General Safety & Performance Requirements — Normal and Deuterated-Glucose supplementation related documents

Introduction to Food Supplementation in Clinical Trials

Regulatory Considerations for Swissmedic / [or local responsible EU-CA]  and Ethics Proposals

Clinical trials involving food supplementation, such as α-D-glucose and 6,6’-d-glucose, require thorough planning and regulatory compliance due to their dual status as food substances and investigational products. While generally recognized as safe under normal dietary circumstances, their controlled use in medical research involves a distinct regulatory perspective. This blog post provides insights into how these substances fit into the framework of Swissmedic / [or local responsible EU-CA]  and Competent Ethics Committee (CEC) applications, particularly for trials involving investigational devices like MRI systems.

Food Law or Drug Law? Understanding the Regulatory Scope

Glucose, including its stable isotope variant 6,6’-d-glucose, falls under food law rather than drug law when used as a food or dietary supplement. However, in a clinical trial setting, its investigational use imposes additional responsibilities. The Swiss Federal Food Safety and Veterinary Office (FSVO) oversees food-related regulations, ensuring the safety of substances classified as food. This contrasts with drug laws under the jurisdiction of Swissmedic / [or local responsible EU-CA] . In most cases, unless glucose is administered in pharmacologically active doses or for therapeutic purposes, it retains its classification as a food substance.

However, when glucose is used in a research setting, particularly with investigational devices, researchers must ensure compliance with specific clinical trial regulations. This is because the investigational nature requires safety evaluations and reporting typically associated with drugs or medical devices.

Key Regulatory Considerations

1. Swiss ClinO-MD:
   • The Swiss Ordinance on Clinical Trials (ClinO-MD) regulates all clinical trials involving medical devices, including trials with investigational food supplements. Annex 4 of the ClinO-MD details the safety and quality requirements for substances administered to trial participants.
   • Relevant sections for ingestible substances:
     • Annex 4: Specify safety, composition, and quality requirements for substances.
     • Outlines documentation duties for any investigational substance, ensuring it does not pose undue risk to participants.
2. ISO Standards:
   • ISO 22000: Food Safety Management Systems:
     • This standard ensures the safety of food substances across the supply chain. It applies to α-D-glucose and 6,6’-d-glucose in a trial context, requiring manufacturers to adhere to hazard analysis and critical control points (HACCP) principles.
     • Researchers should obtain a Certificate of Analysis (CoA) from suppliers demonstrating compliance with ISO 22000.
   • ISO 10993-1: Biocompatibility:
     • Although primarily focused on medical devices, ISO 10993-1 can be applied to evaluate the safety of ingested substances. For example, deuterated glucose may require toxicological assessments under this standard to rule out unintended biological effects.
3. EU Medical Device Regulation (MDR):
   • Annex XV of the MDR: Provides guidance on the conduct of clinical investigations involving medical devices and associated substances. Glucose supplementation, even though classified as a food, may need to meet additional investigational criteria if directly tied to the device’s investigational purpose.
4. Risk Assessment and Safety Testing:
   • Even though glucose is widely considered safe, researchers must document potential risks, such as hyperglycemia or adverse metabolic effects, particularly when administering higher doses or isotopically labeled forms like 6,6’-d-glucose.

Why Standards and Safety Documentation Matter

For researchers conducting trials, obtaining clear documentation on the safety and quality of food supplements is essential. This includes:

1. Certificates of Analysis (CoA): Demonstrating the purity and compliance of the substance with food safety standards.
2. Supplier Documentation: Verifying compliance with ISO 22000 and ISO 9001 for quality management.
3. Safety Studies: For substances like 6,6’-d-glucose, isotopic safety and metabolic data should be included to ensure ethical and regulatory approval.

Importance for Swissmedic / [or local responsible EU-CA]   and Ethics Applications

Swissmedic and ethics committees require comprehensive data to ensure the safe use of food supplements in clinical trials. This includes:

• Dose justification.
• Potential interactions with investigational devices (e.g., MRI systems in the SIGNATURES2023 study).
• Safety testing results, particularly for isotopically labeled substances.
• Traceability to certified manufacturers and suppliers.

Practical Advice for MR Researchers

When planning a trial involving food supplementation:

1. Work Closely with Your Supplier: Ensure that glucose or other substances are produced under ISO 22000 or equivalent food safety standards.
2. Classify the Supplement Correctly: Ensure its status as a food under FSVO or investigational product under Swissmedic / [EMA or local authorities] is properly documented.
3. Prepare Detailed Risk Assessments: Address metabolic risks and any potential adverse effects, especially when using novel isotopes like 6,6′-d-glucose.

