A US cell or gene therapy developer runs starting-material compliance on FDA rails: establishment registration under 21 CFR Part 1271, donor eligibility under Subpart C, cGTP under Subpart D, and the line between products regulated solely under section 361 of the Public Health Service Act and section 351 biologics that decides whether a program needs a biologics license application.121 CFR Part 1271: FDA registration, donor-eligibility and current good tissue practice rules for human cells and tissues; PHS Act §§ 351 and 361. The EU has rebuilt its counterpart layer from the ground up. The SoHO Regulation, adopted on 13 June 2024, applies from 7 August 2027 and replaces the two directives on which the blood-establishment and tissue-establishment agreements in European cell and gene therapy supply chains have been drafted for two decades.2Regulation (EU) 2024/1938 (SoHO Regulation), applicable from 7 August 2027; the Blood and Tissues and Cells Directives are repealed with effect from the same date. The rebuild is not a renumbering exercise. It moves the boundary between tissue law and pharmaceutical law, and it moves it directly through the supply chains of US developers.
1. From Blood, Tissues, and Cells to ATMP Starting Materials
Under the directive-era settlement, the boundary was stable and everyone drafted around it. The Tissues and Cells Directive governed the chain from donation to distribution for tissues and cells applied to patients as such, but where the material fed a manufactured product covered by other directives, its reach stopped early: the Directive applied only to donation, procurement and testing.3Directive 2004/23/EC (Tissues and Cells Directive), Art. 2(1): for manufactured products covered by other directives, it applied only to donation, procurement and testing; Directive 2002/98/EC (Blood Directive). The ATMP Regulation locked that interface in place, requiring that the donation, procurement and testing of human cells contained in an advanced therapy medicinal product comply with the Tissues and Cells Directive, while everything downstream belonged to pharmaceutical law and GMP.4Regulation (EC) No 1394/2007 (ATMP Regulation), Art. 3: donation, procurement and testing of human cells or tissues in an ATMP follow Directive 2004/23/EC. A US sponsor could treat its EU collection sites much as it treats domestic HCT/P establishments: a defined, bounded compliance zone that ends where manufacturing begins.
The SoHO Regulation redraws both the map and the boundary. Its central definition reaches any substance collected from the human body, whether it contains cells or not and whether those cells are living or not, and the Regulation applies to such a substance wherever it is intended for human application, whether directly or through a product regulated by other Union legislation, a combination that sweeps blood, tissues and cells together with substances the directives never reached. Its scope is activity-based: thirteen listed SoHO activities, from donor registration through collection, processing, release and distribution to clinical-outcome registration.5SoHO Regulation (n 2), Art. 2(1)(c) (the thirteen listed SoHO activities), Art. 2(6) (activities applicable where SoHO are collected for manufacturing) and Art. 2(7) (the derogation for products exclusively for therapeutic use on the person from whom the SoHO were collected). For material collected for the manufacture of medicinal products, advanced therapy medicinal products, investigational medicinal products or medical devices, Art. 2(6) SoHO Regulation selects which of those activities remain inside the SoHO perimeter: donor registration, donor history review and medical examination, donor testing, collection and release apply in full, and storage, distribution, import and export are covered up to and including distribution to a manufacturer regulated by other Union legislation.
The SoHO Regulation does not change what a cell becomes in EU law; it changes how far EU law follows that cell before pharmaceutical law takes over.
The practical difference sits in that activity list. Donation, procurement and testing described a handoff that occurred early, at the collection site. Release, storage, distribution, import and export describe a corridor that runs to the manufacturer's door, and the apheresis unit was always inside the old carve-out, since procurement was one of the three activities the Tissues and Cells Directive retained; what sat comfortably outside it were the storage and logistics intermediaries and the release functions downstream, and from the application date those perform regulated SoHO activities. The Regulation also builds machinery for the classification questions that cell and gene therapy generates at the margin. Art. 13 SoHO Regulation requires competent authorities, in all cases where questions arise as to the regulatory status of a substance, product or activity, to consult the authorities responsible under the other Union frameworks, as appropriate, and to put the question to the SoHO Coordination Board for an opinion on regulatory status in every case where that consultation has not produced a decision. That mechanism will matter to any program whose material sits near the line between tissue law and pharmaceutical law, a line the hospital-exemption analysis in Insight 06 approaches from the ATMP side.
