Biotechnology companies developing advanced therapy medicinal products face a path from laboratory to clinic that is rarely straightforward. Cell therapies, gene therapies, and tissue-engineered products occupy a regulatory space that traditional pharmaceutical frameworks were never designed to address.1Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products [2007] OJ L324/121. For Swiss-based companies, the complexity compounds: Switzerland and the EU have adopted fundamentally different regulatory architectures for these products.
1. Where Do Swiss and EU Frameworks Diverge?
The EU established a centralized framework for ATMPs through Regulation (EC) No 1394/2007, creating a distinct product category with mandatory centralized authorization through EMA, where the CAT provides scientific recommendations on ATMP classification and assessment. Switzerland took a different path. Rather than creating standalone ATMP legislation, Swiss authorities integrated these products into existing frameworks: the Bundesgesetz über die Transplantation von Organen, Geweben und Zellen (Transplantationsgesetz)2Transplantationsgesetz (SR 810.21). and the Bundesgesetz über Arzneimittel und Medizinprodukte (Heilmittelgesetz).3Heilmittelgesetz (SR 812.21).
The regulatory philosophy embedded in early development decisions can constrain later market access options in ways that become apparent only when commercial timelines create urgency.
This structural divergence creates immediate practical questions. Swissmedic classifies autologous cell therapies as Transplantatprodukte (transplant products); for non-standardizable products of this kind, authorization attaches to the manufacturing process rather than to the finished product.4Art. 49 Transplantationsgesetz (n 2); AMBV (SR 812.212.1) Anhang 3 (non-standardisable medicinal products requiring process authorization). The EU framework focuses on the finished medicinal product. When a Swiss biotech develops a CAR-T therapy intended for both markets, which regulatory philosophy should guide development strategy? How should quality systems be designed to satisfy both approaches simultaneously?
The regulatory landscape shifted further in August 2023, when Swissmedic became the first regulatory authority globally to receive accreditation for GMP and GDP inspections specific to ATMPs.5Swissmedic, Swissmedic gains accreditation for GMP/GDP inspections in the field of ATMPs (9 August 2023). That accreditation carries particular weight because ATMPs sit outside the FDA-Swissmedic Mutual Recognition Agreement that entered force on 27 July 2023: the MRA's recognition of the other authority's GMP inspections expressly excludes ATMPs, human tissues, and cells.6FDA, Switzerland Mutual Recognition Agreement (27 July 2023) (ATMPs, human blood, plasma, tissues, and cells excluded from scope); Swissmedic Mitteilung (27 July 2023). Swiss-based ATMP manufacturers therefore operate within a distinctive regulatory ecosystem, one whose inspection advantages cannot be read across from the MRA but must be assessed product category by product category.
2. How Far Does the Hospital Exemption Reach?
The EU's hospital exemption under Art. 28(2) Regulation (EC) No 1394/2007 permits non-routine manufacture of ATMPs for individual patients, but the boundaries of "non-routine" vary significantly between Member States.7Art. 28(2) Regulation (EC) No 1394/2007 (n 1); cf Art. 9 HMG (n 3) (formula magistralis exemptions do not extend to cell-based therapies). Switzerland has no direct equivalent; the Swiss process-authorization framework and Art. 49 AMBV's narrower import mechanism mean a development strategy built around the EU hospital exemption may not translate to Swiss market access. The full analysis of hospital exemption boundaries (including the incremental drift from exemption to authorization, Member State variations, and IP entanglements) is examined in Insight 06.
3. What Happens When Starting Materials Cross Borders?
ATMPs often begin with patient-derived materials, autologous cells that must be processed, modified, and returned to the same patient. The regulatory requirements for traceability, chain of custody, and identity verification extend far beyond traditional pharmaceutical manufacturing.8EudraLex Volume 4, Part IV: ATMP GMP Guidelines (November 2017).
The EU framework is evolving. Regulation (EU) 2024/1938 on substances of human origin (SoHO), adopted in June 2024 and published in July 2024, modernizes the quality and safety standards for tissues and cells used as starting materials.9Regulation (EU) 2024/1938 of the European Parliament and of the Council of 13 June 2024 on substances of human origin [2024] OJ L 2024/1938. The Regulation entered into force on 7 August 2024, but the majority of its substantive requirements apply only from 7 August 2027, with a small number of provisions phased in on other dates. This regulation affects the upstream supply chain for ATMPs manufactured from human-derived materials, introducing new oversight requirements that interact with the existing ATMP framework in ways that are not yet fully clarified.
The interaction between pre-GMP and GMP-controlled environments creates documentation gaps. Materials collected at clinical sites operate under different quality frameworks than materials entering pharmaceutical manufacturing. Donor eligibility requirements vary across jurisdictions, and collection sites in different countries may apply inconsistent standards.