---

Documents related to Glucose supplementation were uploaded to Swissmedic / [or local responsible EU-CA] and CEC?

#1 — Deuterated 6,6’-d-glucose

Document

• CambridgeIsotope17025CertScope_V008.pdf

Summary of the Document

This document is a certificate of accreditation for Cambridge Isotope Laboratories, Inc. (CIL), demonstrating compliance with ISO/IEC 17025:2017, the international standard for laboratory testing and calibration. The certificate highlights:

• Testing Scope: Covers testing of chemical properties like purity, isotopic enrichment, and concentration using advanced techniques like HPLC, GC/MS, NMR, and qNMR.
• Validation Period: The accreditation is valid until July 22, 2024, ensuring up-to-date certification for regulatory and scientific uses.
• Standards & Methods: Utilizes recognized protocols such as USP-621, USP-736, and USP-761, emphasizing high reliability and accuracy in isotope measurements.

What is ISO/IEC 17025:2017?

ISO/IEC 17025:2017 is the international standard for the competence of testing and calibration laboratories. It ensures that laboratories can consistently produce valid and reliable results through stringent quality management and operational requirements. Key aspects include:

1. Competence: Laboratories must demonstrate technical capability in testing methods.
2. Quality Management: Adheres to principles of ISO 9001 but tailored for testing environments.
3. Traceability and Calibration: Ensures accurate results through traceable measurement systems.
4. International Recognition: Certifications under ISO/IEC 17025 are accepted globally, reducing regulatory barriers.

The detailed overview of the standard can be found here.

Importance for Swissmedic / [or local responsible EU-CA]  and CEC Applications

For MR-spectroscopy research involving substances like 6,6′-d-glucose, the use of accredited laboratories is essential to meet Swissmedic / [or local responsible EU-CA]  and Cantonal Ethics Committee (CEC) requirements for quality and safety. This document serves to:

1. Demonstrate Laboratory Competence: Validates that the substances provided by CIL meet rigorous international quality standards, giving confidence to regulatory bodies about the reliability of the data.
2. Establish Chain of Compliance: Shows that the isotopes, including deuterated glucose, have been tested and certified in a controlled environment, aligning with requirements for investigational products.
3. Strengthen Regulatory Documentation: Ensures the inclusion of ISO-accredited testing details in the application package, satisfying ClinO-MD provisions for investigational products.

Why Researchers Need This Document

1. Proof of Quality: Helps confirm that the isotopic glucose solutions used in your study meet the required purity, concentration, and isotopic enrichment levels.
2. Regulatory Assurance: Inclusion of such certification ensures compliance with both Swiss and EU regulatory frameworks, such as ISO 22000 for food safety and ISO 10993-1 for biological testing.
3. Project-Specific Relevance: Researchers should request equivalent certifications for the exact batch and isotopic substance they intend to use, as variations may exist between production batches or testing methodologies.

ISO/IEC 17025:2017 accreditation is a cornerstone of regulatory compliance and scientific credibility, and for deuterated glucose trials, it ensures alignment with global quality standards. For more information on the ISO/IEC 17025 standard and its applications, visit the ISO website.

---

#2 — Deuterated 6,6’-d-glucose

Document

• CambridgeIsotope17034CertScope_V009.pdf

TYpe of document: ISO 17034:2016 Accreditation for Cambridge Isotope Laboratories, Inc.

Document Content

This document is an ISO 17034:2016 accreditation certificate issued to Cambridge Isotope Laboratories, Inc. (CIL) by the ANSI National Accreditation Board (ANAB). It certifies that CIL meets the international standards for the production of reference materials, demonstrating technical competence and robust quality management systems.

The document provides the following key details:

1. Scope of Accreditation:
   • CIL produces both Reference Materials (RM) and Certified Reference Materials (CRM).
   • Includes single and multi-component organic materials, both stable isotope-labeled and unlabeled, in neat or diluted forms.
   • Reference materials are validated using advanced techniques such as:
     • Chromatography: HPLC and GC (in accordance with USP-621).
     • Mass Spectrometry: LC/MS and GC/MS (USP-736).
     • Nuclear Magnetic Resonance (NMR): USP-761.
2. Accreditation Validity:
   • Certificate Number: AR-1878.
   • Valid until July 22, 2024.
3. Contact Information:
   • Address: 50 Frontage Road, Andover, MA 01810, USA.
   • Website and email details are included for inquiries regarding the scope of accreditation or specific reference materials.

