Summary Basis of Decision for Trumenba

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

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

Recent Activity for Trumenba

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.

Post-Authorization Activity Table (PAAT) for Trumenba

Updated:  2024-08-15

The following table describes post-authorization activity for Trumenba, a product which contains two purified Neisseria meningitidis serogroup B recombinant lipoprotein 2086 (rLP2086) antigens. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

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

Drug Identification Numbers (DIN):

  • DIN 02468751 - Bivalent recombinant lipoprotein (rLP2086), suspension for intramuscular injection
  • Neisseria meningitidis serogroup B rLP2086 subfamily A 60 mcg/0.5 mL
  • Neisseria meningitidis serogroup B rLP2086 subfamily B 60 mcg/0.5 mL

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 274749

2023-04-27

Issued NOC 2023-12-06

Submission filed as a Level I – Supplement to add an alternate drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 258009

2021-10-26

Issued NOC 2022-10-11

Submission filed as a Level I – Supplement to update the pm regarding a booster dose and additional immunogenicity and safety data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions; Dosage and Administration; and Clinical Trials sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 265419

2022-06-21

Issued NOL 2022-09-09

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

NC # 265213

2022-06-15

Issued NOL 2022-08-05

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

NC # 238252

2020-04-08

Cancellation Letter Received 2020-06-04

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance and drug product release or shelf‐life specifications. Additional information was to be provided so the submission was cancelled by the sponsor before Health Canada completed the review.

NC # 220373

2018-09-21

Issued NOL

2018-12-27

Submission filed as a Level II (90 day) Notifiable Change to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 214857

2018-03-26

Issued NOL

2018-07-24

Submission filed as a Level II (120 day) Notifiable Change to update the PM. As a result of the NC, additions were made to the Dosage and Administration section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN) 02468751 market notification

Not applicable

Date of first sale:

2018-01-31

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

NC # 211262

2017-11-15

Issued NOL

2018-01-04

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions, sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NDS # 195550

2016-05-31

Issued NOC

2017-10-05

Notice of Compliance issued for New Drug Submission.
 
Summary Basis of Decision (SBD) for Trumenba

Date SBD issued: 2017-11-24

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

Bivalent recombinant lipoprotein (rLP2086), suspension for intramuscular injection
Neisseria meningitidis serogroup B rLP2086 subfamily A 60 µg/0.5 mL
Neisseria meningitidis serogroup B rLP2086 subfamily B 60 µg/0.5 mL

Drug Identification Number (DIN):

  • 02468751

Pfizer Canada Inc.

New Drug Submission Control Number: 195550

 

On October 5, 2017, Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the vaccine Trumenba.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit/risk profile of Trumenba is favourable for active immunization to prevent invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B in individuals 10 through 25 years of age.

 

1 What was approved?

 

Trumenba is an active immunizing agent for the prevention of serogroup B invasive meningococcal disease. It is a bivalent vaccine that consists of two purified Neisseria meningitidis serogroup B recombinant lipoprotein 2086 (rLP2086) antigens, one from each of the two factor H binding protein (fHBP) subfamilies (A and B). The antigens are fHBP variants A05 (subfamily A) and B01 (subfamily B).

Trumenba is indicated for active immunization to prevent invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B in individuals 10 through 25 years of age.

Trumenba is contraindicated for patients who are hypersensitive to this vaccine or to any ingredient in the formulation or component of the container. Trumenba is also contraindicated for patients who have had severe allergic reaction (e.g., anaphylaxis) after any previous dose of Trumenba or to any component of this vaccine.

Trumenba was approved for use under the conditions stated in the Trumenba Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

One dose (0.5 mL) of Trumenba contains the following active substances:

  • Neisseria meningitidis serogroup B recombinant lipoprotein (rLP2086) subfamily A: 60 µg
  • Neisseria meningitidis serogroup B recombinant lipoprotein (rLP2086) subfamily B: 60 µg

Trumenba is presented as a suspension for intramuscular injection. In addition to the active substances, the suspension also contains aluminum phosphate, histidine, polysorbate 80, sodium chloride, 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 Trumenba Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Trumenba approved?

 

Health Canada considers that the benefit-risk profile of Trumenba is favourable for active immunization to prevent invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B in individuals 10 through 25 years of age.

