Summary Basis of Decision for Cablivi

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 Cablivi is located below.

Recent Activity for Cablivi

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.

Summary Basis of Decision (SBD) for Cablivi

Date SBD issued: 2020-05-29

The following information relates to the new drug submission for Cablivi.

Caplacizumab

Drug Identification Number (DIN):

  • DIN 02496194 - 11 mg, powder for solution, intravenous or subcutaneous administration

Sanofi-aventis Canada Inc.

New Drug Submission Control Number: 230001

On February 28, 2020, Health Canada issued a Notice of Compliance to Sanofi-aventis Canada Inc. for the drug product Cablivi.

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 Cablivi is favourable for the treatment of adults with acquired thrombotic thrombocytopenic purpura in combination with plasma exchange and immunosuppressive therapy.

1 What was approved?

Cablivi, an antithrombotic agent, was authorized for the treatment of adults with acquired thrombotic thrombocytopenic purpura in combination with plasma exchange and immunosuppressive therapy.

No data are available to Health Canada regarding the use of Cablivi in patients younger than 18 years of age. Consequently, an indication for pediatric use has not been authorized.

Clinical studies of Cablivi did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently to Cablivi than younger patients.

Cablivi is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Cablivi 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.

Cablivi (11 mg caplacizumab) is presented as a powder for solution. In addition to the medicinal ingredient, the powder for solution contains sucrose, citric acid anhydrous, trisodium citrate dihydrate, and polysorbate 80.

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

2 Why was Cablivi approved?

Health Canada considers that the benefit-risk profile of Cablivi is favourable for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy.

Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening, thrombotic microangiopathy. The disease is considered to be the ultimate outcome of a disorder in metabolic processing of the clotting protein, von Willebrand factor (vWF), due to a deficiency of a key protease, "a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13" (ADAMTS13). The ADAMTS13 enzyme is responsible for breaking down ultralarge vWF multimers. A severe deficiency of ADAMTS13 (<10% activity levels) results in the intravascular persistence of ultralarge vWF multimers that bind to, accumulate, and activate platelets, forming excessive vWF-rich platelet microthrombi. These microthrombi scavenge platelets to cause thrombocytopenia, and mechanically destroy passing red blood cells in microvessels, resulting in hemolytic anemia with fragmented red blood cells (schistocytes). Microthrombi may occlude the microcirculation, leading to severe organ ischemia and even death.

Thrombotic thrombocytopenic purpura can be either congenital or acquired. The less common congenital TTP is due to mutations in the ADAMTS13 gene. Acquired TTP (aTTP) is caused by autoantibodies directed against ADAMTS13. The most common triggers for ADAMTS13 autoantibody formation include antiplatelet drugs, immunosuppressive agents, human immunodeficiency virus (HIV), estrogen-containing birth control, and pregnancy. Estimated incidences of TTP are between 1 and 13 cases per million people depending on geographic location, with a 2:1 female to male predominance. The disease most often occurs after 40 years of age, but congenital forms can occur in children. The mortality in TTP without proper treatment is about 90%. Most TTP cases are discovered in the ambulatory setting after a period of days to weeks during which the patient feels poorly. Since the classic TTP pentad of symptoms (fever, severe thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction) only occurs in 50% of cases, clinical and laboratory evaluation plays a critically important role in the early diagnosis of TTP.

Currently, a combination of plasma exchange and immunosuppressive therapy is the mainstay in treatment of TTP worldwide. This treatment should be initiated as soon as possible in all patients who have unexplained hemolytic anemia and thrombocytopenia with a normal prothrombin time, international normalized ratio (PT/INR) and partial thromboplastin time (PTT). Plasma exchange removes the ultralarge vWF multimers and ADAMTS13 autoantibodies, and supplies active ADAMTS13. Reported mortality of TTP has dropped from around 90% to between 10% and 20% since wide acceptance of this treatment. However, even with successful treatment, the rate of relapse was reported to be 8% to 84% in a period of 6 months or up to 13 years after the first plasma exchange treatment. Recurrences typically occur within 1 to 2 years after the initial episode.

