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Oral Drug Product Administration via Enteral Feeding Tubes: In Vitro Testing

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Abstract

Medication administration via enteral feeding tubes (EFT) is a necessary practice for patients unable to swallow oral dosage forms due to a medical condition or treatment that affects the ability to swallow or the function of the gastrointestinal tract. Off-label administration of oral drug products via EFT raises concerns for pharmaceutical sponsors, regulators, and healthcare practitioners (HCPs) because of the potential risks this practice introduces to both the patient and the caregiver. These risks can be mitigated by generating data-supported instructions that patients and HCPs can use to ensure safe and accurate administration of oral drug products via EFT. This commentary presents an industry perspective on the testing that should be conducted to enable development of product-specific instructions in the labeling to support or advise against administration of oral drug products via enteral feeding tube. The proposal outlined in this commentary takes a risk-based approach, addressing recommendations from both regulatory agencies as well as considerations for expanding this testing to address needs specific to neonatal and pediatric populations.

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Data Availability

No data was generated for this commentary.

References

  1. Kozeniecki M, Fritzshall R. Enteral nutrition for adults in the hospital setting. Nutr Clin Pract. 2015;30(5):634–51.

    Article  PubMed  Google Scholar 

  2. Miller KR, McClave SA, Kiraly LN, Martindale RG, Benns MV. A tutorial on enteral access in adult patients in the hospitalized setting. JPEN J Parenter Enteral Nutr. 2014;38(3):282–95.

    Article  PubMed  Google Scholar 

  3. Stegemann S, Gosch M, Breitkreutz J. Swallowing dysfunction and dysphagia is an unrecognized challenge for oral drug therapy. Int J Pharm. 2012;430(1–2):197–206.

    Article  CAS  PubMed  Google Scholar 

  4. Ojo O. The challenges of home enteral tube feeding: a global perspective. Nutrients. 2015;7(4):2524–38.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mundi MS, Pattinson A, McMahon MT, Davidson J, Hurt RT. Prevalence of home parenteral and enteral nutrition in the United States. Nutr Clin Pract. 2017;32(6):799–805.

    Article  PubMed  Google Scholar 

  6. Hubbard GP, Andrews S, White S, Simpson G, Topen S, Carnie L, Murphy C, Collins R, Davies J, Owen A, Barker J, Green L, Patel I, Ridgway J, Lenchner J, Faerber J, Pearce L, Meanwell H, Kominek N, Stark L, Best H, Simons R, Cross T, Stratton RJ. A survey of bolus tube feeding prevalence and practice in adult patients requiring home enteral tube feeding. Br J Nutr. 2019;122(11):1271–8.

    Article  CAS  PubMed  Google Scholar 

  7. Teder K, Jõhvik L, Meos A, Saar M, Visbek A, Volmer D, Karjagin J. Solid oral medications’ suitability for use in enteral feeding tubes. Nurs Crit Care. 2022;27(5):698–705.

    Article  PubMed  Google Scholar 

  8. Song Y, Chang M, Suzuki A, Frost RJ, Kelly A, LaCreta F, Frost C. Evaluation of crushed tablet for oral administration and the effect of food on apixaban pharmacokinetics in healthy adults. Clin Ther. 2016;38(7):1674-1685.e1.

    Article  CAS  PubMed  Google Scholar 

  9. Williams NT. Medication administration through enteral feeding tubes. Am J Health Syst Pharm. 2008;65(24):2347–57.

    Article  CAS  PubMed  Google Scholar 

  10. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings. Centers for Disease Control and Prevention, Publication Number 2016-161. 2016. https://www.cdc.gov/niosh/docs/2016-161/default.html.

  11. Guideline on pharmaceutical development of medicines for paediatric use. European medicines Agency; EMA/CHMP/QWP/805880/2012 Rev. 2. 2013. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmaceutical-development-medicines-paediatric-use_en.pdf.

  12. Quality of medicines questions and answers: part 2 - administration of oral immediate release medicinal products through enteral feeding tubes NEW December 2018. European Medicines Agency. https://www.ema.europa.eu/en/human-regulatory-overview/research-and-development/scientific-guidelines/quality-medicines-qa-introduction/quality-medicines-questions-and-answers-part-2#ema-inpage-item-6963.

  13. Oral drug products administered via enteral feeding tube: in vitro testing and labeling recommendations. Draft Guidance for Industry, U.S. Food & Drug Administration, A. Docket Number: FDA-2021-D-0391. 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oral-drug-products-administered-enteral-feeding-tube-in-vitro-testing-and-labeling-recommendations.

