Summary Basis of Decision for BAT

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 BAT is located below.

Recent Activity for BAT

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 BAT

Updated: 2024-01-29

The following table describes post-authorization activity for BAT a product which contains the medicinal ingredient botulism antitoxin heptavalent (A, B, C, D, E, F, G). 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 Number: 02459612
Botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine), solution, intravenous administration

  • Serotype A antitoxin 4,500 U/vial
  • Serotype B antitoxin 3,300 U/vial
  • Serotype C antitoxin 3,000 U/vial
  • Serotype D antitoxin 600 U/vial
  • Serotype E antitoxin 5,100 U/vial
  • Serotype F antitoxin 3,000 U/vial
  • Serotype G antitoxin 600 U/vial

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 267373

2022-08-26

Issued NOL 2022-11-09

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. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 258301

2021-11-02

Issued NOL 2022-03-04

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the drug substance purification process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 256646

2021-09-13

Issued NOL 2021-12-15

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 # 250784

2021-03-16

Issued NOL 2021-06-22

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 # 243645

2020-09-04

Issued NOL 2020-12-10

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the post‐approval stability protocol of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 242826

2020-08-17

Issued NOL 2020-11-17

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls applied during the drug product manufacturing process or on intermediates. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 218722

2018-07-27

Issued NOL 2018-10-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 215508

2018-04-17

Issued NOL

2018-07-23

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.

NC # 214777

2018-03-22

Issued NOL

2018-07-04

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to make changes regarding the reference standard for Serotype A. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02459612) market notification (restricted sale)

Not applicable

Date of first sale:

2017-10-25

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

NC # 202972

 

2017-02-17

Issued NOL;

2017-05-18

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.

Extraordinary Use NDS # 203882

2017-03-20

Issued NOC

2017-05-09

Submission filed to change the name of the drug sponsor from Cangene Corporation to Emergent BioSolutions Canada Inc. An NOC was issued.

Extraordinary Use NDS # 190645

2015-12-22

Issued NOC

2016-12-08

 

Notice of Compliance issued for Extraordinary Use New Drug Submission.
 
Summary Basis of Decision (SBD) for BAT

Date SBD issued: 2017-04-12

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

Botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine)
     Serotype A antitoxin 4,500 U/vial
     Serotype B antitoxin 3,300 U/vial
     Serotype C antitoxin 3,000 U/vial
     Serotype D antitoxin 600 U/vial
     Serotype E antitoxin 5,100 U/vial
     Serotype F antitoxin 3,000 U/vial
     Serotype G antitoxin 600 U/vial
Solution, intravenous

Drug Identification Number (DIN):

  • 02459612

Cangene Corporation

New Drug Submission Control Number: 190645

 

On December 8, 2016, Health Canada issued a Notice of Compliance to Cangene Corporation for the drug product BAT.

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 BAT 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 BAT is favourable for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G in adults and pediatric patients.

 

1 What was approved?

 

BAT, botulism antitoxin heptavalent (A, B, C, D, E, F, G), is an equine hyperimmune product (a blend of equine plasma-derived immunoglobulin fragments) prepared from plasma of horses that were immunized with a specific serotype of botulinum neurotoxin or toxoid. BAT was authorized for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G in adults and pediatric patients.

The assessment of the effectiveness of BAT is mostly based on efficacy studies demonstrating survival benefit in animal models of botulism, and limited clinical information.

There is no available data for the use of BAT in geriatric patients.

The effectiveness of BAT has not been established in pediatric patients. Limited pediatric safety data is available.

There is no contraindication to the use of BAT if indicated following exposure to botulinum neurotoxin. Patients who have received previous therapy with an equine-derived antivenom/antitoxin, have known allergies to horses, have asthma or get hay fever (seasonal allergies) may be at increased risk of hypersensitivity reactions and should only receive BAT if the benefits outweigh the risks. Patients should be closely monitored with resuscitative measures available, during and following administration.

