Summary Basis of Decision for Elelyso
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Elelyso is located below.
Recent Activity for Elelyso
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Elelyso
Updated: 2023-03-31
The following table describes post-authorization activity for Elelyso, a product which contains the medicinal ingredient taliglucerase alfa. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Drug Identification Number (DIN):
- DIN 02425637 – 200 units/vial taliglucerase alfa, powder for solution, intravenous administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| SNDS # 268539 | 2022-10-07 | Issued NOC 2023-03-07 | Submission filed as a Level II – Supplement (Safety) to update the PM with a revised dosing recommendation for patients less than 30 kg, and migrate the PM to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications and Clinical Use, Contraindications, and Dosage and Administration sections of the PM. An NOC was issued. |
| NC # 266526 | 2022-07-28 | Issued NOL 2022-10-31 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance and the drug product, and to change the stability protocol of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 236084 | 2020-02-12 | Issued NOC 2020-11-12 | Submission filed as a Level I – Supplement to update the PM with data from bioanalytical studies PCL-17-005, 17-006, and 17-007, and to provide a new abbreviated Package Insert. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions, and Clinical Trials sections of the PM. An NOC was issued. |
| NC # 230626 | 2019-08-12 | Issued NOL 2019-09-26 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance, and the working reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 224688 | 2019-02-14 | Issued NOL 2019-04-17 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer quality control testing activities to a new facility. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 198020 | 2016-09-01 | Issued NOC 2017-08-18 |
Submission filed as a Level I - Supplement to provide a safety and efficacy update to the PM based on longer term follow-up of patients in Study PB-06-006 and Study PB-06-007. As a result of the submission, the following sections of the PM were updated: Warnings and Precautions, Adverse Reactions, Dosage and Administration, Overdosage, Actions and Clinical Pharmacology, and Clinical Trials. Corresponding changes were made to the PM Part III: Consumer Information. The benefit/risk profile for Elelyso remains positive when used for its approved indication. The data were reviewed and considered acceptable, and an NOC was issued. |
| NC # 205006 | 2017-04-25 | Issued NOL 2017-07-28 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make changes to the drug substance and drug product specifications and do some method revisions. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 202730 | 2017-02-09 | Issued NOL 2017-04-20 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 202531 | 2017-02-02 | Issued No Objection Letter 2017-03-16 |
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) for Product Monograph (PM) changes related to angioedema. As a result of the NC, an addition was made to the Adverse Reactions section of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 194728 | 2016-05-02 | Issued No Objection Letter 2016-08-09 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the addition of a drug product specification. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 190262 | 2015-12-08 | Issued No Objection Letter 2016-03-16 |
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) for Product Monograph (PM) changes related to urticaria. As a result of the NC, an addition was made to the Adverse Reactions section of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 186888 | 2015-08-11 | Issued No Objection Letter 2015-11-17 |
Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions, Adverse Reactions, and Dosage and Adminstration sections of the Product Monograph. The submission was reviewed and a No Objection letter was issued. |
| SNDS # 178493 | 2014-09-30 | Issued NOC 2015-07-10 |
Submission filed as a Level I - Supplement for the approval of an alternate manufacturing site of the drug product. Drug product manufactured at the new site is comparable to product manufactured at the current site. The data were reviewed and considered acceptable, and a Notice of Compliance was issued. |
| NC # 181205 | 2015-01-09 | Issued Screening Rejection Letter 2015-01-22 |
Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph. The submission was issued a Screening Rejection Letter as some of the changes filed were considered appropriate for a Supplementary New Drug Submission. |
| Drug product (DIN market notification | Not applicable | Date of first sale: 2014-09-08 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 140854 | 2013-06-18 | Issued NOC 2014-05-29 |
Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Elelyso
Date SBD issued: 2014-07-22
The following information relates to the New Drug Submission for Elelyso.
Taliglucerase alfa, 200 units/vial, powder for solution, intravenous
Drug Identification Number (DIN):
- 02425637
Pfizer Canada Inc.
New Drug Submission Control Number: 140854
On May 29, 2014, Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the drug product, Elelyso.
