What GMP requirements apply to cell and gene therapy manufacturing, from Phase 1 to commercial?

1Which rules apply to which products.

In the US, cell and gene therapy (CGT) products that prevent, treat or cure a disease or condition meet the definition of a biological product in section 351(i) of the Public Health Service Act.¹ A human cell or tissue product is regulated only under section 361 and Part 1271 if it meets all of the criteria in 21 CFR 1271.10, including minimal manipulation and homologous use; otherwise it is regulated as a drug, device or biological product.² For these products, Parts 210 and 211, Parts 600 to 680 and, for cell and tissue products regulated as drugs or biologics, Part 1271 “supplement, not supersede, each other”, and where they conflict the more specific regulation wins.³ Part 1271 adds donor eligibility in subpart C and current good tissue practice in subpart D.²

In the EU, cell and gene therapies are advanced therapy medicinal products (ATMPs). The European Commission adopted its GMP guidelines specific to ATMPs on 22 November 2017, under Article 5 of Regulation (EC) No 1394/2007, and manufacturers had to comply by 22 May 2018. They apply to authorised ATMPs and to ATMPs in clinical trials, and the rest of EudraLex Volume 4 does not apply to ATMPs unless the guidelines refer to it. ATMPs made under the hospital exemption must meet equivalent quality standards. Donation, procurement and testing of the human cells and tissues used as starting materials follow Directive 2004/23/EC, or Directive 2002/98/EC for blood-derived cells.⁴

2Phase 1 in the US.

Under 21 CFR 210.2(c), a drug for a Phase 1 study “is subject to the statutory requirements” of CGMP, but its production “is exempt from compliance with the regulations in part 211”. The exemption ends once the drug has been used in a Phase 2 or 3 study or lawfully marketed.³

FDA’s guidance CGMP for Phase 1 Investigational Drugs, issued in July 2008, explains what CGMP means at this stage and names gene therapy and somatic cellular therapy products in its scope. It does not cover products regulated solely under section 361.⁵ It says adherence to CGMP at this stage comes mostly through written procedures, adequately controlled equipment and environment, and accurately recorded data. It recommends a quality control function independent of manufacturing for the review and release of batches, and that the manufacturer “be able to identify and trace all materials used” from receipt to use in each batch.⁵

The guidance accepts that CGT products cannot always meet every recommendation. Some cellular products leave too little material to retain a sample, so the justification for an alternative goes in the records. Where Phase 1 runs one batch per subject, as for autologous cells, FDA recommends periodic, documented internal reviews of manufacturing performance.⁵

3What the EU allows for investigational ATMPs.

The ATMP guidelines build in a risk-based approach. Flexibility matters most in early trials, “phase I and phase I/II”, where knowledge of the product is often incomplete and routines are still changing.⁴ Even so, “the quality, safety and traceability of the product should be ensured also in a clinical trial setting”.⁴

The adaptations they list for investigational ATMPs include calibration and maintenance intervals based on risk analysis, documentation whose formality fits the stage of development, and wider acceptance criteria in phase I and I/II as approved by the competent authority. Exceptionally, a very early or proof-of-concept product may be made in an open system in grade A with a grade C background, but only if a risk assessment supports it, the product treats a life-threatening condition with no alternative, and the competent authorities agree. Traceability “should however be implemented in full”.⁴

4Process validation for licensure.

FDA says there is no set minimum number of process performance qualification (PPQ) batches for CGT products; neither 21 CFR 601.20 nor the CGMP regulations specify one. A BLA is expected to include PPQ data, but the amount can be adjusted when justified, based on the complexity of the process, the controls in place and the manufacturer’s understanding of product and process, with characterisation studies documented in the BLA.⁶

The EU guidelines say it is “generally accepted that, as a minimum, three consecutive batches manufactured under routine conditions constitute a validation of the process”, and that another number may be justified, for example by autologous starting material or a rare disease. Validation with representative surrogate material may be acceptable when starting material is scarce, and concurrent validation may be acceptable if justified, under a protocol, with the results available to the Qualified Person before certification.⁴

5Traceability, release and change.

ATMP manufacturers keep a system for “the bidirectional tracking of cells/tissues” from donation to the recipient, from the first clinical batches, and retain its data for at least 30 years after the product’s expiry.⁴ In the US, 21 CFR 1271.290 requires tracking of each HCT/P from donor to consignee and back with a distinct identification code,² and 21 CFR 600.12 requires biologics records made concurrently so that the successive steps of any lot “may be traced by an inspector”.⁷

Short shelf lives mean some ATMPs are released before all quality control tests are complete. The EU guidelines allow certification in stages, with a written procedure for what happens, including liaison with clinical staff, if a result is out of specification after release. They also cover decentralised manufacture at sites close to patients.⁴

Processes change as programmes mature. FDA’s July 2023 draft guidance on manufacturing changes and comparability for CGT products, not yet final, recommends a risk assessment for every manufacturing change at any stage, comparability studies when a change could adversely affect product quality, and analytical evaluation that grows with the stage of development.¹

6How it runs in Seal.

Seal’s cell and gene therapy blueprint puts patient or donor identity, material genealogy, process versions and release evidence in one record: a mismatched scan stops the step, the batch record branches on what the cells do, and QA reviews while the batch runs. Neil, Seal’s AI agent, drafts receipt and handoff checks, exception paths and process revisions from your requirements, and your team verifies and releases each change.

The model differs by product. For autologous therapies, a treatment order creates one governed therapy case that carries chain of identity and custody, the batch record, testing, quality events and release. For allogeneic therapies, donor lineage, lot identity and recipient allocation are connected identities, so a source concern traces forward to the doses and recipients derived from it. For viral vectors, plasmid, cell and material lineages converge through transfection, harvest, purification and fill, with each result attached to the pool that produced it.