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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Summary Basis for Regulatory Action, June 1, 2011 - Kedbumin

Date

June 1, 2011

From

Yiping Jia, Committee Chair 

Subject

Summary Basis for Regulatory Action

BLA #
Supplement#

STN 125384/0

Applicant

Kedrion, S.p.A.

Date of Submission

August 3, 2010

PDUFA Goal Date

June 3, 2011

Proprietary Name / Established (USAN) names

KEDBUMIN / Albumin (Human)

Dosage forms

25% 50 mL in --(b)(4)-- glass bottles

Proposed Indication(s)

- Hypovolemia:  Restoration and maintenance of circulating blood volume where volume deficiency is demonstrated and colloid use is appropriate.
- Hypoalbuminemia: When the albumin deficit is the result of excessive protein loss, the effect of albumin administration will be temporary unless the underlying disorder is reversed.
- Prevention of central volume depletion after paracentesis due to cirrhotic ascites.
- Ovarian hyperstimulation syndrome (OHSS).
- Adult Respiratory Distress Syndrome (ARDS).
- Burns
- Hemodialysis: For patients undergoing long term dialysis or for those patients who are fluid-overloaded and cannot tolerate substantial volumes of salt solution for therapy of shock or hypotension.
- Cardiopulmonary Bypass Procedures: As part of the priming fluid.

Recommended Action:

Approval

Signatory Authority(ies) Action

 

Jay Epstein____________________________
Offices Signatory Authority:
I concur with the summary review
I concur with the summary review and include a separate review or addendum to add further analysis
I do not concur with the summary review and include a separate review or addendum

 

Material Reviewed/ Consulted      List of specific documentation used in compiling SBRA

Clinical Review

Larry Landow

Statistical Review

Shiowjen Lee

Pharmacology/ Toxicology Review

Paul Buehler

CMC Review/Facilities

Yiping Jia, Wayne Hicks, Sean Byrd, and Lori Peters

Establishment Inspection Report

Lori Peters, Sean Byrd, and Yiping Jia

Biomonitoring Review

Lillian Ortega

Labeling

Alpita Popat

Pharmacovigilance

Craig Zinderman

Advisory Committee Transcript

Not presented at BPAC

1. Introduction

On behalf of Kedrion, S.p.A., Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca) Italy, FFF Enterprises, Inc., 41093 County Center Drive Temecula, CA92591 submitted this original Biological License Application (BLA) for KEDBUMIN. KEDBUMIN is a 25% Human Albumin solution derived from U.S. plasma donors and produced by Kedrion, S.p.A. from an albumin paste intermediate ---------------------------(b)(4)-------------------------------------------.

2. Background

KEDBUMIN is currently manufactured by Kedrion S.p.A., Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (LU), Italy, at its manufacturing facility in Bolognana, Gallicano, Lucca. KEDBUMIN contains 250 g/L of plasma protein of which human albumin constitutes at least 96%. Kedrion also manufactures UMAN ALBUMIN that has been marketed in Italy and other countries for over 40 years. In order to produce a product suitable for the US market, an albumin paste intermediate ----------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------------. The raw material is obtained from Source Plasma that is collected in licensed US plasmapheresis centers according to FDA and EU regulations.

Kedrion, S.p.A. proposed the following indications for the use of KEDBUMIN:

- Hypovolemia: Restoration and maintenance of circulating blood volume where volume deficiency is demonstrated and colloid use is appropriate.
- Hypoalbuminemia: When the albumin deficit is the result of excessive protein loss, the effect of albumin administration will be temporary unless the underlying disorder is reversed.
- Prevention of central volume depletion after paracentesis due to cirrhotic ascites.
- Ovarian hyperstimulation syndrome (OHSS).
- Adult Respiratory Distress Syndrome (ARDS).
- Burns
- Hemodialysis: For patients undergoing long term dialysis or for those patients who are fluid-overloaded and cannot tolerate substantial volumes of salt solution for therapy of shock or hypotension.
- Cardiopulmonary Bypass Procedures: As part of the priming fluid.

3. Chemistry, Manufacturing and Controls (CMC)

General Manufacturing Summary:

KEDBUMIN is a sterile, aqueous solution for single dose intravenous administration. The product contains 0.25 g per mL human albumin and is prepared by cold ethanol fractionation from pooled human plasma obtained from venous blood at FDA-licensed facilities located in the USA. Intermediate source material (albumin paste) is obtained from a U.S. licensed manufacturer. KEDBUMIN is a clear, slightly viscous liquid, with a yellow, amber, or green tint. The product is stabilized by the addition of 0.08 millimole sodium caprylate and 0.08 millimole sodium acetyltryptophan per gram of albumin. Additionally, each liter of material contains 130-160 milliequivalents of sodium ion and ≤ 200 micrograms of aluminum. This product contains no preservatives.

