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In Vitro Testing and Labeling for Oral Drug Products Administered via Enteral Feeding Tubes (DRAFT)

This guidance provides recommendations for in vitro testing and labeling of oral drug products (except solutions) that are administered via enteral feeding tubes. It applies to NDAs and ANDAs where applicants seek enteral tube administration instructions in labeling. The guidance focuses on ensuring drug product quality and bioequivalence when evaluating suitability for enteral tube administration.

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By ReguVirta
4 min read

This is a draft guidance. Not for implementation.

What You Need to Know? 👇

What are the key in vitro testing requirements for oral drug products administered via enteral feeding tubes?

The FDA recommends recovery testing, sedimentation volume and redispersibility testing, in-use stability testing, particle size distribution studies (for modified-release products), acid resistance testing (for enteric-coated products), and dissolution testing (for extended-release products).

Which enteral tube sizes should be tested during drug product development?

Testing should be performed with the smallest intended enteral tube size for each type of material or design. For example, if labeling includes both nasogastric tubes (Fr 8 and above) and gastrostomy tubes (Fr 12 and above), test at Fr 8 and Fr 12 respectively.

Common dispersion media include purified water, apple juice, milk, and liquid nutritional supplements. When water is used, particularly for modified-release products, testing with different pH values (5.5, 7.0, 8.5) is recommended due to potential effects on drug release characteristics.

How should ANDA applicants demonstrate bioequivalence for enteral tube administration?

ANDA applicants must perform comparative in vitro testing using 12 units each of test and reference products, calculate the T/R recovery ratio with 90% confidence intervals, and follow the RLD’s enteral tube administration instructions for testing procedures.

What labeling information is required for drugs suitable for enteral tube administration?

Labeling must include suitable dosage forms/strengths, recommended tube characteristics (type, size range, material), preparation instructions (dispersion media, crushing method, soaking time), administration instructions (volume, rate, positioning), and tube maintenance instructions (flushing requirements).

If testing identifies no successful method for preparation and administration via enteral tube without compromising drug delivery, safety, or tube integrity, the labeling should state this with appropriate rationale and cross-reference supporting information in other labeling sections.

What You Need to Do 👇

  1. Develop comprehensive in vitro testing protocol considering drug product characteristics and intended tube types
  2. Conduct required in vitro testing:
    • Recovery testing
    • Sedimentation and redispersibility
    • Stability testing
    • Additional tests as needed (particle size, acid resistance, dissolution)
  3. Document testing conditions, protocols and results in standardized format
  4. Develop detailed administration instructions based on successful testing results
  5. Prepare appropriate labeling content including:
    • Specific tube requirements
    • Preparation instructions
    • Administration procedures
    • Storage conditions
    • Warnings/contraindications if applicable
  6. Submit complete test reports and proposed labeling in application
  7. Consider early communication with FDA for guidance on testing approach
  8. For ANDAs, ensure testing demonstrates equivalence to RLD when administered via enteral tube
  9. Maintain documentation of test results and justification for specifications

Key Considerations

Non-clinical testing

  • Recovery testing to determine percentage of drug dose passing through tube
  • Sedimentation volume and redispersibility testing
  • In-use stability testing in dispersion media
  • Particle size distribution studies for modified-release formulations
  • Acid resistance testing for enteric-coated products
  • Dissolution testing for extended-release products

Labelling

  • Include information on suitable dosage forms and strengths
  • Specify recommended enteral tube characteristics (type, size, material)
  • Provide detailed preparation and administration instructions
  • Include storage instructions for residual drug product dispersion
  • State if product is NOT recommended for enteral tube administration
  • Cross-reference relevant information in other labeling sections

Biocompatibility

  • Evaluate drug product-enteral tube material interactions
  • Consider pH effects on tube material compatibility

Safety

  • Assess risk of tube occlusion
  • Evaluate stability during preparation and administration
  • Consider microbiological testing for extended holding times

Other considerations

  • Selection of appropriate dispersion media
  • Development of validated analytical methods
  • Documentation of testing conditions and protocols
  • Statistical analysis of test results

Relevant Guidances 🔗

Related references and norms 📂

  • USP <1111>: Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use
  • USP <61>: Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests
  • USP <62>: Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms
  • USP <1151>: Pharmaceutical Dosage Forms

Original guidance

  • In Vitro Testing and Labeling for Oral Drug Products Administered via Enteral Feeding Tubes
  • HTML / PDF
  • Issue date: 2021-06-02
  • Last changed date: 2022-02-01
  • Status: DRAFT
  • Official FDA topics: Chemistry, Pharmaceutical Quality, Medical Devices, Manufacturing, Drugs, Labeling, and Controls (CMC)
  • ReguVirta ID: 6245801c932ad2dd18cc1593e262f19b
FDA guidance, Draft
Chemistry Pharmaceutical Quality Medical Devices Manufacturing Drugs Labeling and Controls (CMC)
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