Summary Basis of Decision for Asparlas

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.


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Summary Basis of Decision (SBD)

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

Recent Activity for Asparlas

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

Summary Basis of Decision (SBD) for Asparlas

Date SBD issued: 2024-06-11

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

Calaspargase pegol

Drug Identification Number (DIN): 02542943 – 3,750 units/5 mL calaspargase pegol, solution, intravenous infusion

Servier Canada Inc.

New Drug Submission Control Number: 268282

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): L01 Antineoplastic agents

Date Filed: 2022-09-29

Authorization Date: 2023-11-08

On November 8, 2023, Health Canada issued a Notice of Compliance to Servier Canada Inc. for the drug product Asparlas.

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 Asparlas is favourable when indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 to 21 years.

1 What was approved?

Asparlas, an antineoplastic agent, was authorized for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 to 21 years.

The safety and efficacy of Asparlas were evaluated in pediatric patients 1 year of age and older in clinical studies. Health Canada has authorized an indication for pediatric use.

No data were available on the safety and efficacy of Asparlas in patients 65 years of age or older, therefore, Health Canada has not authorized an indication for geriatric use.

Asparlas (3,750 units/5 mL calaspargase pegol) is presented as a solution. In addition to the medicinal ingredient, the solution contains monobasic sodium phosphate, dibasic sodium phosphate heptahydrate, sodium chloride, and water for injection.

The use of Asparlas is contraindicated in patients with: anaphylactic or severe hypersensitivity reactions to the active substance (including pegylated L‑asparaginase) or to any of the excipients; severe hepatic impairment; or a history of serious thrombosis, serious pancreatitis or serious hemorrhagic events during previous L-asparaginase therapy.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Asparlas Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Asparlas approved?

Health Canada considers that the benefit-risk profile of Asparlas is favourable for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 to 21 years.

Acute lymphoblastic leukemia is the most commonly diagnosed cancer in children. With contemporary treatments, the long-term survival rate in pediatric ALL patients is approximately 90%.

In Canada, multi-agent chemotherapy is the main treatment for pediatric ALL patients.

Asparaginase has been a critical component of pediatric ALL regimens for decades. Incorporation of asparaginase in ALL regimens has been shown to extend survival. The mechanism of action of asparaginase is to deplete plasma asparagine, leading to the death of leukemia cells that depend on an exogenous source of asparagine for survival.

Pegaspargase, a pegylated Escherichia Coli (E. Coli)-derived L-asparaginase, is the only marketed asparaginase product for front-line treatment of pediatric ALL patients in Canada. There is a need for novel asparaginase products to provide treatment options and to ensure reliable access to asparaginase products for Canadian patients.

Like pegaspargase, Asparlas (calaspargase pegol for injection) is a pegylated E. coli-derived L‑asparaginase product. While the asparaginase is the same as that in pegaspargase, Asparlas uses a more stable succinimidyl carbamate (SC) linker, compared to a succinimidyl-succinate (SS) linker for pegaspargase. As a result, Asparlas has a longer half-life than pegaspargase.

The market authorization was based on the results of two multicentre, randomized, controlled clinical studies, DFCI 11-001 and AALL07P4. In Study DFCI 11-001, patients (total number [n] = 230) were randomized to receive Asparlas 2,500 international units (IU)/m2 every three weeks (Q3W; n = 114) or pegaspargase 2,500 IU/m2 every two weeks (Q2W; n = 116) as a component of the Dana Farber Cancer Institute ALL consortium regimen. In Study AALL07P4, patients (n = 97) were randomized to receive Asparlas 2,500 IU/m2 (n = 42) or pegaspargase 2,500 IU/m2 (n = 55) as a component of the augmented Berlin-Frankfurt-Münster (BFM) ALL regimen. The dosing frequency was the same for Asparlas and pegaspargase. The intervals between the two doses ranged from 2 to 5.5 weeks.

The efficacy of Asparlas was determined based on the achievement and maintenance of nadir serum asparaginase activity (NSAA) ≥0.1 IU/mL in patients treated with Asparlas. In Study AALL07P4, following a single dose administration of 2,500 IU/m2 of Asparlas, the majority of patients achieved asparaginase activity ≥0.1 IU/mL (100% patients in the Asparlas 2,500 IU/m2 group versus [vs.] 95.3% patients in the pegaspargase 2,500 IU/m2 group through 18 days, and 92.9% vs. 29.5% patients through 25 days). Based on modelling and simulation results in patients with evaluable pharmacokinetic samples in Studies AALL07P4 and DFCI 11-001, the NSAA level of ≥0.1 IU/mL is expected to be maintained in 99% of the patients receiving Asparlas 2,500 IU/m2 Q3W.