Invasive meningococcal disease (IMD) is caused by the Gram negative bacterium Neisseria meningitidis. Neisseria meningitidis serogroup B (MnB) is a significant cause of serious endemic meningococcal disease. Trumenba is a bivalent vaccine composed of two serogroup B recombinant lipidated factor H binding proteins (fHBPs) - one each from subfamilies A and B. The lipidated protein induces antibodies that can kill MnB strains expressing fHBPs. Another recombinant, multicomponent MnB vaccine, Bexsero, was authorized for marketing in Canada in 2013 for use in individuals from 2 months through 17 years of age.

The immunogenicity and safety profile of Trumenba was based on data from 11 completed clinical trials in 20,803 subjects. The efficacy of Trumenba was inferred by immunogenicity, as measured by serum bactericidal activity (hSBA) using human complement with 14 MnB test strains (4 primary strains and 10 secondary strains) in two confirmatory Phase III clinical studies. Trumenba was immunogenic and is expected to prevent IMD caused by Neisseria meningitidis serogroup B in individuals 10 through 25 years of age. Trumenba induced immune response to diverse serogroup B IMD strains and was predicted to have a broad coverage in the prevention of serogroup B IMD.

Trumenba provides another option in Canada for the prevention of a serious and debilitating condition (IMD caused by MnB) in addition to the marketed vaccine Bexsero, including a new option for the prevention of MnB IMD in 18 to 25 year olds. Two different dose schedules offer choices for routine immunization or immunization for persons at increased risk of IMD.

Trumenba was well-tolerated in individuals aged 10-25 years. There were very limited safety data in individuals aged 26 years and older.

Trumenba has an acceptable safety profile based on the non-clinical data and clinical studies.

A Risk Management Plan (RMP) for Trumenba 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 be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Trumenba was accepted.

Overall, the benefits of Trumenba overweigh the risks for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroup B in individuals aged 10-25 years.

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 Trumenba?

 

A New Drug Submission (NDS) for Trumenba was filed with Health Canada in May 31, 2016. Due to an issue related to a testing method identified during the quality review, a Notice of Deficiency (NOD) was issued for Trumenba on October 28, 2016. The sponsor submitted a response to the NOD and all of the quality concerns that led to the NOD were satisfactorily addressed. A Notice of Compliance was issued on October 5, 2017.

 

Submission Milestones: Trumenba

Submission Milestone Date
Pre-submission meeting: 2016-03-08
Submission filed: 2016-05-31
Screening 1  
Screening Acceptance Letter issued: 2016-07-22
Review 1  
Notice of Deficiency (NOD) issued by Director General, Biologics and Genetic Therapies Directorate (quality issues): 2016-10-28
Response filed: 2016-11-30
Screening 2  
Screening Acceptance Letter issued: 2016-12-13
Review 1 or 2  
On-Site Evaluation (Austria) and 2017-02-20 - 2017-02-24
On-Site Evaluation (Ireland) 2017-02-13 - 2017-02-17
Quality Evaluation complete: 2017-09-08
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-09-26
Biostatistics Evaluation complete: 2017-09-28
Clinical Evaluation complete: 2017-10-02
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-10-05

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Trumenba was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by 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 Trumenba, 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:

  • To continue the improvement of the in vitro potency assay.
  • To evaluate additional measures to improve the management of reference materials.

 

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

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Trumenba is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Trumenba is a bivalent vaccine that consists of two purified Neisseria meningitidis serogroup B (MnB) recombinant lipoprotein 2086 (rLP2086) antigens, one from each of the two factor H binding protein (fHBP) subfamilies (A and B). The antigens are fHBP variants A05 (subfamily A) and B01 (subfamily B). The lipidated protein (which is the naturally occurring form of fHBP) induces antibodies that can kill MnB strains expressing fHBPs that are heterologous to those in the vaccine, whereas non-lipidated variants are unable to induce broadly cross-reactive bactericidal responses. Each Trumenba fHBP antigen elicits cross-protective responses against serogroup B strains expressing diverse fHBP variants from the same subfamily. Trumenba prevents serogroup B disease by inducing broadly protective bactericidal antibody responses against diverse fHBP variants expressed by serogroup B strains. Bactericidal antibodies elicited by Trumenba may also prevent factor H from binding to fHBP and render the bacteria more susceptible to complement-mediated killing.

