Summary Basis of Decision for Sarclisa

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 Sarclisa is located below.

Recent Activity for Sarclisa

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Sarclisa, a product which contains the medicinal ingredient isatuximab. 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.

Updated: 2024-09-06

Drug Identification Number (DIN):

  • DIN 02498235 ‑ 100 mg/5 mL isatuximab, solution, intravenous administration
  • DIN 02498243 ‑ 500 mg/25 mL isatuximab, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 286574

2024-05-03

Issued NOL 2024-05-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf‐life specifications and a change in the drug product release or shelf‐life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 272393

2023-02-13

Issued NOC 2024-01-12

Submission filed as a Level I – Supplement to update the PM with new efficacy data from the IKEMA study. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Drug Interactions, Clinical Pharmacology; and Clinical Trials sections of the PM. An NOC was issued.

SNDS # 272234

2023-02-08

Issued NOC 2024-01-10

Submission filed as a Level I – Supplement to update the PM with new safety and efficacy data from the ICARIA-MM study. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 270910

2022-12-23

Issued NOC 2023-08-10

Submission filed as a Level I – Supplement to add an alternate drug substance manufacturing facility and a change in scale of the manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 276150

2023-06-09

Issued NOL 2023-07-31

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 considered acceptable, and an NOL was issued.

SNDS # 270256

2022-12-06

Issued NOC 2023-05-11

Submission filed as a Level I – Supplement to update the inner and outer labels to meet Plain Language Labelling requirements. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 264377

2022-05-18

Issued NOC 2022-10-12

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 265325

2022-06-17

Issued NOL 2022-07-18

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 256460

2021-09-07

Issued NOL 2021-11-02

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the cell banks and a change in cell bank/seed bank qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 244601

2020-10-01

Issued NOC 2021-09-13

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Sarclisa (isatuximab for injection) is indicated in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.

SNDS # 247701

2020-12-18

Issued NOC 2021-05-05

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 243282

2020-09-02

Issued NOL 2020-10-15

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

Drug product (DINs 02498235, 02498243) market notification

Not applicable

Date of first sale: 2020-07-03

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

NDS # 229245

2019-06-28

Issued NOC 2020-04-29

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Sarclisa

Date SBD issued: 2020-12-08

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

Isatuximab

Drug Identification Number (DIN):

  • DIN 02498235 - 100 mg/5 mL isatuximab, solution, intravenous administration
  • DIN 02498243 - 500 mg/25 mL isatuximab, solution, intravenous administration

Sanofi-Aventis Canada Inc.

New Drug Submission Control Number: 229245

 

On April 29, 2020, Health Canada issued a Notice of Compliance to Sanofi-Aventis Canada Inc. for the drug product Sarclisa.

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 Sarclisa in combination with pomalidomide and dexamethasone, is indicated for the treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

 

1 What was approved?

 

Sarclisa, an antineoplastic, was authorized for use in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

Sarclisa is not indicated for use in pediatric patients (<18 years of age), as its safety and efficacy have not been established in this population.

No overall differences were observed between geriatric patients (≥65 years of age) and younger patients with respect to safety and efficacy.

Sarclisa 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.

Sarclisa 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.

Sarclisa (100 mg/5 mL and 500 mg/25 mL, isatuximab) is presented as a concentrate for solution for intravenous administration. In addition to the medicinal ingredient isatuximab, the solution also contains the following non-medicinal ingredients: histidine, histidine hydrochloride monohydrate, polysorbate 80, sucrose, and water for injection.

For administration, the 20 mg/mL concentrate is diluted in sodium chloride 0.9% or dextrose 5%.

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

 

2 Why was Sarclisa approved?

 

Health Canada considers that the benefit-risk profile of Sarclisa is favourable for use in combination with pomalidomide and dexamethasone for treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

Multiple myeloma is an incurable disease. If not treated, it can cause serious complications and is life-threatening. Although new therapies have significantly improved the outcome of patients with multiple myeloma in recent years, patients with relapsed and refractory disease who have received at least two prior lines of therapy including lenalidomide and a proteasome inhibitor have limited treatment options. Novel agents and combinations are needed in this patient population to improve disease control, delay progression, prevent myeloma-related complications and ultimately improve survival and overall quality of life.

