Summary Basis of Decision for Siliq
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 Siliq is located below.
Recent Activity for Siliq
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 Siliq
Updated:
The following table describes post-authorization activity for Siliq, a product which contains the medicinal ingredient brodalumab. 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 02473623 - 210 mg/1.5 mL brodalumab, solution, subcutaneous administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NDS # 225816 | 2019-03-28 | Issued NOC2019-06-07 | Submission filed to transfer ownership of the drug product (that is drug sponsor name) from Valeant Canada LP to Bausch Health, Canada Inc., and to update the inner and outer labels and package insert. The information was reviewed and considered acceptable. An NOC was issued. |
| NC # 220721 | 2018-10-03 | Issued NOL2019-01-09 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add drug product testing sites. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Drug product (DIN 02473623) market notification | Not applicable | Date of first sale:2018-07-05 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 195317 | 2017-05-08 | Issued NOC2018-03-06 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Siliq
Date SBD issued: 2018-06-11
The following information relates to the new drug submission for Siliq.
Brodalumab
210 mg/1.5 mL solution, subcutaneous
Drug Identification Number (DIN):
- 02473623
Valeant Canada LP
New Drug Submission Control Number: 195317
On March 6, 2018, Health Canada issued a Notice of Compliance to Valeant Canada LP for the drug product Siliq.
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 Siliq is favourable for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.
1 What was approved?
Siliq (brodalumab), a biological response modifier, is a recombinant human monoclonal immunoglobulin G2 antibody that binds to human interleukin 17 Receptor A (IL-17RA) and blocks the biological activities of the pro-inflammatory cytokines IL-17A, IL-17F, IL-17C, IL-17A/F, and IL-25, resulting in inhibition of the inflammation and clinical symptoms associated with psoriasis. Siliq was authorized for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.
No dose adjustment is recommended in geriatric patients (≥65 years of age).
The safety and efficacy of Siliq in children below the age of 18 years have not yet been established. No data are available.
Siliq is contraindicated in patients with Crohn's disease, as well as patients with clinically significant hypersensitivity to brodalumab or to any of the excipients or component of the container.
Siliq was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Siliq (210 mg/1.5 mL brodalumab) is presented as a solution for injection. In addition to the medicinal ingredient, brodalumab, the solution contains proline, glutamate, polysorbate 20, and water for injection.
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 Siliq Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Siliq approved?
Health Canada considers that the benefit-risk profile of Siliq is favourable for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.
Plaque psoriasis is a chronic immunologically-mediated disease characterized by marked inflammation and thickening of the epidermis that result in thick, red, scaly plaques involving the skin. Plaques are most commonly found on the elbows, knees, scalp, and back. The disease is characterized by exacerbations and remissions that often seem to occur spontaneously. The disease affects 1% to 3% of the general population, with the highest disease prevalence in North America and Europe.
Siliq has been shown to be efficacious in adult patients with moderate to severe plaque psoriasis, who are candidates for systemic therapy or phototherapy. The market authorization was based on three pivotal multicentre, randomized, double-blind, controlled studies with a total of 4,373 patients 18 years of age and older. The patients had at least a 6-month history of moderate to severe plaque psoriasis, defined as having an affected Body Surface Area (BSA) ≥10%, a Psoriasis Area and Severity Index (PASI) score ≥12, a static Physician's Global Assessment (sPGA) score ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis. The co-primary endpoints (compared to placebo) for each of the studies were the proportion of patients who achieved a 75% reduction in the PASI score (PASI 75) and a successful static Physician's Global Assessment (sPGA) score of clear (0) or almost clear (1) at Week 12. In all three studies, patients who were treated with Siliq 210 mg every 2 weeks had higher rates of PASI 75 and PASI 100 responses, as well as sPGA success vs. placebo at Week 12. In Studies 2 and 3, a statistically significant difference in PASI 100 responses were observed for the Siliq 210 mg every 2 weeks dose compared to the comparator drug ustekinumab.