In Study DFCI 11-001, the most common adverse reactions reported in 20% or more of patients treated with Asparlas were: hypoalbuminemia, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, hypertriglyceridemia, hyperglycemia, and decreased blood fibrinogen. The safety findings between the Asparlas and pegaspargase groups were generally similar and no new asparaginase-related adverse reactions were observed.

In Study AALL07P4, adverse events associated with asparaginase were generally increased in the Asparlas group compared to the pegaspargase group. The small sample size and higher representation of older patients in the study limited the interpretation of these findings. However, the role of a higher exposure to asparaginase activity in the Asparlas group could not be ruled out, as the same numbers of doses were administered for Asparlas and pegaspargase in Study AALL07P4. This uncertainty is adequately managed via labelling (e.g., the potential risk is described in the Product Monograph) and enhanced post-market surveillance.

A Risk Management Plan (RMP) for Asparlas was submitted by Servier 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, the revised RMP was considered to be acceptable. As additional pharmacovigilance activities, the sponsor is expected to submit Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports every six months for the initial two years of marketing in Canada. The sponsor is also expected to provide a comprehensive safety review based on age group stratification and a cumulative review on reported cases with fatal outcomes with Asparlas, including those associated with off-label use.

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

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Asparlas was accepted.

Overall, the therapeutic benefits of Asparlas therapy seen in the clinical studies are considered to outweigh the potential risks and remaining uncertainties as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL in pediatric and young adult patients aged 1 to 21 years. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Asparlas 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 issued 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 Asparlas?

The review of the quality and clinical components of the New Drug Submission (NDS) for Asparlas was based on a critical assessment of the data package submitted to Health Canada. For these components, the review completed by the United States Food and Drug Administration (FDA) was used as an added reference, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The review of the non-clinical component was based on a critical assessment of the non-clinical review conducted by the United States FDA, as per Method 2. The data package submitted to Health Canada was referred to as necessary. The Canadian regulatory decision on the Asparlas NDS was made independently based on the Canadian review.

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

Submission Milestones: Asparlas

Submission Milestone

Date

Pre-submission meeting

2021-12-01

New Drug Submission filed

2022-09-29

Screening

Screening Acceptance Letter issued

2022-11-17

Review

One request was granted to pause review clock (extension to respond to clarification request)

56 days in total

Review of Risk Management Plan completed

2023-10-20

Quality evaluation completed

2023-11-03

Non-clinical evaluation completed

2023-11-03

Biostatistics evaluation completed

2023-11-03

Clinical/medical evaluation completed

2023-11-06

Labelling review completed

2023-11-08

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate

2023-11-08
4 What follow-up measures will the company take?

As part of the marketing authorization for Asparlas, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Food and Drug Regulations, commitments include (but are not limited to):

  • The submission of Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports every six months for the initial two years of marketing in Canada.

  • The provision of a comprehensive safety review based on age group stratification and a cumulative review on reported cases with fatal outcome with Asparlas, including those associated with off-label use.

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

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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 Asparlas. 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

As outlined in the What steps led to the approval of Asparlas? section, the clinical review of the New Drug Submission for Asparlas was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

The clinical pharmacology, efficacy, and safety of Asparlas (calaspargase pegol) as a component of multi-agent chemotherapeutic acute lymphoblastic leukemia (ALL) regimens were evaluated in two multicentre, randomized, controlled studies (DFCI 11‑001 and AALL07P4) in pediatric (one year of age or older) and young adult patients with newly diagnosed ALL. Pegaspargase was used as a comparator asparaginase in both studies.

Study DFCI 11-001 was a Dana Farber Cancer Institute (DFCI) cooperative group study. Patients aged 1 to 21 (total number [n] = 230) were randomized to receive Asparlas 2,500 international units (IU)/m2 every three weeks (Q3W; n = 114) or pegaspargase 2,500 IU/m2 every two weeks (Q2W; n = 116) as a component of the DFCI ALL consortium regimen. The Asparlas dosage in Study DFCI 11-001 was consistent with the proposed dosage (no more frequently than every 21 days). The pegaspargase dosage was the same as per its authorized product label.