Caplacizumab, the medicinal ingredient in Cablivi, is a first-in-class humanized bivalent nanobody (a single-domain antibody fragment) directed against the human A1 domain of vWF. Nanobodies are derived from the heavy chain variable domains of immunoglobulins from Camelidae and have a high degree of sequence and structural homology to heavy chain variable region domains of human immunoglobulins. Binding of caplacizumab to vWF inhibits the interaction between vWF and platelets and reduces the vWF-mediated platelet activation and adhesion. Consequently, caplacizumab prevents the formation of ultralarge vWF-rich platelet microthrombi but also increases the risk of bleeding. Caplacizumab treatment affects the disposition of vWF, leading to reduction in the plasma vWF level and the plasma level of coagulation factor VIII (FVIII), since vWF also functions as a carrier for FVIII.

Cablivi, used in conjunction with daily plasma exchange and immunosuppressive therapy, has been shown to be efficacious in adults experiencing an acute episode of aTTP. The market authorization of Cablivi was based on data derived from a pivotal, randomized, double-blind, placebo-controlled, Phase III clinical trial (HERCULES). Compared to placebo treatment, Cablivi significantly reduced the time to platelet count response and the rate of exacerbation during the treatment period. Supportive data stemmed from a Phase II, randomized, single-blind, placebo-controlled, multicentre clinical study (TITAN) in adult patients with an acute episode of aTTP.

In the clinical studies, treatment with Cablivi was generally well tolerated in patients with aTTP. The most frequently reported (in >10% of patients) adverse reactions were epistaxis (29%), headache (21%), gingival bleeding (16%), fatigue (15%), and pyrexia (13%). Bleeding-related adverse reactions were among the most frequent adverse reactions. Serious bleeding adverse reactions were reported in ≥2% of patients and included epistaxis (4%) and subarachnoid hemorrhage (2%). For clinically significant bleeding, it is recommended to interrupt use of Cablivi and, if needed, to administer vWF concentrate.

A relapse of aTTP, especially shortly after stopping Cablivi treatment, is a potential concern. In most of the patients who suffered a relapse within 30 days after discontinuation of Cablivi treatment, ADAMTS13 activity levels were <10% at the end of the Cablivi treatment, indicating that the underlying immunological disease was still active at the time Cablivi was stopped. Therefore, patients, especially those with ADAMTS13 activity <10% at or near the time of discontinuation of Cablivi, should be closely monitored for platelet counts and signs of aTTP for early diagnosis of relapse after stopping or interrupting use of Cablivi.

A Risk Management Plan (RMP) for Cablivi was submitted by Sanofi-aventis 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. The sponsor is expected to submit an updated Canadian RMP to Health Canada prior to the launch of the product in Canada.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Cablivi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

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

Overall, in combination with plasma exchange and immunosuppressive therapy, Cablivi has been shown to provide a benefit to the intended patient population, with an acceptable safety profile. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Cablivi 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 Cablivi?

The drug submission for Cablivi was reviewed under the Priority Review Policy. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Cablivi, in conjunction with plasma exchange and immunosuppression, provides an effective treatment of acquired thrombotic thrombocytopenic purpura, a serious, life-threatening disease for which no drug is presently marketed in Canada.

Submission Milestones: Cablivi

Submission MilestoneDate
Pre-submission meeting:2018-10-26
Request for priority status
Filed:2019-05-17
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics:2019-06-06
Submission filed:2019-07-22
Screening
Screening Acceptance Letter issued:2019-08-16
Review
Review of Risk Management Plan complete:2019-12-30
Quality Evaluation complete:2020-02-10
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2020-02-14
Clinical/Medical Evaluation complete:2020-02-28
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:2020-02-28

The Canadian regulatory decision on the review of Cablivi was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

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 Cablivi?

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 life cycle.

At this time, no PAAT is available for Cablivi. When available, the PAAT will be incorporated into this SBD.

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

Caplacizumab, the medicinal ingredient in Cablivi, is a humanized bivalent nanobody, i.e., a single-domain antibody fragment. It targets the A1 domain of von Willebrand factor (vWF) and inhibits the interaction between vWF and platelets, thereby reducing vWF-mediated platelet activation and adhesion. Thus, caplacizumab prevents the formation of ultralarge vWF-rich platelet microthrombi but increases the risk of bleeding. It also affects the disposition of vWF, leading to reduction in the level of both vWF and coagulation factor VIII during treatment.

Studies in healthy subjects showed a biphasic pharmacokinetic profile for caplacizumab after a single intravenous dose. Due to the high affinity for vWF, caplacizumab appears to exist predominantly as caplacizumab-vWF complexes until all plasma vWF molecules are saturated with bound caplacizumab. Free caplacizumab is rapidly eliminated from the blood, most likely through the kidney, with a half-life of less than 0.5 hours.

