Summary Basis of Decision for Rebinyn

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Rebinyn is located below.

Recent Activity for Rebinyn

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Rebinyn

Updated: 2024-02-13

The following table describes post-authorization activity for Rebinyn, a product which contains the medicinal ingredients coagulation factor IX (recombinant), pegylated. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

  • DIN 02470187 - 500 IU/vial, coagulation factor IX (recombinant), pegylated, powder for solution, intravenous administration
  • DIN 02470268 - 1,000 IU/vial, coagulation factor IX (recombinant), pegylated, powder for solution, intravenous administration
  • DIN 02470276 - 2,000 IU/vial, coagulation factor IX (recombinant), pegylated, powder for solution, intravenous administration
  • DIN 02532964 – 3,000 IU/vial, coagulation factor IX (recombinant), pegylated, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities
Drug product (DIN 02532964) market notification Not applicable Date of first sale: 2024-02-13 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

SNDS # 263051

2022-04-06

Issued NOC 2022-11-22

Submission filed as a Level I – Supplement for the addition of a new strength of drug product (3,000 IU/vial) and for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02532964) was issued for the new strength.

SNDS # 258126

021-10-29

Issued NOC 2022-10-12

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Rebinyn is an anti-hemophilia factor indicated in children with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

NC # 261863

2022-03-01

Issued NOL 2022-06-06

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the qualification of a new lot of reference standard against the approved reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 262770

2022-03-25

Cancellation Letter Received 2022-03-30

Submission filed as a Level I – Supplement for the addition of a new strength of drug product (3,000 IU/vial). The submission was cancelled administratively by the sponsor before screening began.

NC # 253098

2021-05-25

Issued NOL 2021-06-25

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 242376

2020-07-31

Issued NOC 2021-03-17

Submission filed as a Level I – Supplement (use for a quality change) for a change to a drug substance manufacturing facility, involving the addition of two production lines. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 240602

2020-06-15

Issued NOL 2020-08-19

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the modification of a primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 234888

2020-01-06

Issued NOL 2020-02-27

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in scale of the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 222485

2018-11-28

Issued NOL

2019-02-20

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing process for the drug product.The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 214361

2018-03-09

Issued NOC

2018-10-16

Submission filed as Level I - Supplement to make updates to the manufacturing process of the drug substance. The information was reviewed and considered acceptable. An NOC was issued.

Drug product (DINs 02470187, 02470268, 02470276) market notification

Not applicable

Date of first sale: 2018-03-23

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 201114

2016-12-12

Issued NOC 2017-11-29

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Rebinyn

Date SBD issued: 2018-02-02

The following information relates to the New Drug Submission for Rebinyn.

Coagulation Factor IX (Recombinant), Pegylated
500, 1,000 and 2,000 IU/vial, powder for solution, intravenous

Drug Identification Number (DIN):

  • DIN 02470187 - 500 IU/vial, powder for solution,
  • DIN 02470268 - 1,000 IU/vial, powder for solution
  • DIN 02470276 - 2,000 IU/vial, powder for solution

Novo Nordisk Canada Inc.

New Drug Submission Control Number: 201114

 

On November 29, 2017, Health Canada issued a Notice of Compliance to Novo Nordisk Canada Inc. for the drug product Rebinyn. The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Rebinyn is favourable for adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for control and prevention of bleeding episodes; and control and prevention of bleeding in the perioperative setting. Rebinyn is also indicated in patients 18 years of age and older with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

 

1 What was approved?

 

Rebinyn, a blood coagulation factor IX, is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG) conjugated to the protein. Rebinyn is authorized for adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for control and prevention of bleeding episodes; and control and prevention of bleeding in the perioperative setting. Rebinyn is also indicated in patients 18 years of age and older with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Rebinyn is not indicated for immune tolerance induction in patients with hemophilia B.

Rebinyn is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation (including hamster protein), or component of the container.

Rebinyn was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Rebinyn (500, 1,000 and 2,000 IU/vial coagulation rFIX pegylated) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains histidine, mannitol, polysorbate 80, sodium chloride, and sucrose.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Rebinyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Rebinyn approved?

