General Principles for 
Evaluating the Abuse 
Deterrence of  
Generic Solid Oral 
Opioid Drug Products
 
Guidance for Industry 
   
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration  
Center for Drug Evaluation and Research (CDER)  
 
November 2017 
Generics 
 
  General Principles for 
Evaluating the Abuse 
Deterrence of 
Generic Solid Oral 
Opioid Drug Products 
Guidance for Industry 
 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information, 
Center for Drug Evaluation and Research, 
Food and Drug Administration, 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor, 
Silver Spring, MD 20993-0002 
Phone:  855-543-3784 or 301-796-3400; Fax:  301-431-6353 
druginfo@fda.hhs.gov  http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.ht
m 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2017 
Generics 
 
 
 
  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
 
I. INTRODUCTION .............................................................................. 4
   
II. BACKGROUND ................................................................................ 4
   
III. ABUSE DETERRENCE OF GENERIC SOLID ORAL 
 
OPIOID DRUG PRODUCTS .......................................................... 5
 
IV. GENERAL PRINCIPLES FOR EVALUATING THE ABUSE 
 
DETERRENCE OF GENERIC SOLID ORAL OPIOID 
DRUG PRODUCTS .......................................................................... 7
 
V. ROUTES OF ABUSE ........................................................................ 8
   
VI. COMPARATIVE IN VITRO STUDIES ......................................... 9
   
VII. COMPARATIVE IN VIVO STUDIES .......................................... 10
   
Comparative PK Studies ............................................................................................. 10 
Other Studies .............................................................................................................. 12 
VIII.STATISTICAL ANALYSIS ........................................................... 12
   
IX. ADDITIONAL STUDIES ............................................................... 14
   
Appendix 1:  Physical Manipulation and Extractability ...................... 15
 
Physical Manipulation ............................................................................................... 15 
Extractability ............................................................................................................... 17 
Appendix 2:  Abuse by Ingestion (oral route) ....................................... 23
 
Appendix 3:  Abuse by Injection (parenteral route) ............................ 24
 
Appendix 4: Abuse by Insufflation (nasal route) .................................. 26
 
Reduced Bioavailability .............................................................................................. 26 
Reduced Human Abuse Potential .............................................................................. 29 
Appendix 5: Abuse by Smoking (inhalation route) .............................. 31
 
  Contains Nonbinding Recommendations 
 
General Principles for Evaluating the Abuse Deterrence of 
Generic Solid Oral Opioid Drug Products 
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on 
FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA 
office responsible for this guidance as listed on the title page.  
 
 
I.  INTRODUCTION  
This guidance is intended to assist a person who plans to develop and submit an abbreviated 
new drug application (ANDA) (hereinafter potential ANDA applicant) to seek approval of a 
generic version of a solid oral opioid drug product that references an opioid drug product 
with abuse-deterrent properties described in its labeling.  The guidance recommends studies, 
including comparative in vitro and pharmacokinetic (PK) studies, that the potential ANDA 
applicant should conduct and submit to FDA in an ANDA to demonstrate that a generic solid 
oral opioid drug product is no less abuse deterrent than its reference listed drug (RLD) with 
respect to all potential routes of abuse.   
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed 
only as recommendations, unless specific regulatory or statutory requirements are cited.  The 
use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
II.  BACKGROUND 
Prescription opioid analgesics are an important component of modern pain management.  
However, abuse and misuse of these drug products have created a serious and widespread 
public health problem.  One potentially important step toward the goal of creating safer 
opioid analgesics has been the development of opioid drug products with abuse deterrent 
properties.  FDA considers development of these products a high public health priority. 
                                                 
1 This guidance has been prepared by the Office of Generic Drugs, with the assistance of the Office 
Pharmaceutical Quality, in the Center for Drug Evaluation and Research at the Food and Drug Administration. 
4  Contains Nonbinding Recommendations 
 
On April 1, 2015, FDA published in the Federal Register a notice of availability for its final 
guidance, Abuse-Deterrent Opioids  Evaluation and Labeling (80 FR 17765).2  For 
 
