Summary Basis of Decision for Zonovate

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 Zonovate is located below.

Recent Activity for Zonovate

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 Zonovate

Updated: 2023-08-18

The following table describes post-authorization activity for Zonovate, a product which contains the medicinal ingredient turoctocog alfa. 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 that are found in PAATs.

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

Drug Identification Numbers (DINs):

  • DIN 02435187 - 250 IU/vial turoctocog alfa, powder for solution, intravenous administration
  • DIN 02435195 - 500 IU/vial turoctocog alfa, powder for solution, intravenous  administration
  • DIN 02435209 - 1,000 IU/vial turoctocog alfa, powder for solution, intravenous  administration
  • DIN 02435217 - 1,500 IU/vial turoctocog alfa, powder for solution, intravenous  administration
  • DIN 02435225 - 2,000 IU/vial turoctocog alfa, powder for solution, intravenous  administration
  • DIN 02435233 - 3,000 IU/vial turoctocog alfa, powder for solution, intravenous  administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 275734 2023-05-26 Issued NOL 2023-08-17 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 258454 2021-11-08 Issued NOC 2022-05-19 Submission filed as a Level I – Supplement to add a manufacturing site for the production of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 239150 2020-05-06 Issued NOC 2021-04-14 Submission filed as a Level I – Supplement to update the PM with data from studies NN7008-3809 and NN7008-4239. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
NC # 240640 2020-06-15 Issued NOL 2020-08-19 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 233646 2019-11-18 Issued NOL 2020-02-21 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the storage conditions for the drug product and to extend the shelf life of the Zonovate solvent. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 222829 2018-12-07 Issued NOC 2019-11-15 Submission filed as a Level I – Supplement to update the PM with data from studies NN7008-3568 and NN7008-3809. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued. A Regulatory Decision Summary was published.
SNDS # 221435 2018-10-26 Issued NOC 2019-06-12 Submission filed as a Level I – Supplement for an additional drug substance manufacturing suite and changes to the drug substance manufacturing process. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 222491 2018-11-28 Issued NOL 2019-02-20 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 214953 2018-03-28 Issued NOL
2018-05-28		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce a secondary reference standard. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DINs 02435187, 02435195, 02435209, 02435217, 02435225, 02435233) 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.
SNDS # 212520 2017-12-29 Issued NOC
2018-03-08		 Submission filed as a Level I - Supplement to revise the product packaging, including carton labels, primary vial labels and primary solvent syringe labels. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 202690 2017-02-08 Issued NOL
2017-05-19		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the shelf-life of the drug product. As a result of the NC, modifications were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 181517 2015-01-20 Issued No Objection Letter
2015-04-16		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to propose the manufacture of a new Working Cell Bank (WCB) for turoctocog. The submission also contained a protocol for the manufacture of future WCBs. The submission was reviewed and a No Objection Letter was issued.
NDS # 170796 2013-12-16 Issued NOC
2014-12-08		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Zonovate

Date SBD issued: 2015-01-23

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

Antihemophilic Factor (Recombinant, B-Domain Truncated), turoctocog alfa 250, 500, 1,000, 1,500, 2,000, and 3,000 IU/vial, powder, intravenous

Drug Identification Number (DIN):

  • 02435187 - 250 IU/vial
  • 02435195 - 500 IU/vial
  • 02435209 - 1,000 IU/vial
  • 02435217 - 1,500 IU/vial
  • 02435225 - 2,000 IU/vial
  • 02435233 - 3,000 IU/vial

Novo Nordisk Canada Inc.

New Drug Submission Control Number: 170796

 

On December 08, 2014, Health Canada issued a Notice of Compliance to Novo Nordisk Canada Inc. for the drug product, Zonovate.

The market authorization was based on quality (chemistry and manufacturing), non clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Zonovate is favourable for use in adults and children with hemophilia A (congenital Factor VIII deficiency or classic hemophilia) for:

  • Treatment and control of bleeding episodes;
  • Perioperative management;
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Zonovate is not indicated for the treatment of von Willebrand disease.

 

1 What was approved?

 

Zonovate, which belongs to the class of drug antihemorrhagic blood coagulation Factor VIII, was authorized for use in adults and children with hemophilia A (congenital Factor VIII deficiency or classic hemophilia) for:

  • Treatment and control of bleeding episodes;
  • Perioperative management;
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Zonovate is not indicated for the treatment of von Willebrand disease.

Clinical studies with Zonovate did not include patients >65 years old to determine whether they respond differently from younger patients. As with any patient receiving Zonovate, dose selection for an elderly patient should be individualized.