In healthy subjects, a single intravenous dose of caplacizumab (2 mg to 12 mg) resulted in a rapid reduction of the vWF plasma concentration. A maximum reduction was reached between 6 to 8 hours after the start of the 60-minute intravenous dosing, indicating that caplacizumab accelerated elimination of vWF from circulation.

The apparent terminal half-life of caplacizumab in plasma from healthy subjects was generally positively dose-dependent, ranging from 8.2 hours to 40.6 hours, for an intravenous dose range of 0.5 mg to 12 mg. The half-life of vWF in human plasma is reported to be around 16 hours.

Pharmacokinetic studies in healthy subjects showed that the activity and concentration of the plasma vWF returned to their baseline levels within 7 days after discontinuation of the treatment.

The clinical pharmacology data support the use of Cablivi for the recommended indication.

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

Clinical Efficacy

The efficacy of Cablivi, in combination with plasma exchange and immunosuppressive therapy, was established in a Phase III, randomized, double-blind, placebo-controlled, multicentre clinical study (HERCULES), conducted in adult patients experiencing an acute episode of acquired thrombotic thrombocytopenic purpura (aTTP).

After the start of plasma exchange treatment, 145 eligible patients were randomized in a ratio of 1:1 to receive Cablivi (number of patients [n] = 72) or placebo (n = 73) in addition to daily plasma exchange and immunosuppression. The overall study period encompassed a period of study drug treatment and a follow-up period.

Patients received a single intravenous bolus injection of 11 mg of Cablivi or placebo prior to the first plasma exchange on study. Subsequently, daily subcutaneous injections of 11 mg of Cablivi or placebo were administered after completion of each plasma exchange, for the duration of the daily plasma exchange period and for 30 days thereafter. Once the platelet count reached ≥150 x 109/L, daily plasma exchange continued for at least 2 days. If at the end of this treatment period evidence of persistent underlying immunological disease activity remained present, such as suppressed ADAMTS13 activity levels (indicative of a risk of imminent recurrence), treatment could be extended for additional 7-day periods, for a maximum of 4 weeks, along with optimization of immunosuppression.

Patients who experienced a recurrence during the double-blind treatment period were switched to open-label treatment with Cablivi. They were treated with Cablivi for the duration of the daily plasma exchange period and for 30 days thereafter. If at the end of this treatment period there was evidence of ongoing underlying immunological disease, open-label treatment with Cablivi could be extended for additional 7-day periods, for a maximum of 4 weeks, in conjunction with optimization of immunosuppression.

Notably, only 22.7% of patients who had treatment extension actually received optimized immunosuppressive treatment in the study.

The median treatment duration with Cablivi was about 35 days (range: 1 to 65 days). After discontinuation of treatment, patients were followed for up to 28 days.

The primary endpoint was time to platelet count response, defined as initial platelet count ≥150 x 109/L with subsequent cessation of daily plasma exchange within 5 days. It refers to the first time both conditions, platelet count ≥150 x 109/L and the stop of daily plasma exchange within 5 days, were met.

Patients treated with Cablivi achieved a statistically significant (p<0.01) reduction in time to platelet count response and were 1.6 times more likely to achieve a platelet count response at any given time point, compared to patients treated with placebo (hazard ratio [HR] = 1.55; 95% confidence interval [CI]: 1.10, 2.20). Treatment with Cablivi resulted in a lower proportion of patients with aTTP-related death, recurrence of aTTP or at least one treatment-emergent major thromboembolic event (a composite endpoint) during the study drug treatment period (12.7% [9/72] in the Cablivi group versus 49.3% [36/73] in the placebo group, p<0.0001).

The proportion of patients with a recurrence (an exacerbation or a relapse) of aTTP in the overall study period (study drug treatment period and 28-day follow-up period) was 12.7% (9/71) in the Cablivi group compared to 38.4% (28/73) in the placebo group, (p<0.001).