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

BAT, botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine) is presented as a solution for intravenous injection. The seven antitoxin serotypes are blended and supplied in a 50 ml vial, with a fill volume ranging from 10 mL to 22 mL per vial. Each single-use vial, regardless of fill volume contains a minimum potency of:

  • 4,500 U serotype A antitoxin,
  • 3,300 U serotype B antitoxin,
  • 3,000 U serotype C antitoxin,
  • 600 U serotype D antitoxin,
  • 5,100 U serotype E antitoxin,
  • 3,000 U serotype F antitoxin, and
  • 600 U serotype G antitoxin.

Non-medicinal ingredients include 10% maltose and 0.03% polysorbate 80. The formulated bulk material contains approximately 30 mg/mL to 70 mg/mL (3 g% to 7 g%) protein.

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 BAT Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was BAT approved?

 

Health Canada considers that the benefit/risk profile of BAT, botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine), is favourable for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G in adults and pediatric patients. The assessment of the effectiveness of BAT is mostly based on efficacy studies demonstrating survival benefit in animal models of botulism, and limited clinical information.

Botulism is a rare and potentially fatal paralytic illness that occurs when the neuromuscular transmission is interrupted by botulinum neurotoxin produced by the bacterium Clostridium botulinum. All forms of human botulism display neurological symptoms that are characteristically bilateral and symmetric, typically presenting with a cranial nerve paralysis, followed by descending weakness or paralysis. Major complications include respiratory failure caused by diaphragmatic paralysis and pulmonary infections.

Botulinum neurotoxin serotypes A, B, E and F are most commonly associated with illness in humans. These serotypes are the most common cause of food-borne, wound and infant botulism. Botulinum neurotoxin serotype C, although mostly associated with waterfowl deaths, can also affect people. Cases of human botulism caused by botulinum neurotoxin serotype D and G are rare. Each of the seven botulinum neurotoxin serotypes can potentially be used as a biological weapon, which underlies the need for a therapeutic product that is effective against all seven botulinum neurotoxin serotypes.

Therapy for botulism consists of supportive care and passive immunization with botulism antitoxins. Currently, there is no botulism antitoxin authorized for marketing in Canada. BAT has been available through the Health Canada's Special Access Program.

Health Canada has authorized the sale of BAT as an extraordinary use new drug for documented or suspected exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G based on limited clinical testing in humans (see Guidance Document - Submission and Information Requirements for Extraordinary Use New Drugs [EUNDs]).

The efficacy evaluation of BAT was mostly based on the non-clinical data derived from well-controlled, pivotal efficacy studies in symptomatic, botulinum toxin-challenged guinea pigs and rhesus macaques. These studies demonstrated that BAT significantly reduced the risk of death in intoxicated animals. Furthermore, clinical data were derived from an open-label, observational clinical study of BAT. Data were available from 148 patients with suspected or confirmed botulism. The study suggested clinical benefits of treatment with BAT on the duration of hospitalization, duration of stay in intensive care unit, and duration of mechanical ventilation.

There is no available data for the use of BAT in geriatric patients.

The effectiveness of BAT has not been established in pediatric patients. Limited pediatric safety data is available.

The safety of BAT has been evaluated in two clinical studies conducted in healthy adults (study BT-001 and study BT-002 Stage B). These studies also examined the pharmacokinetics and pharmacodynamics of BAT. Additional safety information was gathered from patients with suspected or confirmed botulism who were treated with BAT in the open-label, observational clinical study.

The most common adverse reactions observed in ≥5% of healthy volunteers in clinical studies were headache, nausea, pruritus, and urticaria. In the open-label, observational clinical study, the most common adverse reactions reported in ≥1% of patients were pyrexia, rash, chills, nausea, and edema.

In the post-marketing setting, hypersensitivity/allergic reactions were reported in patients treated with BAT, including anaphylactic shock.

As with any equine-derived serum product, the identified safety concerns include hypersensitivity reactions, infusion reactions, delayed allergic reactions (serum sickness), and transmission of infectious agents. Therefore, a Serious Warnings and Precautions box in the BAT Product Monograph specifically cautions health professionals to prepare for monitoring and management of hypersensitivity reactions, infusion reactions or delayed allergic reactions (serum sickness); and highlights the risk of transmitting infectious agents.

In addition, BAT contains maltose which can interfere with certain types of blood glucose monitoring systems. This interference can result in falsely elevated glucose readings that can lead to untreated hypoglycemia or to inappropriate insulin administration, resulting in life-threatening hypoglycemia. These concerns have been addressed in the Warnings and Precautions section of the BAT Product Monograph.