Liability questions arise when starting material quality issues surface after processing has begun, particularly for autologous products where replacement is not possible. Unlike conventional pharmaceuticals, a failed batch cannot simply be remanufactured from the same inputs; the patient-specific starting material may no longer be available.
Traceability obligations for products with potentially lifelong effects extend far beyond typical pharmaceutical retention periods. And the SoHO Regulation requirements, once applicable from August 2027, will interact with existing tissue establishment authorizations in ways that guidance available as of mid-2025 does not address.
Under Swiss law, the Transplantationsverordnung establishes traceability requirements for human tissues and cells.10Transplantationsverordnung (SR 810.211). These requirements developed independently from the EU framework and use different terminology and documentation standards. A multinational clinical program collecting cells across Swiss and EU sites must reconcile these parallel systems, a task that existing guidance documents do not fully address.
The variability inherent in patient-derived starting materials compounds the comparability challenges that arise when manufacturing processes change. When inputs differ between batches (as they inevitably do with autologous cells), demonstrating that process modifications produce equivalent outputs becomes substantially more complex than for traditional pharmaceuticals with standardized starting materials.
4. When Does a Process Change Require New Clinical Data?
Traditional pharmaceuticals benefit from well-established comparability frameworks when manufacturing processes change. For ATMPs, demonstrating that a process change produces an equivalent product is substantially more complex. The living nature of cellular products means that subtle process variations can result in meaningful functional differences.
ICH Q5E provides the conceptual framework for comparability assessment,11ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (2004). but its application to ATMPs remains contested. The guideline's analytical-functional-clinical hierarchy assumes that analytical similarity can support a conclusion of comparability, an assumption that cellular products, with their inherent variability and complex mechanisms of action, may not satisfy. EMA's product-specific scientific guidelines provide additional requirements for quality, non-clinical, and clinical aspects of gene therapy and cell-based ATMPs,12EMA/CAT/80183/2014 (22 March 2018); EMA/CAT/22473/2025 (20 January 2025). but the interaction between these guidelines and the comparability framework remains incompletely articulated.
The EU GMP guidelines for ATMPs acknowledge this challenge, permitting a risk-based approach to process validation that differs from conventional pharmaceutical manufacturing. But the application of risk-based principles to comparability assessments remains unsettled. When does a process optimization require bridging studies? When does it require returning to earlier clinical development phases?
Consider a concrete scenario: a CAR-T manufacturer transitioning from manual open-system processing to an automated closed-system platform. The change improves sterility assurance and batch consistency, clear quality gains. Yet the altered cell-handling environment may affect transduction efficiency, T-cell phenotype distribution, or expansion kinetics in ways that analytical assays cannot fully capture. Regulators must decide whether the manufacturing change is a process improvement demonstrable through analytical comparability, or a change sufficiently fundamental to require bridging clinical data. The answer depends on product-specific risk assessments that existing guidance addresses only in general terms.
The revision of EudraLex Volume 4, Part IV is underway. EMA published a concept paper in May 2025, with public consultation running through July 2025.13EMA, Concept paper on the revision of Part IV guidelines on GMP specific to ATMPs (EMA/INS/GMP/48771/2025, 8 May 2025). The revision aims to align ATMP GMP requirements with the 2022 revision of Annex 1 (sterile manufacturing), incorporate ICH Q9 quality risk management principles more systematically, and update references following the adoption of the SoHO Regulation. Until the revised guidelines are finalized, manufacturers face uncertainty about future expectations.
These sector-specific revisions take place against the backdrop of a broader overhaul. The European Commission's 2023 proposals to revise the EU general pharmaceutical legislation, COM(2023) 192 (new Directive) and COM(2023) 193 (new Regulation), include provisions that would affect the centralized authorization requirement underpinning the ATMP framework.14European Commission, Proposal for a Directive on the Union code relating to medicinal products for human use, COM(2023) 192 final (26 April 2023); Proposal for a Regulation laying down Union procedures for the authorisation and supervision of medicinal products for human use, COM(2023) 193 final (26 April 2023). As of mid-2025, the legislative process remained ongoing, but the direction of travel (toward longer regulatory data protection periods for ATMPs, revised incentive structures, and modified environmental risk assessment requirements) will shape the regulatory landscape in which development decisions must be evaluated.
The threshold for triggering additional clinical studies remains ambiguous. Bridging study design becomes complex when analytical comparability is inherently limited by product variability. The level of process lock realistically achievable before Phase III trials may not satisfy regulatory expectations that crystallize only during marketing authorization review. And the pending GMP guideline revision introduces prospective uncertainty; manufacturing processes approved as of September 2025 may require modification under standards not yet finalized.
