Summary Basis of Decision for Prehevbrio

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)

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

Recent Activity for Prehevbrio

The 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

The following table describes post-authorization activity for Prehevbrio, a product which contains the medicinal ingredient hepatitis B surface antigen (recombinant). 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.

Updated: 2023-07-06

Drug Identification Number (DIN):

DIN 02533286 – 10 mcg/mL hepatitis B surface antigen (recombinant), suspension, intramuscular administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 271192

2023-01-06

Issued NOL 2023-04-18

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

NDS # 259302

2021-12-06

Issued NOC 2022-12-06

NOC issued for the New Drug Submission.

Summary Basis of Decision (SBD) for Prehevbrio

Date SBD issued: 2023-07-06

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

Hepatitis B Surface Antigen (Recombinant)

Drug Identification Number (DIN): DIN 02533286 - 10 mcg/mL hepatitis B surface antigen (recombinant), suspension, intramuscular injection

VBI Vaccines Inc.

New Drug Submission Control Number: 259302

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): Vaccines

Date Filed: 2021-12-06

Authorization Date: 2022-12-06

On December 6, 2022, Health Canada issued a Notice of Compliance to VBI Vaccines Inc. for the vaccine Prehevbrio.

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 Prehevbrio is favourable for active immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.

It can be expected that hepatitis D will also be prevented by immunization with Prehevbrio as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

1 What was approved?

Prehevbrio, an active immunizing agent, was authorized for active immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.

It can be expected that hepatitis D will also be prevented by immunization with Prehevbrio as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

The National Advisory Committee of Immunization provides additional guidance on the use of hepatitis B vaccines in Canada, including a list of recommended individuals for vaccination against hepatitis B. Please refer to the Canadian Immunization Guide.

Prehevbrio is not authorized for use in pediatric patients (under 18 years of age), as no clinical safety or efficacy data are available to Health Canada for this population.

No overall differences in efficacy or safety were observed in geriatric patients (65 years of age and older) compared to younger patients in clinical studies.

Prehevbrio (10 mcg/mL hepatitis B surface antigen [recombinant]) is presented as an intramuscular injection. In addition to the medicinal ingredient, the intramuscular injection also contains the following non‑medicinal ingredients: aluminium hydroxide, disodium phosphate dodecahydrate, hydrochloric acid, potassium chloride, potassium dihydrogen phosphate, sodium chloride, sodium hydroxide, and water for injection.

The use of Prehevbrio is contraindicated in patients who:

  • are allergic to the active medicinal ingredient or any of the other non-medicinal ingredients of the vaccine,

  • previously had a sudden, life-threatening allergic reaction to any vaccine against hepatitis B,

  • are ill with a high fever.

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

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

2 Why was Prehevbrio approved?

Health Canada considers that the benefit-risk profile of Prehevbrio is favourable for active immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.

It can be expected that hepatitis D will also be prevented by immunization with Prehevbrio as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

Viral hepatitis is an inflammation of the liver resulting from infection with a hepatitis virus. Viral hepatitis is a major cause of death and disability worldwide and is a global public health challenge. Half of all deaths caused by viral hepatitis are attributable to the hepatitis B virus.

In non-endemic countries, such as Canada and the United States, the majority of hepatitis B infections occur in adults through sexual intercourse, injection drug use, household contact with a hepatitis B carrier, and nosocomial infection.

In Canada, 4,905 cases of hepatitis B infection were reported in 2017 (the most recent year for which statistics are available) according to the Public Health Agency of Canada. Of these, 192 were cases of acute infection and 4,086 were cases of chronic infection; 627 cases were unspecified. This number was similar to the number of cases reported the prior year (4,985 in 2016). These rates correspond to 0.5 cases of acute infection per 100,000 people and 11.4 cases of chronic infection per 100,000 people.

In Canada, the current standard of care for active immunization against hepatitis B infection in adults is vaccination with Engerix-B (20 mcg hepatitis B surface antigens) or Recombivax HB (10 mcg hepatitis B surface antigens) delivered as three 1.0 mL doses administered according to the standard regimen at 0, 1, and 6 months according to the National Advisory Committee on Immunization guidelines.

For adults requiring protection against both hepatitis A and hepatitis B, the combination vaccine, Twinrix, which contains Havrix (an inactivated-virus hepatitis A vaccine) and Engerix-B, is also available.

Prehevbrio is a new treatment option for active immunization against hepatitis B infection in adults. Prehevbrio is a sterile injectable suspension for intramuscular use and is presented as a single‑dose vial. Each single‑dose vial contains 10 mcg/mL hepatitis B surface antigens with aluminum hydroxide (Al[OH]3) as an adjuvant with a final aluminum content of 0.5 mg/mL. The vaccination regimen of Prehevbrio consists of three doses (1.0 mL each) administered at 0, 1, and 6 months.

