In Vitro Considerations for Development Abuse Deterrent Dosage Forms Presentation to AAPS Annual Meeting Nov 3, 2014 Nagesh Bandi, Ph.D. Global CMC New Products Pfizer Inc. 1
Disclaimer The thoughts and opinions expressed here are those of the author alone and do not necessarily reflect the views of Pfizer. 2
Presentation Outline History of the Development of Abuse-Deterrent Opioid Formulations Burden of Opioid Use and Misuse Commercial landscape Regulatory pathways for approval Measuring the Impact of Formulations Incorporating Abuse Deterrent Approaches FDA draft guidance In vitro Aspects Regulatory Expectations In vitro considerations: Preapproval vs post approval What is available and where are the gaps FDA Feedback examples Summary and Conclusions
Prescription Drug Abuse: A Global Epidemic Prescription drug abuse is the fastest rising drug abuse category in the US, second only to cannabis (ONDCP Drug Control Strategy 2011). Prescription drug abusers increased from 14.7 (2011) to 16.7 million in 2012 (NSDUH 2012) According to DEA (2011), 17 of the top 25 drugs examined by forensic laboratories, are available as prescription drugs (DEA, NFLIS, 2011 mid year report) Prescription drugs do not fall under the cloud of illegal drugs such as heroin, ecstasy or methamphetamine Availability for Prescription drugs is high due to the development of new products and increased sales Why Prescription Drug Abuse??? Drugs are FDA approved Drugs are frequently obtained free of cost, over 70 percent of opioid abusers get them from friends or relatives 4
Methods and Routes of Abuse Physical Multiple doses Heating or cutting patches Particle size reduction Chewing Grinding hammer, coffee grinder, kitchen utensils Extraction Solvent extraction to remove excipients or additives and/or concentrate active ingredient Oral Smoking IV Snorting 5
Opioid Abuse: Strategies to Stop the Epidemic Jan, 2013 6
Abuse-deterrent Formulations: Part of FDA Efforts to Confront Prescription Drug Abuse and Misuse Improving the use of opioids through careful and appropriate regulations Improving the use of opioid through education of prescribers and patients Improving the safe use of opioids through partnership and collaboration Improving the use of opioids through improved science Jan, 2013 7
Attributes of ADF Products What is deterrent??: thing that discourages or is intended to discourage someone from doing something. Goal of ADF products: To limit access or attractiveness of the highly desired active ingredient for abusers while assuring these products release the medication as designed to insure efficacy and safety for patients. MR Attributes Abuse deterrent formulation (ADF) products must have all of the attributes of the non-adf dosage ADF Attributes form Compendial and/or GRAS inactive ingredients Physicochemical/biopharmaceutical stability Robust and efficient manufacturing process ADF products deter abuse and DO NOT eliminate abuse 8
Abuse Deterrent Formulations FDA has identified 6 approaches to AD formulations (ADF) Physical/Chemical barrier Agonist/Antagonist combinations Aversion Delivery System Depot injectable and sustain release implants Controlled Packaging (films and solutions) Pro-drug Combinations Multiple opioids reformulated with abuse deterrent characteristics have been marketed or are under development
Abuse-Deterrent Opioid Formulations: Commercial Products Physicochemical Barrier Physical barriers conferring resistance to tablet tampering(crushing, chewing or dissolving); and imparting viscosity to prevent intravenous abuse OxyContin; Oxycodone HCl; ER Xartemis; Oxycodone HCl/APAP; ER Opana; Oxymorphone HCl; ER Polyethylene oxide matrix (e.g., OxyContin*, Opana ER) * products with ADF label according to the current FDA Draft Guidance on ADF 10
Commercial Products agonist/antagonist combinations Combining an opioid agonist with an antagonist. The antagonist may be sequestered, and not released in a concentration that produces a clinical effect unless the product is tampered Targiniq ER; Oxycodone/Naloxone Embeda; Morphine Sulphate/Naltrexone; ER Suboxone; buprenorphine/naloxone Combination with available naloxone (e.g. Targiniq*; Suboxone) Bead formulation with sequestered naltrexone (e.g., Embeda*) * products with ADF label according to the current FDA Draft Guidance on ADF Commercial Products Aversion Oxecta; Oxycodone HCl; IR 11
Abuse-Deterrent Opioid Formulations Draft Guidance: Highlights Outline how FDA will evaluate studies Review focus will be on rigor and consistency of studies and analyses Outline potential claims in labeling of abuse-deterrence based on data Pre-marketing Studies Laboratory Manipulation and Extraction Studies (Category 1) Pharmacokinetic Studies (Category 2) Clinical Abuse Potential Studies (Category 3) Post-marketing studies (Category 4) Labeling Tier 1: Claims Product is Formulated with Physicochemical Barriers to Abuse Tier 2: Claims Product is Expected to Reduce or Block the Effect of the Opioid When the Product is Manipulated Tier 3: Claims Product is Expected to Result in a Meaningful Reduction in Abuse Tier 4: Claims Product has Demonstrated Reduced Abuse in the Community 12
Category 1 Studies Overview 13