5. What Makes ATMP Outsourcing Different?
Many biotechnology companies lack internal capability for GMP manufacturing and must rely on contract manufacturing organizations (CMOs). For ATMPs, the selection of manufacturing partners involves considerations that go beyond traditional pharmaceutical outsourcing.
The regulatory implications are significant. Under the EU framework, the marketing authorization holder retains responsibility for product quality regardless of where manufacturing occurs. Under the Swiss process-authorization approach, all manufacturing sites must be specified in the authorization application, and changes require regulatory approval. The interaction between sponsor obligations and CMO responsibilities differs between jurisdictions.
Qualified Person (QP) requirements create concrete compliance challenges that many ATMP developers underestimate.15Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001, Art. 51; EudraLex Volume 4, Part IV, chs 3 and 11 (QP requirements for ATMPs). EU law requires each manufacturing site to have a QP who certifies batch release, and ATMP manufacturing demands QP qualifications that extend beyond traditional pharmaceutical experience, including specific training in cell biology, gene therapy, or tissue engineering depending on the product type. For companies relying on CMOs, ensuring QP availability with appropriate ATMP expertise can constrain site selection. Switzerland's fachtechnisch verantwortliche Person requirements impose parallel but non-identical obligations, meaning dual-market programs may require distinct qualified personnel at each manufacturing location.
Regulatory responsibility in multi-site manufacturing chains spanning Switzerland and the EU does not follow intuitive patterns. Audit rights and quality oversight mechanisms appropriate for traditional pharmaceutical outsourcing may prove insufficient for ATMP production, where process parameters directly affect product characteristics.
Technology transfer must preserve process consistency while allowing CMO operational flexibility, a balance that contractual provisions alone cannot guarantee. Contingency planning for CMO capacity constraints or quality failures becomes more complex when alternative manufacturing sites require separate regulatory authorization.
The FDA-Swissmedic and EU-Switzerland mutual recognition arrangements create opportunities for CMO selection that single-jurisdiction programs cannot access for conventional medicinal products. For ATMPs the calculus differs: ATMP inspections fall outside the scope of these GMP arrangements, so one authority's inspection does not substitute for the other's, and manufacturing strategy cannot assume cross-recognition from the outset.
6. Strategic Implications
The regulatory uncertainties surrounding ATMP manufacturing have strategic implications that extend beyond compliance. Companies must balance the desire for regulatory clarity against the need to advance clinical programs. Waiting for definitive guidance may mean losing competitive position; proceeding without clarity creates regulatory risk.
The divergence between Swiss and EU frameworks adds a layer of complexity that purely EU-focused or purely US-focused competitors do not face. Whether the additional regulatory burden of dual-jurisdiction development is justified by the commercial opportunity depends on variables (product characteristics, development stage, target patient populations) that no general framework can resolve.
A further procedural layer arises from Switzerland's non-participation in the EU Clinical Trials Information System (CTIS). For ATMP clinical programs with sites in both Switzerland and the EU, this means separate submission pathways, different transparency requirements, and non-aligned assessment timelines. Sponsors must maintain parallel regulatory dossiers and coordinate protocol amendments across systems that do not share a common procedural framework, an operational burden that compounds the substantive regulatory divergences discussed above.
The sequencing of regulatory engagement across Swissmedic, EMA, and national competent authorities introduces its own coordination challenges. EMA's scientific advice procedure routes ATMP-specific questions through the CAT, while Swissmedic's formal scientific advice process (wissenschaftliche Beratung) operates under distinct procedural requirements and fee structures. The two authorities may offer divergent guidance on the same manufacturing question, and neither authority's advice binds the other. Whether inconsistent pre-submission guidance from different authorities narrows or widens the range of regulatory uncertainty a sponsor faces depends on the specific divergence and the sponsor's ability to reconcile competing expectations.
Manufacturing platform investments made early in development may hedge against regulatory divergence, or may lock companies into approaches that later prove suboptimal. Reimbursement uncertainties in both Switzerland and the EU compound the regulatory complexity, affecting commercial viability assessments that must be made before clinical data fully mature. For some programs, the complexity of multi-jurisdictional development may justify focusing on a single market first; for others, parallel development creates competitive advantages that justify the additional investment.
These questions interact in ways that resist separation. Whether a process authorization or product authorization is appropriate depends on how the hospital exemption boundaries constrain manufacturing scale, which in turn determines starting material traceability requirements that affect comparability assessments when process changes become necessary, and the choice of CMO may foreclose options that only become apparent when regulatory expectations crystallize at a later development stage. The regulatory gray zones that characterize ATMP manufacturing do not yield to generic frameworks.