Prehevbrio has been shown to be efficacious as an active immunization agent against infection caused by all known subtypes of the hepatitis B virus in adults 18 years of age and older. Support for efficacy was based on two Phase III pivotal comparator studies (Sci-B-Vac-001 and Sci-B-Vac-002) which included 4,445 adult participants aged 18 to 65-years-old. The chosen comparator for the Phase III studies was Engerix‑B (20 mcg hepatitis B surface antigens, adsorbed on 0.5 mg aluminum as aluminum hydroxide) which is an approved standard‑of‑care hepatitis B vaccine for immunization in adults. The results obtained from both pivotal studies indicated that Prehevbrio is non-inferior to the Engerix-B vaccine. Prehevbrio demonstrated a good immune response against hepatitis B surface antigen, as measured by anti‑hepatitis B geometric mean antibody concentrations and seroprotection rate.

Safety data from the studies demonstrated an acceptable safety profile for Prehevbrio. Although Prehevbrio was moderately more reactogenic than Engerix-B, the vast majority of reactions were mild or moderate in severity and resolved quickly. Pain and tenderness at the injection site were the most commonly reported solicited local symptoms following Prehevbrio administration. Myalgia, headache, and fatigue were the most commonly reported solicited systemic symptoms following Prehevbrio administration. Myalgia was the only solicited adverse event reported at a clinically significantly higher frequency in the Prehevbrio group compared to the Engerix-B group. Grade 3 myalgia and fever were uncommon in both treatment groups.

There were no serious adverse events considered causally related to Prehevbrio.

No studies were conducted specifically to assess the safety of Prehevbrio in pregnancy. A total of 18 pregnancies were reported in subjects receiving Prehevbrio, including three pregnancies in the Sci-B-Vac-001 study and fifteen pregnancies in the Sci-B-Vac-002 study. There were no adverse outcomes of pregnancies or birth anomalies that could be associated with the exposure to Prehevbrio. In addition, pharmacovigilance periodic safety reports published since Prehevbrio’s initial approval in Israel in 2000 have not identified any safety concerns associated with the use of Prehevbrio during pregnancy. The sponsor also plans to establish a pregnancy registry to prospectively collect data reported on exposure to Prehevbrio during pregnancy and evaluate pregnancy outcomes.

A Risk Management Plan for Prehevbrio was submitted by VBI Vaccines Inc. to Health Canada. The Risk Management Plan is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the Risk Management Plan was considered to be acceptable.

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

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

Overall, the therapeutic benefits of Prehevbrio therapy seen in the pivotal studies are comparable to the comparators and are considered to outweigh the potential risks. Prehevbrio has been shown to have an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Prehevbrio Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Prehevbrio?

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

Submission Milestones: Prehevbrio

Submission Milestone

Date

Pre-submission meeting

2021-03-03

New Drug Submission filed

2021-12-06

Screening

Screening Acceptance Letter issued

2022-02-09

Review

Non-clinical evaluation completed

2022-06-30

Review of Risk Management Plan completed

2022-10-07

Clinical/medical evaluation completed

2022-11-18

Biostatistics evaluation completed

2022-11-18

Quality evaluation completed

2022-11-30

Labelling review completed

2022-12-05

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

2022-12-06

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

4 What follow-up measures will the company take?

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

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

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 life cycle.

The PAAT for Prehevbrio 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

Prehevbrio contains the full antigenic structure of the hepatitis B virus surface antigen, including the small (S), middle (pre-S2), and large (pre-S1) hepatitis B surface antigens. Prehevbrio confers seroprotection against hepatitis B virus infection through the stimulation of a specific immune response, as measured by the induction of anti‑hepatitis B titres at a level ≥10 mIU/mL. Post‑vaccination antibody concentrations ≥10 mIU/mL to hepatitis B surface antigens are recognized as conferring protection against infection caused by all known subtypes of the hepatitis B virus.

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

For further details, please refer to the Prehevbrio Product Monograph, approved by Health Canada and available through the Drug Product Database. Prehevbrio demonstrated a good immune response against hepatitis B surface antigen, as shown by anti-hepatitis B geometric mean antibody concentrations and seroprotection rate.