Sarclisa is an immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the human cell surface antigen molecule classified as cluster of differentiation 38 (CD38). The CD38 molecule is a transmembrane glycoprotein highly expressed on multiple myeloma cells. In pharmacology studies, isatuximab (the medicinal ingredient in Sarclisa) induced multiple myeloma cell death through both Fc-dependent and -independent mechanisms.

Sarclisa has been shown to be efficacious in adult patients with relapsed and refractory multiple myeloma. The market authorization was based primarily on one pivotal Phase III study ICARIA-MM (EFC14335). This study was a multi-centre, randomized, open-label, two arm study conducted in adult patients with relapsed and refractory multiple myeloma who had received at least two prior lines of therapy including lenalidomide and a proteasome inhibitor. The primary efficacy endpoint in the ICARIA-MM study was progression-free survival (PFS) as assessed by an Independent Review Committee (IRC) using the 2016 International Myeloma Working Group (IMWG) criteria.

Study results from the ICARIA-MM study showed the study met its primary efficacy endpoint by demonstrating a statistically significant improvement in PFS in the Sarclisa in combination with pomalidomide and dexamethasone group versus the pomalidomide and dexamethasone group (median PFS: 11.5 vs. 6.5 months; hazard ratio [HR] 0.596, 95% confidence interval [CI]: 0.436-0.814; p = 0.0010). The hazard ratio indicated a 40.4% reduction in the risk of disease progression or death in patients treated with Sarclisa in combination with pomalidomide and dexamethasone versus the pomalidomide and dexamethasone group. In addition, treatment with Sarclisa in combination with pomalidomide and dexamethasone was associated with a statistically higher overall response rate (ORR; a secondary endpoint) compared with pomalidomide and dexamethasone (60.4% vs. 35.3%; p <0.0001). The PFS and ORR improvements are considered clinically meaningful.

Sarclisa in combination with pomalidomide and dexamethasone was associated with increases in Grade ≥3 adverse events (86.8 vs. 70.5% in the pomalidomide and dexamethasone group) and serious adverse events (61.8% vs. 53.7%). The most common adverse reactions with Sarclisa in combination with pomalidomide and dexamethasone were infections, neutropenia and infusion-related reactions. There was also an increased risk of diarrhea, nausea, and vomiting. Cardiac arrhythmias and second primary malignancies occurred more commonly in patients treated with Sarclisa; therefore, the possibility of Sarclisa playing a role in these events cannot be ruled out.

Adverse reactions of Sarclisa in combination with pomalidomide and dexamethasone were generally manageable by dosage adjustment and symptomatic treatments (e.g., granulocyte colony stimulating factor [G-CSF] for neutropenia). There was no increase in treatment discontinuation due to an adverse event or fatal adverse events in patients treated with Sarclisa in combination with pomalidomide and dexamethasone compared to the pomalidomide and dexamethasone group.

A Risk Management Plan (RMP) for Sarclisa was submitted by Sanofi-Aventis Canada Inc. to Health Canada. 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. Upon review for the RMP, several issues were identified by Health Canada. These issues were communicated to the sponsor and subsequently satisfactorily addressed by the sponsor. As a result, the revised RMP is considered acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Sarclisa 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 Sarclisa was accepted.

Overall, the therapeutic benefits of Sarclisa therapy seen in the pivotal Phase III ICARIA-MM study are considered to outweigh the potential risks. Sarclisa 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 Sarclisa 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 Sarclisa?

 

The New Drug Submission for Sarclisa was reviewed as part of the New Chemical Entities Work Sharing Trial, a work-sharing initiative between Canada, Australia, Singapore, and Switzerland. This partnership aims to promote collaboration between regulatory agencies, optimize the use of resources, reduce duplication, and enhance each agency's ability to ensure consumers have timely access to safe, effective, and high-quality therapeutic products.

