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Thinking about getting your toxicological results published? Go no further until you read this article.

Thinking about placing a toxicological test on your novel ingredient? Go no further until you read this article.

You may have a blockbuster food or dietary supplement ingredient, but if the manufacturing process introduces contaminants, it may not be safe to consume. Contaminants may be introduced into a botanical ingredient during growth, such as heavy metals or herbicides from soil or pesticides or antifungal agents applied to plants. Toxins can be produced by plants or be introduced into plants during storage by fungal contamination. Ingredients that are produced by chemical synthesis may be contaminated with solvents or unintended metabolites, and ingredients that are manufactured by microbial fermentation can be contaminated with the microbes or toxins produced by them. Other sources of contaminants include water, processing aids, filters/columns, fermentation media ingredients and packaging materials. Use of Good Manufacturing Practice (GMP), potable water and food grade materials (by U.S. standards) can help reduce levels of contaminants in an ingredient. However, even if these procedures are in place, contaminants may be present in your ingredient.

Drug development is a complex, multi-phase process, involving rigorous testing to ensure safety and efficacy. Prior to drug or biologic testing in human subjects, approval must be obtained from regulatory authorities like the United States (US) Food and Drug Administration (FDA) if the drug or biologic is to be marketed in the US and Health Canada if Canada is the market of interest. In the US, approval is obtained through an Investigational New Drug (IND) application, while in Canada, the application required is a Clinical Trial Application (CTA).

Natural Health Products (NHPs) are naturally occurring substances that maintain, promote, or restore good health.¹ To receive Health Canada approval, an NHP must carry at least one health claim and that health claim must have a health context. For example, “Source of antioxidants for the maintenance of good health.” In addition to the recommended use or purpose statement(s), there are several parameters that form part of an NHP’s Product Licence or Terms of Market Authorization (TMA), including product classification, product representation, composition / ingredients, directions for use, duration of use, risk information, allergen source disclosure, storage conditions, etc.² Marketing claims can be made around any of these aspects, and while they do not typically appear in the Product Licence Application (PLA) since they lack the required health context, they need to be consistent with the product’s TMA. Product performance, content, comparisons, representations of opinion and authorization, and side effect claims may also be considered marketing language.³ Some examples of acceptable advertising claims are provided in the Table below.

UNDERSTANDING MASTER FILES 

Master Files (MFs) are reference documents that contain proprietary and/or publicly-available data on aspects of drug or Natural Health Product (NHP) safety, efficacy, and/or quality that are submitted to regulatory authorities in support of various application types, including Clinical Trial Applications (CTAs), Investigational New Drugs (INDs), Abbreviated New Drug Applications or Submissions (ANDAs / ANDS), New Drug Applications or Submissions (NDAs / NDS), and Product Licence Applications (PLAs).

MASTER FILES SUBMISSION

MFs are submitted by individuals or companies that develop, manufacture, or supply drugs or NHPs, and are known as the MF Holders. In some jurisdictions the entire MF is strictly confidential between the MF Holder and the regulatory Agency, whereas in others restricted access is granted to Applicants authorized by the MF Holder. Once authorized, the Applicant is allowed to reference the MF in their own submission(s).

The purpose of a MF is to provide sufficient details to the regulatory Agency to satisfy safety, efficacy, and/or quality requirements. The information used in a MF can include specifics about the facilities, processes, and components used in manufacturing, processing, packaging, and storage, without disclosing proprietary information to the Applicant. The MF Holder is responsible for maintaining the MF and ensuring that it is kept up-to-date throughout its lifecycle.

TYPES OF MASTER FILES BY JURISDICTION 

In Canada, an NHP-MF serves the same purpose and follows a similar submission process as that of a Drug Master File (DMF). The United States (US) also has DMFs, whereas they are referred to as Active Substance Master Files (ASMFs) in Europe – both regions do not have a MF pathway for dietary or food supplements.

The type of MF needed depends on the regulated category and information intended to be communicated to the regulatory authority. For example, Health Canada and the US Food and Drug Administration (FDA) recognize five (5) different types of DMFs, yet the European Medicines Agency (EMA) only uses one (i.e., ASMF). Health Canada’s Natural and Non-prescription Health Products Directorate (NNHPD) also has a standalone MF specific to NHPs. The table below provides a summary of the different MF types across each of the three jurisdictions.

