| Manufacturing | Closed systems, campaign separation for different vectors, BSL-2/3 biosafety | Aseptic conditions, cryopreservation validation |
| Patient follow-up | Up to 15 years (for delayed carcinogenesis assessment) | Established in the Risk Management Plan (RMP) per risk profile |
| GMP section (EAEU) | Decision No. 77, Annex 2, Section B9 | Decision No. 77, Annex 2, Section B10 |
Shedding and Biodistribution: The Most Common Source of Queries
For GTMPs, Decision No. 89 requires mandatory biodistribution studies, including analysis of vector persistence in the gonads. If animal data show accumulation in the testes or ovaries, the manufacturer must justify the absence of risk regarding transmission of the genetic modification to offspring.
Shedding — the excretion of the vector through the patient’s biological fluids — requires a dedicated research programme. The results go into Module 4 of the dossier and into the Risk Management Plan (RMP), and are then translated into the product label: warnings for healthcare personnel and protection measures for those in contact with the patient.
At RegLek-2025, regulatory experts emphasized that the shedding section is the most frequent trigger of expert queries during evaluation. Companies either conduct these studies on unsuitable models or fail to budget for them during the planning phase.
What Goes into Module 3 for Viral Vectors
For viral vectors, Module 3 of the registration dossier must include data in several mandatory areas:
- Characterization of the Master Viral Seed (MVS) and the Working Viral Seed (WVS).
- Viral safety: testing for adventitious agents and replication-competent virus — Replication-Competent Retrovirus (RCR) and Replication-Competent Adenovirus (RCA).
- Vector Copy Number (VCN) per cell with a justification of the safe range.
- Validation of analytical methods for determining biological activity (potency).
At RegLek-2024, specialists from the Scientific Centre for Expert Evaluation of Medicinal Products (SCEEMP) noted that the description of the vector purification process — specifically the removal of packaging cell line proteins — remains the most frequent subject of queries when Module 3 is reviewed. Residual proteins from the packaging line can trigger an immune response, so their detailed characterization with established acceptance criteria is mandatory.
GMP for ATMPs under Annex 2 to Decision No. 77
ATMP manufacturing is governed by Annex 2 to the EAEU Rules of Good Manufacturing Practice (approved by EEC Council Decision dated November 3, 2016, No. 77). Sections B9 (gene therapy products) and B10 (somatic cell and tissue-engineered products) establish requirements that fundamentally distinguish ATMP manufacturing from conventional pharmaceutical production.
The core difference from a manufacturing perspective: most ATMPs cannot undergo terminal sterilization. Filtration through a 0.22 µm membrane is not possible when the product contains live cells or viral particles. The aseptic process becomes the sole barrier against contamination, and any breach results in a rejected batch.
For viral vectors, manufacturing zone separation is required to prevent simultaneous work with different vectors. Sections B9 and B10 of Annex 2 explicitly prohibit the parallel production of different gene therapy vectors in the same zone: only a campaign-based mode is permitted, with demonstrated effectiveness of changeover procedures.
For autologous products, traceability must enable the identification of cellular material from donor to finished product container. This requires integration of the manufacturer’s IT system with the medical facility where material is collected.
Containment requirements for work with genetically modified organisms (GMOs) are determined by Biosafety Level (BSL): BSL-2 for most AAV vectors, BSL-3 for certain lentiviral constructs. In Russia, the GMO work permit is issued separately from the GMP manufacturing licence, and some manufacturers discover this only when preparing for inspection.
Topics Discussed at RegLek-2025
Three ATMP topics received particular attention at the RegLek conference in 2024–2025.
Hospital Exemption. In the EAEU, the equivalent of the European Hospital Exemption is established in Clause 5.1 of Decision No. 78. ATMPs prepared on a non-standardized basis for an individual patient and administered in a hospital within the same member state are exempt from registration. Exemption does not mean an absence of requirements: manufacturing must be conducted under a licence and in compliance with GMP rules, and traceability and pharmacovigilance data must be collected in accordance with Union acts. At RegLek-2025, experts discussed how data accumulated under the hospital exemption should form the basis for a subsequent marketing authorization dossier.
Multi-state coordination. A session informally titled «Five Nannies» addressed coordination challenges between the Reference Member State and Member States of Recognition. For ATMPs, this issue is more acute than for conventional medicines: conducting additional local clinical trials (CTs) in each country is practically impossible given the small patient numbers. The regulatory trend is towards strengthening mutual recognition of inspection and evaluation results, although the formal mechanism remains insufficiently rigid.
Scientific advice. According to data presented at the conference, companies that completed scientific advice before dossier submission receive on average 40% fewer expert queries during evaluation. For ATMPs, where a single query can stop the clock for 180 days, this represents a significant case for early regulator dialogue.
Recommended Actions
Step 1. Obtain official product classification. Before developing the research programme, submit a request to the Ministry of Health of Russia (or to the EEC if a Union procedure is planned), describing the mechanism of action, composition, and manufacturing technology. Request written confirmation that the product is classified as an ATMP under Decision No. 89 or as a BCP under FZ-180. This document will serve as the justification for the chosen regulatory pathway.
Step 2. Plan specific studies early. The preclinical programme must include biodistribution (with mandatory gonadal analysis), shedding, and — for viral vectors — VCN determination with justification of the permissible range. These studies take 12–18 months, and they cannot be added at the last moment before dossier submission.
Step 3. Address GMP requirements before manufacturing begins. Confirm that the manufacturing site holds a GMO work permit (separate from the GMP licence), complies with biosafety requirements under Annex 2 to Decision No. 77, and that the traceability system ensures identification from donor to finished product. For autologous products, this requirement is particularly important.
Step 4. Use scientific advice. The scientific advice procedure at the EEC or the competent authorities of EAEU member states allows alignment on the Module 3 data package when transitioning from early CTs to registration, selection of appropriate preclinical models, and agreement on acceptance criteria for specific tests. Given evaluation timelines for ATMPs — from 210 days for primary registration, plus potential clock stops — this is a meaningful time saving.
Step 5. Develop the Risk Management Plan early. The RMP for ATMPs is a substantial document. For GTMPs it covers a 15-year observation period, an immune reaction monitoring programme, measures to prevent vector transmission to third parties, and healthcare personnel training. It makes sense to develop the RMP in parallel with phase II–III CTs, so that the document is ready for inclusion in the registration dossier once CTs are complete.
Normative Framework:
1. Decision of the EEC Council dated November 3, 2016, No. 89 «On Approval of the Rules for Conducting Studies of Biological Medicinal Products of the Eurasian Economic Union» (Chapters 31, 32)
2. Decision of the EEC Council dated November 3, 2016, No. 78 «On the Rules for the Registration and Expertise of Medicinal Products for Medical Use» (including Clause 5.1 on hospital exemption)
3. Decision of the EEC Council dated November 3, 2016, No. 77 «On Approval of the EAEU Rules of Good Manufacturing Practice» (Annex 2, Sections B9, B10)
4. Federal Law of the Russian Federation dated June 23, 2016, No. 180-FZ «On Biomedical Cell Products» (as amended August 4, 2023)
5. Order of the Ministry of Industry and Trade of the Russian Federation dated June 14, 2013, No. 916 «On Approval of the Rules of Good Manufacturing Practice» (Sections 124–144)