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 Elelyso is favourable for the long-term enzyme replacement therapy (ERT) for adults with a confirmed diagnosis of Type 1 Gaucher disease. Elelyso may also be used in paediatric patients with a confirmed diagnosis of Type 1 Gaucher disease, and for the haematological manifestations in paediatric patients with a confirmed diagnosis of Type 3 Gaucher disease. Clinical data in paediatric patients, ages 2 to 17, are limited.
1 What was approved?
Elelyso, an enzyme replacement therapy, was authorized for long-term enzyme replacement therapy (ERT) for adults with a confirmed diagnosis of Type 1 Gaucher disease. Elelyso may also be used in paediatric patients with a confirmed diagnosis of Type 1 Gaucher disease, and for the haematological manifestations in paediatric patients with a confirmed diagnosis of Type 3 Gaucher disease. Clinical data in paediatrics patients, ages 2 to 17, are limited.
Elelyso is contraindicated for patients who have severe allergic reactions to taliglucerase alfa or any of the excipients in the formulation or component of the container. Elelyso was approved for use under the conditions stated in the Elelyso Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Elelyso (200 units/vial, taliglucerase alfa) is presented as lyophilized powder for reconstitution and intravenous infusion. In addition to the medicinal ingredient, the solution contains citric acid anhydrous, polysorbate 80, mannitol, and sodium citrate.
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 Elelyso Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Elelyso approved?
Health Canada considers that the benefit/risk profile of Elelyso is favourable for the long-term enzyme replacement therapy (ERT) for adults with a confirmed diagnosis of Type 1 Gaucher disease. Elelyso may also be used in paediatric patients with a confirmed diagnosis of Type 1 Gaucher disease, and for the haematological manifestations in paediatric patients with a confirmed diagnosis of Type 3 Gaucher disease. Clinical data in paediatric patients, ages 2 to 17, are limited.
Gaucher disease is a rare genetic disease caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GCB) which leads to accumulation of lipids and progressive damage to tissues including the liver, spleen, kidneys, bone marrow, and brain. Gaucher disease has three common clinical subtypes. Clinical manifestations of Type 1 (or non-neuropathic form) Gaucher disease include anaemia, thrombocytopenia, hepatomegaly, splenomegaly, bleeding, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life (QoL). Additional symptoms in Type 2 (or acute infantile neuropathic form) and Type 3 (or chronic neuropathic form) Gaucher disease include extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. While Type 2 Gaucher-affected children usually die by age 2, Type 3 Gaucher patients often live into early adulthood. The estimated number of patients with Gaucher disease in Canada is between 1,000 and 1,500, with Type 1 being most common.
Replacement of the missing or defective enzyme using ERT has been shown to reduce organomegaly and improve haematological parameters. As ERT typically does not cross the blood-brain barrier when administered intravenously, it is not effective at improving neurological symptoms to patients with Gaucher disease.
The market authorization was primarily based on two completed pivotal clinical studies (PB-06-001 and PB-06-005). In pivotal study PB-06-001 (31 adults patients with Gaucher disease), the primary efficacy analysis demonstrated that Elelyso treatment clinically significantly reduced mean spleen volume from screening to Month 9 for both the 30 units/kg and 60 units/kg dosage groups. In pivotal study PB-06-005 (11 patients with Gaucher disease aged 2-14 years), the primary efficacy variable was percent change in haemoglobin from baseline to Month 12 (end of study). A mean increase from baseline in haemoglobin was observed for both the 30 units/kg group (13.8%) and 60 units/kg group (15.8%). A reduction in spleen volume was observed at Month 12 for both the Elelyso 30 units/kg group (28.6% mean reduction from baseline) and 60 units/kg group (41.1% mean reduction from baseline).