The safety profile of Siliq is considered acceptable. Important identified risks for Siliq are worsening of active Crohn's disease, infections, and neutropenia. Important potential risks are suicidal ideation and behaviour (SIB), major adverse cardiovascular events (MACE), and hypersensitivity. Association between treatment with Siliq and risk of SIB has not been established, nevertheless, a warning regarding SIB is included in a Warnings and Precautions box in the Siliq Product Monograph. An enhanced pharmacovigilance plan and a Patient Support Program will be implemented to mitigate the potential risk of SIB. This program is intended to support patients and healthcare professionals with the prescribing, administration, and monitoring of patients who receive Siliq treatment. Prescribers are to register in the Patient Support Program before prescribing Siliq. Prescribers are educated regarding the appropriate use of Siliq and are expected to educate patients on the benefits and risks of treatment, especially the risk of suicidal ideation and behavior.
A Risk Management Plan (RMP) for Siliq was submitted by Valeant Canada LP to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Siliq Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Siliq was accepted.
Overall, the therapeutic benefits of Siliq therapy seen in the pivotal studies are positive. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Siliq Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Siliq?
A New Drug Submission (NDS) for Siliq (brodalumab) was filed with Health Canada on May 24, 2016. Due to several deficiencies and concerns identified in the chemistry and manufacturing information, a Notice of Deficiency (NOD) was issued on April 6, 2017. In response to the NOD, the sponsor provided updated sections to the quality information. The response was deemed acceptable for review and all identified issues were satisfactorily addressed. Health Canada requested and the sponsor agreed to several post-market commitments to mitigate the safety risks of Siliq, and a Notice of Compliance was issued on March 6, 2018.
Submission Milestones: Siliq
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2016-05-24 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2016-07-15 |
| Review 1 | |
| Notice of Deficiency issued by Director General, Biologics and Genetic Therapies Directorate (quality issues): | 2017-04-06 |
| Response filed: | 2017-05-08 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2017-05-10 |
| Review 2 | |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-02-28 |
| Quality Evaluation complete: | 2018-03-02 |
| Clinical Evaluation complete: | 2018-03-05 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2018-03-06 |
The Canadian regulatory decision on the quality (chemistry and manufacturing), non-clinical and clinical review of Siliq was based on a critical assessment of the data package submitted to Health Canada. Clinical and quality questions and answers from the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
As part of the marketing authorization for Siliq, 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 (but are not limited to):
- Development of educational material to highlight the need to inform and counsel patients and caregivers about the potential risk of suicidal ideation and behaviour (SIB) before starting the treatment and at each follow up visit, and to refer the patients to a mental healthcare provider in case of new onset of SIB or worsening of symptoms.
- In addition to the Enhanced Pharmacovigilance Plan, implement additional measures within the Siliq Patient Support Program to minimize the potential risk of SIB as per the proposed Risk Minimization Strategy:
Prescribers are educated regarding the appropriate use of Siliq and are expected to educate patients on the benefits and risks of treatment, especially the risk of suicidal ideation and behavior. Patients who are prescribed Siliq are to enroll in the Siliq Patient Support Program. - Development of tools to assess the effectiveness of the proposed risk minimization measures.
- Update the Canadian Risk Management Plan (RMP) for Siliq to include all risk minimization measures as agreed with Health Canada.
- Provide Health Canada with the revised RMP and, when available, the components of the Patient Support Program (Prescriber Registration Form, Prescriber Guide, Patient Enrolment Form, Patient Educational Material, Pharmacy Registration Form) to assess the adequacy of the documents.
- Provide Health Canada with safety summary analyses of SIB events in Periodic Benefit-Risk Evaluation Reports for a minimum of three years after marketing, and when important safety data becomes available thereafter.
- Provide Health Canada with the final clinical study reports for six clinical studies to be conducted as post-marketing commitments made to the United States Food and Drug Administration (FDA) (3164-1 through 3164-6) when available, and to update the Canadian Siliq Product Monograph as needed.
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.
- 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
Plaque psoriasis is a chronic immunologically-mediated disease characterized by marked inflammation and thickening of the epidermis that result in thick, red, scaly plaques involving the skin. Siliq (brodalumab) is a human monoclonal immunoglobulin (Ig) G2 antibody that binds to interleukin 17 Receptor A (IL-17RA) and blocks the biological activities of the pro-inflammatory cytokines IL-17A, IL-17F, IL-17C, IL-17A/F, and IL-25, resulting in inhibition of the inflammation and clinical symptoms associated with plaque psoriasis.