purposes of that guidance, abuse-deterrent properties are defined as those properties shown 
to meaningfully deter abuse, even if they do not fully prevent abuse.  The term abuse is 
defined in that guidance as the intentional, nontherapeutic use of a drug product or substance, 
even once, to achieve a desired psychological or physiological effect.3  Abuse is not the same 
as misuse, which refers to the intentional therapeutic use of a drug product in an 
inappropriate way and specifically excludes the definition of abuse.4  Because opioid drug 
products must, in the end, be able to deliver the opioid to the patient, there may always be the 
potential for some abuse of these products.  Further, products with abuse-deterrent properties 
do not prevent addiction; opioid analgesics, even when taken as recommended, can result in 
addiction.   
It is important that less costly generic versions of opioids that reference RLDs whose labeling 
describes abuse-deterrent properties are available to ensure access to safe and effective 
analgesics for patients who need them.  However, it is also important that the availability of 
such generics does not exacerbate the public health problems associated with opioid abuse.  
Where abuse-deterrent properties are described in the labeling of an RLD, marketing a 
generic version of the RLD that is less abuse deterrent could lead opioid abusers to 
preferentially seek out and abuse such easier-to-abuse generics.   
The Abuse-Deterrent Opioids  Evaluation and Labeling guidance describes seven 
categories of abuse-deterrent technologies  physical/chemical barriers, agonist/antagonist 
combinations, aversion, delivery system, new molecular entities (NMEs) and prodrugs, 
combinations, and novel approaches.  This guidance focuses on the general principles for 
developing and evaluating the abuse deterrence of generic solid oral opioid drug products 
formulated to incorporate physical or chemical barriers, agonist/antagonist combinations, 
aversive agents, or a combination of two or more of these technologies.  It does not provide 
testing recommendations for generic versions of opioid drug products incorporating other 
technologies (i.e., delivery system, NME/prodrug, or novel approaches), but FDA may 
provide such testing recommendations in future product-specific guidance.  Further, FDA 
will continue to assess the state of science and, as novel technologies develop, will address 
them by issuing additional guidance, as appropriate. 
III.  ABUSE DETERRENCE OF GENERIC SOLID ORAL OPIOID DRUG 
PRODUCTS 
For FDA to approve an ANDA, the Agency generally must find, among other things, that the 
generic drug5 has the same active ingredient(s), conditions of use, dosage form, route of 
                                                 
2 For the most recent version of any guidance referenced in this document, check the FDA Drugs guidance web 
page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
3 Smith SM, Dart RC, Katz NP, et al. Classification and definition of misuse, abuse, and related events in 
clinical trials:  ACTTION systematic review and recommendations. Pain 2013;154:2287-2296. 
4 Ibid. 
5 Throughout this guidance, we use the term generic drug to refer to a new drug product described in an ANDA 
submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)). 
5  Contains Nonbinding Recommendations 
 
administration, strength, and (with certain permissible differences) labeling as the RLD; it is 
bioequivalent to the RLD; the methods used in, and the facilities and controls used for, the 
manufacture, processing, and packing of the drug are adequate to assure and preserve its 
identity, strength, quality, and purity; and the inactive ingredients and composition of the 
generic drug are not unsafe under the conditions of use prescribed, recommended, or 
suggested in the labeling.6 
FDA considers a generic drug to be therapeutically equivalent to its RLD when certain 
conditions are met.  Therapeutic equivalents are approved drug products that are 
pharmaceutical equivalents for which bioequivalence has been demonstrated and that can be 
expected to have the same clinical effect and safety profile.7  With certain limitations, FDA 
believes that products classified as therapeutically equivalent can be substituted with the full 
expectation that the substituted product will produce the same clinical effect and safety 
profile as the prescribed product/RLD.8     
When a potential ANDA applicant develops a generic solid oral opioid drug product, the 
applicant should review the approved labeling for the RLD, particularly the information 
presented in the DRUG ABUSE AND DEPENDENCE section under 9.2 Abuse.  If the 
summary in section 9.2 indicates that FDA has concluded that the product has properties that 
are expected to (or have been shown through postmarketing studies or trials to) deter abuse, 
in addition to other testing that may be needed to support the ANDA, the potential ANDA 
applicant should evaluate its proposed generic drug to show that it is no less abuse deterrent 
than the RLD with respect to all of the potential routes of abuse.9  This will ensure the 
generic drug is no less abuse deterrent than the RLD with respect to all potential routes of 
abuse and minimize the risk of shifting abuse to other, potentially more dangerous, routes.   
The data from in vitro and in vivo studies conducted to evaluate the abuse deterrence of a 
proposed generic product should be included in Module 3.2.P.2 and Module 5, respectively, 
of the Common Technical Document in an ANDA submission.10 
FDA intends to consider the totality of the evidence when evaluating the abuse deterrence of 
a generic solid oral opioid drug product.  That is, FDA intends to consider all of the evidence 
presented in the ANDA including, but not limited to, study type, methodological and design 
quality, number of studies of each type, sample sizes, relevance of the evidence, replication 
of results, and overall consistency of the evidence.  
                                                 
6 See section 505(j)(2)(A) and (j)(4) of the FD&C Act. 
7 See 21 CFR 314.3(b). 
8 Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book), preface at vii. 
9 For questions related to evaluating an RLDs abuse deterrence, the potential ANDA applicant may seek the 
Agencys input through submission of controlled correspondence to the Office of Generic Drugs.  See FDAs 
guidance for industry on Controlled Correspondence Related to Generic Drug Development.   
10 For additional information regarding the information that should be provided in an ANDA submission, refer 
to the draft guidance for industry, ANDA Submissions  Content and Format of Abbreviated New Drug 
Applications. 
6  Contains Nonbinding Recommendations 
 