Adverse events were experienced by 93% (108/116) of the treated adults and 75% of the treated children. Eleven point two percent (11.2%) of adult patients reported a total of 20 serious adverse events, and 2 paediatric patients reported a total of 2 serious adverse events, including musculoskeletal and connective tissue disorders; injury, poisoning and procedural complications; respiratory, thoracic and mediastinal disorders; and infusion reactions. The most commonly (>10%) reported adverse events in adult patients were arthralgia, nasopharyngitis, upper respiratory tract infections, headache, pyrexia, fatigue, pain in extremity, abdominal pain; and in paediatric patients were infusion-related reactions, vomiting, abdominal pain, nasopharyngitis, headache, pain in extremity, tonsillitis, diarrhoea, arthralgia, epistaxis, and tooth extraction. The most commonly observed symptoms of infusion-related reactions were headache, pruritus, hypersensitivity, nausea, peripheral oedema, throat irritation, erythema, and flushing. Safety profiles were similar between paediatric and adult patients except for one case of severe gastroenteritis reported in a child.
Additional adverse reactions recorded in the post-marketing phase included anaphylactic reactions, and adequate safety precautions should be taken to monitor for hypersensitivity reactions. If a severe allergic reaction occurs, immediate discontinuation of the Elelyso infusion is recommended. Patients who experience infusion-related reactions or hypersensitivity can however usually be managed successfully and have therapy continued by slowing the infusion rate, treating with medicinal products such as antihistamines, antipyretics and/or corticosteroids, and/or stopping and resuming treatment with decreased infusion rate. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions.
More hypersensitivity reactions were observed in patients who were positive for anti-taliglucerase alfa antibodies than in those patients who were negative.
Overall, there was sufficient evidence of efficacy and safety based on three Phase III studies to support this indication in adult patients with Type 1 Gaucher disease, with clinically significant improvements in major clinical features. Evidence of long-term efficacy was based on patients who were treated for at least 24 months. Additionally, clinical data reported for a limited number of paediatric patients with Type 1 Gaucher disease, and the trend of haematological changes recorded for the few children who have been genetically diagnosed with Type 3 Gaucher disease, are consistent with those reported in adults.
A Risk Management Plan (RMP) for Elelyso was submitted by Pfizer Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.
The efficacy and safety data reported, considered under the study design and safety consideration limitations imposed by this particular target population and disease type, support a favourable benefit-risk assessment for use of Elelyso for the long-term enzyme replacement therapy for adults with a confirmed diagnosis of Type 1 Gaucher disease. Elelyso may also be used in paediatric patients with a confirmed diagnosis of Type 1 Gaucher disease, and for the haematological manifestations in paediatric patients with a confirmed diagnosis of Type 3 Gaucher disease.
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 Elelyso?
Submission Milestones: Elelyso
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2010-05-25 |
| Submission filed: | 2013-06-18 |
| Screening | |
| Screening Acceptance Letter issued: | 2013-08-02 |
| Review | |
| On-Site Evaluation: | 2014-01-23 |
| Quality Evaluation complete: | 2014-05-28 |
| Clinical Evaluation complete: | 2014-05-26 |
| Labelling Review complete: | 2014-05-23 |
| Notice of Compliance issued by Director General: | 2014-05-29 |
The Canadian regulatory decision on the non-clinical and clinical review of Elelyso was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) were used as an added reference. As well, reports from the United States Food and Drug Administration (FDA) were also used.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
As part of the marketing authorization for Elelyso, 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 Regulations, commitments include:
- Provide the final clinical study reports from any ongoing studies with Elelyso in paediatric patients within six months after their completion.
- If applicable, provide a list of post-marketing commitments made to the United States Food and Drug Administration (FDA) upon completion of the review of the paediatric submission for Elelyso in that jurisdiction.
- Provide Health Canada with Periodic Safety Update Reports on Elelyso every six months according to the existing schedule and every 12 months thereafter, with particular emphasis on paediatric patients.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Gaucher disease is a rare, genetic deficiency of the lysosomal enzyme glucocerebrosidase which leads to progressive tissue and organ damage, typically of the liver, spleen, bone marrow, and brain. Elelyso (taliglucerase alfa) is a recombinant form of human glucocerebrosidase. Replacement of the missing or defective enzyme using enzyme replacement therapy (ERT) has been shown to be effective to reduce organomegaly and, improve haematological parameters. As ERT typically does not cross the blood-brain barrier, it is not effective at improving neurological symptoms when administered intravenously to patients with Gaucher disease.