The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic (PK) studies. The clinical pharmacological data support the use of Siliq for the specified indication.
Bioavailability was estimated by a population PK model to be 55% and the half-life was 10.9 days. The drug exposure, clearance, and distribution were significantly affected by body weight (inverse relationship) but not by sex, age, or race. Exposure in subjects ≤60 kg was 1.5-fold higher than average, and exposure in subjects ≥130 kg was decreased by half. There was a direct correlation between the brodalumab dose and response to treatment.
The PK of Siliq was not affected by the formation of anti-brodalumab antibodies. There were no apparent relationships between subjects with antibodies and PK, efficacy or safety outcomes.
For further details, please refer to the Siliq Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Siliq was evaluated in three multicentre, randomized, double-blind, controlled studies (Studies 1, 2, and 3). Study 1 had a placebo arm, and Studies 2 and 3 each had a placebo arm and an active comparator arm (ustekinumab). The three studies enrolled a total of 4,373 patients 18 years of age and older with at least a 6-month history of moderate to severe plaque psoriasis, defined as having a minimum affected body surface area (BSA) of 10%, a Psoriasis Area and Severity Index (PASI) score ≥12, a static Physician's Global Assessment (sPGA) score ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, and who were candidates for systemic therapy or phototherapy. All three studies included a 12-week placebo-controlled induction phase, a double-blind duration of 52 weeks, and an open-label long-term extension. Patients randomized to Siliq (brodalumab) or placebo received subcutaneous treatment at Weeks 0, 1, and 2, followed by the same dose every 2 weeks through Week 12. In Studies 2 and 3, patients randomized to ustekinumab received the 45 mg dose for patients weighing less than 100 kg and the 90 mg dose for patients weighing greater than 100 kg at Weeks 0, 4, and 16, followed by same dose every 12 weeks.
In all studies, the co-primary endpoints (compared to placebo) were the proportion of patients who achieved a 75% reduction in the PASI score (PASI 75) and sPGA success (clear [0] or almost clear [1]) at Week 12. For Studies 2 and 3, the primary endpoint (compared to ustekinumab) included the proportion of patients who received Siliq 210 mg and achieved a 100% reduction in the PASI score (PASI 100) at Week 12.
Other evaluated outcomes included the proportion of patients who achieved a 90% reduction in the PASI score (PASI 90) and sPGA 0 (clear) at Week 12, and maintenance of efficacy to Week 52. The proportion of patients who achieved Psoriasis Symptom Inventory (PSI) score of 0 (not at all) or 1 (mild) on every item (itch, redness, scaling, burning, stinging, cracking, flaking, and pain) through Week 52, and the proportion of patients who achieved Dermatology Life Quality Index (DLQI) response through Week 52 were also evaluated.
In all three studies, patients who were treated with Siliq had higher rates of PASI 75 and PASI 100 responses compared to those that were treated with placebo, at Week 12 (PASI 75 - Study 1: 83% vs. 3%; Study 2: 86% vs. 8%; Study 3: 85% vs. 6%; and PASI 100 - Study 1: 42% vs. <1%; Study 2: 44% vs. 1%; Study 3: 37% vs. <1%).
Patients who were treated with Siliq also had higher rates of sPGA success vs. placebo at Week 12 (sPGA success - Study 1: 76% vs. 1%; Study 2: 79% vs.4 %; Study 3: 80% vs. 4%). In Studies 2 and 3, statistically significant differences in PASI 100 responses were observed for Siliq compared to ustekinumab (Study 2: 44% vs. 22%; Study 3: 37% vs. 19%). Onset of response as measured by PASI 75 was observed within 2 weeks of treatment with Siliq in all three clinical studies.
The percentage of patients with a DLQI score of 0 or 1 (no impairment) at Week 12 in Studies 1, 2, and 3 was 43%, 61%, and 59%, respectively in the Siliq arms compared with placebo at 5%, 5%, and 7%, respectively.
