Summary Basis of Decision for Anthrasil
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 Anthrasil is located below.
Recent Activity for Anthrasil
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 Anthrasil
Updated: 2024-01-24
The following table describes post-authorization activity for Anthrasil, a product which contains the medicinal ingredient anthrax immune globulin (human). 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.
- DIN 02469588 - ≥60 U/vial anthrax immune globulin (human), solution, intravenous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
NC # 270200 |
2022-11-29 |
Issued NOL 2023-03-06 |
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 involving the replacement of analytical procedures. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 268070 |
2022-09-22 |
Issued NOL 2022-12-22 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf-life specifications involving the replacement of an analytical procedure. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 265456 |
2022-06-22 |
Issued NOL 2022-09-09 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the auxiliary materials/reagents of biological origin. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 256580 |
2021-09-14 |
Issued NOL 2021-12-16 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 240752 |
2020-06-18 |
Issued NOL 2020-09-14 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the post‐approval stability protocol and in the labelled storage conditions for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 223975 |
2019-01-24 |
Issued NOL 2019-03-14 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
Drug product (DIN 02469588) market notification (restricted sale) |
Not applicable |
Date of first sale: 2018-09-26
|
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NC # 211439 |
2017-11-20 |
Issued NOL 2018-02-21 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change testing procedures for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
Extraordinary Use NDS # 200446 |
2016-11-24 |
Issued NOC 2017-11-06 |
Notice of Compliance issued for Extraordinary Use New Drug Submission. |
Summary Basis of Decision (SBD) for Anthrasil
Date SBD issued: 2018-01-11
The following information relates to the New Drug Submission for Anthrasil.
Anthrax immune globulin (human), ≥60 U/vial, solution, intravenous
Drug Identification Number (DIN):
- 02469588
Emergent BioSolutions Canada Inc.
New Drug Submission Control Number: 200446
On November 6, 2017, Health Canada issued a Notice of Compliance for the drug product Anthrasil.
Health Canada recognizes that there are extraordinary circumstances in which sponsors cannot reasonably provide substantial evidence demonstrating the efficacy and safety of a therapeutic product in humans as there are logistical or ethical challenges in conducting the appropriate human clinical trials. Therefore, the Extraordinary Use New Drugs regulatory pathway was used for authorization of Anthrasil based on quality, non-clinical and limited clinical information (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]).
Based on Health Canada's review, the benefit-risk profile of Anthrasil is favourable for the treatment of adult and pediatric patients with toxemia associated with inhalational anthrax. Anthrasil is beneficial in combination with appropriate antibacterial drugs. The effectiveness of Anthrasil is based solely on efficacy studies conducted in animal models of inhalational anthrax.
1 What was approved?
Anthrasil, a human immune globulin drug product, was authorized for the treatment of adult and pediatric patients with toxemia associated with inhalational anthrax. Anthrasil is beneficial in combination with appropriate antibacterial drugs.
The effectiveness of Anthrasil is based solely on efficacy studies conducted in animal models of inhalational anthrax.
Anthrasil is contraindicated in patients with:
- a history of hypersensitivity, anaphylactic, or other severe systemic reaction to Anthrasil or other human immune globulin drug products;
- immunoglobulin A (IgA) deficiencies when the patient has antibodies to IgA or a history of IgA hypersensitivity;
- a history of hypersensitivity, anaphylactic, or other severe systemic reaction to any ingredient in this formulation or component of the container.
There are no available data for the use of Anthrasil in geriatric patients (65 years of age and older). Also, no data are available for the use of Anthrasil in pediatric patients (16 years of age and younger).
Anthrasil 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.
Anthrasil, ≥60 U/vial anthrax immune globulin (human), is presented as a solution. In addition to the medicinal ingredient, the solution contains 10% maltose, 0.03% polysorbate 80, 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 Anthrasil Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Anthrasil approved?
Health Canada considers that the benefit-risk profile of Anthrasil is favourable for the treatment of adult and pediatric patients with toxemia associated with inhalational anthrax. Anthrasil is beneficial in combination with appropriate antibacterial drugs. The effectiveness of Anthrasil is based solely on efficacy studies conducted in animal models of inhalational anthrax.