The clinical pharmacology program included two clinical pharmacokinetic (PK)/pharmacodynamic (PD) studies which were conducted in healthy volunteers and patients with Gaucher disease, respectively.
Exposure to the drug in healthy patients was clearly dose-dependent and appeared to be nearly linear with dose. No gender differences in exposure were observed. At 30 units/kg and 60 units/kg, the clearance was numerically similar to that obtained in animals, and the volume of distribution was consistent with the size of the human plasma compartment.
The PK of taliglucerase alfa was characterized in 31 treatment-naïve subjects with Gaucher disease on Day 1 and Week 38 who received taliglucerase alfa 30 units/kg or 60 units/kg via intravenous infusion over 2 hours every other week. The median terminal half-life was 18.9 to 28.7 minutes for both dose groups at Day 1 and Week 38. The median systemic clearance (CL) values were approximately 30 L/hr and 20 L/hr for 30 units/kg and 60 units/kg, respectively, on Week 38. No significant accumulation in serum taliglucerase alfa concentrations was observed with repeated doses of 30 or 60 units/kg. Taliglucerase alfa PK did not appear to change over time (Day 1 versus Week 38). The maximum plasma concentration and area under the concentration-time curve of taliglucerase alfa were approximately 3-fold higher in subjects who received 60 units/kg than in subjects who received 30 units/kg, which is greater than the expected 2-fold increase assuming dose proportionality. Thus, the PK of taliglucerase alfa appeared dose dependent with a greater than dose-proportional increase in exposure at the doses studied (the CL values were reduced by approximately 30% to 35%).
Together, the clinical and pharmacological data support the use of Elelyso for the recommended indication.
For further details, please refer to the Elelyso Product Monograph, approved by Health Canada and available through the Clinical Efficacy section.
A total of 132 adults and children were exposed to Elelyso in the clinical studies; patients were aged 2-85 years old at the time of the first treatment with Elelyso (55% male). In the adult population, 49 patients received at least 24 months of treatment of Elelyso and 23 patients received more than 36 months. In the paediatric population, 12 children received more than 12 months of exposure to Elelyso.
Adverse events were experienced by 93% (108/116) of the treated adults and 75% of the treated children. Eleven point two percent (11.2%) of adult patients reported a total of 20 serious adverse events, and 2 paediatric patients reported a total of 2 serious adverse events, including musculoskeletal and connective tissue disorders; injury, poisoning and procedural complications; respiratory, thoracic and mediastinal disorders; and infusion reactions. The most commonly (>10%) reported adverse events in adult patients were arthralgia, nasopharyngitis, upper respiratory tract infections, headache, pyrexia, fatigue, pain in extremity, abdominal pain; and in paediatric patients were infusion-related reactions, vomiting, abdominal pain, nasopharyngitis, headache, pain in extremity, tonsillitis, diarrhoea, arthralgia, epistaxis, and tooth extraction. The most commonly observed symptoms of infusion-related reactions were headache, pruritus, hypersensitivity, nausea, peripheral oedema, throat irritation, erythema, and flushing.
Safety profiles were similar between paediatric and adult patients except for one case of severe gastroenteritis reported in a child. Additional adverse reactions recorded in the post-marketing phase included anaphylactic reactions, and adequate safety precautions should be taken to monitor for hypersensitivity reactions. If a severe allergic reaction occurs, immediate discontinuation of the Elelyso infusion is recommended. Patients who experience infusion-related reactions or hypersensitivity can however usually be managed successfully and have therapy continued by slowing the infusion rate, treating with medicinal products such as antihistamines, antipyretics and/or corticosteroids, and/or stopping and resuming treatment with decreased infusion rate. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions. As with all therapeutic proteins, some patients developed Immunoglobulin G (IgG) antibodies to taliglucerase alfa in the clinical studies. More hypersensitivity reactions were observed in patients who were positive for anti-taliglucerase alfa antibodies than in those patients who were negative.