IV.  GENERAL PRINCIPLES FOR EVALUATING THE ABUSE DETERRENCE 
OF GENERIC SOLID ORAL OPIOID DRUG PRODUCTS  
In this guidance, a proposed generic solid oral opioid drug product is referred to as Test (T) 
product and its respective RLD as Reference (R) product.  If the labeling for R product 
does not describe any abuse-deterrent properties, the testing recommendations in this 
guidance are not applicable.  Where the labeling for R product describes properties expected 
to deter abuse, a comparative evaluation of the abuse deterrence of T product relative to R 
product for all potential routes of abuse should be conducted according to the following 
general principles:  
  Tier-based approach to testing.  FDA recommends that potential ANDA applicants 
follow a tier-based approach to efficiently compare a T product to its R product and 
limit the number of tests required for evaluating the abuse deterrence of T product.  A 
tier refers to manipulations of similar complexity, difficulty, and effort that may be 
used by an abuser to release the opioid drug substance.  Each subsequent tier 
increases the complexity, difficulty, or effort of manipulation that may be used.  Thus, 
this tier-based approach allows for hierarchical testing, evaluating abuse-deterrent 
properties under progressively more challenging conditions.  
  Performance-based evaluation of abuse deterrence.  The evaluation of the abuse 
deterrence of T product should be based on its performance relative to R product.  
The proposed generic drug need not have the same formulation design as R product.  
The evaluation of the abuse deterrence of T product for each potential route of abuse 
should be based on the potential ANDA applicants best understanding of the abuse 
deterrence of R product for that route, the particular potential route of abuse being 
evaluated, and the use of specific measures meaningful to the evaluation of abuse by 
that route.  For example, the measure that is expected to be the most meaningful for 
evaluation of abuse by injection is the percentage of opioid drug substance extracted 
from the product under various test conditions (see Appendices 1 and 3). 
  Most effective manipulation.  FDA recommends that a potential ANDA applicant 
identify the most effective manipulation conditions for T and R products before 
comparing them.  Appendix 1 provides recommendations for physical manipulations 
that may be used to evaluate the abuse deterrence of solid oral opioid drug products 
and recommendations for selecting the most effective physical manipulation to use on 
the drug products tested in each relevant tier. 
  Sample selection after physical manipulation.  A potential ANDA applicant should 
select an appropriate sample before conducting comparative in vitro studies.  At a 
minimum, the two extreme forms of a drug product (i.e., the intact and most 
effectively manipulated form) should be selected for evaluation in each relevant tier.  
Further recommendations regarding sample size are discussed in section VIII.  
  Comparing T and R products in extraction studies.  FDA recommends that a 
potential ANDA applicant conduct extraction studies to assess the particular 
7  Contains Nonbinding Recommendations 
 
vulnerabilities of T and R products to inform the comparison of their abuse 
deterrence.  Appendix 1 provides recommendations for extraction studies.  For each 
solvent within a given tier, the potential ANDA applicant should first identify 
whether the most effectively manipulated R product has an observable reduction in 
drug extraction.  If the drug extraction of R product is greater than or equal to 50 
percent in 30 minutes in any solvent within the tier, R product is considered to have 
no abuse deterrence for purposes of that tier of testing, and no further testing to 
compare T and R products is recommended.  Otherwise, the most effectively 
manipulated T product should be compared to the most effectively manipulated R 
product for each solvent within a tier.  Then, the maximum percent extraction of 
opioid drug substance from T product should be compared with the maximum percent 
extraction of opioid drug substance from R product in each solvent.  
  Statistical comparison of T and R products.  Section VIII provides general 
recommendations for conducting statistical analyses.   
The general principles outlined in this section are applicable to all generic solid oral opioid 
drug products within the scope of this guidance.  This testing is in addition to other testing 
that may be needed to support ANDA approval.  FDA may issue product-specific guidances, 
as appropriate, that provide more detailed recommendations for conducting in vitro testing, 
PK testing, or other studies or may issue guidances that provide more detailed 
recommendations for conducting testing to evaluate specific abuse-deterrent technologies.  
Potential ANDA applicants may pose questions regarding evaluation of the abuse deterrence 
for a generic solid oral opioid drug product through FDAs pre-ANDA program.  The goals 
of the pre-ANDA program are to clarify regulatory expectations for prospective applicants 
early in the development process, assist applicants in developing complete submissions, 
promote a more efficient and effective ANDA review process, and reduce the number of 
review cycles required to obtain ANDA approval, particularly for complex products.  FDA 
considers abuse-deterrent opioids to be products that fall within the definition of complex 
product.11  The pre-ANDA program provides for, among other things, submission of 
controlled correspondence and requests for formal meetings between FDA and applicants on 
complex generic drug development issues.12 
V.  ROUTES OF ABUSE  
If the summary in section 9.2 of the RLD labeling indicates that FDA has concluded that the 
RLD has properties that are expected to (or have been shown through postmarketing studies 
or trials to) deter abuse, in addition to other testing that may be needed to support an ANDA, 
                                                 