 

Health Canada considers that the benefit-risk profile of Rebinyn is favourable for adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for control and prevention of bleeding episodes; and control and prevention of bleeding in the perioperative setting. Rebinyn is also indicated in patients 18 years of age and older with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Hemophilia B is a congenital bleeding disorder occurring predominantly in males, characterized by a deficiency of factor IX (FIX). Hemophilia B results in abnormal clot formation, causing prolonged and abnormal bleeding. Bleeding may be life-threatening or result in significant morbidity. There is no available cure for hemophilia B. The treatment focuses on the replacement of FIX with FIX-containing coagulation products.

Rebinyn has been shown to be efficacious in patients with hemophilia B (FIX activity ≤2%). The market authorization was based on one pivotal study (Study 3747), which included one open-label on-demand arm with treatment for approximately 28 weeks and two prophylaxis treatment arms, with single-blind randomization to either 10 IU/kg or 40 IU/kg once weekly for approximately 52 weeks. This Phase III pivotal study included 74 adolescent (aged 13 to 17 years) and adult (aged 18 to 65 years) previously treated patients. Another Phase III study (Study 3773), a multicentre, open-label, non-controlled study with 13 previously treated adolescent or adult patients, evaluated the efficacy and safety during major surgical procedures. An extension study (Study 3775) to Study 3747 and Study 3773 which was a multicentre, open-label, non-controlled study, evaluated the long-term safety and efficacy in routine prophylaxis and treatment of bleeds with 71 previously treated adolescent or adult patients. A pediatric study (Study 3774) included 25 pediatric previously treated patients (1-12 years old) in which subjects received prophylaxis treatment with Rebinyn 40 IU/kg once weekly for approximately 52 weeks. An overall assessment of hemostatic efficacy was performed by the patient or investigator using a 4-point scale of excellent, good, moderate, or poor. The overall success rate (defined as excellent or good) for treatment of bleeding episodes when pooling all trials was 93.2% (551 out of 591). The median annualised bleeding rates (ABR) was 1.03 (ranged from 0.00 to 37.78) for the 40 IU/kg prophylaxis group. The hemostatic effect during surgery was evaluated on a 4-point scale of excellent, good, moderate, or poor. The intraoperative hemostatic effect was rated as excellent or good for the 11/11 (100%) major surgeries.

The benefits of Rebinyn have been shown in routine prophylaxis, control of bleeding episodes, and perioperative management. The safety profile of Rebinyn derived from the clinical studies is generally considered acceptable. Rebinyn was generally well tolerated in the study population.

However, the non-clinical findings of polyethylene-glycol (PEG) accumulation in the choroid plexus (Rebinyn) and vacuolation of the epithelial cells of the choroid plexus (40 kDa PEG alone at 45,000 µg PEG/kg/week) raised concerns about the potential risks of Rebinyn in humans with chronic long-term use. The clinical implications of these findings are not clear. There were no clear safety signals related to the accumulation of PEG observed in the submitted clinical studies; however, these studies were not specifically designed to assess for neurocognitive function.

By taking into account the potential risks of Rebinyn, current availability of FIX products, and currently available experience of other pegylated products, it is concluded that the routine prophylaxis indication for Rebinyn should be limited to patients aged 18 years and older. Since the accumulation of PEG or possible vacuolation in the choroid plexus are more likely related to long-term exposure, short-term use, i.e., on-demand treatment of bleeding episodes and perioperative management is considered acceptable for all ages.

A Risk Management Plan (RMP) for Rebinyn was submitted by Novo Nordisk Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Rebinyn was accepted.

Overall, the therapeutic benefits of Rebinyn therapy seen in the pivotal study are positive. The identified safety issues can be managed through labelling and adequate monitoring. Rebinyn has been shown to have a favourable benefit-risk profile based on non-clinical and clinical studies.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Rebinyn?

 

Submission Milestones: Rebinyn

Submission Milestone Date
Pre-submission meeting: 2016-04-12
Submission filed: 2016-12-12
Screening  
Screening Acceptance Letter issued: 2017-02-02
Review  
Quality Evaluation complete: 2017-11-24
Clinical Evaluation complete: 2017-11-21
Review of Risk Management Plan complete: 2017-10-19
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-11-23
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-11-29

 

The Canadian regulatory decision on the quality, non-clinical, and clinical review of Rebinyn was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Rebinyn?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Rebinyn is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Patients with hemophilia B are deficient in coagulation Factor IX (FIX), which is required for effective hemostasis. Treatment with Rebinyn temporarily replaces the missing clotting FIX.