The Risk Management Plan proposed by the sponsor has been reviewed by Health Canada.
The therapeutic benefits of Elelyso in the pivotal studies are considered positive and to outweigh the risks for the identified target population. It is also considered that the identified safety issues can be managed through labelling and adequate monitoring, and appropriate warnings and precautions are in place in the Elelyso Product Monograph.
For more information, refer to the Elelyso Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical profile (pharmacology and toxicology) of taliglucerase alfa, the active ingredient in Elelyso, has been adequately characterized. The results of the non-clinical studies as well as the potential risks to humans have been included in the Elelyso Product Monograph. In view of the intended use of Elelyso, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
Non-clinical toxicology studies included single-dose toxicity, repeat-dose toxicity, and reproductive toxicity. The clinically relevant intravenous route of administration was used in all of the toxicology studies. A chronic toxicology study in monkeys treated with taliglucerase alfa revealed no significant organ toxicity at doses up to 27.8 mg/kg/day (about 15 times the recommended human dose of 60 units/kg or approximately 2 mg/kg). Anti-drug antibodies were formed in the chronic study in monkeys; however, these antibodies were not neutralizing antibodies. Taliglucerase alfa did not show any significant adverse effect on fertility and early embryonic development in rats and it was not teratogenic in rats or rabbits.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Elelyso Product Monograph.
For more information, refer to the Elelyso Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Elelyso (taliglucerase alfa) is a recombinant form of human glucocerebrosidase that is expressed in a genetically modified carrot cell suspension. The expression system is designed to produce glycosylated protein with exposed terminal mannose structures, which is required for targeted cellular uptake by macrophages. Once internalized by macrophages, the enzyme acts to catalyze the hydrolysis of glucocerebroside to glucose and ceramide.
Elelyso is unique in that it is the first product to seek marketing approval in Canada that is produced in a plant cell host (that is, plant molecular-pharming).
Characterization of the Drug Substance
Detailed characterization studies were performed. The product- and process-related impurities characterizations are considered acceptable.
Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The drug substance, taliglucerase alfa, is produced in host cells derived from domestic carrots using disposable bioreactors. The cells are grown on solid media until a sufficient cell titre is reached to inoculate the first liquid media flask. The cells are then grown and split until a sufficient number of disposable bioreactors have been inoculated. Harvested cells are lysed and filtered before purification. Purification consists of multiple chromatography steps. During process development, several changes were made to the manufacturing process. The sponsor has adequately demonstrated the comparability of the material manufactured during process development and the commercial manufacturing process. The sponsor has also demonstrated that the commercial drug substance manufacturing process is able to consistently produce drug substance of acceptable quality.
The Elelyso drug product is manufactured by thawing and pooling of multiple containers of bulk drug substance, followed by compounding, pre-filtration, sterile filtration, aseptic filling into sterile glass vials, lyophilization, and capping/crimping. The sponsor has demonstrated that the commercial drug product manufacturing process is able to consistently produce drug product of acceptable quality.
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 and in compliance with International Conference on Harmonisation (ICH) guidelines.
Each lot of Elelyso drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
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 shelf-life and storage conditions for the drug substance and drug product are considered acceptable.
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.
An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.
Adventitious Agents Safety Evaluation
In the manufacturing of the taliglucerase alfa drug substance, a single raw material may contain extremely low levels of animal-sourced material (the soy peptone used in production media). This material may employ enzymes from non-transmissible spongiform encephalopathy (non-TSE) relevant species (porcine pancreas) to hydrolyse the plant protein, although soy peptone hydrolysed using microbially-derived enzymes may also be used. During the OSE, the use of the soy peptone was deemed acceptable as satisfactory controls and quality agreements with suppliers were in place to maintain control of the raw material. Therefore the use of porcine enzyme-hydrolysed soy peptone is acceptable.
None of the excipients used in the formulation of the taliglucerase alfa drug product are of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ELELYSO | 02425637 | PFIZER CANADA ULC | TALIGLUCERASE ALFA 200 UNIT / VIAL |