11 Complex product is defined in the GDUFA Reauthorization Performance Goals and Program Enhancements 
Fiscal Years 2018-2022 (commonly referred to as the GDUFA II Goals letter), which can be found at 
https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM525234.pdf.  Among other 
things, complex product generally includes ...products where complexity or uncertainty concerning the 
approval pathway or possible alternative approaches would benefit from early scientific engagement. 
12 See FDAs guidances for industry Controlled Correspondence Related to Generic Drug Development and 
Formal Meetings Between FDA and Applicants of Complex Generic Drug Products under GDUFA. 
8  Contains Nonbinding Recommendations 
 
an ANDA applicant should evaluate the abuse deterrence of its proposed generic solid oral 
opioid drug product for all of the potential routes of abuse: 
  Ingestion (oral route)evaluate oral bioavailability of physically manipulated or 
chewed products, as described in section VII and Appendix 2. 
  Injection (parenteral route)evaluate the extractability and syringeability of intact 
and manipulated products, as described in Appendix 3. 
  Insufflation (nasal route)evaluate the nasal bioavailability and pharmacodynamic 
(PD) effects (i.e., human abuse potential) of manipulated and insufflated products, as 
described in section VII and Appendix 4. 
  Smoking (inhalation route)evaluate the ability to sublimate intact and 
manipulated products, as described in Appendix 5. 
VI.  COMPARATIVE IN VITRO STUDIES 
FDA recommends that potential ANDA applicants follow a tier-based approach to efficiently 
compare the abuse deterrence of T product to R product in in vitro studies.  Appendix 1 
provides recommendations for physical manipulations that may be used to evaluate the abuse 
deterrence of solid oral opioid drug products and recommendations for selecting the most 
effective physical manipulation to use on the drug product tested in the tiers.  In addition, 
Appendix 1 provides recommendations for extraction studies using different levels of 
solvents to assess the particular vulnerabilities of T and R products to inform the comparison 
of their abuse deterrence.   
FDA recommends the following levels of solvents be used in different tiers of comparative in 
vitro extraction studies (Appendix 1): 
  Level 1 solvent:  deionized water 
 
  Level 2 solvents:  commercially available food-grade vinegar, 0.2% baking soda 
solution, 40% ethanol, and carbonated drink  
  Level 3 solvents:  100% ethanol, 100% isopropyl alcohol, acetone, 0.1 N HCl, and 
0.1 N NaOH 
Potential ANDA applicants may use other solvents in addition to those described above or a 
combination of solvents and are encouraged to seek the Agencys input on additional testing 
suitable for product-specific development.  
A potential ANDA applicant seeking approval of more than one strength of a generic solid 
oral opioid drug product should evaluate and compare T product against R product for each 
of the strengths in any in vitro study(ies).  Alternatively, the potential ANDA applicant 
should provide supportive data to demonstrate compositional proportionality across different 
strengths of T and R products or other justification as may be appropriate for not conducting 
9  Contains Nonbinding Recommendations 
 
studies to evaluate T product against R product for all strengths in the in vitro studies.  When 
such justification is provided, a bracketing design covering the extremes of the ratios of 
opioid drug substance to excipients that contribute to the abuse deterrence should be applied 
to in vitro evaluation studies.13  
VII.  COMPARATIVE IN VIVO STUDIES 
Comparative PK Studies 
PK studies to evaluate the abuse deterrence of T product in comparison to R product should 
be conducted in cases in which no reliable in vitro testing methodologies exist or when in 
vitro testing methodology is overly sensitive or cannot adequately assess the abuse deterrence 
of T product relative to R product.  For example, PK studies may be recommended to 
compare the abuse deterrence of T and R products for the nasal and oral routes because no 
reliable in vitro testing currently exists that can adequately assess abuse deterrence by those 
routes.  The potential ANDA applicant may seek the Agencys input on the PK study design 
before conducting the study.  FDAs recommendations for conducting comparative PK 
studies for various routes of abuse follow.   
 
  Nasal PK study:  If in vitro testing suggests that T product is no less resistant to 
physical manipulation than R product and both T and R products can be pulverized to 
a particle size range that is considered safe and tolerable for human insufflation 
studies, the Agency generally recommends that a nasal PK study be conducted using 
the same dose that was used in in vitro testing to evaluate the nasal abuse deterrence 
of the R product.  A potential ANDA applicant should characterize the particle size 
distribution of physically manipulated T and R products used in the nasal PK study 
using an appropriate procedure.  A nasal PK study should be conducted in 
recreational opioid users.  The nasal PK study should incorporate naltrexone or other 
opioid antagonist to block the PD effects of the opioids except for the 
agonist/antagonist combination products.  The recommended PK parameters for the 
opioid drug substance and any metabolites (if recommended for measurement in the 
product-specific guidance) include maximum concentration (C ), time to maximum 
max
concentration (T ), and area under the curve (AUC  and AUC ).  A potential 
max (0-t) (0-)
ANDA applicant should also determine the partial AUCs (p-AUCs), e.g., in the case 
in which there is a clear relationship between the truncated partial area in the PK 
profiles at specific time points and a clinically relevant PD measure (e.g., likability or 
take-drug-again).   
 
