Guidance for industry: Preparation of veterinary abbreviated new drug submissions (generic drugs) - clinical and human safety requirements: Human safety requirements

Part 5: Human safety requirements

Introduction

Human safety requirements primarily pertain to drug products intended for use in food-producing animals such as cattle, swine, chickens, turkeys, sheep, goats, horses, bees and fish. However, some of these requirements also apply to submissions of products intended for use in non-food producing animal species when the proposed use potentially results in human health concerns, such as antimicrobial resistance, or occupational exposure (i.e. user safety).

As noted above, drug submissions are required to contain sufficient information and material to enable the Minister to assess a product's safety and effectiveness. The human safety evaluation of an ANDS includes an assessment of drug residues in edible tissues and food products (i.e. milk, eggs, and honey) intended for human consumption, and under certain circumstances, a review of toxicological and/or microbiological safety information.

It is recommended that sponsors contact VDD to request a pre-submission meeting to seek regulatory guidance on specific human safety data requirements prior to filing a submission: vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca

5.1 Toxicological studies

Toxicological studies, including laboratory animal toxicity studies, are typically not required for an ANDS. The toxicological information for a medicinal ingredient in the CRP is applicable to generic products. This information would include the Acceptable Daily Intake (ADI), Acute Reference Dose (ARfD) Maximum Residue Limits (MRLs), and occupational safety issues for the medicinal ingredient(s). This information is then applied to generic versions of the CRP.

However, under certain circumstances additional toxicity data/information may be required. For example, when new toxicological information or pharmacovigilance data has become available regarding the safety of the medicinal ingredients and products since the approval of the CRP, and/or in the case when non-medicinal ingredient(s) of the generic products pose a human safety concern. Accordingly, ANDS sponsors should provide a scientific summary of any updated toxicological information, including an assessment of any implications on human safety of the generic products (such as any updates to product labels to address occupational and/or user safety).

5.2 Microbiological safety studies

Microbiological safety studies focusing on antimicrobial resistance (AMR) and the impact on human microbiota are required for new (innovator) veterinary antimicrobial drug submissions (including antibacterial and antifungal drugs). VDD has categorized antimicrobials based on their importance in human medicine which helps to facilitate AMR risk assessments and promote antimicrobial stewardship. Also refer to List A - List of certain antimicrobial active pharmaceutical ingredients for those that are important in human medicine.

Given that microbiological safety is an evolving issue and in the context of antimicrobial stewardship, for an ANDS of medically important antimicrobials (or other antimicrobials with potential human health risks), sponsors are required to provide a microbiological safety update on AMR associated with the antimicrobial medicinal ingredient(s) of their products. The update should include information from the sponsor and/or literature data, including surveillance studies, about the prevalence of AMR in bacteria of public health and food safety concern, as well as in target animal pathogens. Antimicrobial susceptibility data (such as the minimal inhibitory concentrations of antimicrobials) for these bacteria should be provided. The update may include an AMR risk assessment to address potential risks associated with the proposed use of the product in a Canadian context. Since package sizes may have an impact on prudent use of antimicrobial products and human safety implications, should a larger package size (with respect to that of the CRP) be submitted to Health Canada for approval, a justification for the difference should be included as part of the risk assessment.

Additionally, when a (re)determination of microbiological ADI is needed, data on the effects of the antimicrobial drug on human gut microbiota (such as those detailed in the VICH GL36 guideline "Studies to evaluate the safety of residues of veterinary drugs in human food: General approach to establish a microbiological ADI") will also be required.

Information relevant for microbiological safety can be found in section 9.2.1, "Microbiological safety studies," in the Guidance for Industry Preparation of Veterinary New Drug Submissions.

5.3 Residue depletion studies

Typically, data from an abbreviated residue depletion study conducted in the intended animal species with analysis of the marker residue in the relevant target commodities, such as tissues, milk, eggs and honey, is required for an ANDS for a drug intended for administration to food-producing animals to confirm that the withdrawal period and/or milk withholding time for the generic drug is identical to that of the CRP. In cases where the CRP is indicated for use in more than one food-producing animal species, an abbreviated tissue residue depletion study is typically required for each major food-producing species on the label.

As per paragraph C.08.002.1(2)(e) of the FDR, a generic product intended for administration to food-producing animals must have an identical withdrawal period/milk withholding time to that of the CRP. As a result, such a generic product filed under the ANDS pathway will not be granted an NOC for the withdrawal period or milk withholding time for a target animal species that is different (i.e. shorter or longer) than that established for the CRP, even if residue depletion data is available to support the differing time. A generic drug manufacturer wishing to pursue a shorter or longer withdrawal period/milk withholding time than the CRP will be required to follow the NDS process.

