Summary Basis of Decision for Pombiliti

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 Pombiliti is located below.

Recent Activity for Pombiliti

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 Pombiliti. When the PAAT for Pombiliti becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Pombiliti

Date SBD issued: 2025-06-09

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

Cipaglucosidase alfa

Drug Identification Number (DIN): DIN 02556898 – 105 mg cipaglucosidase alfa/vial, powder for solution, intravenous administration

Amicus Therapeutics Canada Inc.

New Drug Submission Control Number: 284815

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): A16 Other alimentary tract and metabolism products

Date Filed: 2024-03-08

Authorization Date: 2025-04-14

On April 14, 2025, Health Canada issued a Notice of Compliance to Amicus Therapeutics Canada Inc. for the drug product Pombiliti. The market authorization of Pombiliti 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 Pombiliti is favourable when indicated in combination with the enzyme stabiliser Opfolda (65 mg miglustat capsule) for the treatment of adult patients with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency) weighing ≥40 kg.

Pombiliti must be used in combination with 65 mg miglustat capsules. Consult the Product Monograph of Opfolda (65 mg miglustat capsule) for detailed information.

1 What was approved?

Pombiliti, enzyme replacement therapy, was authorized in combination with the enzyme stabiliser Opfolda (65 mg miglustat capsule) for the treatment of adult patients with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency) weighing ≥40 kg.

Pombiliti must be used in combination with 65 mg miglustat capsules. Consult the Product Monograph of Opfolda (65 mg miglustat capsule) for detailed information.

No efficacy and safety data in pediatric patients (under 18 years of age) are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

Limited evidence from clinical studies suggests that in the geriatric population (65 years of age or older), the use of Pombiliti in combination with 65 mg miglustat capsules is not associated with differences in safety or effectiveness.

Pombiliti (105 mg cipaglucosidase alfa/vial) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains citric acid monohydrate, mannitol, polysorbate 80, and sodium citrate dihydrate.

The use of Pombiliti is contraindicated in:

  • Patients with a history of life-threatening hypersensitivity or infusion-associated reactions (e.g., anaphylaxis and severe cutaneous reactions) to cipaglucosidase alfa, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container when rechallenge was unsuccessful.

  • Patients with a contraindication to 65 mg miglustat capsules, including:

    • Patients who are hypersensitive to miglustat or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

    • Women who are or may become pregnant. If Pombiliti in combination with 65 mg miglustat capsules are administered to women of reproductive potential, they should be informed of the potential hazard to the fetus.

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 Product Monograph for Pombiliti 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 Pombiliti approved?

Health Canada considers that the benefit-risk profile of Pombiliti is favourable in combination with the enzyme stabiliser Opfolda (65 mg miglustat capsule) for the treatment of adult patients with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency) weighing ≥40 kg.

Pompe disease is a rare genetic disorder caused by mutations in the gene that encodes human GAA, an enzyme responsible for the breakdown of lysosomal glycogen. The accumulation of glycogen in body tissues leads to progressive muscle weakness and damages the heart, skeletal muscles, liver, and nervous system. There are two clinical types of the disease: infantile-onset Pompe disease and late-onset Pompe disease. Clinical manifestations of Pompe disease include difficulty walking, climbing stairs, and progressive limitations of motor activities of daily living with progression to a need for ambulatory support, followed by wheelchair dependence. These are compounded by respiratory involvement, initially as sleep disordered breathing and orthopnea (shortness of breath in the supine position). The progressive nature of Pompe disease generally results in the use of different types of assisted ventilation. Death from respiratory failure and lung insufficiency is the most common cause of mortality. The overall incidence of Pompe disease, including all subtypes, varies depending on ethnicity and geographic region and ranges from 1 in 14,000 to 1 in 300,000 births.

Pombiliti (cipaglucosidase alfa) is a novel enzyme replacement therapy. The mechanism of action of Pombiliti involves binding to the cation-independent mannose 6-phosphate receptor, which mediates the internalisation and delivery of the enzyme to lysosomes, where it catalyzes the degradation of glycogen to glucose and therefore reduces glycogen substrate levels.