2. SoHO Establishments, Authorisation, and Oversight
The oversight architecture is two-tier, and the tiers do not map onto anything in the FDA scheme. Every organization legally established in the Union that carries out a covered SoHO activity is a SoHO entity and must register as such. The limit is jurisdictional rather than functional, and it is exactly where the US supply chain sits: a US collection site performing the same activity is not a SoHO entity at all, but a third-country supplier reached indirectly through the importing establishment that brings its material in. A subset becomes SoHO establishments: entities that both process and store SoHO, or that release, import or export it. Establishments do not merely register; they must hold an authorisation, granted after assessment by a SoHO competent authority, and entities importing SoHO from third countries need a further, distinct authorisation as importing SoHO establishments, available only after the authority has assessed the procedures in place at the applicant to ensure that the imported material is equivalent, in quality, safety and effectiveness, to SoHO preparations authorised under the Regulation itself, with the express possibility of inspections of third-country suppliers, particularly where the application concerns regular and repeated import from the same third-country supplier.6SoHO Regulation (n 2), Art. 35 and Art. 45 (registration and authorisation obligations), Art. 25 and Art. 26 (authorisation of SoHO establishments and importing SoHO establishments), Art. 54 (voluntary and unpaid donation) and Art. 13 (consultation on regulatory status, with opinions of the SoHO Coordination Board). The FDA model of registration, listing and inspection against cGTP has no ex-ante authorisation gate of this kind. The EU model is authorisation-first, and the authorisation attaches to functions that US supply-chain design often distributes across several parties without much thought.
Two further features deserve attention precisely because they look familiar and are not. The first is the SoHO preparation authorisation: SoHO that have been processed, carry a specific clinical indication and are intended either for human application to a recipient or for distribution require their own authorisation, assessed against an evidence gradient that can extend to clinical-outcome monitoring plans. Material destined for ATMP manufacture travels a different route, because processing and quality control are exactly the activities that Art. 2(6) leaves outside the perimeter for manufacture-destined material. An apheresis unit that collects for a transplant program and for a CAR-T manufacturer in the same facility therefore operates under two different slices of the same Regulation, and which slice applies to a given collection is a function of where that collection is headed. The second is donor protection. SoHO donation must be voluntary and unpaid; entities may not provide donors, or those consenting on their behalf, with financial incentives or inducements; Member States may permit compensation of living donors, including through fixed allowances or in non-financial form, on conditions set in national legislation and subject to an upper limit that must endeavour to guarantee financial neutrality, a best-efforts standard rather than a hard one; and promotion of donation may not refer to compensation. For an industry whose US donor recruitment includes payment as a matter of course, the collision is structural, and because compensation conditions remain national, it has as many local configurations as there are Member States.
3. Where SoHO Meets the ATMP and GMP Supply Chain
Traced along an autologous campaign, the redrawn boundary is easy to see, and it sits closer in than the perimeter just described. A patient undergoes leukapheresis at an EU hospital. Because the resulting product is exclusively for therapeutic use on the person from whom the material was collected, the Regulation derogates from the manufacture-destined rule: only two entries on the activity list survive, the testing of the person from whom the SoHO are collected and the collection itself. Release, storage and shipment to the manufacturer, which for allogeneic manufacture-destined material sit inside the perimeter, fall outside it here; the manufacturing itself, the genetic modification and expansion, belongs to GMP; and the finished product returns to the clinic as an ATMP under pharmaceutical law. The autologous corridor is therefore the narrower one, and a program that maps its obligations off the allogeneic rule will over-read them. Every cell and gene therapy sponsor already runs chain-of-identity and chain-of-custody systems across precisely this corridor. From August 2027, those systems acquire a statutory shadow across only part of it: SoHO traceability and vigilance obligations sit on the entities that test and collect, and the contractual architecture must reconcile the two so that a deviation is reported once, to the right regime, by the party that actually holds the duty. None of it reaches the autologous patient, because the autologous patient is not a SoHO donor: the definition is confined to a person who volunteers with a view to donation for use in someone other than themselves. The donor-protection chapter is therefore an allogeneic instrument, and a program that applies it to its autologous arm is regulating something the Regulation does not.
Allogeneic programs meet the Regulation earlier and harder. Donor panels are built through registration, eligibility assessment and testing that are squarely SoHO activities; recruitment sits under the voluntary-and-unpaid principle and the national compensation frameworks; and the commercial reality that a single qualified donor can seed material for many batches concentrates regulatory and contractual risk in a small number of collection relationships that were rarely drafted with any of this vocabulary in mind.
Cross-border flows add a third layer. Material collected in the United States for EU manufacturing must enter through an authorised importing SoHO establishment, whose authorisation depends on demonstrating equivalence for material collected under a different donor-eligibility regime and, frequently, a paid-donor model; how far the equivalence assessment will reach into the donor-protection architecture, as distinct from quality and safety testing, is one of the questions the Regulation leaves to authorisation practice and to the implementing framework. Material collected in the EU for manufacturing elsewhere runs the corridor in reverse, and export is itself an activity that makes the exporting entity a SoHO establishment requiring authorisation. And because Art. 2(6) SoHO Regulation extends to material collected for investigational medicinal products, a clinical program whose apheresis schedule crosses 7 August 2027 changes regulatory regime in mid-study, with whatever consent, contract and filing consequences follow from that.