Importance for Swissmedic / [or local responsible EU-CA]   and CEC Applications

For researchers conducting MR-supplementation studies using deuterated glucose or other isotopes:

• Assurance of Quality: This certificate ensures that reference materials (e.g., 6,6′-d-glucose) are produced under a quality system compliant with global standards, meeting the highest requirements for purity, stability, and isotopic enrichment.
• Regulatory Documentation: ISO 17034:2016 certification validates the traceability and reliability of reference materials. Such documentation strengthens the scientific rigor and regulatory compliance of Swissmedic / [or local responsible EU-CA] and Cantonal Ethics Committee (CEC) applications.
• Mandatory Compliance: Researchers must ensure that reference materials used in investigational devices or clinical trials originate from accredited providers like CIL to meet Swiss ClinO-MD and EU MDR documentation standards.

Why Researchers Should Request Similar Documents

When using reference materials for MR-spectroscopy or supplementation trials, ensure that:

1. The exact batch of the substance is certified with detailed properties and uncertainties.
2. Documentation aligns with ISO 17034:2016 and other relevant standards (e.g., ISO 22000 for food safety, if applicable).
3. Validation techniques (e.g., NMR, mass spectrometry) used to determine purity or isotopic enrichment are provided for inclusion in your regulatory application.

By integrating such certification, researchers can confidently demonstrate adherence to global quality standards, ensuring seamless approval processes with Swissmedic / [or local responsible EU-CA] and other regulatory bodies. For more details about the ISO 17034:2016 standard, visit the ISO website.

---

#3 — Deuterated 6,6’-d-glucose

Document

• DLM_349_mpt_PR_33016-pdf

Type of document: Certificate of Analysis for 6,6′-D2-Glucose (DLM-349-MPT)

Overview

This Certificate of Analysis (COA) from Cambridge Isotope Laboratories, Inc. (CIL) details the quality and specifications for 6,6′-D2-glucose (deuterated glucose), including its isotopic and chemical purity, microbial testing, and storage requirements. This document serves as a critical piece of documentation for researchers conducting MR supplementation studies, ensuring the material’s compliance with regulatory and safety standards.

Key Details

1. Product Information
   • Product Name: D-Glucose (6,6-D2, 99%)
   • Catalog Number: DLM-349-MPT
   • Lot Number: PR-33016
   • Chemical Formula: HOCD₂(CHOH)₄CHO
   • Molecular Weight (MW): 182.17 (fully enriched)
   • Chemical Purity: >98%
   • Isotopic Enrichment: 99.4%
   • Storage Instructions: Room temperature, protected from light and moisture, with a stability of 5 years under specified conditions.
2. Testing and Validation
   • 13C and 1H NMR Tests: Confirm chemical identity, purity, and isotopic enrichment.
   • Additional Chemical Tests: Verified levels of salts, water content, elemental impurities, and microbial limits. Specific highlights:
     • Endotoxin Levels: <0.0050 EU/mg.
     • Total Water Content: 3388 ppm.
     • Chloride Content: <0.001%.
     • Arsenic Content: <0.02 ppm.
   • Microbial Testing: Absence of pathogens such as Staphylococcus aureus, Salmonella sp., and Escherichia coli.
3. Intended Use
   • This product is designated for research use only and is not intended for diagnostic or therapeutic procedures.
4. Compliance and Standards
   • The COA states adherence to ISO 17034, ISO/IEC 17025, ISO 13485, and cGMP standards where applicable, demonstrating a commitment to quality and reliability.

Importance for Swissmedic / [or local responsible EU-CA] and CEC Applications

• Quality Assurance: The document ensures the deuterated glucose meets high-quality and isotopic enrichment standards, which is crucial for MR spectroscopy and supplementation studies.
• Regulatory Compliance: Swissmedic /  [or local responsible EU-CA]  and Cantonal Ethics Committees (CEC) often require detailed product documentation, especially for investigational studies involving non-drug substances. This COA provides vital data for ensuring that the material aligns with clinical research requirements.
• Safety Standards: The extensive testing outlined in the COA, including endotoxin and microbial testing, demonstrates that the glucose is safe for human supplementation in research settings.