The safety and efficacy of Zonovate have been demonstrated in pediatric patients from 1 to <18 years old.

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

Zonovate (coagulation Factor VIII) contains the active ingredient Antihemophilic Factor (Recombinant, B-Domain Truncated), turoctocog alfa. Each single-use vial contains 250, 500, 1,000, 1,500, 2,000 or 3,000 IU of Factor VIII. Each Zonovate vial also contains calcium chloride dihydrate, L histidine, L methionine, polysorbate 80, sodium chloride, and sucrose. Zonovate powder should be reconstituted with the prefilled syringe containing 4 mL 0.9% sodium chloride solution for injection.

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 Zonovate Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Zonovate approved?

 

Health Canada considers that the benefit/risk profile of Zonovate is favourable for use in adults and children with hemophilia A (congenital Factor VIII deficiency or classic hemophilia) for:

  • Treatment and control of bleeding episodes;
  • Perioperative management;
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Hemophilia A is a rare congenital bleeding disorder occurring predominantly in males, characterized by a deficiency of Factor VIII (FVIII), which results in abnormal clot formation, causing prolonged and abnormal bleeding. Bleeding may be life-threatening or result in significant morbidity. Currently, there is no cure for hemophilia A. The treatment focuses on the replacement of FVIII with FVIII containing coagulation products. Currently available FVIII products in Canada include concentrates that are purified from human plasma and recombinant products.

Zonovate has been shown to be efficacious in hemophilia A patients in the prevention and treatment of bleeding episodes. The market authorization was based primarily on three multicentre, open-label, non-controlled studies. These studies include one pivotal study, one study in pediatric patients, and one extension study. In the pivotal study, the estimated mean annualized bleeding rate was 5.6 bleeds/patient/year for adolescents and 6.7 bleeds/patient/year for adults. In the pediatric study, the estimated mean annualized bleeding rate for young children (1 to <6 years) was 4.7 bleeds/patient/year while for older children (6 to <12 years) it was 5.9 bleeds/patient/year. A total of 1,377 breakthrough bleeds were reported during the studies. Hemostatic efficacy was considered a success (Excellent or Good) in 88% of the cases. Furthermore, hemostasis was reported to be successful in all of the 14 surgeries performed during the studies.

Zonovate demonstrated an acceptable safety profile in all of the studies. None of the patients developed inhibitors to Factor VIII. The most frequently reported adverse reactions were injection site reactions (2.3%) and increased levels of hepatic enzymes (1.4%).

A Risk Management Plan (RMP) for Zonovate 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 Zonovate has been deemed appropriate and acceptable.

Overall, the therapeutic benefits seen in the clinical studies are considered positive and the benefits of Zonovate therapy outweigh the potential risks. Zonovate has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Zonovate Product Monograph to address the identified safety concerns.

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 Zonovate?

 

Submission Milestones: Zonovate

Submission Milestone Date
Pre-submission meeting: 2012-12-04
Submission filed: 2013-12-16
Screening Acceptance Letter issued: 2014-02-13
On-Site Evaluation: 2014-10-06 - 2014-10-10
Quality Evaluation complete: 2014-12-05
Clinical Evaluation complete: 2014-12-02
Labelling Review complete: 2014-12-02
Notice of Compliance issued by Director General: 2014-12-08

 

The Canadian regulatory decision on the non-clinical and clinical review of Zonovate was based on a critical assessment of the Canadian data package. The European Medicines Agency (EMA) review (Day 120 and Day 180 Questions and Responses) and the United States Food and Drug Administration (FDA) (Summary of FDA Information Requests and Responses) documents were reviewed and considered during the evaluation and recommendation for Zonovate.

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 Zonovate?

 

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Zonovate 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

Hemophilia A is a bleeding disorder characterized by a deficiency of functional clotting Factor VIII (FVIII), which leads to prolonged clotting time in the activated partial thromboplastin time assay, a conventional in vitro test for the biological activity of FVIII. Zonovate is used as replacement therapy to increase plasma levels of FVIII, thereby enabling a temporary correction of the factor deficiency and the bleeding tendency. In vitro studies were performed with normal and FVIII-deficient human blood or plasma. The studies demonstrated that the primary pharmacodynamic properties of Zonovate are consistent with those described in the literature for endogenous FVIII. Zonovate acts as an important co-factor in the activation of coagulation Factor X in the human coagulation cascade leading to thrombin generation and the formation of a stable fibrin clot.

The clinical pharmacokinetics of Zonovate were evaluated in adult, adolescent, and pediatric patients with severe hemophilia A.