In Study 1, patients randomized to receive Siliq and who were responders at Week 12 were re-randomized to receive either placebo or Siliq. Among responders at Week 12, 83% of the ''sPGA clear'' responders and 87% of the PASI 75 responders, re-randomized to continued treatment with Siliq, maintained this response at Week 52 compared to none in the control group.
Studies 2 and 3 included a re-randomized phase during which patients originally randomized to receive Siliq during the first 12 weeks were re-randomized to one of four Siliq regimens at Week 12, and patients who received placebo were crossed over to receive Siliq. Patients who received ustekinumab continued the same treatment until they were crossed over at Week 52 to brodalumab. Of the patients who received continuous brodalumab or ustekinumab dosing, PASI 100 was achieved by 51% of brodalumab-treated patients and by 28% of ustekinumab-treated patients. For ''sPGA clear or almost clear'' responders at Week 12, the percentage of patients who maintained this response at Week 52 was 79% for patients treated with brodalumab. For PASI 100 responders at Week 12, 72% of the patients who continued on brodalumab maintained the response at Week 52.
Overall Analysis of Efficacy
Siliq was superior to placebo and/or ustekinumab for the co-primary endpoints and for key secondary endpoints in the three pivotal clinical studies.
The submitted clinical studies support the use of Siliq for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. The recommended indication is the same as the indication filed with the submission.
For more information, refer to the Siliq Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety profile of Siliq (brodalumab) was based on data from 5,205 patients who had a total of 5,904 patient-years of Siliq exposure of which 3,207 had at least 12 months of exposure. In the clinical program for psoriasis, 4,461 patients had a total of 5,402 patient-years of Siliq exposure of which 3,072 had at least 12 months of exposure. The safety profile of Siliq was acceptable compared to placebo during the initial 12-week double-blind period of the Phase II and Phase III studies. Also, its safety profile over 52 weeks was acceptable, and comparable to that of ustekinumab, the active comparator drug used in two of the Phase III studies.
Data from three Phase III clinical studies (described in the Clinical Efficacy section), as well as one Phase II study were pooled to evaluate the safety of Siliq in comparison to placebo for up to 12 weeks after the treatment was initiated. Of the 1,496 patients who were treated with Siliq, the most common adverse reactions reported at a higher rate than placebo were headache (4.3%), arthralgia (4.7%), fatigue (2.6%), oropharyngeal pain (2.1%), and diarrhea (2.2%). No dose-response relationship was evident across the most common adverse events (AEs); however, one was seen with respect to candida and tinea infections (both non-serious) and neutropenia. The overall frequency of AEs was slightly higher in the Siliq and ustekinumab treatment groups compared to placebo. Nasopharyngitis and upper respiratory tract infections were the most commonly reported AEs (≥5%) among the patients treated with Siliq during the 12-week placebo-controlled period. Through Week 52 of treatment, the most commonly reported AEs (≥10 per 100 patient-years) among patients treated with Siliq were nasopharyngitis, upper respiratory tract infections, arthralgia, and headache.
The frequency of serious adverse events (SAEs) was similar across all groups during the 12-week, placebo-controlled period. The incidence of SAEs was 1.6% in patients who received Siliq, 1% in patients who received ustekinumab, and 1.7% in patients who received placebo. The proportion of Siliq-treated patients who discontinued treatment in the first 12 weeks of treatment due to AEs was similar (approximately 1%) in all treatment arms.
The important identified risks for Siliq are worsening of active Crohn's disease, infections, and neutropenia.
Important potential risks are suicidal ideation and behaviour (SIB), major adverse cardiovascular events (MACE), and hypersensitivity.
Overall Analysis of Safety
Overall, the safety data support the approval of Siliq for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. Appropriate warnings and precautions are in place in the approved Siliq Product Monograph to address the identified safety concerns. In order to ensure that this benefit continues to outweigh any risk after authorization, Health Canada has required several post-approval activities to be carried out, including an Enhanced Pharmacovigilance Plan and a Siliq Patient Support Program to mitigate the risk of SIB.
For more information, refer to the Siliq Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical pharmacology and toxicology studies support the use of brodalumab, the medicinal ingredient of Siliq, for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.