Clinical Efficacy

The support for efficacy of Prehevbrio was based on two Phase III randomized, active‑controlled, double‑blinded, multicentre clinical studies (Sci‑B‑Vac-001 and Sci‑B‑Vac‑002) which included a total of 4,445 adult participants 18 years of age and older. In both Phase III pivotal studies, the immunogenicity of Prehevbrio was assessed by comparing Prehevbrio against a licensed hepatitis B vaccine, Engerix-B. Prehevbrio and Engerix‑B were administered as a three‑dose regimen with vaccinations given at 0, 1, and 6 months. A total of 2,920 individuals received at least one dose of Prehevbrio in the two Phase III pivotal clinical studies. Enrolled participants had no history of hepatitis B vaccination or infection.

Study Sci-B-Vac-001: Adults 18 years of age and older

The Sci‑B‑Vac‑001 study was a comparative study against a licensed hepatitis B vaccine, Engerix‑B. The study included two co‑primary endpoints. The first co‑primary endpoint was to demonstrate that the seroprotection rate following three doses of Prehevbrio was non‑inferior to the seroprotection rate induced by three doses of the approved hepatitis B vaccine Engerix‑B at Day 196. The second co‑primary endpoint was to demonstrate that the seroprotection rate following Prehevbrio administration was statistically higher than Engerix-B at Day 196 in adults 45 years of age and older. The seroprotection rate was defined as the percentage of subjects with anti-hepatitis B titre levels of ≥10 mIU/mL.

A total of 2,472 participants were screened for the study and 1,607 adult subjects were subsequently enrolled and randomized in a 1:1 ratio to receive either Prehevbrio (number of subjects [n] = 796) or Engerix‑B (n = 811; the active control). Enrolled subjects were stratified by age group into three categories (18 to 44 years; 45 to 64 years; and 65 years or older) with 81% of participants aged 45 years or older and 37.2% aged 65 years or older. Subjects with controlled common chronic conditions were also eligible and enrollment was targeted to be 20% of participants 18 to 44 years of age.

Most subjects in both treatment groups completed the study as planned, including 756 (95.0%) in the Prehevbrio treatment arm and 769 (94.8%) in the Engerix‑B treatment arm. Early discontinuation from treatment was reported for 40 (5.0%) subjects in the Prehevbrio treatment arm and 42 (5.2%) subjects in the Engerix‑B treatment arm. The most common reasons for treatment discontinuation were lost to follow‑up and withdrawal of consent. Treatment discontinuation due to non‑serious adverse events or serious adverse events was uncommon, reported in 1 (0.1%) subject in the Prehevbrio treatment arm and 3 (0.4%) subjects in the Engerix‑B treatment arm.

Results

The results from the Sci‑B‑Vac‑001 study demonstrated that both co‑primary endpoints were met. The estimated difference in the seroprotection rate was 14.9% (95% confidence interval [CI]: 11.2, 18.6), meeting the non‑inferiority margin of -5%. The estimated difference in the seroprotection rate in adults 45 years of age and older was 16.4% (95% CI: 12.2, 20.7%), meeting the superiority criteria.

Study Sci-B-Vac-002: Adults 18 to 45 years of age

The Sci‑B‑Vac‑002 study was a lot‑to‑lot consistency study designed to establish the manufacturing consistency of Prehevbrio. The study included two co‑primary endpoints. The first co‑primary endpoint was to demonstrate manufacturing equivalence based on a pairwise comparison between three lots of Prehevbrio as determined by adjusted geometric mean concentration ratios of anti-hepatitis B titres at Day 196. The second co‑primary endpoint was to demonstrate non‑inferiority of Prehevbrio compared to Engerix‑B at Day 196, based on seroprotection rate.

A total of 4,452 participants were screened for the study and 2,838 adult subjects were subsequently enrolled and randomized. A total of 712 subjects were randomized to the Engerix‑B treatment arm, and 2,126 subjects were randomized to one of three Prehevbrio treatment arms (711 to Lot A, 709 to Lot B, and 706 to Lot C). Of the 2,838 subjects, 2,836 (99.9%) subjects received their assigned treatment. Two subjects were randomized to receive Prehevbrio but did not receive the vaccination. Of these two subjects, one subject withdrew consent before receiving any vaccination and the other subject was discontinued due to non-compliance with the study procedures.

Most subjects (93%) completed study treatment as planned. Early discontinuation from treatment was reported in 159 (7.5%) subjects who received Prehevbrio and in 41 (5.8%) subjects who received Engerix‑B. The most common reason for treatment discontinuation was lost to follow‑up or withdrawal of consent by the subject.

Results

The results from study Sci‑B‑Vac‑002 demonstrated that both co‑primary endpoints were met. The lot‑to‑lot manufacturing consistency of Prehevbrio was demonstrated. Additionally, the non‑inferiority of Prehevbrio compared to Engerix‑B, based on seroprotection rate, was established. The estimated difference in seroprotection rate at Day 196 was 4.49% (95% CI: 2.90, 6.63%).