4. The 2027 Application Runway and Contractual Repapering
The dates are unusually clean for EU law, and that is what makes them contractually consequential. The Regulation applies from 7 August 2027, and the Blood Directive and the Tissues and Cells Directive are repealed with effect from the same date; there is no long tail of directive-era certificates running alongside the new regime, as there is for legacy devices under the MDR. Existing counterparties do not simply fall out of authorisation: blood establishments designated, authorised, accredited or licensed under the Blood Directive and tissue establishments accredited, designated, authorised or licensed under the Tissues and Cells Directive before 7 August 2024 are deemed registered SoHO entities and authorised SoHO establishments, tissue establishments authorised to import carry over as importing SoHO establishments, and previously authorised preparation processes carry over as authorised SoHO preparations. The snapshot date precedes the Regulation's general application by three years, and that gap is the part worth checking: a counterparty first accredited under a directive-era national regime in 2025 or 2026 carries no deemed status at all and reaches the new regime only through a fresh authorisation. The deemed status is a bridge, not a settlement. The Regulation tasks authorities and the Commission with verifying the transitioned population against the new definitions, and an entity that does not meet the establishment definition is re-sorted to registered-entity status. A supply agreement that simply recites a counterparty's directive-era accreditation therefore documents a status that will be translated, and possibly reclassified, underneath it.
The import machinery changes character as well. Until the application date, imports of tissues and cells run through the importing-tissue-establishment regime of Commission Directive (EU) 2015/566, built on written agreements with third-country suppliers and a certificate from the competent authority.7Commission Directive (EU) 2015/566: importing tissue establishments, written agreements with third-country suppliers, equivalence verification. From August 2027, that machinery gives way to the importing-SoHO-establishment authorisation, with its equivalence assessment and its inspection reach toward third-country collection sites. Agreements between EU manufacturers or sponsors and US collection networks will need to be repapered against the new categories: which party holds the import authorisation, who answers the authority's equivalence questions, what audit and inspection access the US site must grant, how donor-eligibility and compensation representations are drawn, and how SoHO vigilance interlocks with the GMP deviation and recall systems already in the quality agreement. Much of the operative detail sits in delegated and implementing acts that the Regulation empowers the Commission to adopt, and the SoHO Coordination Board, whose founding provisions applied from August 2024, was still assembling the practical framework in spring 2026, adopting an implementation information paper in March 2026.8SoHO Coordination Board, information paper on getting started with the SoHO Regulation, adopted 16 March 2026. Contracts drafted in the run-up to August 2027 are therefore drafted against a regime whose operative detail is still arriving.
Switzerland adds a quiet complication for any program routed through Basel. Switzerland is not an EU Member State, and the SoHO Regulation will not apply there; a Swiss collection or processing site supplying an EU manufacturer is a third-country supplier in EU law, exactly as a US site is, and sits behind the same import gate from August 2027. Domestically, Swiss law regulates the handling of human tissues and cells under its own framework, the TxG, with Swissmedic competent for transplant products,9Transplantationsgesetz (SR 810.21): transplant products treated analogously to medicinal products, with Swissmedic competent. and that framework is not aligned to the SoHO Regulation's categories. A supply chain that treats Europe as one regulatory space will find that its Swiss node needs separate analysis on both sides of the border.
5. Strategic Considerations
The questions that remain open are the ones that determine exposure. The first is cartographic: which nodes of an existing network become SoHO entities, which become establishments, and which functions, release above all, sit with a party that has never held an EU authorisation of any kind? Sponsors tend to assume the answer follows the quality agreement; the Regulation allocates by activity, and the two allocations do not necessarily coincide. The second is the import question: who should hold the importing-establishment authorisation for US-collected material, the manufacturer, the sponsor's EU affiliate or a specialist intermediary, and what happens to a program if an equivalence assessment stalls on donor-compensation grounds that no quality audit ever measured? The third is temporal: a deemed authorisation that is verified away mid-program, a trial that crosses August 2027 mid-enrollment, or a marketing application whose starting-material dossier is written in directive-era categories: each converts a regulatory transition into a commercial one. And the fourth runs back across the Atlantic: a starting-material interruption in Europe is a disclosure and oversight question for a US public company, and a board that has never heard the term SoHO may be asked, after the fact, when management first understood the dependency.
None of these questions has a general answer. Whether a given network's release function sits inside or outside establishment status, whether a given compensation practice survives a given Member State's conditions, and whether a given program should re-sequence its collection schedule around the application date are determinations that turn on the specific contracts, the specific counterparties and the specific timeline. These questions require analysis tailored to the supply chain actually being run, not the one the template assumed.