A Risk Management Plan (RMP) for BAT was submitted by Cangene Corporation 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.

Enhanced pharmacovigilance activities were proposed in addition to the routine pharmacovigilance activities. Thus, a post-marketing study BT-010 (a patient registry) of treatment with BAT is currently ongoing in the United States in adult and pediatric patients with a confirmed or suspected exposure to botulinum toxin. The study BT-010 generates global post-marketing data, which verify the efficacy and safety of BAT under the intended conditions of use in the Canadian market. Upon study completion, annual and final reports of the study BT-010 will be submitted to Health Canada. In addition, a mass exposure study BT-012 is planned in the United States to evaluate the efficacy and safety of BAT in the case of a mass exposure with botulinum neurotoxin. In the event of a mass exposure scenario in the United States, the final study report from BT-012 study will be submitted to Health Canada. (See What follow-up measures will the company take?)

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

Overall, the therapeutic benefits of BAT are considered to outweigh the potential risks. BAT has an acceptable safety profile based on the non-clinical and limited clinical safety data. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the BAT 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 BAT, 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 BAT?

 

Submission Milestones: BAT

Submission Milestone Date
Pre-submission meeting: 2015-09-29
Submission filed: 2015-12-22
Screening  
Screening Acceptance Letter issued: 2016-02-12
Review  
Quality Evaluation complete: 2016-12-06
Clinical Evaluation complete: 2016-11-07
Review of Risk Management Plan complete: 2016-09-06
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2016-12-07
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2016-12-08

 

The Canadian regulatory decision on the non-clinical and clinical review of BAT, botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine), was based on a critical assessment of the Canadian data package. 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?

 

As part of the marketing authorization for BAT, botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine), Health Canada requested and the sponsor agreed to several commitments to be addressed post-marketing. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) submitting to Health Canada the following:

  • The interim and final reports of the post-marketing study BT-010 (a patient registry ongoing in the United States), upon study completion (including annual report).
  • The final study report from the mass exposure study BT-012 (intended to be implemented in the event of a mass exposure) in case the event occurs in the United States.
  • The required annual report, in the form of the Periodic Benefit Risk Evaluation Report, within 70 days of March 22 (the international birth date of BAT).

 

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

 

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 decision was negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for BAT 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

BAT, botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine), exerts its action by passive immunization with the equine polyclonal antibody fragments, primarily F(ab')2 and Fab, targeted against botulinum neurotoxin A, B, C, D, E, F, and G. The polyclonal antibody fragments bind to free botulinum neurotoxin in the circulation. This prevents the botulinum neurotoxin from interacting with ganglioside anchorage sites and protein receptors on the cholinergic nerve endings, thereby preventing botulinum neurotoxin internalization into the target cells. The formed antibody-antigen complexes are then cleared from the circulation by the organs involved in processing immune complexes.

The pharmacokinetic parameters of the seven botulism antitoxin serotypes were established in 40 healthy human subjects following intravenous administration of either one (number of subjects, n = 20) or two vials (n = 20) of BAT (study BT-001).

An exploratory pharmacodynamic study (BT-002) used the extensor digitorum brevis (EDB) muscle of the foot as a model for measuring muscle paralysis after exposure to botulinum neurotoxin. The primary endpoint of the study was to evaluate the percent muscle function of the EDB muscle in both feet following exposure to botulinum toxins, type A (Botox) in the left foot and type B (Myobloc) in the right foot, 24 hours after intravenous administration of BAT or placebo. The percent muscle function was based on the preservation of the compound muscle action potential (CMAP) wave amplitude and area of the EDB muscle measured using a reference electrode. Subjects treated with placebo (n = 10) demonstrated a loss of greater than 50% EDB muscle function within 3 days of exposure to both botulinum toxin serotypes. In the BAT arm of the study (n = 16), the EDB muscle function was stable over time, indicating that the antitoxin was effective in preserving muscle function for up to 28 days following exposure to both botulinum toxin serotypes.

The clinical pharmacological data support the use of BAT for the specified indication.