Supportive data were derived from TITAN, a Phase II, randomized, single-blind, placebo-controlled, multicentre clinical study in adult patients with an acute episode of aTTP. There were 75 eligible patients randomized in a ratio of 1:1 to receive Cablivi (n = 36) or placebo (n = 39), in addition to daily plasma exchange and immunosuppressive therapy. Generally, patients received a single intravenous bolus injection of 10 mg Cablivi or placebo prior to the first plasma exchange on study. This was followed by daily subcutaneous injections of 10 mg Cablivi or placebo after completion of each plasma exchange, for the duration of the daily plasma exchange period and for 30 days thereafter. Discontinuation of daily plasma exchange treatment depended on the normalization of platelet count (≥150 x 109/L), neurological status, and other clinical and laboratory parameters. The study drug administration continued in case of a reinitiation of plasma exchange for an exacerbation of aTTP, with a maximum total treatment duration limited to 90 days after the first study drug administration. Patients were followed for up to 12 months after discontinuation of study drug treatment. The median duration of exposure was 36 days (range: 3 to 77 days) for Cablivi and 37 days (range: 2 to 90 days) for placebo. Overall, 55.6% (20/36) of patients in the Cablivi treatment group and 53.8% (21/39) of patients in the placebo treatment group completed the study. The data from this study are considered supportive, as the study was prematurely terminated due to recruitment challenges in a rare disease setting.

Indication

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

  • Cablivi (caplacizumab) is indicated for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).

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

  • Cablivi (caplacizumab) is indicated for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP) in combination with plasma exchange (PE) and immunosuppressive therapy.

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

Clinical Safety

The safety of Cablivi for the treatment of adult patients with aTTP was assessed in two placebo-controlled clinical studies, HERCULES and TITAN (described in the Clinical Efficacy section). The safety analysis set included data from 106 patients, aged 18 to 79 years, who received at least one dose of Cablivi during the blinded periods of both studies. The median treatment duration with Cablivi was 35 days (range: 1 to 77 days).

The most frequently reported (in >10% of patients) adverse reactions were epistaxis (29%), headache (21%), gingival bleeding (16%), fatigue (15%), and pyrexia (13%). Bleeding-related adverse reactions were among the most frequent adverse reactions. Serious bleeding adverse reactions were reported in ≥2% of patients and included epistaxis (4%) and subarachnoid hemorrhage (2%).

Relapses were observed in both clinical trials, especially shortly after discontinuation of Cablivi.

During the one-month follow-up period after stopping the study drug in the HERCULES study, relapses occurred in the Cablivi group (6/72, 8.3%) and in the patients who switched from placebo to open-label Cablivi due to exacerbation (3/25, 12%). No relapses were reported in patients who received only placebo (0/48). All but one of the observed relapses occurred 4 to 11 days after the last dose of Cablivi. One of these patients in the Cablivi group experienced severe thrombocytopenia and cerebral ischemia 6 days after stopping Cablivi treatment and died 2 days later.

During the first 150 days in the 12-month follow-up period of the TITAN study, 27.7% (10/36) of the patients in the Cablivi group experienced relapses as compared to none in the placebo group (0/39). In the first 30 days of the follow-up period, the rate of relapses in the Cablivi group was 22% (8/36). Most of these relapses (7/8) occurred within 10 days after discontinuation of Cablivi.

In 15 of 16 patients who had a relapse in the first 30-day period during these two clinical trials, ADAMTS13 activity levels were <10% at the end of the treatment with Cablivi.

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

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

7.2 Non-Clinical Basis for Decision

The primary pharmacology of caplacizumab has been characterized in vitro using recombinant von Willebrand factor (vWF) fragments, purified vWF, plasma, platelets or whole blood. In the in vitro assays, the sponsor demonstrated that binding of caplacizumab to the A1 domain of vWF resulted in complete blockage of platelet binding to multimeric vWF in plasma from healthy volunteers and patients with acquired TTP. In particular, the pharmacodynamic effects of caplacizumab were evaluated with the ristocetin cofactor (RICO) assay. The RICO assay measures the ability of vWF to interact with the platelet glycoprotein (GP)Ib-IX-V receptor complex, which is the pharmacological target of vWF. Based on the crystal structure of caplacizumab bound to the A1 domain of vWF, it is believed that caplacizumab disrupts the interaction of vWF with the glycoprotein receptor complex by an allosteric inhibition mechanism.

In vivo studies showed that caplacizumab could prevent and treat acute episodes of TTP in an established disease model in baboons.

In tissues isolated from different animal species, the nanobody cross-reacted with tissues where vWF is expected to be expressed.

The secondary pharmacodynamic studies demonstrated no interference with vWF binding to collagen type VI, ADAMTS13, fibrillary collagens, and coagulation factor VIII (FVIII). Caplacizumab does not interfere with the enzymatic activity of ADAMTS13. Also, it was shown that caplacizumab does not bind to human blood cells. Lower levels of vWF and FVIII were observed in animals treated with caplacizumab. These results are consistent with results from the repeat-dose toxicology and clinical pharmacology studies.

