The use of opioid medications for pain management continues to increase, generating an inevitable association with abuse and addiction. Government officials and pharmaceutical professionals alike are in need of risk mitigation approaches (Katz, 2008). The Abuse Deterrent Access Act of 2018 requires Medicare and Medicaid to report to Congress the availability of abuse-deterrent opioid pain treatments. The bill is meant to decrease the amount of barriers for their enrollees (Carter, 2018).
“The U.S. Department of Health and Human Services (HHS) has estimated that in 2016, the most recent year for which complete data are available, over 42,249 Americans died from opioid overdoses, the most of any year on record. More than 2.1 million Americans had an opioid use disorder (addiction) in 2016, with economic costs from the epidemic estimated to be as high as $504 billion dollars (Johns Hopkins University Bloomberg School of Public Health, 2018).” Pharmaceutical companies have responded to this need through more stringent abuse-deterrent formulations and studies.
Current US Food and Drug Administration (FDA) guidelines for determining the effectiveness of abuse deterrence for a drug substance involve four main studies termed Category 1, 2, 3, and 4.
Category 1 Studies
“In these (Category 1) studies the product is evaluated and compared to currently marketed formulations for the ability to defeat or compromise the abuse-deterrent properties. This testing is done in-vitro and provides the physical characteristics of the product and its ability to resist crushing, grinding, melting, etc. to limit nasal abuse. Extraction studies provide information on the product’s ability to isolate the antagonist, or resist abuse by injection, or in larger volumes, diminish abuse by ingestion,” says Angela Moore, MSc, head of Alcami’s abuse-deterrent studies program. “One of the most important aspects of Category 1 testing is study design and repeatability. Multiple replicates give confidence in results. Also, a well-thought-out design of experiment and testing to failure is vital for these studies. Exact study requirements are not clearly defined through current guidance and the FDA uses a ‘totality of evidence’ approach when evaluating these formulations.”
Key examples of Category 1 testing include: physical manipulation evaluations, large volume extractions, syringeability testing, smoking studies, liquid-liquid, free-base extractions, and, if needed, isolation of opioid/antagonist studies.
When conducting Category 1 abuse-deterrent testing, typical studies mimic real world abuse of the opioid in question. Real life filters, such as cotton Q-tips and cigarette filters, should be used as drug abusers tend to use these instead of lab syringe filters. The route of drug abuse depends on the person’s personal preference; routes of abuse include oral, insufflation, injection, and smoking.
Standard Syringeability Studies
According to the 2015 FDA guidance for the industry, “the amount of opioid that can be obtained in a syringe should be based on studies of intact and manipulated test product and comparators using small volumes of water (5-10 mL) at room temperature and at 90-95°C with and without agitation (Administration, 2015).” The FDA also advises from the 2017 FDA generic guidance: “10mL volume, 5-60 minute extraction times, and needle gauge 21 or finer (US Food and Drug Administration, 2017).”
Moore states, “Unlike common dissolution studies or large volume extraction studies, when performing syringeability studies in the laboratory, an individual sample must be prepared for each time point evaluated. This is due to the large amount of data needed for each individual sample. For samples intended to deter intravenous abuse, start with the largest recommended needle— size 21 gauge. If a 21 gauge needle is efficient, evaluate other smaller sizes. These are very large studies and generate a lot of data. For example, for each formulation tested, Alcami recommends the following conditions be studied: intact and manipulated, room temperature and high temperature, with and without agitation, multiple time points, multiple solvents, and triplicate testings.” To measure syringeability in the lab, look for the following:
When designing syringeability studies, different parameters each play a critical role determining abuse deterrence. Parameters include appropriate sample containers, sample handling, and agitation selection. With these studies, it is necessary to represent the worst case scenario— always try to test a product to failure. “If a product is tested to failure and shows that it’s better than the comparators under the worst situations for your product, you have a compelling story to tell the FDA,” states Moore.
Additional Syringeability Studies
Gel blob study— abusers may manipulate a drug product by adding a small of amount of aqueous liquid and continue to add liquid until the formulation no longer swells. The additional liquid surrounding the formulation contains drug substance and might be syringeable.
Crispin’— a reformulation of opioid drug products using excipients that form a “gel” when exposed to aqueous conditions. Drug abusers will heat, or “brown” a manipulated formulation using an oven, microwave heat, or hand-held lighter. In a laboratory setting, the heat source will either be a microwave or a muffle furnace to test how long it takes to heat a product to defeat the gelling properties of the formulation. “One of the key considerations when testing the ‘crispin’ method is to ensure the API is not destroyed, only the excipients,” states Moore.
Other experiment variations may be required by the FDA including variability in extraction solvents, such as ethanol, and different extraction volumes. All of these are based on each individual formulation and how it behaves— and should be discussed carefully with the FDA once preliminary data is available.
In conclusion, when designing Category 1 testing, it is best to anticipate what drug users will do to manipulate the drug and test to failure— abuse-deterrent medications can save lives. Alcami specializes in Category 1 syringeability studies, has full GMP traceability, and uses a team-based approach when applying appropriate resources to effectively utilize and meet client deadlines. This is especially important as Category 1 strategies and results drive the in-vivo Category 2 and 3 studies required for abuse-deterrent labeling of drug products.
Angela Moore, M.Sc. has over 12 years of experience performing analytical testing in the pharmaceutical industry for both branded and generic products and their active pharmaceutical ingredients. She has considerable experience successfully executing several FDA Category 1 in vitro abuse-deterrent studies on drug products that are designed to help combat opioid abuse. She also performs development and validation studies for API and Drug Products, generates technical test protocols and reports, and is the subject matter expert for the company in abuse-deterrent products and testing. Angela holds both Master of Science and Bachelor of Science degrees in Chemistry from East Carolina University.
Carter, R. E. (2018). H.R.5582 - Abuse Deterrent Access Act of 2018. 115th Congress. https://www.congress.gov/bill/115th-congress/house-bill/5582.
Johns Hopkins University Bloomberg School of Public Health. (2018). Health insurance plans may be fueling opioid epidemic. https://www.ncbi.nlm.nih.gov/pubmed/18457606.
Katz, N. (2008). Abuse-deterrent opioid formulations: are they a pipe dream? Current Rheumatology Reports. https://www.sciencedaily.com/releases/2018/06/180625122611.htm.
US Food and Drug Administration. (2015). Abuse-Deterrent Opioids -- Evaluation and Labeling Guidance for Industry.
US Food and Drug Administration. (2017). General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products Guidance for Industry.