Study AALL07P4 was a Children’s Oncology Group (COG) study in which patients aged 1 to 26 (n = 97) were randomized to receive Asparlas 2,500 IU/m2 (n = 42) or pegaspargase 2,500 IU/m2 (n = 55) as a component of the augmented Berlin-Frankfurt-Münster (BFM) ALL regimen. The dosing frequency was the same for both treatments with intervals between the two doses ranging from 2 to 5.5 weeks.

Clinical Pharmacology

Asparlas (calaspargase pegol) is a pegylated L-asparaginase, an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacological effect of calaspargase pegol is thought to be due to the depletion of plasma asparagine which leads to the death of leukemic cells. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.

Pharmacodynamics

The pharmacodymanic response of calaspargase pegol is related to a sustained depletion of L-asparagine. This was assessed through the measurement of asparagine concentrations in both plasma and cerebrospinal fluid (CSF) via a liquid chromatography-mass spectrometry (LC-MS)/MS assay.

In Study AALL07P4, during the induction phase, asparagine concentrations in the plasma of patients (n = 41) who were between the ages of 1 to 26 years were maintained below the assay limit of quantification for more than 18 days following a single dose of Asparlas 2,500 IU/m2. Mean CSF asparagine concentrations decreased from a pre-treatment concentration of 0.8 µg/mL (n = 10) to 0.2 µg/mL on Day 4 (n = 37) and remained decreased at 0.2 µg/mL (n = 35) 25 days after the administration of this single dose.

The exposure-response of calaspargase pegol is uncertain; however, it cannot be excluded that the higher number of asparaginase-associated adverse events in the Asparlas 2,500 IU/m² arm is related to the higher systemic exposure to asparaginase activity when compared to the pegaspargase 2,500 IU/m² arm in Study AALL07P4, where the two drugs were administered at the same dose and frequency.

Pharmacokinetics

The plasma asparaginase activity (PAA) pharmacokinetics was characterized in 43 patients (1 to 26 years) with newly diagnosed high risk B-precursor ALL treated with a multidrug backbone therapy. Pharmacokinetic (PK) comparability (asparaginase activity) was determined by comparing PK parameters following the single dose administration of Asparlas (calaspargase pegol) 2,500 IU/m2 or pegaspargase 2,500 IU/m2. Measurements of PAA were taken at various sampling time points during the induction phase (Days 4 to 29) and the consolidation phase (Days 15 to 43).

In the induction phase, PK comparability between Asparlas 2,500 IU/m2 and pegaspargase 2,500 IU/m2 showed comparable exposure as measured by the area under the concentration-time curve from 0 to 25 days (AUC[0‑25d]) and maximum concentration (Cmax). In the consolidation phase, only Cmax was found comparable between the two treatments. In terms of the area under the concentration-time curve from 0 to infinity (AUC[0-inf]), which was supposed to be the most discriminating PK parameter reflecting the difference in half-lives between calaspargase pegol and pegaspargase, systemic exposure was substantially greater for Asparlas 2,500 IU/m2 compared with pegaspargase 2,500 IU/m2 with the upper limit of the 90% confidence interval (CI) of the geometric mean ratio exceeding 125% in both the induction and consolidation phases.

Based on these results, calaspargase pegol is not a bioequivalent alternative to pegaspargase. In a multiagent chemotherapeutic regimen, Asparlas at the same dose and frequency as pegaspargase may result in higher asparaginase activity exposures, which may increase toxicities. These findings were added to the Asparlas Product Monograph as a precaution.

The clinical pharmacology data support the use of Asparlas for the recommended indication and dosage. For further details, please refer to the Asparlas Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Asparlas was determined based on the achievement and maintenance of nadir serum asparaginase activity (NSAA) ≥0.1 IU/mL in patients treated with Asparlas 2,500 IU/m2. This threshold of asparaginase activity is associated with an adequate asparagine depletion and is considered as an acceptable clinical efficacy endpoint.

In Study AALL07P4, following a single dose administration of 2,500 IU/m2 of Asparlas, the majority of patients achieved asparaginase activity ≥0.1 IU/mL (100% patients in the Asparlas 2,500 IU/m2 group versus [vs.] 95.3% patients in the pegaspargase 2,500 IU/m2 group through 18 days, and 92.9% vs. 29.5% patients through 25 days).

