Chemistry Manufacturing and Controls (CMC) Review Memo - Ruconest

From:                   Todd L. Mollan, JD, PhD; Laboratory of Biochemistry and Vascular Biology (LBVB), Division of Hematology (DH), Office of Blood Research and Review (OBRR); Telephone: 301-827-3155
Through:              Abdu I. Alayash, PhD, DSc; Chief, LBVB, DH, OBRR; Telephone: 301-827-3813
 Basil Golding, MD; Director, DH, OBRR; Telephone: 301-496-4396
To:                        Nannette Cagungun; Regulatory Project Management Branch (RPMB), Division of Blood Applications (DBA), OBRR; Telephone: 301-827-6174 
 Elena Karnaukhova, PhD, lead; LBVB, DH, OBRR; Telephone: 301-402-4638

Subject:                Chemistry, manufacturing, and controls (CMC) review memo of original BLA 125495/0 Module 3 (Quality), chapters 3.2.S.3: Drug Substance Characterization, 3.2.S.4: Control of Drug Substance, 3.2.S.5: Reference Standards or Materials, and 3.2.S.7.3: Drug Substance Stability Data


To the file: STN 125495/0

Action Recommended:

Based on my review of the above-referenced sections of original BLA 125495/0 submitted by Pharming Group NV, Leiden, Netherlands (Pharming), for recombinant human C1 esterase inhibitor (rhC1INH), Sponsors validations of analytical procedures and consistency of drug substance (DS) manufacturing processes have been adequately demonstrated, and this part of the BLA can be approved.

Background

Pharmings original BLA seeks US licensure for rhC1INH under the proprietary name Ruconest (non-proprietary international name conestat alfa). The proposed indication for Ruconest is for use in adults and adolescents experiencing acute attacks of hereditary angioedema (HAE). This product has been granted marketing authorization by European Medicines Agency (EMA) in 2010, and is currently available in more than 30 countries for the same indication for use in adults age 18 and over.

The active ingredient in Ruconest consists of rhC1INH, which is a ~90 kDa glycoprotein and serine protease inhibitor (serpin) which is known to inhibit activation of the complement system and enzymes of the contact phase of coagulation.1,2 Hereditary deficiencies in endogenous C1 esterase inhibitor (C1INH) expression and mutations affecting this proteins function have been linked to HAE in humans, which is a condition which results in episodic and rapid swelling of the extremities, face, throat, and/or intestinal tract.1,3 HAE affects approximately 1 in 50,000 people worldwide.4 Intravenous C1INH replacement therapy using purified and pasteurized C1INH concentrates has been reported to ameliorate HAE clinical outcomes.2

Currently, there are two native C1INH (human) products which are licensed in US for the treatment of HAE in adults and adolescents (Berinert, CSL Behring GmbH; and Cinryze, Lev Pharmaceuticals, Inc.). Berinert is indicated for the treatment of acute abdominal or facial attacks associated with HAE, and Cinryze is indicated for routine prophylaxis against angioedema attacks. Cinryze has been granted marketing authorization by EMA under the proprietary name Cetor.

The active pharmaceutical ingredient (API) of Ruconest, rhC1INH, is produced in transgenic rabbits and purified from the milk of these animals. Production animals are milked, the resulting milk is skimmed, and Skimmed Milk Intermediate is subjected to the following processes: (a) SP Sepharose BB chromatography; (b) solvent/detergent treatment; (c) Q Sepharose HP chromatography; (d) Zinc Chelating Sepharose FF chromatography; (e) -----(b)(4)-------; (f) nanofiltration; (g) ----(b)(4)-----; and (h) final filtration. Drug product (DP) is formulated in 20 mM sodium citrate, 6.5% sucrose, pH 6.8, in vials containing 2100 units per vial.

Drug Substance Characterization (3.2.S.3)
 The specification for rhC1INH formulated drug substance has been reproduced from Pharmings submission materials as follows:

(b)(4)

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References

 1.            Caliezi, C. et al. C1-Esterase Inhibitor: An Anti-Inflammatory Agent and Its Potential Use in the Treatment of Diseases Other Than Hereditary Angioedema. Pharmacol. Rev. 52, 91112 (2000).
 2.            De Serres, J., Grner, A. & Lindner, J. Safety and efficacy of pasteurized C1 inhibitor concentrate (Berinert P) in hereditary angioedema: a review. Transfus. Apher. Sci. 29, 247254 (2003).
 3.            Nzeako UC, Frigas E & Tremaine WJ. Hereditary angioedema: A broad review for clinicians. Arch. Intern. Med. 161, 24172429 (2001).
 4.            Gompels, M. M. et al. C1 inhibitor deficiency: consensus document. Clin. Exp. Immunol. 139, 379394 (2005).
 5.            Reboul, A., Prandini, M. H. & Colomb, M. G. Proteolysis and deglycosylation of human C1 inhibitor. Effect on functional properties. Biochem. J. 244, 117121 (1987).
 6.            Liu, D., Cramer, C. C., Scafidi, J. & Davis, A. E. N-Linked Glycosylation at Asn3 and the Positively Charged Residues within the Amino-Terminal Domain of the C1 Inhibitor Are Required for Interaction of the C1 Inhibitor with Salmonella enterica Serovar Typhimurium Lipopolysaccharide and Lipid A. Infect. Immun. 73, 44784487 (2005).