  14. Klek S, Pawlowska D, Dziwiszek G, Komon H, Compala P, Nawojski M. The evolution of home enteral nutrition (HEN) in Poland during five years after implementation: a multicentre study. Nutr Hosp. 2015;32(1):196–201.

    PubMed  Google Scholar 

  15. White R, Bradnam V. Handbook of drug administration via enteral feeding tubes, 3rd ed. Aust Prescr. 2016;39(2):53. https://doi.org/10.18773/austprescr.2016.004.

  16. Folwarski M, Kłęk S, Zoubek-Wójcik A, Szafrański W, Bartoszewska L, Figuła K, et al. Home enteral nutrition in adults-nationwide multicenter survey. Nutrients 2020;12(7). https://doi.org/10.3390/nu12072087.

  17. Ojo O. Managing patients on enteral feeding tubes in the community. Br J Community Nurs. 2010;15:S6–13.

    Article  Google Scholar 

  18. McIntyre CM, Monk HM. Medication absorption considerations in patients with postpyloric enteral feeding tubes. Am J Health-Syst Pharm. 2014;71(7):549–56.

    Article  CAS  PubMed  Google Scholar 

  19. Crushing tablets or opening capsules: many uncertainties, some established dangers. Prescrire Int 2014;23(152):209–11, 213–4. https://pubmed.ncbi.nlm.nih.gov/25325120/#:~:text=The%20active%20ingredient%20released%20may,They%20are%20sometimes%20allergenic.

  20. Use of liquids and/or soft foods as vehicles for drug administration: general considerations for selection and in vitro methods for product quality assessments. U.S. Food & Drug Administration, Docket Number: FDA-2018-D-2544. 2018. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-liquids-andor-soft-foods-vehicles-drug-administration-general-considerations-selection-and-vitro.

  21. Powers JE, Cascella PJ. Comparison of methods used to prepare tablets for nasogastric tube administration. J Pharm Technol. 1990;6(2):60–2.

    Article  Google Scholar 

  22. Salmon D, Pont E, Chevallard H, Diouf E, Tall ML, Pivot C, Pirot F. Pharmaceutical and safety considerations of tablet crushing in patients undergoing enteral intubation. Int J Pharm. 2013;443(1–2):146–53.

    Article  CAS  PubMed  Google Scholar 

  23. Boullata JI. Enteral medication for the tube-fed patient: making this route safe and effective. Nutr Clin Pract. 2021;36(1):111–32.

    Article  PubMed  Google Scholar 

  24. Wallace T, Steward DK. Gastric tube use and care in the NICU. Newborn Infant Nurs Rev. 2014;14:103–8.

    Article  Google Scholar 

  25. Guha S, Niswander W, Herman A, Antonino MJ, Venkataraman Rao P, White K, Haugen S, Vesnovsky O. Assessing dosing errors in legacy and low dose tip ENFit(®) syringes. J Clin Pharm Ther. 2022;47(2):218-227.

  26. Hofstetter J, Allen LV Jr. Causes of non-medication-induced nasogastric tube occlusion. Am J Hosp Pharm. 1992;49(3):603–7.

    CAS  PubMed  Google Scholar 

  27. Smith AL, Santa Ana CA, Fordtran JS, Guileyardo JM Unsuitability of sump tubes for delivery of enteral nutrition and medications to intensive care unit patients. Proc (Bayl Univ Med Cent) 2021;34(5):560-565.

  28. Elia M, Crozier C, Martin S, Neale G. Flow and aspiration of artificial feeds through nasogastric tubes. Clin Nutr. 1984;2(3–4):159–66.

    Article  CAS  PubMed  Google Scholar 

  29. Gaither KA, Tarasevich BJ, Goheen SC. Modification of polyurethane to reduce occlusion of enteral feeding tubes. J Biomed Mater Res B Appl Biomater. 2009;91(1):135–42.

    Article  PubMed  Google Scholar 

  30. Hoover A, Chitranshi P, Momot M, Tyner K, Wokovich A. In vitro evaluation of enteral tube administration of lansoprazole orally disintegrating tablets. Pharm Dev Technol. 2021;26(8):846–51.

    Article  CAS  PubMed  Google Scholar 

  31. Karkossa F, Lehmann N, Klein S. A systematic approach for assessing the suitability of enteral feeding tubes for the administration of controlled-release pellet formulations. Int J Pharm. 2022;612: 121286.