No significant effects, including any organ toxicity or undesirable effects on immune function were observed in cynomolgus monkeys administered brodalumab by subcutaneous (SC) injection up to dose levels of 90 mg/kg/week for 6 months (26 times the maximum recommended human dose).
Exposed cynomolgus monkeys did not display any effects on surrogate fertility endpoints. No effects on embryo-fetal toxicity or postnatal development (up to 6 months of age), including morphological and immunological development, were observed in infants from pregnant cynomolgus monkeys administered brodalumab by SC injection from the period of organogenesis to parturition up to dose levels of 90 mg/kg/week.
No dedicated studies were conducted to assess the carcinogenic potential of brodalumab.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Siliq Product Monograph. In view of the intended use of Siliq, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Siliq Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The drug substance of Siliq, brodalumab, is a human monoclonal immunoglobulin (Ig) G2 (IgG2) antibody directed against human interleukin 17 Receptor A (IL-17RA). Brodalumab is comprised of 1,312 amino acids and has an estimated molecular mass of 144,000 Daltons.
Siliq (brodalumab) is a sterile solution that is clear to slightly opalescent, colourless to slightly yellow liquid, practically free from particles.
Each Siliq single-use prefilled syringe contains 210 mg of brodalumab and is supplied in 1.5 mL solution (140 mg/mL brodalumab) in a single-use syringe.
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that brodalumab consistently exhibits the desired characteristic structure and biological activity.
Impurities arising from manufacturing were reported and characterized. These products were found to be within established limits and are considered to be acceptable.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The drug substance, brodalumab, is expressed in a Chinese Hamster Ovary (CHO) cell line. The manufacturing process consists of inoculation, fermentation, harvest, centrifugation, viral inactivation, as well as a series of chromatographic and filtration steps. The control strategy in place for ensuring consistency of the manufacturing process includes ensuring control of all raw materials through testing and qualification of suppliers, testing of the two-tiered cell banking system in accordance with International Council for Harmonisation (ICH) guidelines, use of key and critical operating parameters and performance parameters, in-process control testing, batch-release testing, and stability testing.
The drug product manufacturing process consists of drug substance thawing, pooling to reach target drug product batch size, mixing, bioburden reduction filtration, sterile filtration, and aseptic filling into pre-sterilized glass syringes. All process parameters, in-process controls, and release testing results were consistent between the process validation lots and well within specification limits, demonstrating that the manufacturing process is capable of consistently manufacturing a brodalumab drug product which meets pre-established specifications.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and considered to be adequately controlled within justified limits.
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 Council for Harmonisation (ICH) guidelines.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.
Validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substance and drug product.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
Stability of the Drug Substance and Drug Product
The in-house release and stability methods have been appropriately validated. Stability data support the proposed drug product shelf life of 48 months at 5°C, protected from light. Additionally, accelerated stability data support the optional short-term room temperature exposure (20-25°C) of the drug product for up to 2 weeks within the proposed 48 month drug product shelf life, protected from light.
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.
On-Site Evaluations (OSEs) of the facilities involved in the manufacture and testing of the drug substance, brodalumab, and the drug product, Siliq, were not performed for the following reasons:
- The drug substance manufacturing facility has a history of compliance (OSE in June 2009 resulted in a compliant rating) and is currently the approved manufacturing site for multiple biologics.
- An OSE was recently performed (March 2017) at the drug product manufacturing facility, with a compliant rating.
- No major issues were identified that warranted an OSE during the preliminary review of this updated submission.
Adventitious Agents Safety Evaluation
No materials of animal origin are used in the manufacturing process of the brodalumab drug; however, fetal bovine serum was used during early cell line development. Based on the risk assessment performed and the viral safety program, it was concluded that the risk of bovine spongiform encephalopathy (BSE)/transmissible spongiform encephalopathy (TSE) associated with brodalumab is negligible. Appropriate Certificates of Analysis/Origin and/or TSE Certificates of Suitability have been provided.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SILIQ | 02473623 | BAUSCH HEALTH, CANADA INC. | BRODALUMAB 210 MG / 1.5 ML |