Based on modelling and simulation in patients with evaluable pharmacokinetic samples in Studies AALL07P4 and DFCI 11-001 (n = 124), a NSAA level ≥0.1 IU/mL is expected to be maintained in 99% of patients receiving Asparlas 2,500 IU/m2 every 3 weeks (Q3W).

Other efficacy endpoints, including complete remission rate, event-free survival (EFS) and overall survival (OS), were evaluated in the two studies without pre-defined statistical hypotheses and significance tests. In Study DFCI 11-001, the EFS and OS results appeared to be comparable between patients treated with Asparlas 2,500 IU/m2 Q3W and pegaspargase 2,500 IU/m2 Q2W. These efficacy endpoints were inconclusive in Study AALL07P4 due to the small sample size and other limitations. Nevertheless, no apparent detriment was observed in patients treated with the Asparlas 2,500 IU/m2 dose.

Overall, the achievement and maintenance of an NSAA level ≥0.1 IU/mL in pediatric and young adult ALL patients treated with Asparlas at the proposed dosage in Studies ALL07P4 and DFCI 11-001 is considered substantial evidence of effectiveness. Other efficacy results described in Study DFCI 11‑001 are deemed supportive.

Indication

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

Asparlas is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia.

Health Canada revised the proposed indication, taking into consideration the age population evaluated in the clinical studies. Accordingly, Health Canada approved the following indication:

Asparlas is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 to 21 years.

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

Clinical Safety

The clinical safety of Asparlas was assessed in studies DFCI 11‑001 and AALL07P4 described above. The adverse reactions reported in the two studies were generally consistent with the known safety profile of asparaginase.

In Study DFCI 11-001, for patients treated with Asparlas, the most commonly reported adverse reactions (occurring in 20% or more of patients) were: hypoalbuminemia, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood bilirubin, hypertriglyceridemia, hyperglycemia, and blood fibrinogen decreased. Safety findings were generally similar between the groups treated with Asparlas 2,500 IU/m2 Q3W or pegaspargase 2,500 IU/m2 Q2W.

In Study AALL07P4, adverse events associated with asparaginase were generally increased in the Asparlas 2,500 IU/m2 group compared to the pegaspargase 2,500 IU/m2 group. These included hyperglycemia, febrile neutropenia and infections, increased lipase, pancreatitis, coagulopathy events (prolonged activated partial thromboplastin time, increased international normalized ratio, and decreased blood fibrinogen decreased), hepatic events (increased blood bilirubin, increased ALT, increased gamma-glutamyl transferase, and hypoalbuminemia), anaphylactic reactions and encephalopathy. On-treatment deaths were reported in 2 (4.9%) patients in the Asparlas 2,500 IU/m2 group vs. 1 patient (1.9%) in the pegaspargase 2,500 IU/m2 group, all related to infections. In addition, adverse events leading to dose/treatment interruption were more frequent in the Asparlas group compared with the pegaspargase group. The small sample size of the study limits the interpretation of these findings. However, the role of higher exposure to asparaginase activity in the Asparlas group could not be ruled out, as the same numbers of doses were administered for Asparlas and pegaspargase in Study AALL07P4.

This uncertainty regarding the safety evidence was mitigated through labelling and enhanced post-market surveillance. The following key measures were implemented to mitigate the potential risk and facilitate the safe use of Asparlas post-authorization:

  • The proposed indication was modified to restrict the use to patients age 1 to 21 years to be consistent with the demographics of the patients in Study DFCI 11‑001, as no clinical data were available for Asparlas in patients younger than 1 year of age, and the clinical data in adult patients older than 21 years of age were limited.

  • The approved dose frequency for Asparlas is no more frequent than every 21 days to account for its longer half-life.

  • Safety findings in Study AALL07P4 were described in the Asparlas Product Monograph and a precautionary statement was added to the Dosing Considerations section of the Product Monograph to highlight the potential risk of increased toxicities with Asparlas due to its longer half-life when used at the same dosage as pegaspargase.

  • The sponsor was requested to conduct additional post-market risk monitoring and analyses.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). Immunogenicity was assessed using enzyme linked immunosorbent assays (ELISA) in Study DFCI 11-001. Of 98 evaluable patients treated with Asparlas, 15 (15%) patients developed new or an increased titer of ADAs during treatment. Of these 15 patients, 14 were positive for anti-polyethylene glycol (PEG) antibodies. The presence of ADAs correlated with the occurrence of hypersensitivity reactions. There is insufficient information to determine whether the development of antibodies is associated with altered pharmacokinetics (i.e., loss of asparaginase activity). These finding are described in the Asparlas Product Monograph.