Anthrax is a serious and life-threatening disease caused by Bacillus anthracis, a Gram-positive, rod-shaped bacterium that forms highly resistant spores under stressful environmental conditions. Resulting from the inhalation of aerosolized Bacillus anthracis spores, inhalational anthrax is the most serious form of the disease and has been associated with fatality rates as high as 80%. It is recognised that Bacillus anthracis can be used as a biological weapon.
In Canada, no specific authorized therapies are currently available to treat inhalational anthrax. Symptomatic anthrax patients are treated with antimicrobial agents with known activity against Bacillus anthracis. Although these therapies can address bacteremia caused by the organism, they do not directly inhibit toxemia, the main cause of anthrax pathogenesis.
Anthrasil, anthrax immune globulin (human), is a human hyperimmune product that is prepared from source plasma obtained from selected healthy donors who have been immunized with BioThrax (anthrax vaccine adsorbed). Anthrasil contains a purified gamma globulin (immunoglobulin G, IgG) fraction of human plasma containing antibodies to Bacillus anthracis, mainly directed against protective antigen (PA) to prevent PA mediated cellular entry of anthrax edema factor and lethal factor. Anthrasil is administered in combination with appropriate antibiotic therapy as the product by itself is not known to have direct antibacterial activity against Bacillus anthracis, which otherwise may continue to grow and produce anthrax toxins.
The evaluation of new treatment options for anthrax in placebo-controlled human trials faces logistical and ethical challenges due to the sporadic nature of natural exposure cases, the fact that sites of the emergency rapid intervention cannot be predetermined, and the ethically unacceptable intentional intoxication of human volunteers. Accordingly, Health Canada has authorized the sale of Anthrasil as an extraordinary use new drug for inhalational anthrax based on limited clinical testing in humans (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]). The effectiveness of Anthrasil for treatment of inhalational anthrax is based on well-controlled efficacy studies conducted in two animal models of inhalational anthrax, the rabbit and the cynomolgus macaque. The animal efficacy studies demonstrated a survival benefit (an improvement in overall mortality) in both animal species when Anthrasil was used as monotherapy. Also, there was a trend of higher survival rates in animals who received both Anthrasil and appropriate antibiotic therapy compared to animals who received antibiotic therapy plus placebo (non-specific intravenous immunoglobulin), although the difference in survival rates did not reach statistical significance.
Safety data were obtained in healthy volunteers at three different dose levels of Anthrasil (210 U, 420 U, and 840 U), and in a limited number of patients with a confirmed anthrax disease, who were administered Anthrasil at the recommended dose of 420 U. There were no specific safety concerns for Anthrasil. Anthrasil is expected to exhibit a safety profile similar to that of other authorised immune globulin products.
The most common adverse reactions to Anthrasil observed in >5% of subjects in the healthy volunteer clinical trial were headache, infusion site pain, nausea, infusion site swelling, and back pain. The safety profile of Anthrasil may be different in patients with severe inhalational/systemic anthrax from that seen in healthy volunteers.
Anthrasil contains trace amounts (lower than 40 µg/mL) of immunoglobulin A (IgA). Patients with known antibodies to IgA may have a greater risk of severe hypersensitivity and anaphylactic reactions. Consequently, Anthrasil is contraindicated in IgA deficient patients with antibodies against IgA or a history of IgA hypersensitivity.
Anthrasil contains maltose. Maltose in immune globulin products may give falsely high blood glucose levels when some point-of-care blood glucose testing systems are used (for example, systems based on glucose dehydrogenase-pyrroloquinolineequinone [GDH-PQQ] or glucose-dye-oxidoreductase methods). This could result in an inappropriate administration of insulin and life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Due to the potential for falsely elevated glucose readings, only testing systems that are glucose specific should be used to test or monitor blood glucose levels in patients receiving Anthrasil. This safety issue is highlighted in a Serious Warnings and Precautions box in the Anthrasil Product Monograph.
Thrombosis occurrence with the use of immune globulin products, including Anthrasil, is specifically addressed in the Serious Warnings and Precautions box, with recommendations for use of a minimum infusion rate practicable when administering Anthrasil to patients at risk of thrombosis, adequate patient hydration, and monitoring.
A Risk Management Plan (RMP) for Anthrasil was submitted by Emergent BioSolutions 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.