The efficacy and safety of Pombiliti in combination with Opfolda in adult patients with late-onset Pompe disease is based on the results of Study ATB200-03, a pivotal, Phase III, randomized, double-blind, active-controlled study. In total, 123 patients with late-onset Pompe disease weighing 40 kg or more were randomized 2:1 to receive study treatment (Pombiliti in combination with Opfolda; 85 patients) or active control (alglucosidase alfa plus placebo; 38 patients) every other week for 52 weeks. The doses of Pombiliti and alglucosidase alfa were 20 mg/kg of body weight. The dose of Opfolda was 195 mg for patients weighing 40 kg to less than 50 kg and 260 mg for patients weighing 50 kg or more.

The primary endpoint assessed the efficacy of Pombiliti in combination with Opfolda on motor function, as measured by change in 6-Minute Walk Distance (6MWD) from baseline to Week 52. The first key secondary endpoint assessed the efficacy of Pombiliti in combination with Opfolda on pulmonary function, as measured by change in sitting percent-predicted forced vital capacity (FVC) from baseline to Week 52. The efficacy population included 122 patients, of which 78% had received prior enzyme replacement therapy (ERT) with alglucosidase alfa (ERT-experienced) and 22% had never received ERT (ERT-naïve).

Efficacy results were clinically meaningful but not statistically significant. The results represented improvements compared to the control therapy. Both the primary efficacy endpoint and the first key secondary efficacy endpoint met the numerical “disease stabilization” criteria. The primary efficacy endpoint also almost met the “disease improvement” criterion. Additionally, primary and key secondary efficacy results showed a favorable trend over the first 52 weeks of treatment. This is the first randomized, controlled clinical trial in late-onset Pompe disease where a majority of the adult patients were ERT-experienced.

The safety profile for Pombiliti was derived primarily from Study ATB200-03. The overall safety database included two pools. Pool 1 comprised the 123 patients from Study ATB200-03 and Pool 2 comprised 151 patients from Study ATB200-03, Study ATB200-07 (the open label extension of Study ATB200-03) and the open-label extension of Study ATB200-02. The interpretation of safety data from the open-label extension studies was limited by a lack of a comparator arm. Therefore, it was difficult to draw definitive conclusions regarding long-term safety. The mean exposure was 11.9 (standard deviation [SD]: 1.5) months for each group in Pool 1 and 28.0 (SD: 14.3) months in Pool 2.

The most frequently (occurring in 5% or more of patients) reported adverse reactions across all studies in patients treated with Pombiliti in combination with Opfolda were: headache (13.9%), diarrhea (9.3%), fatigue (8.6%), nausea (7.3%), abdominal pain (6.6%), pyrexia (6.6%), and chills (5.3%). Important potential risks of Pombiliti included hypersensitivity/anaphylaxis, and infusion-associated reactions. These risks are consistent with already established safety profiles of existing enzyme replacement therapies and are listed in a Serious Warnings and Precautions box in the Product Monograph for Pombiliti. No fatal events attributed to treatment with Pombiliti in combination with Opfolda were reported. Uncertainties (i.e., missing information) related to the safety profile of Pombiliti included use in pregnant and breastfeeding patients and long-term safety.

A Risk Management Plan (RMP) for Pombiliti was submitted by Amicus Therapeutics 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 RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Product Monograph for Pombiliti 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 Pombiliti was accepted.

Overall, Pombiliti has been shown to have a favourable benefit-risk profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and monitoring. Appropriate warnings and precautions are in place in the Product Monograph for Pombiliti 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 Pombiliti?

As per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the review of the non-clinical and clinical components of the New Drug Submission (NDS) for Pombiliti was based on a critical assessment of the non-clinical and clinical review conducted by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA). As per Method 2, the review of the quality component of the NDS was based on a critical assessment of the quality review conducted by the EMA. The data package submitted to Health Canada was referred to as necessary. The Canadian regulatory decision on the Pombiliti 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: Pombiliti

Submission Milestone

Date

Pre-submission meeting

2023-11-08

New Drug Submission filed

2024-03-08

Screening

Screening Deficiency Notice issued

2024-04-19

Response to Screening Deficiency Notice filed

2024-06-03

Screening Acceptance Letter issued

2024-06-19

Review

Biostatistics evaluation completed

2025-04-03

Review of Risk Management Plan completed

2025-04-07

Labelling review completed

2025-04-08

Quality evaluation completed

2025-04-10

Non-clinical evaluation completed

2025-04-11

Clinical/medical evaluation completed

2025-04-11

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

2025-04-14
4 What follow-up measures will the company take?