Manufacturing Overview:

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Heat treatment within 24 hours after filling with the temperature/time conditions of 60°C ± 0.5°C maintained for 10-11 hours in accordance with 21 CFR 640.81

Incubation --(b)(4)-- for at least 14 days according to 21 CFR 640.81

Visual inspection

Labeling and Packaging

DRUG PRODUCT KEDBUMIN, 25%

General warehouse Storage ≤ 30°C

Additional Manufacturing Issues Addressed During The Review Cycle:

i. The sponsor accepted the FDA recommendation to replace the abbreviated testing time schedule of the stability program with a full testing schedule, i.e. with testing points at 0, 3, 6, 9, 12, 18, 24, and 36 months.

ii. The sponsor accepted the FDA recommendation to carry out additional viral inactivation validation studies for HIV inactivation by heat treatment to provide a more accurate estimate of the process capacity at this step.

Drug Product Composition

Ingredient

Amount

Function of ingredient

Human plasma albumin > 96%

25%

Active ingredient

Sodium caprylate (mmol/g protein)

0.064 – 0.096

Excipient

N-acetyl-DL-tryptophan (mmol/g protein)

0.064 – 0.096

Excipient

Drug Product Release Specifications

Tests

Specifications/limits

Character

A slightly viscous liquid, it is almost colorless, yellow, amber or green

Total protein (g/L)

235 - 265

pH

6.4 - 7.4

----------(b)(4)-----------

--------(b)(4)---------

Identity

The main component of the preparation corresponds to main component of human serum

Protein composition (%)

≥ 96

Sodium (mEq/L or mmol/L)

130 - 160

Potassium (mEq/L or mmol/L)

≤ 2

Aluminum (ppb or μg/L)

≤ 200

-----(b)(4)------

(b)(4)

---------------(b)(4)---------------

--(b)(4)--

----------(b)(4)-----------

----------(b)(4)-----------

Sterility

Sterile

Pyrogens

Pyrogens free
(--------(b)(4)-----------)

Sodium caprylate (mmol/g proteins)

0.064 – 0.096

N-Acetyl-DL-tryptophan (mmol/g protein)

0.064 – 0.096

----------(b)(4)---------

--(b)(4)--

Heat Stability (50 hrs/57°C)

Unchanged after 50 h at 57°C

General safety

--------(b)(4)-----------
No unexpected response or weight loss in mice and guinea pigs after 7 days

-------(b)(4)-------

(b)(4)

----------(b)(4)---------

--(b)(4)--

------(b)(4)------

(b)(4)

Validation of the Viral Clearance Capacity of the Manufacturing Process

KEDBUMIN (25%) is manufactured by Kedrion S.p.A. starting from an intermediate albumin paste -------------------(b)(4)---------------------. The overall viral safety of KEDBUMIN (25%) was evaluated by assessing the viral inactivation/removal capacity of the manufacturing steps performed ----------------(b)(4)-------------- at Kedrion.

Kedrion provided viral clearance data in order to support the safety of the product with regard to a potential contamination from both enveloped and non-enveloped viruses. Two precipitation steps in the manufacturing process: 1) Fractionation of Effluent I to effluent II+III; and 2) Depth filtration of Fraction V, were investigated for their capacity to clear viruses. In addition virus inactivation was validated using terminal heat treatment (Pasteurization) at 60º C for 10 hours.  Therefore, the total viral clearance in the manufacturing process of KEDBUMIN, shown in the table below, is achieved through a combination of fractionation steps and final container heat treatment step.

 

Mean Reduction Factor (log10)

 

Enveloped viruses

Non –enveloped viruses

Manufacturing Step

HIV-1

BVDV

PRV

REO

PPV

HAV

EMCV

Fractionation of Effluent I to Effluent II +III

3.4

3.5

3.9

2.1

1.0

1.4

 

Fractionation of Effluent IV-1 to Effluent IV-4

 

 

 

 

 

 

3.7

Depth Filtration of Fraction V suspension

3.4

 

≥ 3.4

4.9

4.2

2.0

 

Heat treatment

≥ 6.06

> 5.17

> 5.07

4.62

 

 

 

Overall Reduction Factor

> 12.86

> 8.67

≥ 12.37

11.62

5.2

3.4

3.7

HIV-1: Human Immunodeficiency Virus Type 1
BVDV: Bovine Viral Diarrhoea Virus
PRV: Pseudorabies Virus
REO: Reovirus Type 3
PPV: Porcine Parvovirus
HAV: Hepatitis A Virus
EMCV: Encephalomyocarditis virus

Stability Testing

Stability studies were initiated to verify that albumin solution maintains its physico-chemical and biological characteristics for a period of 3 years when stored at a temperature of 30 (b)(4).