The clinical pharmacology program for Zonovate included five pharmacokinetic (PK) studies. One of the five studies was a multicentre, multinational, open-label and single dose study which evaluated the PK profile of the product in 23 adolescent and adult patients aged 13 to 54 years. These patients received 50 IU/kg of Zonovate intravenously. Two patients were below the age of 18 years (13 and 17 years). The PK parameters were measured with both the one stage clot and the chromogenic assay after Zonovate administration and were considered acceptable. The patients from this study continued into the pivotal Phase III study in which they had a second PK assessment carried out after 3-6 months of preventive dosing with Zonovate to evaluate changes in PK parameters as indicators of FVIII inhibitor formation. The results indicate that the FVIII activity was comparable following 3-6 months of preventive administration of the product.

In another study conducted in pediatric patients, the pharmacokinetics of a single dose of Zonovate was evaluated in children 0–<12 years of age. A total of 28 children with severe hemophilia A (14 patients <6 years of age and 14 patients between 6 and <12 years of age) received a single dose of 50 IU/kg of Zonovate.

Some variations were observed in the PK parameters of Zonovate between pediatric and adult patients. The higher clearance and the shorter half-life seen in pediatric patients compared to adult patients with hemophilia A may be due in part to the known higher plasma volume per kilogram body weight in younger patients.

Overall the PK profile of Zonovate in adults, adolescents and children with severe hemophilia is considered acceptable.

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

Clinical Efficacy

The clinical efficacy of Zonovate in the prevention and treatment of bleeding episodes (BEs) was evaluated primarily in three multicentre, open-label, non controlled studies with previously treated patients with severe hemophilia A (FVIII activity ≤1%). These studies include one pivotal study (Study 3543), one study in pediatric patients (Study 3545) and one extension study (Study 3568).

A total of 213 patients were administered Zonovate. In the pivotal study, there were 150 patients; 24 adolescents (12-18 years old) and 126 adult patients (18-60 years old). In the pediatric study, there were 63 pediatric patients (31 aged 1 to <6, and 32 aged 6 to <12). Of the 213 patients, 187 continued in the efficacy and safety extension study.

All patients received preventive treatment. Breakthrough bleeding episodes (BEs) in patients treated for routine prophylaxis and in 14 patients who underwent surgery (14-54 years) were treated at the investigator's discretion.

Efficacy in Routine Prophylaxis

A total of 213 patients received Zonovate for routine prophylaxis, the prevention of bleeding. The prophylactic regimen for the 150 adolescent and adult patients consisted of 20-40 IU/kg every other day or 20–50 IU/kg three times per week. The prophylactic regimen for the 63 pediatric patients consisted of 25–50 IU/kg every other day or 25–60 IU/kg three times per week. The majority of the patients (>80%) were treated with the three times per week regimen.

In the pivotal study (Study 3543), the mean ABR (bleeds per patient per year) was 5.6 for the 24 adolescents, and 6.7 for the 126 adults. The mean prophylactic dose (IU/kg body weight) was 23.3 for the adolescents and 24.6 for the adults.

In the pediatric study (Study 3545), the mean ABR was 4.7 for the 31 children 0 to <6 years of age, and 5.9 for the 32 children 6 to <12 years of age. The mean prophylactic dose (IU/kg body weight) was 37.8 for the children 0 to <6 years of age, and 35.8 for the children 6 to <12 years of age.

In the extension study (Study 3568), the mean ABR was 2.3 [number of patients (n) = 27], 2.8 (n = 28), 2.8 (n = 23), and 3.4 (n = 109), for the children 0 to <6 years of age, children 6 to <12 years of age, adolescents, and adults, respectively. The mean prophylactic dose (IU/kg body weight) was 42.1, 38.1, 29.5, and 29.0, respectively.

The mean prophylactic dose used in the pediatric population was higher than in the adults and adolescents participating in the pivotal study. In addition, the mean prophylactic dose was increased in the adult/adolescent and pediatric patients who continued in the extension study. This could explain the differences in the bleeding rates observed between adult /adolescent and pediatric patients and the decrease in the rates observed in the extension study.

Overall, the annualised bleeding rates observed were considered to be in an acceptable range.

Efficacy in Control of Bleeding

The hemostatic efficacy of Zonovate in the treatment of BEs was assessed in 499 bleeds in adolescents and adults participating in the pivotal study (Study 3543), 126 bleeds in pediatric patients (Study 3545), and an additional 752 bleeds that occurred in patients participating in the extension study (Study 3568, all age groups). Traumatic bleeds were more frequent among pediatric patients whereas spontaneous bleeds were more frequent among adolescents and adults. The vast majority of the bleeds were of mild/moderate severity and most frequently localized in articular joints.

