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Vaccines, Blood & Biologics
Division of Hematology
Office of Blood Research & Review
To: BL 125416/0 (cross-reference, Octagam, STN # 125062)
Reviewer: M. Keith Wyatt, Ph. D., Pharmacologist, CBER\OBRR\DH
Through: Anne M. Pilaro, Ph. D., Supervisory Toxicologist, CBER\OBRR\DH
Applicant: Octapharma USA
Product: OctaplasLG™, pooled (human) plasma, solvent detergent treated
Indication: Management of preoperative or bleeding patients who require replacement of multiple coagulation factors or substitution of intentionally removed plasma (e.g., plasma exchange in patients with thrombotic thrombocytopenia purpura - TTP)
Purpose: Summary Basis for Regulatory Action (SBRA)
Date: October 3, 2012
OctaplasLG™, a virally-inactivated and prion-reduced plasma, appears reasonably safe for use during the treatment of several hematologic indications proposed by Octapharma (Applicant). OctaplasLG™ is approved for licensure based on results from both a risk assessment, and nonclinical toxicology studies conducted with the inactivating detergents and extractables/leachables from the components used in the manufacture of OctaplasLG™. The safety of residual levels of tri-(n-butyl) phosphate (TNBP) and octyl phenyl ethoxylate (Triton X-100) detergents used to achieve viral inactivation was assessed by conducting: (1) acute, sub-chronic and developmental and reproductive toxicity (DART) studies in animals; (2) mutagenicity studies using (b)(4) and other in vitro assays; (3) clastogenicity studies using the ---(b)(4)------------------------- -----(b)(4)-------------- assays and; (4) assays to assess hemolytic potential. The results from the in vivo toxicology studies, including DART testing, indicate the no observable adverse effect levels (NOAELs) for the TNBP plus Triton combination were far greater than the residual levels of both detergents present in the final OctaplasLG™ product. Results from ---(b)(4)---------- and the hemolysis assays suggest TNBP and Triton residuals at the expected human doses of ----(b)(4)---------, respectively, are not mutagenic, clastogenic, teratogenic or hemolytic.
The toxicity and mutagenicity of ---(b)(4)----- that potentially leach from the (b)(4) column used in-process to bind and reduce prion levels were also evaluated in a rat repeat-dose study and by the method of (b)(4), respectively. The risk associated with
---(b)(4)----- that potentially migrate from the (b)(4) column matrix, used to (b)(4)---------(b)(4)------ binding prions, was assessed using results generated during extraction and analytical studies. The extractions were performed by the matrix manufacturer with either -----(b)(4)----------------------------- at temperatures that exceeded those used in-process. The results from the analytical studies were used to assess risk to TTP patients repeatedly exposed to matrix leachates in OctaplasLG™. The results from the repeat-dose toxicity study in rats and the (b)(4) assay suggest that the levels of ---(b)(4)-- that potentially leach from the in-process (b)(4) column into the OctaplasLG product are reasonably safe in the approved indications for this BLA. The safety of leachates from the column resin itself, specifically ---(b)(4)--- and its derivatives, has been qualified by data from published literature and from safety data in short-term clinical uses (e.g., in the management of preoperative or bleeding patients who require replacement of multiple coagulation factors). Additional data regarding the safety of the----(b)(4)---- column leachates will be requested from the Applicant as a post-marketing commitment, to support the use of OctaplasLG™ in patients receiving either high volume or chronic treatment with OctaplasLG™.