------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------.

For long term stability testing at 30°C (b)(4), available long term stability data showed all parameters tested up to date were within both the US and EU requirements. In addition, the stability study report related to the EU product UMAN ALBUMIN 25% has been submitted to support a shelf life of 3 years. The stability specifications, namely protein composition, total protein, pH, and (b)(4) are in compliance with the EU requirements, the results are also all within the US requirements and remain unchanged over the 3 years stability period. On the basis of the stability data obtained so far (up to 12 months) together with the existing data for the EU product UMAN ALBUMIN, no significant difference is expected in the results of the stability studies which are still ongoing. A shelf life of 36 months is proposed and accepted for the product KEDBUMIN.

The sponsor committed to perform routine stability testing on at least one lot of KEDBUMIN 25% each year, using the approved stability protocol.

CBER Lot Release

Lot Release Protocols were reviewed and approved by CBER. CBER will release lots of KEDBUMIN based upon the review of results generated by the manufacturer and submitted for the Lot Release Protocols.

Facilities Review/Inspection

The Pre-License Inspection of Kedrion’s manufacturing facility at Via Provinciale; Bolognana, Gallicano (Lucca); Italy 55027 was conducted for the 25% Human Albumin Solution product, product trade-name KEDBUMIN. The dates of the inspection were 23 – 25, 28 February 2011; 1 – 2 March 2011. The Facility Establishment Identifier (FEI) number for the facility is 3008919567.

This inspection was the first United States FDA inspection ever conducted at this facility. During the inspection, the inspectors completed a facility tour and viewed the production areas and laboratories, and were able to observe the following production processes: aseptic operations including sterile filtration, filling, pasteurization, vial washing, and capping; visual inspection process; packaging; and albumin paste solubilization.

The inspectors were able to review documentation regarding the following areas:  quality systems including deviation reporting and investigation procedures, change control procedures, document control procedures, training, manufacturing agreements, vendor qualifications, and auditing programs;  facilities including HVAC and environmental monitoring, water systems, compressed gasses, and facility cleaning and sanitization; equipment including equipment qualifications, preventive maintenance and calibration, cleaning and sterilization, and computer validations;  container closure;  materials management including warehouse, material receipt and tracking, and material sampling;  sterile filtration;  aseptic processing including gowning qualification, and environmental monitoring in aseptic areas; production processes including batch records, stability, reprocessing procedures, analytical testing methods, visual inspection process, and media fills;  and laboratory controls.

The inspection revealed objectionable conditions regarding the incomplete validation of the visual inspection process, inadequate stability frequency testing, inadequate protein composition testing for the drug substance, and inadequate qualification of the vial washing machine. A 4-item FDA Form-483 was issued regarding these observations. The firm agreed to provide a written response to each of the observations and implement corrective actions. No samples were collected during the inspection and no refusals were encountered. The firm’s responses to the observations listed on FDA Form 483 were acceptable and all inspectional items have been resolved.

Kedrion purchases the albumin paste intermediate product from --------------------(b)(4)-----------------------------. An inspection of the ---(b)(4)--- facility was waived by DMPQ and OBRR since the manufacturing process of the albumin paste remains unchanged at           --(b)(4)--. Also, --(b)(4)-- facility was recently inspected in -----(b)(4)---- by DMPQ and in (b)(4) by ORA with decision outcomes of voluntary action indicated and no action indicated.

The primary facilities reviewer considers this submission approvable on the basis of the facilities information provided.

Environment Assessment:

A categorical exclusion under 21 CFR 25.31(c) was submitted to the file. The request is justified based on the review of the information provided.

Summary of CMC Review:

The CMC review team finds that sufficient data and information have been provided on the chemistry, manufacture and controls to support licensure of KEDBUMIN.