For further details, please refer to the BAT 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 BAT has been demonstrated in two well-characterized animal models of botulism, the guinea pig and rhesus macaque (described in the section Non-Clinical Basis for Decision).

 

To provide additional support for the efficacy of BAT demonstrated in the animal models, an open-label, observational clinical study of BAT was conducted in patients with suspected or confirmed botulism. The study suggested clinical benefits of treatment with BAT on the duration of hospitalization, duration of stay in intensive care unit, and duration of mechanical ventilation.

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

Clinical Safety

The safety of BAT has been evaluated in two clinical studies in healthy human subjects (study BT-001 and study BT-002 Stage B). Additional safety information was gathered from patients with suspected or confirmed botulism treated with BAT in an open-label, observational clinical study.

Study BT-001 was a Phase I, randomized, single-centre, double-blind clinical study which evaluated the pharmacokinetics and safety of BAT in 40 healthy adults following administration by intravenous infusion of either one (n = 20) or two vials (n = 20) of BAT. It was determined that one vial of BAT was an adequate dose for adult humans regardless of body weight. No safety concerns have been identified in the study.

Study BT-002 stage B was a Phase I/II, randomized, double-blind, parallel arm pharmacodynamic and safety study following administration by intravenous infusion of either BAT (n = 16) or placebo (n = 10) to healthy adults. The study used the extensor digitorum brevis (EDB) muscle of the foot as a model for measuring muscle paralysis after exposure to botulinum neurotoxins, as described in the Clinical Pharmacology section.

The most common adverse reactions in all healthy subjects were headache (9%), nausea (5%), pruritus (5%), and urticaria (5%). Other adverse reactions reported in less than 4% of subjects included pyrexia and throat discomfort. All reported adverse reactions were considered mild or moderate. No serious adverse reactions were reported.

A total of 231 patients with suspected or confirmed botulism were treated with BAT in the open-label, observational clinical study. The majority of adult (213/216) and pediatric (13/15) patients (aged 10 days to 17 years; including 1 newborn, 3 infants and toddlers, 4 children, and 7 adolescents) received one dose of BAT. Three adult patients were given a second dose of BAT, and two pediatric patients received two infant doses (10% of the adult dose). The administration of a second dose varied from seven hours to one month after the first dose. Safety information was available for 228 patients. Adverse reactions were reported in 10% of all patients. The most common adverse reactions were pyrexia (4%), rash (2%), chills (1%), nausea (1%), and edema (1%). Other adverse reactions were reported in less than 1% of patients. None of the patients experienced anaphylaxis. One patient experienced a serious adverse reaction of hemodynamic instability characterized by bradycardia, tachycardia, and asystole during BAT administration. One subject experienced mild serum sickness (<1%) with myalgia, arthralgia, and dark urine twelve days after BAT administration. The observed mortality rate was 11/228 (4.8%). None of these deaths were considered related to treatment with BAT.

In the post-marketing setting, hypersensitivity/allergic reactions were reported in patients treated with BAT, including anaphylactic shock.

The identified safety concerns have been appropriately addressed in a Serious Warnings and Precautions box in the BAT Product Monograph.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The efficacy of BAT has been demonstrated in two animal models: the guinea pig intramuscular challenge model, and the rhesus macaque intravenous challenge model.

Study 1180-G005630 was a therapeutic efficacy study of BAT conducted in guinea pigs intoxicated with one of the seven botulinum neurotoxin serotypes (A, B, C, D, E, F or G) at a dose equivalent to 1.5x guinea pig intramuscular lethal dose 50% (GPIMLD50). There were overall 476 guinea pigs intoxicated and each of the seven botulinum neurotoxin serotype groups included 68 animals. The primary objective of this study was to evaluate the treatment effect of BAT on the overall survival of intoxicated guinea pigs. A single dose (1x scaled human dose based on weight) of BAT administered to symptomatic animals resulted in a statistically significant (p<0.0001) improvement in survival at 21 days after treatment with BAT when compared to animals that received placebo, for all serotypes. The efficacy of BAT was also supported by a lessened severity and more rapid disease resolution in animals treated with BAT compared to those that received placebo.