  Oral PK study:  FDA recommends an oral PK study (e.g., chewed) be conducted on 
manipulated products if the summary in section 9.2 of the RLD labeling indicates that 
FDA has concluded that the product has properties that are expected to deter abuse by 
the oral route (e.g., Drug X is expected to reduce  . . . oral abuse when chewed.) or 
FDA otherwise recommends such a study in product-specific guidance.  Such studies 
                                                 
13 For additional information regarding bracketing design, refer to the guidance for industry, Bioequivalence 
Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA. 
10  Contains Nonbinding Recommendations 
 
should be designed to compare the PK profile of the orally administered T product to 
that of the R product when physically manipulated (e.g., cut, grated, or milled) or 
chewed.  A potential ANDA applicant should ensure that a suitable level of physical 
manipulation(s) or chewing has been applied to both T and R products to achieve the 
maximum percent extraction of opioid drug substance for T product and the 
maximum percent extraction of opioid drug substance for R product.  For an oral PK 
study of physically manipulated products, T and R products should be physically 
manipulated (e.g., cut, grated, or milled) into a particle size range that can 
discriminate between T products and R products ability to deter abuse.  For an oral 
chewing PK study, patient-relevant chewing conditions (e.g., 10 minutes) should be 
identified.  
 
Oral PK studies should compare the rate and extent of absorption of physically 
manipulated or chewed and ingested drug products in healthy volunteers.  Oral PK 
studies should incorporate naltrexone or other opioid antagonist to block the PD 
effects of the opioids except for the agonist/antagonist combination products.  The 
recommended PK parameters for the opioid drug substance and any metabolites (if 
recommended for measurement in the product-specific guidance) include C , T , 
max max
AUC , and AUC .  A potential ANDA applicant should also determine p-AUCs, 
(0-t) (0-)
e.g., in the case in which there is a clear relationship between the truncated partial 
area in the PK profiles at specific time points and a clinically relevant PD measure 
(e.g., likability or take-drug-again). 
 
  Agonist/antagonist combination:  For any agonist/antagonist combination product, 
both the agonist and the antagonist, along with their metabolites (if recommended for 
measurement in the product-specific guidance), should be measured in a PK study.  
Appropriate bioanalytical methods should be developed to measure the concentration 
of both the agonist and the antagonist in the PK study.  The oral PK study should be 
conducted to demonstrate that minimal antagonist absorption occurs when fully intact 
agonist/antagonist combination products are orally administered.  When an oral PK 
study on the physically manipulated or chewed agonist/antagonist combination 
product is recommended, the oral PK study should compare both agonist and 
antagonist levels from manipulated T and R products to confirm that the antagonist is 
sequestered within the formulation and released upon physical manipulation or 
chewing followed by oral ingestion.  Appropriate methods should be used to 
manipulate both T and R products to obtain the maximum percent extraction of 
opioid drug substance for R product and the maximum percent extraction of opioid 
drug substance for T product, based on extraction studies (Appendix 1).  In addition, 
if T and R products can be manipulated into fine particles (Appendix 4), the potential 
ANDA applicant generally should conduct a human insufflation PK study, 
administering physically manipulated T and R products in recreational opioid users, 
and measure both the agonist and the antagonist, along with their metabolites, if 
recommended in the product-specific guidance (Appendix 4). 
 
  Multiple strengths:  When PK studies are conducted to evaluate the abuse deterrence 
of T product in comparison to R product for approval of more than one strength of a 
11  Contains Nonbinding Recommendations 
 
proposed generic solid oral opioid drug product, the strength(s) selected for the PK 
studies should be based on the strength(s) used to evaluate the R products abuse 
deterrence.  Clinical abuse potential studies conducted to evaluate the abuse 
deterrence for new drug applications submitted under section 505(b) of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b)) are generally 
conducted using an intermediate strength.  If the labeling for the R product does not 
identify the strength(s) tested, FDA intends to provide recommendations in a product-
specific guidance. 
 