The FIX is activated by Factor XIa and by Factor VII/tissue factor complex. Upon activation of Rebinyn the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activated FIX molecule. Activated FIX in combination with activated Factor VIII activates Factor X. Activated Factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic (PK) studies. The clinical pharmacological data support the use of Rebinyn for the specified indication.

A Phase I study evaluated the safety and pharmacokinetics of Rebinyn in non-bleeding previously-treated patients with hemophilia B (FIX activity level ≤2%) using three dose levels (25, 50, and 100 IU/kg). The PK parameters after a single dose of Rebinyn and a previously received FIX product had been evaluated in 15 adult patients (5 in each dose group). The mean incremental recovery of Rebinyn was numerically higher compared to the previously used FIX product. The mean half-life of Rebinyn was much longer than the previously used FIX product. After dosing with Rebinyn, all patients had a FIX activity >1% after 168 hours in all dose cohorts. In general, Rebinyn was well tolerated after a single dose at the study-dose levels. One patient (1/16) had a serious allergic reaction.

For further details, please refer to the Rebinyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Rebinyn was evaluated in four Phase III studies (a pivotal study, surgery study, extension study, and a pediatric study). The objectives of the Phase III studies were to evaluate the efficacy of Rebinyn in routine prophylaxis, control and prevention of bleeding episodes, and perioperative management in previously treated male patients with hemophilia B (FIX activity ≤2%). Previously treated patients were defined as patients receiving treatment with other FIX products for ≥150 exposure days for adolescents and adults, and ≥50 exposure days for pediatric patients. The key exclusion criteria across the studies included known or suspected hypersensitivity to the study drug or related products, known history of FIX inhibitors or current inhibitor ≥0.6 Bethesda units (BU), human immunodeficiency virus (HIV)-positive status with a viral load ≥400,000 copies/mL or CD4+ lymphocyte count ≤200/µL, additional congenital or acquired coagulation disorders, previous arterial thrombotic events, as well as receiving immune modulating or chemotherapeutic medication.

The Pivotal Study (Study 3747)

Study 3747 was a multicentre, single-blind, non-controlled, randomized study with three treatment arms; 10 or 40 IU/kg once-weekly prophylaxis for 52 weeks (randomized), or on-demand treatment for 28 weeks. The dosage for prophylaxis was 10 or 40 IU/kg once-weekly. Mild and moderate bleeds were treated with injection(s) of 40 IU/kg; and severe bleeds were treated with 80 IU/kg. A total of 74 previously treated adolescent or adult patients received Rebinyn (prophylaxis: 59 and on-demand: 15).

A total of 345 bleeds were treated in 55 patients during the pivotal study. The hemostatic response to Rebinyn in 341 bleeds was evaluated by patients: in 91.3% of the bleeds the response was rated as excellent or good (89.4% for the spontaneous bleeds and 94.8% for the traumatic bleeds). The hemostatic response was also analyzed by the location of bleeding: in 91.2% joint bleeds, 96.3% muscle/skin/soft tissue bleeds, and 83.3% mouth/gums/nose bleeds the response was rated as excellent or good. All bleeds were classified as mild/moderate, except one joint bleeding episode was classified as severe.

Out of 345 bleeds, 300 bleeds were treated with 1 injection of Rebinyn, 36 bleeds were treated with 2 injections of Rebinyn, and 9 bleeds were treated with ≥3 injections of Rebinyn. The median annualised bleeding rates (ABR) were 1.04 for the 40 IU/kg prophylaxis group (number of patients [n] = 29) and 2.93 for the 10 IU/kg prophylaxis group (n = 30).

The Surgical Study (Study 3773)

Study 3773 was a multicentre, open-label, non-controlled study that evaluated the efficacy of Rebinyn during major surgical procedures. The surgery study included 13 previously treated adolescent and adult patients in which patients received one injection of Rebinyn 80 IU/kg on the day of a major surgery, and post-operatively, injections of 40 IU/kg at the investigator's discretion for up to 3 weeks after surgery. A total of 11 major surgical procedures in 11 patients (15-56 years old) were reported. Overall, the study results demonstrated the hemostatic effect of Rebinyn during surgical procedures in the study population. In addition, the safety profile of short-term exposure of Rebinyn for the perioperative management was generally acceptable.

