Alcohol Induced Dose Dumping Fact Sheet
AMRI provides cGMP dissolution support for APIs and a wide variety of dosage forms in various buffered, biorelevant, and mixed organic-phase media. We have capability with various USP dissolution apparatus, including multi scale and automated rotating disc intrinsic dissolution. Our experience in comparative dissolution, combined with our expertise in solid-state chemistry, positions us well for in vitro comparative product evaluation, specifically alcohol induced dose dumping.
Quality by design is a key component of pharmaceutical development, as detailed in ICH Q8, by which the quality, safety and efficacy of a drug product are evaluated, which considers items such as the route of administration, dosage form, bioavailability, strength, and stability. This serves to identify, through prior knowledge, experimentation, and risk assessment, the material attributes and process parameters that can affect critical quality attributes of the product, such as drug release.
Alcohol induced dose dumping is a critical parameter to consider when designing and developing modified release formulations. Some modified release solid oral dosage forms can contain drugs or excipients that are highly soluble in ethanol. Ingestion of alcohol, either intentionally or unintentionally, may lead to dangerously high drug exposure if the control release formulation is sensitive to ethanol concentration. Clinical impact should be considered during formulation development, in order to develop formulations and dosages that are resistant to dose dumping and failure mode analyses should be performed early in development.
Products are classified into “vulnerable” and “rugged” categories, with only “rugged” product designs developed and progressed in the clinical development program. Routine recommendation for a pharmacokinetic study on an alcohol-formulation interaction may not be the preferred approach for many reasons. Studies in healthy subjects involve co-administration of high alcohol loads. Modified-release products pose a risk due to alcohol load and because of the potential for dose dumping in cases where high exposure may be dangerous, therefore an in vivo model poses major challenges. While antagonists have been employed to reduce risks (e.g. naltrexone block for opiates), this may not be feasible or provide adequate protection for most drugs. To be consistent with FDA principles (minimize risk to subjects) reliable alternate approaches to in vivo evaluation are preferred.
AMRI provides cGMP support to meet the FDA requirements for in vitro dissolution testing of a variety of dosage forms, including those modified release products noted to be vulnerable to alcohol induced dose dumping. Several key factors in robust formulation preparation are directly related to the solid form (solubility, wettability, swellability, mechanical properties of the API and the excipients). Polymorph and solubility screens are a key component to “rugged” formulation design and development. As the world-leader in solid-state chemistry services, AMRI possesses a unique combination of resources required for “rugged” formulation evaluation. Combined with an excellent regulatory record, AMRI is the clear choice for a partner in development of modified release drug products.
In addition to in vitro dissolution, AMRI’s offers a wide array of analytical services to support regulatory submission of modified release drug products.
 Christine M. V. Moore. “An FDA Perspective on Drug Development and the Global Regulatory Landscape”. AAPS Annual Meeting, Washington, DC, 25 October 2010.
 R. J. Meyer, A. S. Hussain. “Awareness Topic: Mitigating the Risks of Ethanol Induced Dose Dumping from Oral Sustained/Controlled Release Dosage Forms.” FDA’s ACPS Meeting, October 2005.
 O. Anand, L.X. Yu, D.P. Conner, B.M. Davi. “Dissolution Testing for Generic Drugs: An FDA Perspective.” The AAPS Journal, Vol. 13, No. 3, Pages 328-335 (September 2011)
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