    Article  CAS  PubMed  Google Scholar 

  32. GEDSA Unified ENFit Conversion Message Book 20220628. 2022. https://stayconnected.org/gedsa-unified-enfit-conversion-message-book-20220628/.

  33. Guenter P, Lyman B. ENFit enteral nutrition connectors: benefits and challenges. Nutr Clin Pract. 2016;31(6):769–72.

    Article  PubMed  Google Scholar 

  34. Potential for medication overdose with ENFit low dose tip syringe: FDA safety communication; November 18, 2021 update. https://www.fda.gov/medical-devices/safety-communications/potential-medication-overdose-enfit-low-dose-tip-syringe-fda-safety-communication.

  35. Guha S, Herman A, Antonino M, Silverstein JS, Venkataraman-Rao P, Myers MR. Synthesis of research on ENFit gastrostomy tubes with potential implications for US patients using these devices. Nutr Clin Pract. 2022;37(4):752–61.

    Article  PubMed  Google Scholar 

  36. Feeding Tube Awareness Foundation, What you need to know now: a parent’s introduction to tube feeding. https://jldtherapy.com/wp-content/uploads/2021/08/ParentGuide-English.pdf.

  37. Thomson FC, Naysmith MR, Lindsay A. Managing drug therapy in patients receiving enteral and parenteral nutrition. Hospital Pharmacist. 2000;7:155–64.

    Google Scholar 

  38. Dandeles LM, Lodolce AE. Efficacy of agents to prevent and treat enteral feeding tube clogs. Ann Pharmacother. 2011;45(5):676–80.

    Article  PubMed  Google Scholar 

  39. Lord LM. Restoring and maintaining patency of enteral feeding tubes. Nutr Clin Pract. 2003;18(5):422–6.

    Article  PubMed  Google Scholar 

  40. Boullata JI, Carrera AL, Harvey L, Escuro AA, Hudson L, Mays A, McGinnis C, Wessel JJ, Bajpai S, Beebe ML, Kinn TJ, Klang MG, Lord L, Martin K, Pompeii-Wolfe C, Sullivan J, Wood A, Malone A, Guenter P. ASPEN safe practices for enteral nutrition therapy. JPEN J Parenter Enteral Nutr. 2017;41(1):15–103.

    Article  PubMed  Google Scholar 

  41. Chiwele I, Jones BE, Podczeck F. The shell dissolution of various empty hard capsules. Chem Pharm Bull. 2000;48(7):951–6.

    Article  CAS  Google Scholar 

  42. Kunieda K, Kurata N, Yoshimatsu Y, Ohno T, Shigematsu T, Fujishima I. A safe way to administer drugs through a nutrition tube—the simple suspension method. Dysphagia. 2022;37(2):318–22.

    Article  PubMed  Google Scholar 

  43. Ankrum JA, Olechowski A, Canseco JA, Greenblatt E, Roberts MP, Hanumara NC, et al. Nasogastric tube design to reduce clogging and simplify flushing. J Med Devices 2011;5(2).

  44. Avanos enteral nutrition delivery. https://avanosmedicaldevices.com/product-catalog/digestive-health/nicu-and-pharmacy/enteral-nutrition-delivery/. Accessed Jul 2023.

  45. Kangaroo™ neonatal & pediatric feeding system, pp. https://www.cardinalhealth.com/en/product-solutions/medical/enteral-feeding/kangaroo-neonatal-pediatric-feeding-system/kangaroo-polyurethane-feeding-tubes-with-safe-enteral-connections.html. Accessed Jul 2023.

  46. Pediatric nasogastric feeding tubes. https://www.vescomedical.com/copy-of-ng-tubes. Accessed Jul 2023.

  47. USP 〈1111〉 Microbiological examination of nonsterile products: acceptance criteria for pharmaceutical preparations and substances for pharmaceutical use. Official Prior to 2023. https://online.uspnf.com/uspnf/document/1_GUID-5D1EDF19-6C70-4F74-A474-07D9B25B1C58_1_en-US?source=Quick%20Search&highlight=usp%201111.

  48. ISO 10993-17:2023, Biological evaluation of medical devices — part 17: Toxicological risk assessment of medical device constituents.

