Kymriah: was the clinical lot tested, or a surrogate or earlier version?

Pharmacology used experimental CAR T batches without lot numbers; clinical drug product lots used for insertion site and growth studies. Bridging: Per certificates of testing, nonclinical experiment batches met the clinical lot release specifications

Human eASC expanded with the manufacturing method to the clinical population doubling level, in most studies. Bridging: Same manufacturing method and population doubling level as the clinical product

No studies with the product; published data on similar murine and human tumor-derived T lymphocytes. Bridging: None; FDA noted the GEN2 process differs from the published TIL expansion methods

Nonclinical CAT19 CAR T cells from healthy donor PBMCs; clinical product from patient leukapheresate. Bridging: Constructs, including the binding domain, identical; nonclinical product judged appropriate despite minor process differences

Cryopreserved preclinical JCAR017 lots from preclinical production runs, expanded by a protocol mimicking the commercial post-transduction process. Bridging: Cells expanded according to a protocol that mimics the post-transduction manipulation process for BREYANZI

CAR T cells made with lentiviral vectors from different developmental stages; CAR identical in all cases. Bridging: CAR expressed by the CAR-T cells identical across lentiviral vector versions

Human chondrocytes and autologous goat cells expanded by the ChondroCelect culture process

In-process ATA129 product (Day 27 of culture) used for in vitro pharmacology

Dog pharmacology study used an early 11 mm prototype device; the clinical device is 6.5 mm. Bridging: None; reviewers judged the prototype study preliminary for the pharmacology of NT-501

Apligraf, stated to be identical to Apligraf (oral). Bridging: Apligraf used in the studies is identical to Apligraf (oral)

Six batches cultured from the drug product, tested in vitro (karyotype)

No studies with LANTIDRA; published studies of transplanted allogeneic or syngeneic animal islets

Published rabbit study used analog fibroblasts prepared by mincing and dispase, unlike the IT process. Bridging: None; rabbit analog cell preparation did not duplicate the IT procedure

Analogous products: ACI-Maix membrane seeded with rabbit or horse cells. Bridging: Same ACI-Maix membrane as the clinical product, seeded with animal instead of human cells

Products from different development stages, before the final omidubicel-onlv manufacturing process was implemented

Rat splenic cells loaded with PAP antigens instead of PBMCs, made by a process differing from sipuleucel-T

Allogeneic neonatal thymus under candidate culture conditions, implanted in nude rats

Human bone marrow ceMSC and surrogate animal-derived ceMSC, made with an early manufacturing process. Bridging: Not bridged; reviewers concluded the studies provide limited support for RYONCIL

Human Spherox or autologous animal spheroids produced in an analogous way

STRATAGRAFT batches from earlier development processes that differed from the commercial process. Bridging: Differences from the commercial process were listed; the batch reflecting each change was not specified

Some in vitro pharmacology used NCI-made CAR T cells from a similar but not equivalent process; additional studies used KTE-X19-process cells. Bridging: Additional in vitro pharmacology studies with CAR T cells manufactured using the KTE-X19 process, per CHMP protocol assistance

Human Tregs and Tcons manufactured similarly to intended clinical DP lots. Bridging: Manufactured similarly to clinical lots; unclear dose basis limits comparison of biological activity with clinical doses

In vitro pharmacology used CAR T cells from earlier NCI processes CLP-1.0 and CLP-2.0, not the current CLP-2.2. Bridging: NCI split-apheresis comparison of CLP-1.0 and CLP-2.0; murine surrogate CAR T cells used in vivo; repeat studies with CLP-2.2 not required

MM-TK made with the original SFCMM-3 #35 vector and the optimized Mut2 #48 vector and process

Earlier culture processes; only study ECT/2018-12-001 used the clinical process (35 mM UM171, 4F, no LDLs, 7-day culture). Bridging: No thorough non-clinical study of the final clinical culture conditions all together