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

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

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 Pombiliti. 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?

Refer to the What steps led to the approval of Pombiliti? section for more information about the review process for this submission.

7.1 Clinical Basis for Decision

Clinical Pharmacology

Pompe disease (acid maltase deficiency, glycogen storage disease type II, glycogenosis type II) is a rare metabolic myopathy caused by a deficiency of acid alpha-glucosidase (GAA) enzyme that degrades glycogen in the lysosome. Cipaglucosidase alfa, the medicinal ingredient in Pombiliti, is a hydrolytic glycogen-specific enzyme intended to replace absent or impaired endogenous GAA enzyme. Cipaglucosidase alfa contains bis- mannose-6-phosphate N-glycans for high affinity cation-independent mannose-6-phosphate receptor (CI-MPR) binding. After binding, it is internalized in the lysosome where it undergoes proteolytic cleavage and N-glycan trimming necessary to produce the mature form of the enzyme. Cipaglucosidase alfa is stabilised by miglustat, the medicinal ingredient in Opfolda, minimizing the loss of enzyme activity in the blood during infusion.

The clinical pharmacology package consisted of data from Study ATB200-02 (Phase I/II) and Study ATB200-03 (Phase III; described in the Clinical Efficacy section below) as well as simulated data from population pharmacokinetic and pharmacokinetic/pharmacodynamic models that were built upon data from these two studies.

In Study ATB200-02, following the dose ranging stage, fasting adult patients with Pompe disease received a single dose of 260 mg miglustat in combination with 20 mg/kg cipaglucosidase alfa. The total GAA protein level, as measured by the partial area under the plasma concentration-time curve from the time to reach maximum observed plasma concentration to 24 hours after the start of infusion (AUCTmax-24h), increased by 44% relative to the levels observed in patients who received 20 mg/kg of cipaglucosidase alfa alone. This extended exposure was supportive of the use of cipaglucosidase alfa in combination with miglustat.

A two-compartment population pharmacokinetic model with parallel linear and nonlinear clearance was used to characterize cipaglucosidase alfa pharmacokinetics. A two-compartment population pharmacokinetic model with sequential zero- and first-order absorption and linear clearance was used to characterize miglustat pharmacokinetics. Based on the pooled population pharmacokinetic analyses, age and sex did not have a clinically meaningful effect on cipaglucosidase alfa exposure in combination with miglustat. As such, the proposed dose of 20 mg/kg cipaglucosidase alfa was considered appropriate without any further adjustments based on age and sex.

Overall, there was no apparent association between immunogenicity and safety or pharmacokinetic effects. However, patients should be monitored for signs and symptoms of systemic immune complex-related reactions. This is reflected in the Product Monograph for Pombiliti.

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

Clinical Efficacy

The efficacy of Pombiliti in combination with Opfolda in the treatment of adult patients with late-onset Pompe disease was assessed in Study ATB200-03, a pivotal Phase III, randomized, double-blind, active-controlled study in 123 patients with late-onset Pompe disease weighing 40 kg or more. Demographics and baseline 6-Minute Walk Distance (6MWD) and forced vital capacity (FVC) results were representative of the population and similar in the two treatment arms. Patients ranged from 19 to 74 years of age (mean: 46.8 years) and the majority were female (67 patients [54.5%]) and White (104 patients [84.6%]).

In the intention-to-treat population, 123 patients were randomized 2:1 to receive study treatment (Pombiliti in combination with Opfolda; 85 patients) or active control (alglucosidase alfa plus placebo; 38 patients) every other week for 52 weeks. The doses of Pombiliti and alglucosidase alfa were 20 mg/kg of body weight. The dose of Opfolda was 195 mg for patients weighing 40 kg to less than 50 kg and 260 mg for patients weighing 50 kg or more.