  49. ISO 10993-12:2021 Biological evaluation of medical devices — part 12: Sample preparation and reference materials.

  50. Instructions for Use — Patient labeling for human prescription drug and biological products — content and format. U.S. Food & Drug Administration; Docket Number: FDA-2019-D-1615. 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/instructions-use-patient-labeling-human-prescription-drug-and-biological-products-content-and-format.

  51. https://www.ema.europa.eu/en/documents/assessment-report/ravicti-epar-public-assessment-report_en.pdf.

  52. pi_eliquis.pdf(bms.com)

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Acknowledgements

On behalf of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org), the objective of this document is to present a commentary of a workflow to support enteral feeding tube (EFT) testing for pharmaceutical products in development incorporating FDA, EMA, and health care practitioner (HCP) information needs. IQ is a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader research and development community.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Eli Lilly and Company, Indianapolis, Indiana, 46285, USA

    Selina Wilson

  2. Merck & Co., Inc., Rahway, New Jersey, 07065, USA

    Julianne Farabaugh, Zhao Liu & Karen Thompson

  3. AbbVie Inc., 1 N Waukegan Road, North Chicago, Illinois, 60064, USA

    Yemin Liu

  4. Ernest Mario School of Pharmacy, Rutgers University, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA

    Rachel Meyers

  5. Pfizer Inc., Groton, Connecticut, 06340, USA

    Matthew Santangelo

  6. Cooperman Barnabas Medical Center, Livingston, New Jersey, 07039, USA

    Rachel Meyers

Authors
  1. Selina Wilson
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  4. Zhao Liu
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Contributions

All authors contributed to this publication providing substantial contributions to the conception or design of the work; the analysis, or interpretation of data for the work; drafts and critical revisions of the work for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Appendix

Appendix

See Table IV

Table IV High-Level Strategy for Analytical Testing to Support of Administration of Oral Drug Products via Enteral Feeding Tubes
Full size table

Glossary

ASD

Amorphous Solid Dispersion

Compounding pharmacy preparation

Custom drug product preparation by a licensed pharmacist or physician

Dispersibility

Ability of a powder, granule(s), or monolithic solid oral dosage form to be dispersed in a designated vehicle

Dispersing/Disperses

Powder is distributed in a selected vehicle without lumps or clumps

Dispersion

The resulting mixture of a powder, granule(s), or monolithic solid oral dosage form in a designated vehicle for administration

Distal end

The terminal end of the feeding tube which goes into the GI tract

EFT

Enteral feeding tube

Enteric coated

Coating of material for administration designed to not release in stomach acid

GEDSA

Global Enteral Device Supplier Association; formed to help introduce international standards in medical device tubing connectors to enhance patient safety

HCP

Health care practitioner

Holding period/holding (hold) time

Time between completed dose preparation and required dose delivery to the patient

IFU

Instructions for Use

In-use (stability)

Covers stability of the manipulated oral drug product during the total preparation and holding time period

IR

Immediate release

Legacy Enteral Tubes

Non-Enfit enteral feeding systems

Manipulated/manipulation

Manipulation of the dosage form to enable enteral administration

Monolithic solid oral dosage form

A solid oral dosage form in which the full dose is delivered via a single unit—e.g., tablets or capsules

Multiparticulates

A solid oral dosage form consisting of multiple, small, discrete active-containing units that, taken together, make up a single dose. Examples include pellets, microparticles, granules, and mini-tablets

Neonatal/neonate

0–4 weeks of age

ODT

Orally disintegrating tablets

Oral granules

A multiparticulate solid oral dosage form

Port

The proximal end of the feeding tube through which nutrition and medicine are administered

Preparation time

Time for manipulation of the drug product to prepare enteral feeding solution/dispersion. Note: could include a wetting period prior to mixing

“Ready to Use” suspension/solution

Drug product is described as a suspension or solution

Reconstitution

Addition of water or other specified vehicle to a powder or granule to prepare a solution/suspension

Shelf-life (stability)

Stability of the drug product as packaged

SmPC

Summary of Product Characteristics; the EMA equivalent of the USPI

Tube occlusion

Tube blockage requiring unacceptable pressures for material flow

USPI

United States Prescribing Information; FDA equivalent of the SmPC

XRPD

X-ray powder diffraction

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Wilson, S., Farabaugh, J., Liu, Y. et al. Oral Drug Product Administration via Enteral Feeding Tubes: In Vitro Testing. AAPS J 26, 43 (2024). https://doi.org/10.1208/s12248-024-00896-9

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