FIND OUT MORE:

Nutrasource’s NHP & Pharmaceutical Regulatory Sciences team is well-versed in MF dossier preparation and submission to various regulatory authorities.

Our experts can help navigate between MF types and the requirements for each section. Contact us today. 

REFERENCES:

1. Drug MF https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/master-files-procedures-administrative-requirements.html

2. NHP MF https://www.canada.ca/en/health-canada/services/drugs-health-products/natural-non-prescription/legislation-guidelines/guidance-documents/master-file-procedures.html

3. Drug MF https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/master-files-procedures-administrative-requirements.html#a21

4. Drug MF https://www.fda.gov/drugs/guidances-drugs/drug-master-files-guidelines

5. Drug MF https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs

6. US Dietary Supplement https://www.fda.gov/news-events/press-announcements/fda-updates-draft-guidance-premarket-safety-notifications-dietary-supplement-industry

7. Drug MF https://www.fda.gov/media/85079/download

8. Active Substance Master File https://www.ema.europa.eu/en/documents/report/final-guideline-active-substance-master-file-procedure-revision-4_en.pdf

As a result of the pandemic, respiratory and seasonal illnesses, and other emerging threats, consumers are more interested, invested, and involved in their wellbeing than ever before. When it comes to health products, consumers are motivated by those that are clean or naturally-sourced, convenient, scientifically substantiated, and tailored to meet their personal needs. Thus, driving industry trends towards transparency, sustainability, personalization, and virtual approaches.

If you're already selling your supplement on Amazon in the U.S. or elsewhere around the globe, Canada is a natural next step to achieve growth and gain market share.

But if you're looking to enter the Canadian market for the first time via Amazon.ca, be warned - it's not as simple as setting up an account and listing your products!

Companies looking to obtain authorization to market a new pharmaceutical must either file a New Drug Submission (NDS) to Health Canada or a New Drug Application (NDA) to the United States Food and Drug Administration (U.S. FDA), depending on their market-of-interest.

The regulatory dossier must include data around the following:

• Pre-clinical (in vitro and in vivo) studies
• Clinical (human) studies
• Details on the manufacturing, packaging, and labelling of the drug substance and drug product
• Therapeutic claims and side-effects
  

In summary, what this means is that the regulatory dossier must provide enough information to ensure the safety, efficacy, and quality of the drug product, showing that the benefits of the drug outweigh the risks.

Common Technical Document (CTD)

The information to be presented to the Agency is organized into five (5) modules, using the CTD format, as follows:

• Module 1: Regional Administrative Information
• Module 2: Quality Overall Summaries
• Module 3: Quality, including Chemical, Manufacture and Controls (CMC) sections
• Module 4: Non-clinical Study Reports
• Module 5: Clinical Study Reports

Process and Timeline

As seen in this flowchart, the entire regulatory journey from the initial drug application to its approval takes approximately 6 months for drugs that qualify for accelerated approval and up to 2 years for drugs that follow regular processing timelines, avoiding any delays.

Here are some key points of what happens at each stage:

1. Pre-Submission Meeting: An option to get questions or concerns addressed by the regulatory Agency prior to filing the submission.  
2. Submission Filing: The application must contain all the necessary information to satisfy the regulatory requirements of the appropriate division or directorate within the Agency.
3. Review of the Submission: The Agency assigns a review team to evaluate the safety, efficacy, and quality of the product. Additionally, the Agency reviews the labeling of the drug product and inspects the facilities where the drug will be manufactured.
4. Decision: If the information provided is deemed adequate, a positive decision is made, and the drug is approved to be released to the market. 
5. Post-Marketing Activities: Post-market management of the product is critical and includes activities like monitoring of adverse events, Phase 4 clinical trials, reporting of post- approval changes (e.g., manufacturing, labeling, stability, etc.), and risk management plans.

SGS Nutrasource offers full-service consulting in this to make sure the new drug submission process is smooth. The team of regulatory experts extensively researches, compiles, and reviews drug submissions for compliance in Canada and/or the U.S. and files the application to the appropriate Agency, helping clients to achieve regulatory confidence and market access. 

Speak to a member of our team on how we help you successfully bring your pharmaceutical to market.

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