Appropriate warnings and precautions are in place in the approved Asparlas Product Monograph to address the identified safety concerns. For more information, refer to the Asparlas Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

As outlined in the What steps led to the approval of Asparlas? section, the review of the non-clinical component of the New Drug Submission for Asparlas was conducted as per Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

In a non-clinical embryofetal development study, the administration of calaspargase pegol during pregnancy was associated with decreases in maternal body weight and reduced gravid uterine weight. Published non-clinical studies suggest harms to animal offspring when L-asparaginase is administered during pregnancy. These findings are described in the Asparlas Product Monograph to warn physicians and patients of potential risks to the fetus.

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

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

7.3 Quality Basis for Decision

As outlined in the What steps led to the approval of Asparlas? section, the review of the quality component of the New Drug Submission for Asparlas was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Characterization of the Drug Substance

Asparlas (calaspargase pegol) is a pegylated L-asparaginase indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL). Asparlas was developed as a more stable and longer acting form of pegaspargase by covalently binding L-asparaginase to the PEG (polyethylene glycol) moiety via a succinimidyl carbonate linker that is more stable than the succinimidyl succinate linker currently used in pegaspargase.

Detailed characterization studies were performed to provide assurance that calaspargase pegol 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 of the Drug Substance and Drug Product and Process Controls

Calaspargase pegol results from the pegylation of L-asparaginase, whereby the PEG is attached to L-asparaginase via a succinimidyl carbonate linker.

The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

An L‑asparaginase drug substance intermediate is produced using a non-recombinant Escherichia coli cell line. Cell culture is initiated by thawing one working cell bank vial followed by expansion, production, harvest, homogenization, separation, dilution, and filtration into disposable bags for transfer to the downstream process. L-asparaginase is then purified through several chromatography and ultrafiltration/diafiltration steps, followed by filtration and filling into containers.

The calaspargase pegol drug substance manufacturing process consists of buffer solution preparation, L-asparaginase solution preparation, L-asparaginase pegylation, clarification, diafiltration, and dilution.

The calaspargase pegol drug product manufacturing process consists of sterile filtration of the drug substance into vials. The filled vials are stoppered, capped, inspected, and labelled prior to being packaged into cartons. The manufacturing process for calaspargase pegol drug product is based on the process used to manufacture Oncaspar.

Asparlas is supplied as a preservative-free, isotonic sterile, clear and colourless solution in single-dose vials. Each vial contains 3,750 units (U) of calaspargase pegol in 5 mL (750 U/mL) of phosphate-buffered solution, pH 7. Each vial is filled to approximately 5.3 mL to ensure withdrawal of the labelled volume of 5.0 mL. Asparlas is diluted in 0.9% sodium chloride or 5% dextrose solution prior to administering as an intravenous infusion.

Changes made throughout pharmaceutical development to both the drug substance and drug product manufacturing processes did not impact their quality and are considered acceptable upon review.

The materials used in the manufacture of the drug substance (including biological-sourced materials) and drug product are considered suitable and/or meet standards appropriate for their intended use. The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the calaspargase pegol with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The proposed calaspargase pegol drug substance and drug product release and stability specifications follow ICH guidelines and include assays for identity, biological activity, protein content, purity and impurities, polyethylene glycol (PEG) modification, and safety. Analytical procedures are validated and in compliance with ICH guidelines.

A nitrosamine risk assessment was provided. No risks were identified for the presence of N-nitrosamine impurities in Asparlas. Therefore, no confirmatory testing or mitigation plans are required.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured drug product lots were tested using a subset of release methods. The testing results supported the authorization of Asparlas.

Asparlas is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 is acceptable when Asparlas is stored between 2 to 8 °C, protected from light.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies.

The proposed packaging and components are 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.

Based on a risk assessment score determined by Health Canada, an on-site evaluation of the drug substance intermediate manufacturing facility was not deemed necessary.

An on-site evaluation was not recommended for the drug substance and the drug product manufacturing facility given that the relatively low-complexity manufacturing operations performed at this site (i.e., pegylation step and drug product filling) could be sufficiently assessed via the review of the dossier submitted.

All sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The L-asparaginase drug substance intermediate is expressed in Escherichia coli, a bacterial cell line that does not support replication of viral agents which may infect humans.

The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens. The excipients used in the drug product formulation are not of animal or human origin.

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