In accordance with the Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs], an extraordinary use new drug submission must contain a proposed post-market study plan for the collection of information on the safety and efficacy of the extraordinary use new drug. The submitted post-market study plan for Anthrasil includes two study protocols, Study 003A (to be conducted in the event of a mass exposure scenario), and Study 003B (for collection and analysis of data on future sporadic cases of systemic anthrax that are treated with Anthrasil). These studies are expected to confirm the safety and efficacy of the product in humans with inhalational anthrax, and the appropriateness of the recommended dosing regimen. In addition, data in special populations could be generated, if Anthrasil is used in these populations (e.g., children).
A Look-alike Sound-alike brand name assessment was performed and the proposed name Anthrasil was accepted.
Overall, the potential benefit of Anthrasil, as inferred from the submitted animal efficacy studies, outweighs the known and expected risks of the product. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Anthrasil Product Monograph to address the identified safety concerns.
This Extraordinary Use 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. The sale of Anthrasil, as an authorized extraordinary use new drug, is restricted to authorized entities such as the federal, provincial, territorial, and municipal government(s).
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 Anthrasil?
Submission Milestones: Anthrasil
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2016-07-19 |
| Submission filed: | 2016-11-24 |
| Screening | |
| Screening Acceptance Letter issued: | 2017-01-12 |
| Review | |
| Quality Evaluation complete: | 2017-09-19 |
| Clinical Evaluation complete: | 2017-10-10 |
| Review of Risk Management Plan complete: | 2017-08-17 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2017-11-02 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2017-11-06 |
The Canadian regulatory decision on the non-clinical and clinical review of Anthrasil was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.
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?
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
The polyclonal immunoglobulin G (IgG) in Anthrasil is a passive immunizing agent that neutralizes anthrax toxin. Anthrasil binds the protective antigen (PA) component of Bacillus anthracis lethal toxin and edema toxin and prevents the PA mediated cellular entry of anthrax edema factor and lethal factor.
The pharmacokinetic profile of Anthrasil was characterized in animals and humans. The animal and human pharmacokinetic data suggest that there might be differences between healthy subjects and patients with inhalational anthrax in some pharmacokinetic parameters, and patients are expected to have greater clearance of anti-PA antibodies and lower area under the curve (AUC), compared to healthy subjects.
Because the effectiveness of Anthrasil cannot ethically be tested in placebo-controlled trials in humans, a comparison of Anthrasil exposures achieved in healthy human subjects to those observed in therapeutic efficacy studies in animal models of inhalational anthrax was used to support the dosage regimen. A dose of 420 U has a similar exposure to the efficacious dose of 15 U/kg administered to New Zealand white rabbits and cynomolgus macaques. In cynomolgus macaques treated with Anthrasil monotherapy, a higher dose of 30 U/kg, with a similar exposure to a human dose of 840 U, may result in improved survival. As a result, the initial dosing regimen is given as a range of 420 to 840 U, and the recommended regimen includes the potential for repeat dosing.
For further details, refer to the Anthrasil Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Health Canada recognizes that there are circumstances in which sponsors cannot reasonably provide substantial evidence demonstrating the efficacy and safety of a therapeutic product in humans as there are logistical or ethical challenges in conducting the appropriate human clinical trials. The Extraordinary Use New Drugs (EUND) submission pathway was developed to allow a mechanism for authorization of these drugs based on non-clinical and limited clinical information (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]). Accordingly, the efficacy of Anthrasil has been demonstrated in two well-characterized animal models of inhalational anthrax, the rabbit and cynomolgus macaque (described in the section Non-Clinical Basis for Decision).
For more information, refer to the Anthrasil Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
Overall, Anthrasil was administered to 93 individuals, including 74 healthy subjects in Study AX-001 and 19 anthrax patients treated through the United States Centers for Disease Control and Prevention (CDC) Expanded Access Program.
Study AX-001
Study AX-001 was a double-blind, randomized, placebo-controlled study designed to assess the safety and pharmacokinetics of three doses of Anthrasil after a single intravenous infusion in healthy volunteers. A total of 72 healthy adult subjects were randomized to receive a dose of 210 U, 420 U or 840 U of Anthrasil, as determined by toxin neutralization assay (TNA), or an equal volume of saline placebo. A total of 54 healthy volunteers (18 subjects per dosing group) received one of the three Anthrasil doses, while 18 healthy volunteers (6 subjects per dosing group) received a saline placebo.