The pharmacodynamics of Trumenba was assessed through the analysis of immunogenicity described in the Clinical Efficacy section.

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

Clinical Efficacy

A total of 11 completed clinical trials (3 Phase III, 5 Phase II, and 3 Phase I studies) were included in the drug submission to assess the final formulation of Trumenba in 20,803 adolescents and adults. Among them, 15,294 subjects received at least 1 dose of Trumenba, 14,153 subjects received 2 or more doses, and 5,509 subjects served as controls. A total of 12,268 subjects received 3 doses of 120 µg Trumenba.

No efficacy studies were available for Trumenba due to the low incidence of invasive meningococcal disease. The efficacy was instead inferred from immunogenicity, measured in vitro with a serum bactericidal assay using human complement (hSBA) with 4 primary MnB strains (PMB80 [A22], PMB2001 [A56], PMB2948 [B24], and PMB2707 [B44]).

Five co-primary endpoints were used in the evaluation of immunogenicity in the Phase II and Phase III studies. The endpoints included the proportion of subjects who achieved at least a 4-fold increase in hSBA titre for each of the 4 primary MnB test strains, and the proportion of subjects who achieved an hSBA titre greater than or equal to the lower limit of quantitation (LLOQ) for all 4 primary MnB test strains combined. Immune responses were tested 1 month following a 2-dose or 3-dose vaccination. Immunogenicity of Trumenba was also assessed by hSBA with 10 additional secondary strains in two Phase III studies, suggesting that the vaccine can induce an immune response to diverse invasive meningococcal disease (IMD) strains.

The majority of subjects were ≥10 to <26 years of age. There were only 53 subjects ≥26 years of age evaluated for safety and 6 subjects evaluated for immunogenicity against the 4 primary test strains. The data support an indication for individuals 10 to 25 years of age, but insufficient for individuals ≥26 years of age.

Various doses of Trumenba were assessed. The dose of 120 µg was selected and tested in most of the Phase II and Phase III studies. The immunogenicity following the 0, 1 and 6-month dosing schedule was comparable to that following the 0, 2 and 6-month dosing schedule (95% confidence intervals [CI] of hSBA fold rise ≥4 and composite response overlapped between these two dosing schedules). The proportion of subjects in the 0 and 6-month schedule who achieved an hSBA titre of ≥1:8 after 2 doses of Trumenba was comparable to the corresponding proportion for strains A22 and A56, but was numerically lower than the corresponding proportion for B24 and B44 in the 3-dose schedules. The immune responses for the PMB2948 [B24] and PMB2707 [B44] test strains were improved following a third dose of Trumenba. In addition, the 3-dose dosing schedule could induce a quicker immune response than the 2-dose schedule as the response to the first dose was moderate and declined before the second dose in the 0 and 6-month schedule.

Co-administration of Trumenba was assessed with Repevax, Gardasil, Menactra and Adacel. The data from the clinical studies supported the concomitant use of Trumenba with Gardasil, Menactra and Adacel. However, the geometric mean ratio (GMR) for human papilloma virus type 18 (HPV-18) had a lower bound of the 95% CI of 0.62 and was lower than the pre-specified threshold for non-inferiority in healthy subjects aged ≥11 to <18 years. The clinical relevance remains unknown, however, one month after the 3rd Gardasil dose, ≥99% of subjects seroconverted to all 4 HPV antigens in both the saline + Gardasil and Trumenba + Gardasil groups.

Limited data in Study B1971005 (Stage 2) examined antibody persistence for up to 4 years after the third dose of Trumenba. The proportion of subjects who achieved hSBA titres ≥LLOQ declined following 1 month after Dose 3, and then remained stable and ranged from 51% to 69% for PMB80 (A22), PMB2001 (A56) and PMB2948 (B24), and from 20% to 29% for PMB2707 (B44) from 12 months through 48 months after Dose 3. However, as withdrawals during Stage 2 of the study have not been accounted for in the analysis of the persistence of immune response, the results should be interpreted with caution. Study B1971033 is ongoing and will provide further data on antibody persistence.

No data are available in children ≤10 year of age, immunocompromised individuals, and pregnant and lactating woman.

Indication

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

  • Trumenba is indicated for active immunization to prevent invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B in individuals 10 years of age and older.