Abuse-Deterrent Opioid Formulations: In Vitro Evaluation Physico-chemical properties of API Formulation properties Abuse patterns Initial laboratory evaluations Extractability Syringeability & injectability Inhalation Free base isolation Initiation Exploration Physical manipulation processes Extractability Condition effects Test variance Define strengths Define weaknesses Need for further test? Execution Iteration Adherence to guidance provides orderly R&D pathway and decision framework Laboratory assessments must be tailored to API, formulation, and abuse deterrent platform Experimental designs should be dynamic in nature and explore strengths and vulnerabilities Wise choices Flexible, adaptive, approach Iteration when necessary Develop written protocols that produce statistically valid, reproducible results Include related comparator product Include controls and statistical procedures
Laboratory Manipulation and Extraction Studies Preparation for abuse by: Oral (Swallowing) Chewing Intravenous Injection Insufflation (Snorting) Inhalation (Smoking) Mechanical Manipulation Extractability and Solubility Manipulation (test or comparator) Evaluate Ease of Manipulation - Crush, Cut, Grate, or Grind. Use a variety of tools: Pill Crusher, Hammer, Cutters, Mortar/Pestle, Grinders Evaluate the Size of the Resulting Particles/Pieces Resulting Powders Particle Size Distribution Analysis Extraction (test or comparator) Common Solvents Should be based on polarity attributes. Solvents with Relevant Characteristics (e.g., ph, polarity) Buffers Conditions for Extraction temperature, ph, agitation. time
Route Specific Studies Intravenous (injectability) Referred to as Syringeability and Injectability Studies Ability to prepare an injectable solution (i.v. abuse) Suggested Conditions: Intact, Cut, and Ground (product and comparator) Water as solvent Small Volumes (1-5 ml) effects of extraction time, temperature, & agitation Suggested Data : injection volume & Amount of opioid in the injection volume Snorting (Insufflation) Particle Size Achieved With Manipulation Volume of Crushed/Ground Material Concentration of Opioid in Powder Gelling on Contact With Water (Moisture) Inhalation (Smoking) Vaporization Temperature for Salt and Base Degradation Temperature for Salt and Base Vaporization of Opioid (Product & Comparator) Ease of Converting Salt to a Base (acid/base extraction) 16
In Vitro Study Design/Protocol Agency/Sponsor Key Discussion Topics What are the appropriate comparators? Other ADFs equivalent or better IR formulation (better?) Multiple conditions for injection Limited to water/saline Shaking, intact/cut/crushed tablets Minutes to hours, customized to product attributes Extraction Common solvents with different characteristics Test to plateau or failure Standardization of in vitro testing In-house testing vs 3 rd party? 17
In Vitro Evaluation - Remoxy (Original) vs. OxyContin (Original) Ref: Zamloot et al; J Applied Res; 10(3) 2010 Household Solvents Aqueous buffers Frozen/Crushed/Household Solvents Volatilization Compared to Comparator (Original OxyContin), Remoxy Exhibits Superior Abuse Deterrent Attributes 18
Abuse-deterrent Products - FDA Feedback IR Product Expand the physical manipulation assessment to evaluate the use of a pill crusher, hammer, and knife (cutting) for physically manipulating the product. for several different time periods, such as 0.5, 1, and 2 minutes, to determine particle size distribution. Particle size determination for selecting the grinding methodology to be followed in the intranasal abuse potential studies. chemical extraction studies to assess the potential for intravenous abuse that is syringeability and injectability, using the intact tablet and partially manipulated product. ER Product placing manipulated and intact drug product and comparator in 5-10 ml of water and using extraction times of 1, 5, and 10 minutes out to 30 minutes. effect of water temperature in the 90 C-95 C range. Opioid/Antagonist evaluate the amount of antagonist extracted under every study condition.
Post-Approval (CMC) Considerations - Bridging Abuse Deterrent (AD) Formulations? SUPAC guidance documents (IR and MR) do not consider the impact of CMC changes on the abuse deterrent properties 2013 Draft FDA guidance is targeted for new product approvals Nothing in guidance for post-approval CMC changes Post-approval changes need to be evaluated based on product platform, level of CMC change (minor/moderate/major), and impact on AD properties Need to closely examine what critical attributes to evaluate during (CMC) change process Product platform (antagonist vs physicochemical) Depending on the level of CMC change proposed, in vitro abuse deterrent studies may not be adequate to bridge the equivalence (preand post-change) 20
Summary and Take-home Messages Developing products with meaningful abuse-deterrent properties is an enormous challenge from a pharmaceutical perspective, to deliver on two opposing goals Desired drug release profile Prevent the release of the opioid agent No dose dumping in ethanol Release rate Abuse deterrence Understanding the properties of the active drug substance and finished drug product design are very critical in designing route-specific in vitro studies Rigor and consistency of in vitro studies and analyses is important for label and also the design of category 2 and 3 studies seek agency feedback on the protocol design and rationale US draft guidance (2013, ADF) provides direction for preapproval phase Need to carefully evaluate how post approval CMC changes should be bridged for abuse deterrence? w/o impacting the label claims. 21
Acknowledgements Pfizer In vitro Working Group Global CMC Leadership AAPS 22
Questions??? 23