A second stage of the study, designed only for additional safety assessment, was a randomized, open-label study in 20 healthy adult volunteers. Subjects were randomized to receive a dose of 840 U, as determined by TNA, from one of two additional product lots (10 subjects per lot). There was no placebo group.
Infusions were permanently discontinued in four subjects due to: infiltration of the infusion site (one subject), pain distal to the infusion site (one subject), chest discomfort, flushing, tachycardia and throat tightness (one subject), and urticaria, pruritus, lip swelling and dry/sore throat (one subject).
A total of 65 subjects (71%) reported 251 adverse events. Frequently reported adverse events (those reported by more than 10% of total subjects) included headache, pharyngolaryngeal pain, and nausea. There were no deaths or other serious adverse events.
Notably, blood samples tested by glucose non-specific point of care (GNSPOC) monitoring devices demonstrated transient false elevations of glucose, in contrast to glucose specific point of care (GSPOC) device determinations. The potential of falsely elevated glucose readings when GNSPOC monitoring devices are used in patients receiving maltose-containing parenteral products is included in a Serious Warnings and Precautions box in the Anthrasil Product Monograph.
Patient experience
Nineteen adult patients with severe systemic anthrax have been dosed with single 420 U doses of Anthrasil, including three patients with inhalational anthrax. Patients were receiving antimicrobial therapy before, during, and after Anthrasil administration. Two out of the three patients with inhalational anthrax treated with Anthrasil plus antimicrobial therapy survived and one died from progression of anthrax disease, systemic candidiasis, and multiorgan failure. There were no specific safety concerns identified for Anthrasil.
Given the polyclonal nature of Anthrasil and the overlap between the recommended doses of Anthrasil and those of other hyperimmune globulin and immune globulin intravenous (IGIV) products, adverse reactions that have been causally associated with those products may also occur with Anthrasil. These would include: hypersensitivity reactions/anaphylaxis, thrombotic events, acute renal dysfunction/failure, hemolysis and hemolytic anemia, aseptic meningitis syndrome, transfusion-related acute lung injury, and transmission of infectious agents from human plasma. These safety concerns have been addressed in the Anthrasil Product Monograph.
For more information, refer to the Anthrasil Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The evaluation of new treatment options for anthrax using placebo-controlled human trials is unethical and infeasible. Therefore, the efficacy of Anthrasil has been studied in two well-characterized animal models of inhalational anthrax, the rabbit and cynomolgus macaque.
Rabbit monotherapeutic study (1207)
In a monotherapeutic efficacy study (1207), New Zealand white rabbits were exposed to a target dose of 200x the lethal dose fifty (LD50) aerosolized anthrax spores and then administered 15 U/kg of Anthrasil or a single dose of placebo (immune globulin intravenous, IGIV) at the onset of toxemia, as determined by the presence of protective antigen (PA) in serum samples. Detection of PA was used as the trigger for initiation of treatment, while bacteremia status provided a retrospective confirmation of disease. Ninety-eight (98) percent of the treated animals were bacteremic prior to treatment. Of the animals that were toxemic and bacteremic prior to treatment, Anthrasil treatment resulted in a survival rate of 26% (13/50) in comparison to a survival rate of 2% (1/48) with placebo (IGIV) treatment over the 36-day duration of the study. The difference in survival rates between the groups was statistically significant.
Non-human primate monotherapeutic study (828)
The efficacy of Anthrasil was also assessed in cynomolgus macaques exposed to a target dose of 200xLD50 aerosolized anthrax spores. Treatment with placebo or one of three dose levels of Anthrasil was initiated after animals became toxemic (positive for PA detection in serum samples). Bacteremia status provided a retrospective confirmation of disease. Survival was assessed over a period of 88 days in toxemic animals that were confirmed to be bacteremic at the time of treatment. The survival rate was 0% (0/11) in placebo-treated animals. Animals treated with 7.5 U/kg exhibited 36% (4/11) survival, those treated with 15 U/kg had 43% (6/14) survival, and those treated with 30 U/kg exhibited 70% (7/10) survival. Compared to IGIV placebo, these survival rates were statistically significant.