Due to the very limited supporting data for subjects ≥26 years of age, Health Canada approved the following indication:

  • Trumenba is indicated for active immunization to prevent invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B in individuals 10 through 25 years of age.

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

Clinical Safety

The core clinical safety dataset was derived from the 8 controlled studies with the final formulation of Trumenba at the dose of 120 µg, administered at 0, 2, and 6 months. The overall safety dataset included data from all 11 completed clinical studies.

Local Reactions

Based on the core safety data, the proportion of subjects who reported pain at the injection site within 7 days after any dose was greater among subjects who received Trumenba (89.6% to 98.1%) than those who received the control vaccine (18.2% to 64.8%). Severe pain was reported by 3.0% to 15.1% of subjects who received Trumenba and by 0.0% to 2.4% of subjects who received the control vaccine. Control vaccine consisted of either saline alone, a licensed vaccine alone (Havrix, Adacel, Repevax, Gardasil or Menactra) or saline and a licensed vaccine.

The frequency of redness that occurred within 7 days after any dose was higher among subjects who received Trumenba (22.0% to 40.0%) than those who received the control vaccine (0.0% to 8.1%). The frequency of swelling after any dose was higher after Trumenba (25.1% to 40.7%) than after the control vaccine (0.0% to 12.2%). Large local reactions of redness and/or swelling (>21 caliper units) occurred in <2% of subjects who received Trumenba and were more frequently reported after the administration of Trumenba than after the control vaccine.

Most local reactions were generally transient and mild to moderate in intensity. Percentages of subjects withdrawn from the studies due to local reactions were 0.35% and 0.04% in the Trumenba group and the control group, respectively.

Systemic Events

Most types of systemic events were reported at a higher frequency among subjects in the Trumenba group than those in the control group (headache, fatigue, muscle pain, chills, joint pain, and fever). The most frequently reported systemic events after any dose of Trumenba were fatigue and headache. The proportion of subjects who reported fatigue after any dose ranged from 60.6% to 85.0% versus (vs.) 41.7% to 79.6%; and the proportion reporting headache ranged from 59.1% to 83.9% vs. 48.4% to 74.3% after receiving Trumenba and control, respectively. Muscle pain was reported more frequently after Trumenba (34.3% to 61.8%) than after the control vaccine (18.3% to 52.4%).

 

Fever (≥38ºC) was also reported more frequently among subjects who received Trumenba (4.4% to 17.4%) than those who received the control vaccine (1.7% to 9.0%). Severe fever (39.0ºC to 40.0ºC) was reported for 0.2% to 2.7% of subjects after any dose of Trumenba and for 0.4% to 1.7% of subjects after the control vaccine. Chills was reported at 20.7% to 55.8% vs. 13.3% to 44.4% of subjects, and joint pain, 22.7% to 37.7% versus 14.2% to 30.7% of subjects with Trumenba and control, respectively.

For systemic events in both the Trumenba and control groups, the reporting rates were generally highest after Dose 1, with lower rates observed after Dose 2 and Dose 3. Most reports of systemic events were mild or moderate. For most types of systemic events, the median duration of the event was generally 1 to 2 days. Co-administration of Gardasil and the quadrivalent meningococcal conjugate vaccine and acellular pertussis vaccine (MCV4+Tdap) with Trumenba did not substantially increase the reporting rates or the duration of systemic events as compared with the administration of Trumenba alone.

For unsolicited adverse events (AEs), similar percentages of subjects in the Trumenba group and the control group reported AEs during the vaccination phase (42.68% vs. 41.68%, respectively), within 30 days after any vaccination (30.95% vs. 28.37%), and within 30 days after Dose 1 or Dose 2 (25.46% vs. 22.91%). During the vaccination phase, the frequency of AE reports was also similar between the Trumenba group and the control group for severe AEs (3.25% vs. 2.89%) and immediate AEs (1.64% vs. 1.28%), while a higher proportion of subjects in the Trumenba group than in the control group reported related AEs (11.37% vs. 6.10%). The percentages of subjects experiencing serious adverse events (SAEs), medically attended events (MAEs), newly diagnosed chronic medical conditions (NDCMCs), autoimmune conditions, and neuroinflammatory conditions were comparable in the Trumenba group and the control group.

Overall Analysis of Safety

Overall, Trumenba was well-tolerated in individuals aged 10-25 years. There were limited safety data in individuals aged 26 years and older.