For this submission, Australia's Therapeutic Goods Administration led review of the clinical and non-clinical data. Health Canada led review of the quality (chemistry and manufacturing) data and the proposed Risk Management Plan. Although the review of the submission was collaborative, each jurisdiction reviewed their respective country-specific information including product labels and made independent decisions regarding market authorization.

 

Submission Milestones: Sarclisa

Submission Milestone Date
Pre-submission meeting: 2017-10-27
Submission filed: 2019-06-28
Screening  
Screening Acceptance Letter issued: 2019-07-29
Review  
Review of Risk Management Plan complete: 2019-10-31
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2020-04-24
Quality Evaluation complete: 2020-04-24
Clinical/Medical Evaluation complete: 2020-04-27
Notice of Compliance issued by Director General, Biologics and Radiopharmaceutical Drugs Directorate: 2020-04-29

 

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

 

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.

The PAAT for Sarclisa 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

 

The clinical review of Sarclisa was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Canada, Singapore, and Switzerland. Health Canada's review of clinical efficacy and safety data was therefore primarily based on the TGA Clinical Evaluation Reports. However, where applicable, Health Canada also consulted source data for additional details, such as the patient eligibility criteria, sponsor's recommendations for the investigators on the management of certain adverse reactions and on the dosage and administration of the study medications, less common adverse events, case narratives of some adverse events, including cardiac adverse events, and second primary malignancies. Additionally, Health Canada also conducted an in-depth review of the pivotal population pharmacokinetics report (POH0503). While the review of the submission was collaborative, with each regulatory agency sharing the outcome of their reviews, each regulatory agency independently made their own decision regarding the authorization of Sarclisa.

Clinical Pharmacology

Isatuximab (the medicinal ingredient in Sarclisa) is an immunoglobulin G1 (IgG1) monoclonal antibody that binds to a specific extracellular epitope of CD38 and triggers several mechanisms leading to the death of CD38 expressing tumour cells. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, expressed in hematological malignancies, including multiple myeloma cells, as well as other cell types and tissues at various levels.

The pharmacokinetic profile of isatuximab was characterized primarily by population pharmacokinetics given the long half-life of isatuximab which limited the use of non-compartmental analysis. The POH0503 population analysis comprised of data from isatuximab single agent and isatuximab/pomalidomide/dexamethasone combination studies including the pivotal Phase III study (i.e., ICARIA-MM [EFC14335]). Isatuximab pharmacokinetics was described by a 2-compartment structural kinetic model with parallel linear and Michaelis-Menten eliminations from the central compartment and a time-varying function on linear clearance. While there were considerable limitations associated with the final model, the model is considered adequate for the context of use in describing the pharmacokinetic profile of isatuximab.

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

Clinical Efficacy

The efficacy and safety of Sarclisa in combination with pomalidomide and dexamethasone were evaluated primarily in the pivotal ICARIA-MM (EFC14335) study. This pivotal study was a Phase III multicentre, multinational, randomized, open-label, two-arm, clinical study conducted in adult patients with relapsed and refractory multiple myeloma. Patients had received at least two prior therapies including lenalidomide and a proteasome inhibitor. All patients had refractory disease to the last prior therapy. Patients with primary refractory disease or who had received prior anti-CD38 therapy were excluded.

A total of 307 patients were randomized in a 1:1 ratio to receive either Sarclisa in combination with pomalidomide and dexamethasone (Isa-Pd) or pomalidomide and dexamethasone (Pd). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. Sarclisa was administered at 10 mg/kg as a weekly intravenous infusion in the first four weeks, and once every two weeks thereafter. Pomalidomide 4 mg was taken orally once daily from day 1 to day 21 of each 28-day cycle. Dexamethasone (orally or intravenously) 40 mg (20 mg for patients ≥75 years of age) was given on days 1, 8, 15, and 22 for each 28-day cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 67 years (range 36 to 86).