 Other Studies 
For generic drugs, comparative in vitro and PK studies generally provide sufficient evidence 
to demonstrate that T product is no less abuse deterrent than R product.  Other studies are 
generally not recommended, except in certain circumstances in which such studies may be 
needed to establish that a generic product can rely on the finding of safety and effectiveness 
for the RLD.  For example, where R product contains a known aversive agent and T product 
contains a different aversive agent, FDA may recommend that the potential ANDA applicant 
conduct a PD study to compare human abuse potential (e.g., willingness to take the drug 
again) between T product and R product.  Potential ANDA applicants are encouraged to seek 
the Agencys input on study design before conducting such studies.   
VIII.  STATISTICAL ANALYSIS   
Potential ANDA applicants should use inferential analyses to evaluate the abuse deterrence 
of T product versus R product.  A non-inferiority approach should be taken when comparing 
T product with R product to conclude that T product is no less abuse deterrent than R 
product. In the analyses recommended in this guidance, a hierarchical set of null hypotheses 
serves as a gatekeeper for subsequent null hypotheses, evaluating the abuse deterrence of T 
and R products under progressively more challenging conditions.  A hierarchical inferential 
approach is used to maintain a fixed family-wise experiment Type 1 error rate. Typically, the 
acceptable Type I error probability () will be set at 5 percent.   
Tiers, defined by the complexity, difficulty, and effort of manipulations, start with the 
mildest set of manipulations in Tier 1.  Tier 1 serves as a serial gatekeeper for the subsequent 
tiers.  All the null hypotheses within Tier 1 should be rejected prior to testing the null 
hypotheses in the next tiers, which are defined by a relevant parameter describing T or R 
product (e.g., the percent of opioid drug substance extracted from T or R product in 
extraction studies) under progressively more challenging conditions.  In Tier 1, all the null 
hypotheses are evaluated at the Type I error level of  without adjusting for the number of 
hypotheses; this follows from the closed testing principle.   
12  Contains Nonbinding Recommendations 
 
With tiers (sets) labeled T , T , T , etc., and arranged hierarchically (i.e., in strictly 
1   2 3
increasing order), T  (j > 1) is tested only if all null hypotheses in the preceding tiers have 
j
been rejected by their within-tier -level tests.  From the closed testing principle, it follows 
that this partially ordered procedure controls the -level for all null hypotheses in the tiers T ,
1  
T , T , etc. (Maurer et al.14). 
2 3
Dmitrienko et al.15 further generalized this hierarchical testing procedure.  They proposed 
tree-structured gatekeeping tests that rely on a decision tree with multiple branches 
corresponding to multiple objectives within a tier.  This approach could be used, for example, 
in evaluating extractability, where the effects of solvents at elevated temperature are of 
interest distinct from those at room temperature. 
 
For example, to evaluate the extractability of opioid drug substance from T product and R 
product using this tier-based approach, a potential ANDA applicant should first find and use 
the most effective physical manipulation for R product and evaluate the percent extraction of 
opioid drug substance from R product in each solvent within the tier.  If at 30 minutes the 
percent extraction of opioid drug substance from R product is statistically less than 50 
percent (Type I error = 0.05) in all solvents for the extraction studies, the potential ANDA 
applicant should evaluate whether or not the maximum percent extraction of opioid drug 
substance from T product in each solvent is greater than or equal to maximum percent 
extraction of opioid drug substance from R plus 10 percent in the same solvent, 10 percent 
being an absolute margin (e.g., if the percent of opioid drug substance extracted from R 
product is 25 percent, the percent extracted from T product must be less than 35 percent). 
 
When abuse deterrence is evaluated by comparing the percent of opioid drug substance 
extracted from a product, if the percent of opioid drug substance extracted from T product is 
statistically greater than or equal to the percent of opioid drug substance extracted from R 
plus 10 percent in any of the solvents within the tier, then T product is considered to be less 
abuse deterrent than R; thus, T product will not be tested further.  In contrast, if the percent of 
opioid drug substance extracted from T product is statistically less than the percent of opioid 
drug substance extracted from R plus 10 percent in all the solvents within the tier, the abuse 
deterrence of T product is then evaluated in the next tier.  The percent of opioid drug 
substance extracted from T product must be less than the percent of opioid drug substance 
extracted from R plus10 percent for each set of study conditions for which it is evaluated in 
order to claim it is no less abuse deterrent than the corresponding R product (see Tables 1 and 
2 in the appendices for more detail). 
All inferential comparisons involve the mean of the measure of the abuse deterrence or a 
function of the mean (e.g., the mean of T product minus the mean of R product).  The 
inferential tests used to evaluate the hypotheses are left to the discretion of the potential 
ANDA applicant.  In general, FDA recommends conducting all in vitro tests using 6 units 
                                                 
14 Maurer W, Hothorn LA, Lehmacher W.  Multiple comparisons in drug clinical trials and preclinical assays:  
A-priori ordered hypotheses. Biometrie in der Chemisch-pharmazeutischen Industrie. 1995;6:3-18. 
15 Dmitrienko A, Wiens BL, Tamhane AC, Wang X. Tree-structured gatekeeping tests in clinical trials with 
hierarchically ordered multiple objectives. Stat Med. 2007;26(12):2465-2478. 
13  Contains Nonbinding Recommendations 
 