Study FY10-066 was a therapeutic efficacy study of BAT conducted in non-human primates (rhesus macaques). Rhesus macaques were intoxicated intravenously with botulinum neurotoxin serotype A (1.7x nonhuman primate intravenous lethal dose 50% [NHPLD50] units per kilogram of body weight) and administered either 1x scaled human dose of BAT (n = 30) or placebo control (n = 30) intravenously at the onset of clinical signs. The objective of this study was to confirm the therapeutic effect of a single intravenous dose of BAT when administered at the onset of clinical signs in comparison to placebo controls. Treatment with BAT resulted in a statistically significant (p<0.0001) improvement in survival at 21 days after the treatment with BAT as compared to placebo controls. At the end of the study, there were no survivors among the rhesus macaques challenged with botulinum neurotoxin serotype A and treated with placebo, whereas 14 of 30 (46.7%) rhesus macaques treated with BAT survived the exposure to botulinum neurotoxin serotype A.

The studies demonstrated the efficacy of BAT against all seven botulinum neurotoxin serotypes in the guinea pig, and against botulinum neurotoxin serotype A in the rhesus macaque.

Toxicity studies were not conducted for BAT. Other pharmacokinetic/pharmacodynamic studies performed in guinea pigs (n = 264) and rhesus macaques (n = 12) in support of BAT efficacy did not reveal any toxicity concerns with up to 5x scaled human dose of BAT.

The results of the non-clinical studies as well as the potential risks to humans have been included in the BAT Product Monograph. In view of the intended use of BAT, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine), the drug substance of BAT, contains F(ab')2 and F(ab')2-related polyclonal antibody fragments manufactured from the plasma of horses that have been immunized with a specific serotype of botulinum neurotoxin or toxoid.

The seven antitoxin serotypes are blended to obtain the final heptavalent product. Potency is expressed in units (U) based on the amount of toxin-specific neutralizing antibodies to each toxin serotype as determined by the mouse neutralization assay. Each unit of BAT is designed to neutralize 10,000 mouse intraperitoneal lethal dose 50% (MIPLD50) units of botulinum neurotoxin for serotype A, B, C, D, F, and G and 1,000 MIPLD50 units of serotype E.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine) consistently exhibits the desired 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 Drug Product

The manufacturing process for each antitoxin serotype includes cation exchange chromatography to purify the immune globulin fraction, digestion with pepsin to produce F(ab')2 and F(ab')2-related immune globulin fragments, anion exchange chromatography to remove the pepsin and digested protein impurities. In addition, the manufacturing process includes two dedicated viral inactivation/removal steps: solvent/detergent treatment, and virus filtration.

An appropriate control regime including testing for known and potential adventitious viral contaminants is in place for the equine plasma used for BAT production. Comprehensive testing is carried out on the porcine pepsin, and the properties of the chromatographic resins are well-established. Overall, the materials proposed for use in the BAT drug product manufacture are of appropriate quality, and under adequate control.

An appropriate control strategy has been implemented for the monovalent bulks and the heptavalent finished product manufacturing processes based on defining critical quality attributes and critical process parameters for significant unit operations for which defined operating ranges have been put in place. Through the extended validation program, a good understanding of the underlying relevant control parameters has been established.

The manufacturing process is considered to be adequately controlled within justified limits.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the botulism antitoxin heptavalent (A, B, C, D, E, F, G) - (equine) with the excipients is supported by the stability data provided.

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±5oC for BAT 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.

The manufacturing of BAT is a campaign activity. As the manufacturing for 2016 concluded early in the review cycle for this submission, a formal On-Site Evaluation of the facility involved in the manufacture and testing of the drug product was not conducted.

The site involved in production is compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

The viral safety of BAT is based on adequate raw material control, and two validated virus clearance steps which are part of the BAT manufacturing process (solvent/detergent treatment and virus filtration). The solvent/detergent treatment step is effective at inactivating known lipid-enveloped viruses such as the equine encephalitis virus, equine arteritis virus, West Nile virus, equine infectious anemia virus, equine herpes virus, rabies virus, and equine influenza virus. In addition, a robust virus filtration step removes viruses based on size. This step is deemed effective for all aforementioned lipid-enveloped viruses as well as for non-enveloped viruses including equine rhinovirus, equine adenoviruses and adeno-associated viruses, and equine parvovirus.

 

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