The primary efficacy endpoint of the study was progression-free survival (PFS). Progression-free survival results were evaluated by an Independent Review Committee (IRC) based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria. Key secondary efficacy endpoints were overall response rate (ORR) per the IRC assessment and overall survival (OS).

Efficacy results from the ICARIA-MM (EFC14335) study demonstrated that the primary efficacy endpoint was met by showing a statistically significant improvement in PFS in the Isa-Pd group compared to the Pd group. The median PFS was 11.5 months (95% confidence interval [CI]: 8.9-13.9) in the Isa-Pd group versus 6.5 months (95% CI: 4.5-8.3) in the Pd group (hazard ratio [HR] = 0.596; 95% CI: 0.436-0.814, p = 0.0010), representing a 40.4% reduction in the risk of disease progression or death in patients treated with Isa-Pd. The results of pre-planned sensitivity and subgroup analyses of PFS were generally consistent with that of the primary analysis.

In regards to secondary efficacy endpoints, in the Isa-Pd group the ORR as assessed by the IRC was statistically higher compared with the Pd group (60.4% vs. 35.3%, p <0.0001). At the time of analysis, the OS was not mature, and the interim OS analysis was not statistically significant. No detrimental effect on OS was observed in the Isa-Pd group compared to the Pd group (HR 0.687, 95% CI: 0.461-1.023). The study is ongoing, and a final OS analysis is planned.

In sum, the efficacy results are considered clinically meaningful for the treatment of patients who have received at least two prior lines of therapy including lenalidomide and a proteasome inhibitor. The uncertainty about the clinical efficacy evidence is related to the exclusion of patients with primary refractory disease or who have received a prior anti-CD38 therapy in the study. These exclusion criteria were adequately described in the Sarclisa Product Monograph.

Indication

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

  • Sarclisa (isatuximab for injection), in combination with pomalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least two therapies including lenalidomide and a proteasome inhibitor.

Health Canada approved the following indication:

  • Sarclisa (isatuximab for injection), in combination with pomalidomide and dexamethasone, for the treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.

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

Clinical Safety

The clinical safety of Sarclisa in combination with pomalidomide and dexamethasone (Isa-Pd) for the treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior therapies (including lenalidomide and a proteasome inhibitor) was evaluated in the pivotal Phase III randomized, open-label, two-arm ICARIA-MM (EFC14335) study previously described in the Clinical Efficacy section.

In the ICARIA-MM (EFC14335) study, the most frequent treatment-emergent adverse events (TEAEs, in >20% of Isa-Pd patients) were neutropenia, infections, and infusion-related reactions (IRRs). There was also an increased risk of diarrhea, nausea, and vomiting, mostly Grade 1 or 2, in the Isa-Pd group. Cardiac arrhythmias and second primary malignancies (mainly non-melanoma skin cancers) occurred more commonly in the Isa-Pd group and a potential role of Sarclisa in these events cannot be excluded.

The overall incidence of serious TEAEs was 61.8% in the Isa-Pd group and 53.7% in the pomalidomide and dexamethasone (Pd) group. Most common serious TEAEs (≥2%) with at least a 2% higher incidence in the Isa-Pd group versus the Pd group were infections (39.5 vs. 30.5%), febrile neutropenia (6.6% vs. 2.0%), neutropenia (3.3% vs. 1.3%) and infusion-related reactions (3.9% vs. 0.7%). Fatal adverse events (AEs) were reported in 11.2% of patients in the Isa-Pd group and 11.4% in the Pd group. Fatal AEs reported in >1% of patients in the Isa-Pd group were pneumonia and other infections (3.3%).

Permanent discontinuation of treatment because of TEAEs was reported in 11 patients (7.2%) treated with Isa-Pd and in 19 patients (12.8%) treated with Pd. The most common TEAEs leading to treatment discontinuation in the Isa-Pd group were infections (2.6%). In the Isa-Pd group, Sarclisa dose delay because of TEAEs was reported in 58.6% of patients, most frequently (≥3% of patients) due to neutropenia (27.0%), pneumonia (6.6%), bronchitis (4.6%), upper respiratory infection (3.9%) and diarrhea (3.9%).