Since 2014, approximately 170,000 doses have been distributed up to November 30, 2015. The analysis of the reported events by the sponsor did not show any new significant safety findings.

Appropriate warnings and precautions are in place in the approved Trumenba Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

A number of non-clinical studies have demonstrated immunogenicity of Trumenba in mice, rabbits, and non-human primates. Trumenba was well-tolerated in the two 5-cycle repeat-dose toxicity studies and there were no vaccine-related effects on female fertility or fetal or postnatal development in the combined fertility and developmental toxicity studies in rabbits. The non-clinical toxicity studies support the clinical development and support the specified indication. The results of the non-clinical studies as well as the potential risks to humans have been included in the Trumenba Product Monograph. In view of the intended use of Trumenba, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Trumenba is a bivalent vaccine, consisting of two recombinant lipidated factor H binding protein (fHBP) variants (rLP2086) from Neisseria meningitidis serogroup B, one from fHBP subfamily A and one from subfamily B (A05 and B01, respectively). A single human dose of Trumenba contains 60 µg of each of the two antigens.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that both medicinal ingredients consistently exhibit the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

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

Trumenba is composed of two recombinant lipidated factor H binding protein (fHBP) variants (rLP2086) from Neisseria meningitidis serogroup B, one from fHBP subfamily A and one from subfamily B (A05 and B01, respectively).

The rLP2086 (subfamily A and B) proteins are individually produced in Escherichia coli. Production strains are grown in defined fermentation growth media to a specific density. The recombinant proteins are extracted from the production strains and purified through a series of column chromatography steps. Polysorbate 80 is added to the drug substances and is present in the final drug product.

Although there were multiple changes to the manufacturing process and sites for both drug substances and drug product, sufficient data have been provided to support the comparability of the final products manufactured throughout the clinical development stage. Additionally, commercial lots will be manufactured at the same sites, where Phase II and III clinical lots were produced and shown to have an acceptable safety profile and to induce an immune response that is predicted to provide protection against invasive meningococcal disease.

The information submitted supports the suitability of the manufacturing process to produce vaccine lots that are consistent in terms of quality attributes relevant to those lots used in the clinical trials.

Control of the Drug Substance and Final Product

Validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substances. The specifications provided for each of the drug substances are considered acceptable. Data from the batch analyses of each of the drug substances were reviewed and are within the proposed acceptance criteria.

The drug substance packaging is also considered acceptable.

Throughout the development stage, the potency of Trumenba was assessed using both an in vivo assay and an in vitro assay. Given the inherent variability of all in vivo assays, Health Canada requested that the potency of Trumenba commercial lots be assessed using the in vitro potency test.

An issue concerning the in vitro potency test of the drug product was identified, and led to the issuance of a Notice of Deficiency (NOD) on October 28, 2016. The sponsor responded to the NOD on November 30, 2016 and addressed the noted deficiency accordingly. The response to NOD was accepted and as a result, the test specifications and analytical methods used are considered acceptable for all assay procedures used for in-process, release, and stability testing for the drug product. The specifications proposed were in line with the characteristics of the vaccine lots tested in clinical studies. Data from the batch analyses of each of the drug product components were reviewed and were within the proposed acceptance criteria.

In conclusion, the manufacturing process and control of Trumenba is considered acceptable, and it is expected that the process will be further strengthened once the post-NOC commitments are implemented.

Stability of the Drug Substance and Final Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and final product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life at 2-8°C for Trumenba is considered acceptable.

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 acceptance criteria.

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.

The On-Site Evaluations conducted at both manufacturing sites with the supporting facility information in the submission provided sufficient assurance that the process and conditions of manufacture are suitable to ensure the drug product will not be unsafe for use as required by Section 12 of the Food and Drugs Act.

Adventitious Agents Safety Evaluation

Raw materials of animal origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents.

Bioburden and sterility controls are in place at appropriate stages of production, and the final product is a sterile suspension.

The vaccine is composed of components derived from microbial fermentation, and is not a viral product. Raw/starting materials used for Trumenba manufacturing are adequately tested and controlled, and risk for viral contamination is considered negligible.

Based on the assessment of the raw/starting materials, the risk of transmissible spongiform encephalopathy, non-viral and viral contamination of Trumenba is considered negligible.

 

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