(e.g., tablets or capsules) of each T and R product.  The potential ANDA applicant may 
propose a different sample size if the applicant can provide justification that such sample size 
allows for accurate characterization of the mean.  FDA recommends that the potential ANDA 
applicant develop an analysis plan that has contingencies for various scenarios (e.g., data that 
are not normally distributed and data that are left-censored (i.e., values below the limit of 
quantification)).  
Tables 1 and 2 found in the appendices guide potential ANDA applicants through the 
recommended series of study conditions and statistical analyses for extractability and abuse 
by smoking (sublimation), respectively.  As the first step in each tier, the potential ANDA 
applicant should identify the most effective physical manipulations and compare R product to 
a constant (in the case of extractability, see Appendix 1) or R product directly to T product 
(in the case of sublimation).  If the percent of opioid drug substance extracted from R product 
is less than a constant in case of extractability, the testing should continue to the second step 
within that tier.  If, at the end of the second step, it is possible to conclude that T product is 
no less abuse deterrent than R product, then testing of T product should move on to the next 
tier.  This process continues for the remaining tiers within a table until:  
  The percent extraction of opioid drug substance from R product is greater than or 
equal to the constant in the case of extractability, in which case R product is 
considered to have no abuse deterrence for the route of abuse being tested; or  
  The percent extraction of opioid drug substance from T product is greater than or 
equal to that from R plus 10 percent.  
In order to show that T product is no less abuse deterrent than R product, T product should be 
shown to be non-inferior to R product at each tier for which it is evaluated.  
IX.  ADDITIONAL STUDIES 
There may be instances in which the testing recommended in this guidance cannot adequately 
capture the complete profile for T product because of factors including, but not limited to, 
inclusion of novel inactive ingredients, use of new technology, and formulation design.  In 
such instances, FDA may, as permitted under section 505(j) of the FD&C Act, request that 
additional studies, aside from the ones described in Appendices 2 to 5, be conducted to 
evaluate the abuse deterrence of T product.  As new technologies emerge, FDA intends to 
continue adapting its recommendations for developing and evaluating generic solid oral and 
other opioid drug products formulated to deter abuse to help ensure access to effective 
analgesics for patients who need them. 
14  Contains Nonbinding Recommendations 
 
APPENDIX 1:  PHYSICAL MANIPULATION AND EXTRACTABILITY 
Physical Manipulation 
The extent to which a solid oral opioid drug product can be physically manipulated is a 
function of several factors including, but not limited to, tampering skills, time, and tampering 
resources available.  This appendix describes some of the ways in which solid oral opioid 
drug products can be physically manipulated using readily available household equipment.  
There are additional ways in which products could be physically manipulated (e.g., crushing, 
hammering).  The Food and Drug Administration (FDA) recommends that potential 
abbreviated new drug application (ANDA) applicants use the physical manipulation(s) most 
likely to be used by abusers when they conduct studies to evaluate the abuse deterrence of a 
specific Test (T) product.   
 
Some of the questions that the physical manipulation evaluation should address include:  
 
  What is the degree of difficulty of the manipulation?  
  How successful is each manipulation method in achieving its goal (e.g., 
compromising a tablets integrity)?  
  If the structure of the dosage form is compromised, what are the size and size 
distribution of the resulting particles?  
 
Physical manipulation should be used to gain an understanding of the robustness of the 
abuse-deterrent properties.  To identify the most effective physical manipulation, potential 
applicants should use a relevant endpoint, which may vary based on formulation design.  For 
example, for a tablet dosage form designed to be crush resistant, such an endpoint could be 
the size of the fragment after cutting, grating, or milling.  In this case, the potential applicant 
should provide particle size distribution data to justify the selection of the manipulation 
method.  Particle size for physically manipulated products can be analyzed using techniques 
including, but not limited to, photograph with scale, image analysis, sieve analysis, and laser 
diffraction.  In addition, if deemed useful, the extraction data in deionized water of 
manipulated dosage forms may be used to further justify the selection of the most effective 
physical manipulation that will result in high extraction levels.  
Manipulation by cutting 
As illustrated in Figure 1 below, progressive manipulation by cutting involves: 
  Cutting without thermal pretreatment:  If a drug product can be cut in less 
than 5 minutes at room temperature (RT) into 10 or more small pieces 
using a knife, manipulation with thermal pretreatment (freezing or heating) 
is not needed. 
  Cutting with thermal pretreatment:  If a drug product cannot be cut at RT as 
described above, suitable thermal pretreatment should be developed and 
used.  
15  Contains Nonbinding Recommendations 
 
Cut T and R products into 10 or 
more small pieces using a knife at 
RT
NO Is it possible to cut T and R 
products to the desired size in 
less than 5 min?
Cut T and R products into 10 or 
more small pieces using a knife 
with thermal pre-treatment YES
Subject the physically manipulated products to 
testing
 
Figure 1: Physical Manipulation by Cutting for Solid Oral Opioid Drug Products 
Manipulation by grating  
As illustrated in Figure 2 below, progressive manipulation by grating involves: 
  Grating without thermal pretreatment:  If a drug product can be grated in 
less than 5 minutes at RT to a size less than 1 millimeter (mm) using a 
household grater, manipulation with thermal pretreatment (freezing or 
heating) is not needed. 
  Grating with thermal pretreatment:  If a drug product cannot be grated at 
RT as described above, suitable thermal pretreatment should be developed 
and used.  
Grate T and R products at RT to more 
than 50 wt% of particles having the 
size < 1 mm using a household grater
NO Is it possible to grate T and R 
products to the desired size in less 
than 5 min?
Grate T and R products with 
thermal pre-treatment to 
more than 50 wt% of particles 
having the size < 1mm using a  YES
household grater
Subject the physically manipulated products to 
testing
 