Indication

The New Drug Submission for Prehevbrio was filed by the sponsor with the following indication, which Health Canada subsequently approved:

Prehevbrio (3‑antigen, recombinant Hepatitis B vaccine) is indicated for active immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 years of age and older.

It can be expected that hepatitis D will also be prevented by immunization with Prehevbrio as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

Additionally, at Health Canada’s request the sponsor included the following statement:

The National Advisory Committee of Immunization provides additional guidance on the use of hepatitis B vaccines in Canada, including a list of recommended individuals for vaccination against hepatitis B. Please refer to the Canadian Immunization Guide.

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

Clinical Safety

The clinical safety profile of Prehevbrio is mainly based on two Phase III pivotal clinical studies (Sci‑B‑Vac‑001 and Sci‑B‑Vac‑002), previously described in the Clinical Efficacy section. A total of 2,920 adults received at least one dose of Prehevbrio.

The safety evaluation comprised an assessment of local and systemic reactogenicity monitored from days 0 to 7 after vaccination, with unsolicited adverse events and serious adverse events monitored within 28 days of any vaccine dose.

Pain and tenderness at the injection site were the most commonly reported solicited local symptoms after Prehevbrio administration. Both events were reported in a majority of subjects and at greater frequencies in the Prehevbrio treatment group than in the Engerix‑B treatment group.

Myalgia, headache, and fatigue were the most commonly reported solicited systemic symptoms after Prehevbrio administration. Myalgia was the only solicited adverse event reported at a clinically significantly higher frequency in the Prehevbrio group compared to the Engerix‑B group. Grade 3 myalgia and fever were uncommon in both treatment groups.

No clinically significant differences in reactogenicity were identified between the three lots of Prehevbrio.

No clinical studies were conducted specifically to assess the safety of Prehevbrio in pregnancy. A total of 18 pregnancies were reported in subjects receiving Prehevbrio, including 3 pregnancies in the Sci‑B‑Vac‑001 study and 15 pregnancies in the Sci-B-Vac-002 study. There were no adverse outcomes of pregnancies or birth anomalies that could be associated with the exposure to Prehevbrio. Pharmacovigilance periodic safety reports published since Prehevbrio’s initial approval in Israel in 2000 have not identified any safety concerns associated with the use of Prehevbrio during pregnancy.

Overall, while there are some limitations in the submitted safety data (e.g., no data available in special populations such as pregnant and breastfeeding women), these limitations have been managed through appropriate labeling and the Risk Management Plan. The sponsor is also expected to add a pregnancy outcomes registry as a post-marketing commitment.

The safety data submitted demonstrates an acceptable safety profile for Prehevbrio and appropriate warnings and precautions are in place in the approved Prehevbrio Product Monograph to address any safety concerns. Although Prehevbrio was moderately more reactogenic than Engerix-B, the vast majority of reactions were mild or moderate in severity and resolved quickly. There were no serious adverse events considered causally related to Prehevbrio. Therefore, the benefit‑risk assessment for Prehevbrio is favorable and supports the use of Prehevbrio in subjects aged 18 years and older.

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

7.2 Non-Clinical Basis for Decision

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

The non‑clinical program for Prehevbrio included studies to assess the pharmacological properties and toxicity profile of Prehevbrio components (Chinese hamster ovary cell-derived S, pre-S2, and pre-S1 hepatitis B surface antigens). The primary pharmacodynamic studies investigated the seroconversion of the Prehevbrio components (S, pre-S2 and pre-S1) in mice when compared to the marketed, yeast-derived hepatitis B virus vaccines, Engerix-B and H-B-Vax II, which contain only non-glycosylated ‘S’ hepatitis B surface antigens. Balb/C mice were used for testing, as well as B10/S and B10/M mice, which are known to be less responsive to the ‘S’ antigen.

The ability of the current formulation of Prehevbrio to induce a strong immune response was established in another study in Balb/C mice to which doses were administered by intraperitoneal injection on Day 0 and Day 21. In this study, adjuvanted Prehevbrio was found to elicit stronger responses than unadjuvanted Prehevbrio or a yeast-derived hepatitis B vaccine after one dose. One month after the second dose, a 100% seroconversion rate was observed for adjuvanted Prehevbrio, which was almost three times the seroconversion rate noted with unadjuvanted Prehevbrio (37.5%).

In an embryo‑fetal developmental study, the vaccine administration did not have any effects on female productivity and fetal/embryonal development. No adverse effects of preweaning development were observed. There were no female reproductive effects and no effects on fetal/embryonal development and postnatal development up to Day 23.