The primary endpoint assessed the efficacy of Pombiliti in combination with Opfolda on motor function, as measured by change in 6MWD from baseline to Week 52. The first key secondary endpoint assessed the efficacy of Pombiliti in combination with Opfolda on pulmonary function, as measured by change in sitting percent-predicted FVC from baseline to Week 52. The efficacy population included 122 patients of which 78% had received prior enzyme replacement therapy (ERT) with alglucosidase alfa (ERT-experienced) and 22% had never received ERT (ERT-naïve). More than two thirds (67%) of ERT-experienced patients had been on ERT treatment for more than 5 years prior to entering the study (mean = 7.4 years).

Efficacy results were clinically meaningful but not statistically significant. The results represented improvements compared to the control therapy. Both the primary efficacy endpoint and the first key secondary efficacy endpoint met the numerical “disease stabilization” criteria. The primary efficacy endpoint also almost met the “disease improvement” criterion. Additionally, primary and key secondary efficacy results showed a favorable trend over the first 52 weeks of treatment.

Overall, the results were clinically meaningful both in the intent-to-treat population and the ERT-experienced patient subgroup. This is the first clinical trial in late-onset Pompe disease where a majority of the adult patients were ERT-experienced.

Indication

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

Pombiliti (cipaglucosidase alfa for injection) is indicated for use in combination with the enzyme stabilizer miglustat for long-term treatment in adult patients with late-onset Pompe disease (acid α-glucosidase [GAA] deficiency).

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

Pombiliti (cipaglucosidase alfa for injection) is indicated in combination with the enzyme stabiliser Opfolda (65 mg miglustat capsule) for the treatment of adult patients with late-onset Pompe disease (acid α glucosidase [GAA] deficiency) weighing ≥ 40 kg.

Pombiliti must be used in combination with 65 mg miglustat capsules. Consult the Product Monograph of Opfolda (65 mg miglustat capsule) for detailed information.

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

Clinical Safety

The safety profile of Pombiliti was derived primarily from the pivotal Study ATB200-03 described in the Clinical Efficacy section. The overall safety database included two pools. Pool 1 comprised the 123 patients from Study ATB200-03 and Pool 2 comprised 151 patients from Study ATB200-03, Study ATB200-07 (the open label extension of Study ATB200-03), and the open-label extension of Study ATB200-02. The interpretation of safety data from the open-label extension studies was limited by a lack of a comparator arm. Therefore, it was difficult to draw definitive conclusions regarding long-term safety. The mean exposure was 11.9 (standard deviation [SD]: 1.5) months for each group in Pool 1 and 28.0 (SD: 14.3) months in Pool 2.

The most frequently (occurring in 5% or more of patients) reported adverse reactions across all three studies in patients treated with Pombiliti in combination with Opfolda were headache (13.9%), diarrhea (9.3%), fatigue (8.6%), nausea (7.3%), abdominal pain (6.6%), pyrexia (6.6%), and chills (5.3%). Reported serious adverse reactions in all three studies were urticaria (2.0%), anaphylaxis (1.3%), chills (0.7%), cough (0.7%), flushing (0.7%), pyrexia (0.7%), presyncope (0.7%), dyspnoea (0.7%), pharyngeal oedema (0.7%), wheezing (0.7%), and hypotension (0.7%).

Important potential risks of Pombiliti included hypersensitivity/anaphylaxis and infusion-associated reactions. These risks are consistent with already established safety profiles of existing enzyme replacement therapies and are listed in a Serious Warnings and Precautions box in the Product Monograph for Pombiliti. No fatal events attributed to treatment with Pombiliti in combination with Opfolda were reported. Uncertainties (i.e., missing information) related to the safety profile of Pombiliti included use in pregnant and breastfeeding patients and long-term safety.

The identified safety issues can be managed through labelling and monitoring. Appropriate warnings and precautions are in place in the approved Product Monograph for Pombiliti to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

The non-clinical package for Pombiliti (cipaglucosidase alfa) was acceptable based on in vitro studies, single- and repeat-dose toxicity studies in rats and monkeys; reproductive/developmental toxicity studies spanning fertility, embryo-fetal development, pre- and postnatal development in rabbits and rats; and sufficient primary pharmacodynamic characterization in a disease-relevant knock out mouse model.