Recommendations for Researchers

• Request COAs: Always request a current Certificate of Analysis for the exact batch of glucose (or similar substance) you plan to use in your study.
• Verify Specific Standards: Ensure that the product complies with relevant ISO standards, as listed in the COA, and meets Swiss or EU regulatory guidelines for food safety and supplementation trials.
• Document Inclusion: Include this COA in your Swissmedic / [EMA or local authorities] and CEC applications to substantiate the safety and quality of the material used in your investigation.

By using certified reference materials with robust documentation like this COA, researchers can confidently address regulatory and ethical requirements for their studies.

---

#4 — Crystalline α-D-Glucose (Thermo Fischer)

• alpha_D-glucose-ThermoFischer.pdf

Type of document: Scientific Safety Data Sheet (SDS) for α-D-Glucose by Thermo Fisher

This Safety Data Sheet (SDS) for α-D(+)-Glucose, anhydrous, provided by Thermo Fisher Scientific, serves as a critical document for ensuring safe handling, storage, and usage of this laboratory chemical. The document is relevant to researchers intending to use α-D-Glucose in clinical or investigational trials, particularly in MR-supplementation studies. Below is a general summary of its content and importance:

Key Features of the Document

1. Product Identification and Supplier Information (Section 1):
   • Lists the chemical name, formula (C₆H₁₂O₆), synonyms (e.g., Dextrose), and supplier details.
   • Includes important emergency contact numbers for various regions, including Europe and Switzerland.
2. Hazards Identification (Section 2):
   • States that α-D-Glucose is not classified as hazardous under applicable regulations.
   • Highlights safety precautions and labeling information.
3. Composition and Properties (Sections 3 & 9):
   • Provides the molecular weight (180.16 g/mol) and physical appearance (white powder).
   • States its solubility in water, non-flammability, and stability under standard conditions.
4. First Aid Measures (Section 4):
   • Offers instructions for handling accidental ingestion, skin contact, eye exposure, and inhalation.
5. Firefighting and Accidental Release Measures (Sections 5 & 6):
   • Includes details on appropriate firefighting media and safe clean-up procedures for spills.
6. Handling and Storage Guidelines (Section 7):
   • Recommends keeping the material in a cool, dry, and well-ventilated place, tightly sealed to avoid contamination.
7. Toxicological and Ecological Data (Sections 11 & 12):
   • Confirms the absence of known toxic or hazardous effects under normal use.
   • Indicates the compound’s high solubility in water and low environmental persistence.
8. Transport and Regulatory Information (Sections 14 & 15):
   • Classifies α-D-Glucose as non-hazardous for transport.
   • Details compliance with international chemical safety standards, including European Union (REACH) regulations.

Why This Document is Important for Applications

For researchers preparing Swissmedic / [or local responsible EU-CA]  and Ethics Committee submissions:

• Regulatory Compliance: The SDS verifies that α-D-Glucose is a laboratory-grade compound with no significant toxic or hazardous classification, simplifying regulatory approval.
• Safety Assurance: Demonstrates a clear understanding of safe handling, which is crucial for ethics applications.
• Documentation Requirement: Such documents are necessary to ensure that all chemicals used in a trial meet the required safety and compliance standards.

Recommendation

Ensure that the SDS version matches the specific batch and supplier of the compound you are using. Regulators may request this as part of the documentation for clinical investigations, particularly when substances are ingested or administered in studies.

This SDS is particularly helpful for demonstrating that α-D-Glucose is safe and compliant with international chemical standards, which are key considerations for investigators conducting trials involving supplementation.

---

#5 — Crystalline α-D-Glucose (Thermo Fischer)

• Certificate_Analysis-alpha_D-glucose-A16828-Z13I023.pdf

Type of document: Certificate of Analysis (COA) for α-D-(+)-Glucose (Thermo Fisher Scientific)

Overview

This Certificate of Analysis (COA) for α-D-(+)-Glucose, anhydrous (Product No. A16828, Lot No. Z13I023), issued by Thermo Fisher Scientific, confirms the product’s quality and compliance with analytical standards. The document is essential for researchers conducting clinical or investigational trials involving glucose supplementation, particularly in MR-based studies.

Key Information

1. Product Specifications:
   • Appearance: White crystalline powder.
   • Assay (Dry): 99.9% purity.
   • Optical Rotation: +53.1°, confirming the chirality of the compound.
   • Identification: Matches reference spectrum, ensuring the material’s authenticity.
2. Retest Date:
   • The product is valid until December 13, 2027, provided it is stored under the recommended conditions.
3. Regulatory Compliance:
   • Produced under ISO 9001:2015 Quality Management Systems, demonstrating adherence to international quality assurance standards.
   • Suitable for research and development use only, and not intended for direct administration to humans or animals without further validation by the end user.
4. Usage Guidelines:
   • Thermo Fisher highlights the responsibility of the final formulator or end user to ensure the product’s suitability and validation for specific applications.

