Everything You Should Know about FDA’s Draft Guidance on Abuse-Deterrent Generic Opioids, Part Two

March 31, 2016

FDA Touches on Routes of Abuse, Comparative In Vitro Studies, and Various Other Factors to Consider Regarding Abuse-Deterrent Generic Opioids

FDA Issues Draft Guidance on Abuse-Deterrent Generic Opioid Medications

Due to recent increases in the prevalence of opioid abuse and misuse, the opioid epidemic has attracted a lot of attention lately. As such, the FDA is taking an active approach to reduce the occurrence of this issue in the U.S.

As we reported yesterday, the Agency’s latest effort in the fight against opioid abuse is the release of its draft guidance entitled “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products.”

Routes of Abuse

When attempting to abuse opioids, there are a number of ways they can be ingested. These include:

  • Injection – parenteral route
  • Ingestion – oral route
  • Insufflation – nasal route
  • Smoking – inhalation route

When ingesting opioids orally, users can do so in a variety of ways. As such, opioids can be swallowed as intact dosage forms or “after chewing, cutting, crushing, grating, milling, or extracting the opioid from the intact or mechanically manipulated form.”

In order to help combat these alternate routes of administration, the FDA believes that all potential routes of abuse should be taken into consideration when evaluating the abuse deterrence of generic opioids.

Comparative In Vitro Studies

FDA recommends that sponsors use a tier-based approach when comparing the abuse deterrence of the generic and reference products. This means that “in vitro testing should start with simple and gentle manipulations and progress to complex and more destructive manipulations.”

In addition to mechanical manipulation, the draft guidance states that sponsors can also use chemical manipulation, in which different levels of solvents may be used to extract the opioid. The guidance “recommends the following levels of solvents be used for chemical manipulation in comparative in vitro studies:

  • Level 1 solvent: water.
  • Level 2 solvents: commercially available food-grade vinegar, 0.2% baking soda solution, 40% ethanol, and carbonated drink.
  • Level 3 solvents: cooking oil, isopropyl alcohol, acetone, 0.1 N HCl, and 0.1 N NaOH.”

Applicants interested in using other solvents are encouraged to seek input from the Agency regarding additional testing suitable for product-specific development.

Other Considerations

In addition to the recommendations provided above and in our previous FDA News article, the draft guidance includes a number of factors to consider, including:

  • Multiple Strengths
    • Sponsors “seeking approval of several strengths of a generic solid oral opioid drug product should evaluate and compare the generic product against the reference product for each of the strengths.”
  • Pharmacokinetic (PK) Studies
    • “PK studies to evaluate the abuse deterrence of the generic product in comparison to the reference product should be conducted in cases where there are no reliable in vitro testing methodologies. Potential ANDA applicants may also propose to conduct PK studies in cases where available in vitro testing methodology is overly sensitive or cannot adequately assess the abuse deterrence of the generic product relative to the reference product.”
  • Other Studies
    • “Generally, comparative in vitro and PK studies provide sufficient evidence to demonstrate that the generic product is no less abuse-deterrent than the reference product.”

FDA is seeking public feedback on the draft guidance and is asking interested parties to submit comments electronically or by mail no later than May 24, 2016.

For additional information on FDA’s recommendations, view the full draft guidance.

Want to learn more about the opioid epidemic? View our additional FDA News articles on the subject:

Additional information on FDA’s draft guidance regarding abuse-deterrent generic opioids is available in our preceding FDA News article entitledEverything You Should Know about FDA’s Draft Guidance on Abuse-Deterrent Generic Opioids, Part One.”


Are you developing a generic version of an opioid or other FDA approved product? We can help you obtain FDA approval for your product. To learn more about our services and how we can help you, contact us today.


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