The Extension Study (Study 3775)

Study 3775 was an extension study of Study 3747 and Study 3773. The extension study was a multicentre, open label, non-controlled study that evaluated long-term safety and efficacy in routine prophylaxis and treatment of bleeds with 71 patients. There were four treatment arms: 10 or 40 IU/kg once-weekly prophylaxis, 80 IU/kg once every second week prophylaxis, or on-demand treatment. Free choice between available treatment arms, and switching of treatment arm during the study was allowed.

A total of 207 bleeds were treated in 71 patients during the study. The hemostatic response to Rebinyn in 205 bleeds was evaluated by patients: in 93.7% of the bleeds the response was rated as excellent or good. All bleeds were classified as mild/moderate. The mean and median annualized bleed rates for both prophylaxis dose levels were in line with the pivotal Study 3747. The mean FIX trough level was also in line with Study 3747.

The Pediatric Study (Study 3774)

Study 3774 was an open-label study that evaluated the efficacy of Rebinyn in prophylaxis and on-demand treatment of children (≤12 years) with hemophilia B and a FIX activity level ≤2%. In the main phase of the study, a total of 25 patients received Rebinyn at a dose level of 40 IU/kg once weekly for prophylaxis; of which 24 patients completed 52 weeks of this study.

A total of 15 patients received 51 injections of Rebinyn for 42 bleeds during the study. All bleeding episodes were classified as mild/moderate bleeds. The majority of bleeding episodes were traumatic bleeds. The most frequent location was in the joint (41.9%) in the 7-12 years of age group and subcutaneous bleeds (45.5%) in the 1-6 years of age group. The majority of bleeds (36/42) were resolved with 1 injection; while 5 bleeds required 2 injections and 1 bleed required 5 injections. Out of 42 bleeding episodes, the hemostatic response for the treatment of Rebinyn in 39 bleeds was rated as excellent or good.

The mean and median annualized bleed rates in the study population were in line with the results obtained from adults in Study 3747. For the children ≤12 years of age, the mean incremental recovery was in line with adolescent/adult data (Studies 3639 and 3747). However, the mean single-dose FIX trough level was numerically lower and the mean half-life was numerically shorter, compared to adolescent/adult data.

Indication

The New Drug Submission for Rebinyn was filed by the sponsor with the following indication:

Rebinyn (Coagulation Factor IX [Recombinant], pegylated) is a long-acting anti-hemophilic factor indicated in adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for:

  • control and prevention of bleeding episodes
  • routine prophylaxis to prevent or reduce the frequency of bleeding episodes
  • control and prevention of bleeding in the perioperative setting.

Safety concerns with chronic long-term use arose after the non-clinical studies demonstrated polyethylene glycol (PEG) accumulation in the choroid plexus (Rebinyn) and vacuolation in the choroid plexus (45,000 µg/kg/week PEG alone).

To ensure safe and effective use of the product, Health Canada approved the following indication:

Rebinyn (Coagulation Factor IX [Recombinant], pegylated) is an anti-hemophilic factor indicated in adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for:

  • control and prevention of bleeding episodes
  • control and prevention of bleeding in the perioperative setting.

Rebinyn is also indicated in patients 18 years and above with hemophilia B for:

  • routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Overall Analysis of Efficacy

Overall, the efficacy results obtained from the above-mentioned studies support the use of Rebinyn for the treatment and prophylaxis of bleeding episodes. The benefits of Rebinyn have been demonstrated in routine prophylaxis, control of bleeding episodes, and perioperative management.

For more information, refer to the Rebinyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

During the clinical studies, 115 previously treated male patients received at least one dose of Rebinyn for routine prophylaxis, treatment of bleeding episodes, perioperative management, and in a single-dose pharmacokinetic study. There were a total of 8,801 exposure days equivalent to 170 patient years. A total of 40 patients (35%) were treated for more than 2 years. Common adverse reactions (incidence ≥1% in previously treated patients were pruritus and injection site reactions. Rarely, hypersensitivity and/or allergic reactions were observed. The safety profile of Rebinyn for the previously treated pediatric patients was consistent with the previously treated adult patients in the clinical studies.

Overall, Rebinyn was generally well tolerated in the study population. No inhibitors were detected. The binding antibodies detected in 3/74 patients (Study 3747) were transient and had no inhibitory effect. However, in the non-clinical findings, PEG accumulation in the choroid plexus (Rebinyn) and vacuolation of the epithelial cells of the choroid plexus (45,000 µg/kg/week PEG alone) raised concerns about the potential risks of Rebinyn in humans with chronic long term use, especially in the pediatric and elderly populations. The clinical implications of these findings are not clear. No clear safety signal related to accumulation of PEG was observed in the submitted clinical studies; however, these studies were not specifically designed to assess for neurocognitive function.