Toxicology studies have been conducted in guinea pigs and cynomolgus monkeys with doses yielding exposures of up to 50 times and 24 times, respectively, the expected exposure from the daily human dose. Safety pharmacology parameters were evaluated as part of the repeat-dose studies.

Consistent with its mode of action, toxicology studies of caplacizumab have shown an increased bleeding tendency in guinea pigs (hemorrhagic subcutaneous tissue at the injection sites) and cynomolgus monkeys (hemorrhagic subcutaneous tissue at the injection sites, nose bleed, exaggerated menstrual bleeding, hematoma at sites of animal handling or experimental procedures, prolonged bleeding at injection sites). Furthermore, pharmacology-related decreases of vWF antigen, and consequently FVIII activity, were noted in cynomolgus monkeys and, to a lesser extent, for FVIII activity, in guinea pigs.

The pharmacokinetic studies in animals showed that free caplacizumab was distributed mainly in the liver and kidney. Caplacizumab was detected in the urine of animals. However, the pharmacokinetic studies did not produce evidence relevant to humans regarding the distribution and/or elimination of caplacizumab-vWF complexes.

In some monkeys, anti-drug antibodies against FVIII were observed following treatment with caplacizumab. In two male animals in the low-dose and mid-dose caplacizumab groups, a transient positive anti-FVIII antibody response was noted at selected time points, which was absent during the recovery period. However, one male animal in the high-dose group had marked decreases of the FVIII antigen and FVIII activity during treatment that corresponded to a positive anti-FVIII antibody response, and resulted in bleeding leading to a scheduled sacrifice on day 85 of the study.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Cablivi Product Monograph. In view of the intended use of Cablivi, no pharmacological or toxicological issues were identified within this submission to preclude authorization of the product.

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

Caplacizumab, the medicinal ingredient in Cablivi, is a bivalent nanobody (a single-domain antibody fragment) directed against the human A1 domain of the von Willebrand factor. It inhibits the interaction between von Willebrand factor and platelets, thereby reducing von Willebrand factor-mediated platelet activation and adhesion. The protein consists of two identical humanized (originally derived from Camelidae) heavy chain variable domains linked by a tri-alanine sequence. Caplacizumab has 259 amino acids and a molecular weight of 27,876 Da.

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

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

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

The drug substance is expressed in Escherichia coli as a secreted protein. The clarified harvest from the fermentation process is sequentially processed using chromatography steps. Following these steps, the eluate undergoes ultrafiltration and diafiltration prior to final formulation, filtration, and storage at ≤-60°C. The sponsor has demonstrated the comparability of the drug substance across the developmental stages and the ability of the proposed manufacturing facility to consistently manufacture caplacizumab of appropriate quality at the commercial scale.

The drug product manufacturing process consists of thawing, dispensing, pooling, and mixing of the bulk drug substance. Subsequently, the pooled batch undergoes bioburden reduction filtration and sterile filtration, followed by filling at a target of 1.0 mL (12.5 mg) in glass vials, partial stoppering, lyophilization, stoppering, crimping, visual inspection, and storage at 2°C to 8°C. The sponsor has demonstrated that the drug product is comparable across the developmental stages and that the proposed facility can consistently manufacture Cablivi of appropriate quality at the commercial scale.

The diluent used for reconstitution of Cablivi is sterile water for injection. It is manufactured with a filter/fill and terminal sterilization process. The sponsor has demonstrated that the manufacturing facility is capable of consistently producing sterile water for injection of acceptable quality.

The method of manufacturing and the controls used during the manufacturing process for the drug substance, drug product and diluent are validated and considered to be adequately controlled within justified limits.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of caplacizumab with the excipients is supported by the stability data provided.

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 guidelines.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and 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 and drug product were adequately supported and are considered to be satisfactory.

The stability data support the proposed shelf life of 48 months for the drug product, Cablivi, when stored at a temperature of 2°C to 8°C.

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.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

Based on risk assessment scores determined by Health Canada, on-site evaluations of the facilities involved in the manufacture and testing of the drug substance, the drug product, and the diluent were not deemed necessary.

All sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The manufacturing process of Cablivi incorporates adequate control measures to prevent contamination and maintain microbial control.

The prokaryotic expression system used does not support the growth of viral adventitious agents. Bacteriophage, bioburden and endotoxin testing are integrated in the control strategy and meet relevant guidelines and requirements.

Raw materials, product contact materials, and excipients used for the manufacturing of the drug substance and drug product present no bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE) transmission risk.

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