In study 3543, the proportion of BEs with successful treatment (defined as hemostatic effect rated as good or excellent) was 80.8%. The rate of BEs successfully treated with just 1 or 2 infusions was 89.4%. In Study 3545 and Study 3568, the success rates were 92.1% and 88.3%, respectively, and the percentage of bleeds stopped by 1 or 2 infusions was 95.2% and 90.2%, respectively.

In Study 3543, Study 3545, and Study 3568, the mean dose used for the treatment of the BEs was 30.4, 40.4, and 36.2 IU/kg/body weight, respectively.

The success rates for the treatment of breakthrough bleeding episodes are considered in an acceptable range. The percentage of bleeds stopped by one or two infusion is considered as a good efficacy response, and the proposed dose range is considered supported by the above findings.

Efficacy in Perioperative Management

The efficacy of Zonovate in perioperative management was assessed in patients who during the course of the pivotal study and extension study needed to undergo a major or minor surgical procedure requiring at least 7 days of daily FVIII treatment, including the day of surgery. A total of 14 surgeries were performed in 14 patients (9 patients from Study 3543 and 5 patients from Study 3568). Apart from 1 adolescent, all the patients undergoing surgery were adults. The surgery indications included arthropathy for 7 patients, synovitis for 1 patient, semi-impacted tooth and removal of tooth root for 1 patient, circumcision for 1 patient, recurrent haemarthrosis for 1 patient, pain in left ankle for 1 patient, familial adenomatous polyposis for 1 patient, and trauma for 1 patient. Hemostatic efficacy was assessed according to a predefined four point scale: excellent, good, moderate, or none. Hemostasis was successful (excellent or good) in all 14 surgeries. Data from surgeries conducted in pediatric patients were not available.

Efficacy of Zonovate in perioperative management is considered supported by the success rate observed in patients who underwent surgeries.

Overall Analysis of Efficacy

Based on the clinical data provided, the efficacy of Zonovate in adults and children with hemophilia A is considered acceptable for routine prophylaxis, for the treatment and control of bleeding episodes, as well as perioperative management. Together the clinical and pharmacological data support the use of Zonovate for the specified indication.

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

Clinical Safety

The clinical safety of Zonovate was based on information from all of the clinical studies of the development program, including data from the three efficacy and safety studies discussed above where the vast majority of exposure to Zonovate was observed, and from the studies that investigated the PK profile of Zonovate.

A total of 214 previously treated patients received at least one infusion of Zonovate as part of either on-demand treatment of bleeding episodes, peri-operative management, routine prophylaxis, or PK evaluation. These patients had a total of 54,956 exposure days during the prevention or treatment of bleeding episodes. An exposure day was defined as one day where at least one Zonovate dose had been administered.

A total of 783 adverse events were reported in 179 patients during the prevention and treatment of bleeds. The most commonly reported adverse events were related to dosing (medication errors), headache, and nasopharyngitis. No differences in the safety profile of Zonovate were observed between children and adults.

Events reported more frequently in young children as compared to the other age groups included upper respiratory tract infection, vomiting, and cough. Two events in one child (contusion and incorrect dose administered) were evaluated by the investigator as possibly or probably related to the study drug.

A total of 30 adverse events in 19 patients of 214 patients exposed to Zonovate were evaluated by the investigator as possibly or probably related to the study drug. Of these 30 adverse reactions, 2 were reported in 1 out of 31 patients <6 years of age, none in patients from 6 to 18 years of age, and 28 were reported in 18 of 127 adults.

The most frequently reported adverse reactions were injection site reactions (2.3%) and increased levels of hepatic enzymes (1.4%). Less common adverse drug reactions (<1%) included sinus tachycardia, pyrexia, fatigue, feeling hot, peripheral edema, contusion, increased heart rate, arthropathy, musculoskeletal pain, musculoskeletal stiffness, pain in extremity, dizziness, headache, insomnia, rash, hypertension, and lymphedema.

There was one unrelated death reported during the extension study. A 27-year old experienced a fatal subdural hemorrhage after an assault. The patient received Novoeight peri-operatively, including two days post-operatively before he was pronounced dead.

None of the 214 patients developed FVIII inhibitors during the clinical studies, and no events of allergic reactions towards Zonovate were reported. One twenty-two month old child had a positive neutralizing antibody to FVIII of 1.3 in the Bethesda assay after 15 exposure days that was not confirmed when checked after 20 exposure days. In vivo recovery was normal for this child and no clinical adverse findings were observed.