Cipaglucosidase alfa, a hydrolytic glycogen-specific enzyme, is unstable at physiological pH and is stabilized in the presence of miglustat. The in vitro data demonstrated cellular uptake of the enzyme. In vivo studies using wild-type and knockout mouse models supported treatment-related tissue glycogen reductions and increased enzyme activity, and improved markers of muscle function when administered alone or in combination with miglustat.

No adverse toxicity or changes in cardiovascular or other safety pharmacology parameters were observed in rats or monkeys up to the highest dose, with or without miglustat.

In a fertility study, increased preimplantation loss occurred when miglustat was administered alone or in combination with cipaglucosidase alfa to males or females prior to mating. In a rabbit embryo-fetal development study, increased incidence of heart and cardiovascular malformations occurred when cipaglucosidase alfa was co-administered with miglustat. In a rat pre- and postnatal development study, increased total litter loss associated with maternal toxicity was observed. This study detected both cipaglucosidase alfa and miglustat in milk 13 days following parturition. These findings occurred at systemic exposures (as measured by area under the concentration-time curve [AUC]) greater than 16-fold the exposures observed in humans at the maximum recommended human dose and were captured accordingly in the Product Monograph for Pombiliti.

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

Cipaglucosidase alfa is a human recombinant acid α-glucosidase (GAA), an enzyme responsible for the breakdown of lysosomal glycogen. It is derived from recombinant Chinese hamster ovary (CHO) cell culture. The structure contains 896 amino acids. Notably, Pombiliti was developed to have increased mannose 6-phosphate content that enables cellular uptake via cation-independent mannose 6-phosphate receptors on the cell surface and increased terminal sialic acids on N-glycans to reduce hepatic clearance.

The drug substance was well characterized in terms of primary and higher order structure, carbohydrate and disulfide structure, mass, size and charge heterogeneity, biological function, and both process- and product-related impurities. It was found to consistently exhibit the desired characteristic structure and biological activity. Impurities and degradation products arising from manufacturing and/or storage were found to be within established limits and are considered to be acceptable.

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

The drug substance is manufactured in CHO cells. The manufacturing process is initiated with the thawing of a single working cell bank vial followed by expansion and inoculation in a bioreactor. Culture broth is continuously harvested and captured on an anion exchange chromatography column. The downstream process continues with two additional chromatography steps, a low pH viral inactivation step, and a virus filtration step. Ultrafiltration is used to buffer exchange the purified enzyme into its final formulation buffer, which is then concentrated before addition of polysorbate-80 and final filtration and filling. The cipaglucosidase alfa bulk drug substance is stored frozen in pre-sterilised polycarbonate carboys.

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 comparability was addressed. All acceptance criteria for the critical operational parameters, the in-process and release tests, and ancillary supportive studies were met, demonstrating that the manufacturing process consistently produces cipaglucosidase alfa of acceptable quality.

The manufacturing process of the Pombiliti drug product begins with the fully formulated drug substance being thawed, pooled and mixed, and then sterile filtered and filled into vials. The vials are partially stoppered, lyophilised, fully stoppered, capped, and visually inspected.

Comparability of drug product from all stages of development has been demonstrated. The drug product manufacturing process was successfully validated with the manufacture of three consecutive batches which bracketed the batch size range. All acceptance criteria for the critical operational parameters, the in-process and release tests, and ancillary supportive studies were met, demonstrating that the manufacturing process consistently produces Pombiliti drug product of acceptable quality.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient 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 of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

Each lot of Pombiliti drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

Pombiliti 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 Pombiliti is stored at 5 ± 3 °C and protected from light. The in-use shelf life for the reconstituted product is 24 hours at 5 ± 3 °C. The in-use shelf life for the diluted product is 24 hours when stored at 5 ± 3 °C and 6 hours when stored at room temperature (up to 25 °C) to allow for infusion.

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

No on-site evaluations of the facilities involved in the manufacture and testing of Pombiliti were recommended or conducted as the review of the quality component of the New Drug Submission for Pombiliti was based on a critical assessment of the quality review conducted by the European Medicines Agency, which concluded that the facilities are considered suitable for the manufacturing of Pombiliti drug substance and drug product.

Adventitious Agents Safety Evaluation

The raw materials used in the production of Pombiliti and the excipients used in the drug product formulation are not of animal or human origin.

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