Appropriate warnings and precautions are in place in the approved Rebinyn Product Monograph to address the identified safety concerns.

For more information, refer to the Rebinyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical studies investigated the pharmacology, pharmacokinetics, and toxicity of Rebinyn. The results of the non-clinical studies as well as the potential risks to humans have been included in the Rebinyn Product Monograph.

Generally, Rebinyn was well tolerated after a single dose up to 2,000 IU/kg in rats, and after repeat doses up to 1,200 IU/kg every fifth day for 26 weeks in rats and 1,300 IU/kg/week for 4 weeks in monkeys. However, four repeat-dose toxicity studies of Rebinyn in rats and monkeys showed accumulation of PEG in the choroid plexus by positive immuno histochemical staining for PEG. In addition, two repeat-dose studies of 40 kDa PEG alone (at 45,000 µg PEG/kg/week) in rats and monkeys, showed vacuolation of the epithelial cells of the choroid plexus. These findings raise concerns about the potential safety of Rebinyn in humans with chronic long-term use (a weekly dose of 40 IU/kg corresponds to 230 µg PEG/kg/week), especially in pediatric and elderly population. For this reason, Health Canada limited the use of Rebinyn for routine prophylaxis to patients 18 years of age and older. Appropriate warnings and precautionary measures are in place in the Rebinyn Product Monograph to address the identified safety concerns.

For more information, refer to the Rebinyn Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

Rebinyn is a purified recombinant human factor IX (rFIX) with a 40 kDa PEG conjugated to the protein. The average molecular weight of Rebinyn is approximately 98 kDa and the molecular weight of the protein moiety alone is 56 kDa. The rFIX protein in Rebinyn consists of a gamma-carboxylated domain (Gla domain), two epidermal growth factor-like (EGF-like) domains, an activation peptide (which is cleaved off upon activation) and a protease domain. A 40 kDa PEG-group is selectively attached to specific N-linked glycans in the rFIX activation peptide, with monoPEGylated rFIX as the predominant form of Rebinyn. Once activated, the resulting rFIX has structural and functional properties similar to those of plasma derived factor IX. The nominal specific activity of Rebinyn is 152 IU/mg protein.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that the rFIX protein consistently exhibits the desired characteristic structure and biological activity.

Comparability of lots used in clinical trials and lots produced during process validation was assessed and comparable physicochemical, biochemical and functional characteristics were demonstrated.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These impurities were found to be within established limits and are considered to be acceptable.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

The rFIX protein is produced by recombinant deoxyribonucleic acid (DNA) technology in Chinese Hamster Ovary (CHO) cells. No additives of human or animal origin are directly used in the cell culture, purification, conjugation or formulation of the product. The conjugation of the PEG-group to the rFIX is done by an enzymatic reaction. The production process includes two dedicated and validated viral clearance steps, namely a detergent treatment step for inactivation and a 20 nm filtration step for removal of viruses. The materials used in the manufacture of the drug substance including processing enzymes are considered suitable and/or meet standards appropriate for their intended use.

The drug product manufacturing procedures are comprised of thawing drug substances, dilution with formulation buffer, sterile filtration, filling and lyophilisation using validated pharmceutical equipment and facilities.

All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.

The sponsor has demonstrated that the full-scale drug substance and drug product manufacturing process is able to consistently produce product of acceptable quality.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines. The test specifications and analytical methods are considered acceptable.

The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all process validation batches were within the proposed specification limits.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The consistency sample test results positively supported the quality review recommendation.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance as modified during the review process and the drug product were adequately supported and are considered to be satisfactory. For Rebinyn, the proposed 24-month shelf life at 2°C to 8°C or 18 months at 2°C to 8°C followed by 6 months at 30°C protected from light is considered acceptable. The proposed shelf life of 36 months for the reconstitution diluent stored at 2°C to 8°C with up to 12 months at or below 30°C is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of Rebinyn was waived as successful OSEs had been recently performed for other products that had similar manufacturing processes in the same facilities.

Adventitious Agents Safety Evaluation

Biological starting materials including cell banks for the product and affinity ligand used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.

 

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