Rabbit combination therapeutic study (1182)
The efficacy of Anthrasil co-administered with levofloxacin was evaluated in New Zealand white rabbits when treatment was delayed to 96 hours after anthrax spore inhalation. The dose of levofloxacin was chosen to yield a comparable exposure to that achieved by the recommended dose in humans. Of the animals that survived to be treated (19% of those challenged, 64/336), antibacterial drug plus Anthrasil (15 U/kg) resulted in 58% (18/31) survival compared to 39% (13/33) survival in rabbits treated with antibacterial drug and placebo. The observed increase in survival following treatment with Anthrasil in addition to levofloxacin did not reach statistical significance as compared to IGIV given in addition to levofloxacin.
There were no dedicated toxicology studies of Anthrasil. Two toxicity studies conducted for the related immune globulin intravenous (IGIV) were submitted. The toxicity data obtained for the IGIV are considered to be applicable to Anthrasil, because of the similarities in the active ingredients and the manufacturing process. There were no significant toxicological findings in the single-dose acute toxicity and local tolerance studies conducted with the IGIV.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Anthrasil Product Monograph. In view of the intended use of Anthrasil, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Anthrasil Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The polyclonal immunoglobulin G (IgG) in Anthrasil is a passive immunizing agent that neutralizes anthrax toxin. Anthrasil binds the protective antigen (PA) component of Bacillus anthracis lethal toxin and edema toxin and prevents the PA mediated cellular entry of anthrax edema factor and lethal factor.
Characterization of the Drug Substance
Detailed characterization studies were performed to demonstrate that anthrax immune globulin (human) exhibits the desired structure and biological activity.
Data available from process validation studies demonstrate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The manufacturing process of the drug substance, anthrax immune globulin (human), consists of purification of IgG from donor plasma pools containing high titres of antibodies to Bacillus anthracis toxins. The source plasma is collected from eligible healthy donors vaccinated with BioThrax (anthrax vaccine adsorbed).
All source plasma screening, collection, storage and processing procedures comply with applicable United States regulations. Applicant donor procedures and policies are adopted from the Plasma Protein Therapeutic Association (PPTA). Plasma units shipped to the manufacturing facility must have originated from donors qualified in accordance with the International Quality Plasma Program (IQPP) standards.
The manufacturer's hyperimmune platform process, which includes an anion-exchange column chromatography purification method and solvent detergent treatment step for virus inactivation, is a well-established manufacturing process used for production of other hyperimmune products authorized in Canada. Process validation and the consistent commercial production of approved hyperimmune products provide sufficient data demonstrating a well-controlled manufacturing process and consistent product quality.
The drug product, Anthrasil, is a clear to opalescent sterile liquid of purified IgG fraction of human plasma containing polyclonal antibodies that bind the PA component of Bacillus anthracis lethal and edema toxins. The product potency, as determined by an in vitro toxin neutralization assay, is expressed in units (U) traceable to the Centers for Disease Control and Prevention (CDC) standard AVR414. A single-use 50 mL vial contains anti-anthrax antibodies at ≥60 U of toxin neutralization activity, regardless of fill volume. The total protein concentration ranges from 40 to 70 mg/mL. Non-medicinal ingredients include 10% maltose and 0.03% polysorbate 80.
The manufacturing process and controls for both the drug substance and drug product are appropriate.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in Anthrasil.
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. The 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, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 60-month shelf life at ≤-20°C for Anthrasil is considered acceptable.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facility and equipment involved in the production are considered suitable for the activities and products manufactured.
An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance and the drug product was waived as the Biologics and Genetic Therapies Directorate, Health Canada had recently participated in a satisfactory routine Good Manufacturing Practices (GMP) inspection of the facility, and products using the same manufacturing process have a long history on the Canadian market.
The site involved in production is compliant with GMP.
Adventitious Agents Safety Evaluation
Control of viral agents is achieved through virus screening of plasma and through dedicated steps in the manufacturing process (nanofiltration and solvent/detergent treatment) designed to remove or inactivate enveloped and non-enveloped viruses. Additional viral clearance may occur though the anion-exchange chromatography step.
The adventitious agent evaluation and viral reduction studies using scaled-down models were previously reviewed and approved for other products manufactured on the human hyperimmune platform, which claim identical virus reduction factors. The adventitious agent safety profile of Anthrasil was found to be acceptable.