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

7.3 Quality Basis for Decision

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

Prehevbrio is a recombinant hepatitis B vaccine indicated for active immunization against infection caused by all known subtypes of hepatitis B virus in adults 18 years and older. Prehevbrio is comprised of three protein components (pre‑S1, pre‑S2, and S protein).

Prehevbrio is supplied as a sterile aqueous suspension in single‑dose (1.0 mL) glass vials. Each vial contains a dosage of 10 mcg/mL hepatitis B surface antigens adsorbed on aluminum hydroxide as an adjuvant, for intramuscular administration. The vaccine does not contain any preservatives. Prehevbrio is administered as a three-dose regimen with vaccinations given at 0, 1, and 6 months.

Characterization of the Drug Substance

Prehevbrio is characterized by the expression of three envelope proteins, pre‑S1 (6%), pre‑S2 (11%), and S (83%) hepatitis B surface antigens, derived from a transfected Chinese hamster ovary cell line. The hepatitis B surface antigen proteins are covalently linked to one another by intermolecular disulfide bonds between the S domains and partially embedded in the membrane lipids creating virus-like particles.

The cloning strategy and generation of this stable transfected Chinese hamster ovary cell line has been appropriately characterized. Genetic stability has been maintained over several years of production. The master cell bank and the working cell banks have been thoroughly analyzed for growth kinetics and hepatitis B surface antigen productivity. They also are regularly tested to ensure they are free from adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines.

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

Prehevbrio contains the full antigenic structure of the hepatitis B virus surface antigen. The drug substance is manufactured in a Chinese hamster ovary cell line using recombinant deoxyribonucleic acid technology and is based on a master and working cell bank system. The drug substance comes from transfected Chinese hamster ovary cells which are propagated initially in tissue culture flasks, roller bottles, and cell factories, and then grown in bioreactors. Meanwhile, the Chinese hamster ovary cells secrete particles carrying the three antigens into the harvest media, which is then collected. The harvest media is held for a certain time, then undergoes viral removal and bioburden testing prior to downstream processing. The harvest media is clarified and further concentrated. The concentrated harvest is then purified and undergoes inactivation steps. Finally, the purified harvest media is sterile filtered to obtain the hepatitis B surface antigens bulk drug substance.

The drug product manufacturing process includes formulation of the drug substance diluted in a buffer solution followed by sterile filtration, mixing, aseptic filling, capping, and crimping, which then is followed by visual inspection and storage.

The final drug product is presented as a sterile aqueous suspension supplied in single‑dose glass vials. Each vial contains 10 mcg/mL hepatitis B surface antigens formulated with aluminum hydroxide (0.5 mg/mL) as an adjuvant. The final drug product appears turbid when mixed, and forms a clear colorless upper solution and white precipitate upon settling. The final drug product composition includes buffers and adjuvant that are of pharmaceutical grade and are commonly used in the formulations of other vaccines.

Minor changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

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. All analytical procedures are adequate to control the quality of the intermediates for both the drug substance and drug product and have been validated appropriately. The control of the process and environment is assured with adequate specifications set for microbial contamination and endotoxin. The product was found to be stable over time at proposed storage conditions and thus the release and stability specifications are adequate.

During the submission review, issues were identified relating to the in vitro potency analytical procedure (enzyme‑linked immunosorbent assay) and the proposed acceptance criteria for drug product quality control release. However, following further discussion with the sponsor, both issues were then resolved.

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

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life when stored at 5 °C ± 3 °C for Prehevbrio 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 validation test acceptance criteria.

Facilities and Equipment

Based on a risk assessment score determined by Health Canada and considering the drug product manufacturing facility had no history of on-site evaluations conducted by Health Canada, an on-site evaluation of the drug product manufacturing facility was planned. However, following the review of several inspection reports prepared by other regulators which indicated minimal issues were observed, Health Canada decided to pivot in favor of conducting a virtual site evaluation on August 12, 2022. Following completion of the virtual site evaluation, the facilities and equipment were deemed adequate.

Adventitious Agents Safety Evaluation

The sponsor has applied a comprehensive risk mitigation strategy in compliance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use to ensure the safety of the drug substance and drug product by minimizing the risk of adventitious agent contamination. Risks resulting from non‑viral as well as viral adventitious agents have been assessed and adequate testing for microbial and viral contaminants has been performed on raw materials and cell banks. Viral clearance studies have shown that the manufacturing process has sufficient capacity to inactivate and/or remove a broad range of viruses should they be present. Collectively, the information provided is sufficient to ensure product safety from adventitious agent contamination.