4. Nonclinical Pharmacology/Toxicology

Pharmacology:

Albumin is the most osmotically active plasma protein due its abundance and small size and accounts for about 75% of the osmotic activity of plasma.  Another major function of albumin is as a general binding and transport protein.  Human albumin accounts quantitatively for more than half of the total protein in the plasma and represents about 10% of the protein synthesis activity of the liver1,2,3.

Pharmacokinetics:

No pharmacokinetic studies for human albumin in animals are provided in the current application.  The pharmacokinetic properties in humans are well summarized – the average half-life is about 19 days1,2,3.

Toxicology:

Albumin (Human) is a normal constituent of human plasma and acts like physiological albumin1,2,3.  Albumin (Human) is well tolerated by animal species and, therefore, additional animal studies are not requested.

Single Dose Toxicity:

No single dose toxicity study was requested. In animals, single dose toxicity testing does not permit the evaluation of toxic or lethal doses or a dose-effect relationship due to considerations of volume and protein load in otherwise normal volume animals.  No single or acute toxicity have been tested in animal models1,2,3.  Symptoms shown to occur with high volumes of concentrated albumin solutions are volume and protein overload related4.

Repeat-Dose Toxicity:

No repeat-dose toxicity study was requested. Previous pathological findings with daily administration over 3 months were not related to the test substance (Albumin), but characterized by signs of protein overload, and by protein or antigen/antibody deposits in different organs1.

Genotoxicity:

No genotoxicity study was requested. To date human albumin has not been reported to be associated with mutagenic potential1,2,3.  ICH guidance on the preclinical safety evaluation of biotechnology-derived pharmaceuticals currently does not recommend genotoxicity studies.

Carcinogenicity:

Carcinogenicity studies are not needed for albumin.

Reproductive Studies:

Studies not required1,2,3.

5. Clinical Pharmacology/6. Clinical/Statistical-Efficacy

The CMC assessments have been the basis for approval of Albumin (Human) products without requiring new preclinical or clinical studies.

7. Safety

Review of the postmarketing database for Kedrion Albumin (Human) products already marketed in Europe raises no significant safety concerns.

8. Advisory Committee Meeting

No advisory committee meeting was recommended.

9. Pediatrics

The sponsor requested a Full Pediatric Research Equity Act (PREA) waiver for all age groups because “necessary pediatric studies with the product are highly impractical given the nature of the risk/benefit and safety profile of the product.” At a meeting of the PeRC on May 18, 2011, consensus was reached between PeRC members and DH that (a) a waiver should be granted for all indications in the 12-16 y/o subpopulation based on extrapolation from the adult population for efficacy and bridging studies for safety, (b) a waiver should be granted for -----------------(b)(4)-----------------, prevention of central volume depletion after paracentesis due to cirrhotic ascites, and ovarian hyperstimulation syndrome in the 0-12 y/o subpopulation based on insufficient number of patients/nonexistence of the disease in the pediatric population, and (c) a deferral should be granted for the remaining indications, except for hypovolemia. Consensus also was reached on a draft protocol proposed by the sponsor to evaluate product safety for the treatment of hypovolemia in the 0-12 y/o subpopulation (“A prospective, randomized, multicenter, controlled, open label study to evaluate the safety of Kedbumin 25% compared to normal saline solution in the treatment of postsurgical hypovolemia associated with hypoalbuminemia in pediatric patients undergoing major elective surgery”), with a recommendation that moderate-severely hypoalbuminemic patients be excluded from the trial because it would be unsafe to withhold albumin if such patients were randomized to the normal saline treatment cohort.

10. Other Relevant Regulatory Issues

No other relevant regulatory issue to disclose.

11. Labeling

Several iterations of the draft labeling were reviewed and comments sent to the sponsor. The final labeling is acceptable.

12. Post-Marketing Studies

Post-Marketing Requirement:

The final protocol was submitted on 20 May 2011 and is acceptable to evaluate product safety for the treatment of hypovolemia in the 0-12 y/o subpopulation.

Post-Marketing Commitment:

----------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------.

13. Recommendation

Approval

References:

  • FDA. Summary Basis for Approval for Octapharm Albumin (Human) 5% and 25%; STN: 12515 (2006).
  • EMEA. Guideline on the Core SPC for Human Albumin Solution (CPMP.PhVWP/BPWG/2231/99 rev.2)2005.
  • (The European Medicines Agency's Committee for Medicinal Products (EMEA), 2005)
  • Simpson LO and Shand BI. Morphological changes in kidneys of mice with proteinuria induced by albumin overload. Br J Exp Pathol. 64 (4), 1983, 396-402