Zonovate was well tolerated in all of the studies and no unexpected patterns in the reported adverse events or serious adverse events were observed. The reported safety data were considered supportive of the safety of Zonovate for the proposed clinical uses of the product.

Overall, the safety profile derived from the clinical studies was considered acceptable. Appropriate warnings and precautions are in place in the approved Zonovate Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical development program for Zonovate consisted mainly of studies undertaken in various animal species to show the pharmacology and pharmacokinetics of Zonovate, as well as to evaluate the toxicity potential of the product and its tolerance. Based on the results of these studies, Zonovate was considered to have an overall acceptable safety profile for its subsequent use in clinical studies. The results of the non-clinical studies, as well as the potential risks to humans, have been included in the Zonovate Product Monograph. In view of the intended use of Zonovate, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Zonovate (coagulation FVIII) is an Antihemophilic Factor (Recombinant, B Domain Truncated) produced by recombinant deoxyribonucleic acid (DNA) technology in Chinese Hamster Ovary (CHO) cells. The cell culture and purification processes used in the manufacture of Zonovate employ no additives of human or animal origin. An alternate common name for the active ingredient is turoctocog alfa.

Characterization of the Drug Substance

Antihemophilic Factor (Recombinant, B-Domain Truncated), turoctocog alfa, is a purified protein that has 1,445 amino acids with an approximate molecular mass of 166 kDa (calculated excluding post-translational modifications). The molecule has been designed as a polypeptide containing a heavy chain of 87 kDa and a light chain of 79 kDa, held together by non-covalent interactions. The B-Domain which normally forms part of the heavy chain in native FVIII is truncated to 21 amino acid residues.

Detailed characterization studies were performed to provide assurance that the recombinant FVIII (rFVIII) exhibits the desired characteristic structure and biological activity. The rFVIII synthesized by the CHO cells has the same biological effects on clotting as native human FVIII.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These product- and process- related 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 turoctocog alfa drug substance manufacturing process consists of cell culture production in CHO cells, followed by harvest capture and purification steps, including chromatography using an in-house manufactured FVIII specific monoclonal antibody (mAb) immune affinity column. This process is well defined and has appropriate in process controls for critical steps and intermediates. All materials used in the manufacture of turoctocog alfa are considered suitable and meet standards appropriate for their intended use. The monoclonal antibody used in the production of the anti FVIII mAb matrix is consistently manufactured by a cell culture process in CHO cells and adequately purified and controlled.

The final product, Zonovate, is formulated, sterile filled, and lyophilized to nominal strengths containing 250, 500, 1,000, 1,500, 2,000, and 3,000 IU/vial. The manufacturing process of the drug product consists of four main steps: compounding, sterile filtration, aseptic filling and lyophilisation. Data were provided to support the suitability of container closure components and container closure integrity. Validation and batch analysis demonstrate consistent and reliable filling for all final product strengths.

The manufacturing process for both the drug substance and drug product is considered to be adequately controlled within justified limits. In-process controls and release control tests were established and justified. All in-process control tests and release tests meet the pre-defined acceptance criteria.

Control of the Drug Substance and Drug Product

Validation reports are considered satisfactory for all analytical procedures used for in process, release, and stability testing of the drug substance and drug product. The specifications provided are considered acceptable. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.

Through Health Canada's lot release testing and evaluation program, final product lots were tested, evaluated, and found to consistently meet the established requirements.

Zonovate will be placed in lot release group 2 which requires the sponsor to submit final product samples as well as Certificates of Analysis for Drug Substance, Drug Product, and Diluent for review and testing prior to release to the Canadian market.

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 were adequately supported and are considered to be satisfactory.

Drug product stability studies for clinical and commercial scale lots support a shelf life limit of 24 months when stored at 5°C ±3°C, with an allowable 6 months at room temperature up to 30°C.

The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all validation test acceptance criteria. The proposed container closure system is considered acceptable.

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 of the facilities involved in the manufacture and testing of the drug substance and the drug product was successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

Adventitious Agents Safety Evaluation

The manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. The capture chromatography with detergent wash, anti FVIII affinity chromatography, anion exchange chromatography and nanofiltration steps were identified as viral clearance steps for the Zonovate drug substance manufacturing process. Additional data were provided supporting viral reduction in the purification process for the anti-FVIII monoclonal antibody used for the affinity chromatography step. The total reduction factor for relevant and model viruses demonstrates that the manufacturing process provides sufficient viral clearance of potential adventitious viruses.

 

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