Overall, adverse reactions of Sarclisa were generally manageable, by dose adjustment and symptomatic treatment (e.g., granulocyte colony stimulating factor [G-CSF] for neutropenia). There was no increase in treatment discontinuation due to an adverse event or fatal adverse events in the Isa-Pd group compared with the Pd group.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical review of Sarclisa was completed by Australia's Therapeutic Goods Administration (TGA) as part of a work-sharing initiative with Canada, Singapore, and Switzerland. Therefore, Health Canada's review of the non-clinical data was based on the TGA's non-clinical evaluation report.

According to the TGA's report, the non-clinical package complied with the International Council for Harmonisation (ICH) S6(R1) and S9 guidelines for non-clinical evaluation of anticancer pharmaceuticals and biotechnology-derived pharmaceuticals. However, the non-clinical evaluation was limited due to the species specificity of isatuximab (the medicinal ingredient in Sarclisa). The submitted studies were of high quality, and the main toxicity study was Good Laboratory Practice (GLP) compliant. Consistent with relevant ICH guidelines, no studies on genotoxicity, carcinogenicity, fertility and early embryonic development, and pre- or post-natal development were submitted. Effects on embryofetal development were not investigated due to the absence of appropriate animal models.

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

 

 

7.3 Quality Basis for Decision

 

The quality review of Sarclisa was completed by Health Canada as part of a work-sharing initiative with Australia, Singapore, and Switzerland. The review of the submission was collaborative, with each regulatory agency sharing the outcome of their review with the others. However, each regulatory agency made their decision regarding authorization independently.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that isatuximab (the medicinal ingredient in Sarclisa) consistently exhibits the desired characteristic structure and biological activity. Detailed studies were conducted for appearance and description, identity and structural characterization, determination of size variants (product-related impurities), total protein content, potency, polysorbate 80 content, and safety.

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

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

Isatuximab (the drug substance) is produced by recombinant deoxyribonucleic acid (DNA) technology from a mammalian cell line (Chinese Hamster Ovary, CHO). The manufacture of isatuximab is based on a CHO master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of isatuximab consists of a series of steps which include cell culture, harvest, purification (including viral inactivation/removal steps), and formulation buffer exchange. The purification process includes a combination of chromatographic steps. The materials used in the manufacture of the drug substance are considered suitable and meet standards appropriate for their intended use.

The manufacturing of Sarclisa (the drug product) consists of steps which include drug substance thawing, pooling and homogenization, prefiltration, sterilizing filtration of the pre-filtered solution at the point of fill, aseptic filling into glass vials, and stoppering and crimping of the vials. The vials are closed with sterilized rubber stoppers, crimped with aluminum seals with a plastic flip-off cap, visually inspected, and stored. The drug product manufacturing process uses appropriate aseptic process techniques, equipment, and facilities.

In-process controls and lot release tests for the drug substance and drug product were established and validated.

The manufacturing processes are 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 isatuximab 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, and analytical procedures are validated in accordance with International Council on Harmonisation (ICH) guidelines.

Each lot of isatuximab is tested for appearance, content, identity, potency, purity, impurities, and safety (endotoxins and microbial contamination or sterility). Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured drug product lots were tested, evaluated, and found to meet the specifications of the drug product for a subset of the release tests and confirm both the sponsor's results and the suitability of those methods for routine lot release.

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 proposed 36-month shelf life at 2° to 8°C, protected from light, for Sarclisa is considered acceptable.

Facilities and Equipment

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

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

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

Adventitious Agents Safety Evaluation

No materials of animal/human origin are used directly in the production of the drug substance isatuximab, or the drug product Sarclisa, other than the CHO cells. The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

Bovine tallow derivatives are used indirectly in the manufacturing process, but there is no bovine spongiform encephalopathy/transmissible spongiform encephalopathy risk associated with this product given these derivatives are adequately tested to ensure freedom from adventitious agents.

 

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