Requests for a waiver of the residue depletion studies may be considered on a case-by-case basis. Residue depletion requirements may be waived for an ANDS in the following cases:

For generic products that are considered pharmaceutically equivalent to the CRP, and for which a waiver of in vivo bioequivalence studies has been granted by VDD. (See Table 1 for more details on biowaiver eligibility criteria based on dosage forms). In general, when a waiver of in vivo bioequivalence cannot be granted, a waiver for the residue depletion study requirements will also not be considered.
For generic products that have not been granted a waiver of in vivo bioequivalence studies (as described above) and are indicated for use in food-producing species other than cattle, swine, and chickens, a waiver of residue depletion studies will still be considered for those food-producing species, provided that the withdrawal period and/or milk withholding time of the CRP has been confirmed in a related major species (i.e. cattle, swine, or chickens) by an abbreviated residue depletion study.
For generic products where bioequivalence is demonstrated based on blood level studies, and the withdrawal period of the CRP is within the period of detectable plasma concentrations in the bioequivalence study, and correlation data between the depletion of drug residue from plasma and target tissue is known, a waiver of residue depletion studies may be considered. Conversely, if the withdrawal period of the CRP is longer than the duration of quantifiable plasma concentrations in the bioequivalence study, a waiver of residue depletion studies will not be considered based on the bioequivalence study alone.

Residue depletion studies will generally not be waived for an ANDS for the following product formulations:

Oral and parenteral emulsions
Oral and parenteral suspensions
Oral pastes
Feed premixes (powder or granules) with a water insoluble medicinal ingredient
Modified release dosage forms (such as enteric-coated tablets, and extended-release medicinal ingredients tablets, capsules, boluses, implants, or inserts or some intra-ruminal boluses)
Topical dosage forms, other than solutions, that are systemically absorbed
Intra-mammary suspensions, pastes, or gels
Intrauterine products
Intra-ruminal devices

There are some exceptional circumstances in which abbreviated residue depletion studies may be required, even if the formulation would typically be eligible for a waiver of residue depletion studies. Examples include:

Products where the formulation differs from that of the CRP (e.g. pH, vehicle, excipients, etc.), and concerns about residue depletion are evident
Substances of particular toxicological concern or other increased risk to human safety

5.4 Abbreviated residue depletion study

The purpose of an abbreviated residue depletion study is to confirm that the withdrawal period and/or milk withholding time of the generic product intended for administration to food-producing animals is identical to those established for the CRP. As mentioned above, in cases where the CRP is indicated for use in more than one food-producing animal species, an abbreviated residue depletion study for each edible commodity (e.g. tissues and milk) is typically required for each major food-producing species on the label. Each study should be conducted following the specified criteria below:

Sample size
- For confirming withdrawal period, a minimum of:
  - 6 animals, evenly mixed by sex, for ruminants, pigs, food-producing horses, and rabbits
  - 12 birds for poultry
  - 15-20 fish
- For confirming milk withholding time, a minimum of 20 lactating dairy animals (e.g. cows, goats, and sheep)
- For guidance on the number of colonies and number of sites for honeybees, contact us: vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca
Administration should be consistent with the CRP label instructions, which includes the same dose, route, and frequency of administration. If multiple dosing regimens have been approved for the CRP, the regimen that encompasses the worst-case scenario from a residue perspective should be used to conduct the study.
For generic drug products where the CRP has been approved with a zero-day withdrawal period/milk withholding time, the abbreviated residue depletion study should be conducted at 1.0X the maximum label dose to confirm suitability of a zero-day withdrawal period/milk withholding time.
Determination of the concentration levels of the marker residue(s) in the target tissue, and injection site (if applicable) at the established withdrawal period for the CRP, using a validated analytical method. The marker residue and target tissue for approved veterinary drugs can be found in VDD's published "List of preferred tissue(s) for residue analysis".
For generic combination drug products, the abbreviated residue depletion study should be conducted using the combination drug product as per the CRP label instructions as indicated under item (2) above. However, only the marker residue of the drug substance that persists in the target tissue for the longest period of time and is responsible for the establishment of the withdrawal period assigned to the CRP will need to be quantified in the target tissue and injection site (if applicable) of the intended species. Non-interference of the residue assay method for the individual drug substances present in the combination product should be demonstrated to ensure that the presence of one drug substance does not interfere with the detection and quantification of the other.
Slaughter of the animals at the withdrawal period established for the CRP or collection of milk at the milk withholding time established for the CRP.
Determination of the 99^th upper tolerance limit of residue concentrations with 95% confidence using a single-point statistical procedure. The 99^th percentile (with 95% confidence) of marker residue concentrations in the target tissue/commodity should fall below the established Canadian MRL at the withdrawal period/milk withholding time assigned to the CRP. If there are questions about MRLs or there is no MRL established, contact us: vdd.skmd.so-dgps.dmv.cp@hc-sc.gc.ca

5.5 Analytical methodology

When choosing analytical methods to determine marker residue concentrations, generic drug manufacturers should consider the suitability of the method for its intended purpose. If an analytical method other than the approved method of analysis is used, they should provide method validation data based on the criteria listed in the VICH GL49 guidelines, "Studies to evaluate the metabolism and residues kinetics of veterinary drugs in food-producing animals: validation of analytical methods used in residue depletion studies". Analytical methodology requirements are described in the section "Residue Studies," Guidance for Industry Preparation of Veterinary New Drug Submissions.

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Date modified:: 2025-03-14

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