Why This Document is Important for Swissmedic/ [or local responsible EU-CA] /CEC Applications

• Quality Assurance: Provides detailed proof of purity, identity, and compliance with internationally recognized standards, which is critical for ensuring reproducibility and safety in clinical studies.
• Regulatory Support: The COA can be included in Swissmedic/ [or local responsible EU-CA]  and Ethics Committee submissions to demonstrate the safety and consistency of the glucose used for supplementation.
• Batch-Specific Documentation: Certificates like this one are specific to the batch used in the trial. Regulators may request such detailed documentation to verify the source and quality of the material.

Recommendations for Researchers

• Request Updated COAs: Ensure you obtain a COA for the exact lot number of the glucose batch being used in your study.
• Verify Suitability: Even though this product is highly pure and well-characterized, additional safety validation may be required for clinical use, depending on local regulations.
• Include in Applications: Attach this document to your regulatory submissions to strengthen your case for material quality and compliance.

The inclusion of such certificates is crucial for demonstrating the high standards of material preparation and validation in any investigational or clinical research involving supplementation.

---

#5 — Crystalline α-D-Glucose (Thermo Fischer)

• UFAG-AG-Toxicologic-Test-Report-21-24696.pdf

Type of document: Independent Toxicological Analysis for alpha-D-Glucose

Importance of Independent Toxicological Reports:

An independent toxicological analysis ensures that the materials used in research or supplementation trials are safe for human or experimental use. This is especially vital for substances such as α-D-glucose used in investigational studies, as regulatory authorities like Swissmedic / [or local responsible EU-CA]  or Ethics Committees require robust evidence to confirm the safety profile of any ingested substances. Researchers benefit from obtaining these reports to address any concerns about contaminants or unapproved manufacturing practices.

Key Details from the Report

Laboratory Conducting the Analysis
The report was conducted by UFAG Laboratorien AG, an accredited laboratory located in Sursee, Switzerland. UFAG is recognized for its expertise in food and pharmaceutical safety testing, ensuring reliability and compliance with international standards.

Purpose of the Analysis
To evaluate the toxicological safety of α-D-glucose (99%+ purity) provided for clinical and investigational use.

Sample Details:

• Substance: α-D-glucose (99%+ purity).
• Lot Number: A0426247.
• Source: Acros Organics.
• Packaging: Provided in a 37 g plastic container.

Key Findings:

• Heavy Metals Testing (performed via ISO 15763-modified ICP-MS standards):
  • Arsenic (As): Not detectable (<0.02 mg/kg).
  • Lead (Pb): Not detectable (<0.003 mg/kg).
  • Cadmium (Cd): Not detectable (<0.002 mg/kg).
  • Mercury (Hg): Not detectable (<0.005 mg/kg).

  These results demonstrate that the glucose sample does not contain harmful levels of heavy metals and meets stringent safety standards.

• Compliance:
  The laboratory confirmed that all testing was performed according to validated methods, and the results comply with internationally accepted thresholds for heavy metal contaminants.

Why This Report is Important for Swissmedic/ [or local responsible EU-CA] /CEC Applications

1. Regulatory Compliance:
   It provides essential evidence to Swissmedic / [or local responsible EU-CA] and Cantonal Ethics Committees that the substance being administered meets rigorous safety standards.
2. Transparency and Reliability:
   Independent toxicological testing ensures that no conflicts of interest influence the results, bolstering the credibility of the application.
3. Validation of Supplier’s Claims:
   Even when suppliers provide Certificates of Analysis (COAs), an independent toxicology report adds an additional layer of assurance, which is often crucial for regulatory acceptance.

Recommendations for Researchers

• Always include a toxicological analysis report when submitting applications for trials involving ingested substances, particularly if the substance is not CE-marked or is considered investigational.
• Ensure the laboratory performing the analysis is accredited and recognized for regulatory testing.
• For maximum compliance, pair these reports with the manufacturer’s COAs and regulatory documentation.

This document underscores the safety and suitability of α-D-glucose for investigational use, addressing key concerns for regulators and supporting the ethical integrity of the trial.