Figure 2: Physical Manipulation by Grating for Solid Oral Opioid Drug Products 
16  Contains Nonbinding Recommendations 
 
Manipulation by milling  
As illustrated in Figure 3 below, progressive manipulation by milling involves: 
  Milling without thermal pretreatment: If a drug product can be milled in 
less than 5 minutes at RT to a size less than 1 mm using a household coffee 
grinder, manipulation with thermal pretreatment (freezing or heating) is not 
needed. 
  Milling with thermal pretreatment: If a drug product cannot be milled at RT 
as described above, suitable thermal pretreatment should be developed and 
used.  
Mill T and R products at RT to more than 
50 wt% of particles having the size < 
1mm using a household coffee grinder
NO Is it possible to mill T and R 
products to the desired size in 
less than 5 min?
Mill T and R products with 
thermal pre-treatment to more 
than 50 wt% of particles having 
the size < 1mm using a 
household coffee grinder YES
Subject the physically manipulated products to 
testing
 
Figure 3: Physical Manipulation by Milling for Solid Oral Opioid Drug Products 
Extractability 
Evaluation of the extractability of physically manipulated opioid drug products   
The potential ANDA applicant should conduct comparative extractability testing on T and 
Reference (R) products to assess the particular vulnerabilities of each product to inform the 
comparison of their abuse deterrence.  Comparative extractability testing should be 
conducted on both the intact and most effectively physically manipulated (e.g., cut, grated, or 
milled) drug products.  To conclude that T product is no less abuse deterrent than R product 
in terms of its extractability, the potential applicant should test the intact and physically 
manipulated T products and show they are no worse than the intact and manipulated R 
products, respectively. 
17  Contains Nonbinding Recommendations 
 
Extractability of the opioid drug substance into large volumes of water or an organic solvent 
may be assessed at RT16 or elevated temperature (ET).17  The focus of the extraction studies 
is to assess the extractability of the opioid drug substance and measure the amount of opioid 
drug substance available in solutions, determined experimentally by measurement of the 
concentration and volume of the extraction media. 
The percent of opioid drug substance extracted is determined as follows:  (CONC*V/labeled 
strength of the R product) *100, where CONC is the concentration of opioid drug substance 
in the extraction medium and V is the volume of the extraction solution.  If R product is an 
agonist/antagonist combination, both the percent of opioid drug substance extracted and the 
ratio of percent of agonist and antagonist extracted should be determined. 
 
Study conditions 
Extractability testing should be conducted for intact and physically manipulated product at 
RT and ET with relevant solvents using the tiered approach.  Some of the ways in which 
solid oral opioid drug products can be physically manipulated are described above.  At a 
minimum, the potential ANDA applicant should compare the intact T and R products and 
most effectively physically manipulated T and R products.    
Because different solvents could be used to extract the opioid drug substance from the opioid 
drug product, all solvents within relevant tiers (see section VI) should be tested to assess 
extractability.  For example, the following range of extraction conditions can be used:  
extraction volume of 240 milliliters (mL), RT or ET for the relevant extraction media, 
duration 30 minutes, with or without stirring. 
The tier-based approach for evaluating extractability is illustrated in Figure 4. The parallel 
tier-based approach (e.g., Tier 1 Tier 2A  Tier 3A and Tier 1  Tier 2B  Tier 3B) to 
the comparative extractability studies is based on using different levels of solvents and 
increasing temperature within the recommended range of study conditions.   
                                                 
16 U.S. Pharmacopoeia (USP) controlled room temperature (20C to 25C). 
17 Boiling temperature of the solvents used.  
18  Contains Nonbinding Recommendations 
 
 
Figure 4: Parallel Tiered Approach for Determining the Extractability of Opioid Drug 
Substance  
 
If the percent of opioid drug substance extracted from T product is less than that extracted 
from R product plus an absolute 10 percent in Tier 1, the potential ANDA applicant should 
conduct the extractability study in both Tiers 2A and 2B.  If the percent of opioid drug 
substance extracted from T product is less than that from R plus an absolute 10 percent in 
Tier 2A, the potential ANDA applicant should proceed with the extractability study in Tier 
3A.  If the percent of opioid drug substance extracted from T product is less than that from R 
plus an absolute 10 percent in Tier 2B, the potential ANDA applicant should proceed with 
the extractability study in Tier 3B.  Figure 5 and Table 1 guide potential ANDA applicants 
through the recommended series of study conditions and statistical analyses for determining 
extractability. 
Tier 1:  Extraction of intact and manipulated (e.g., cut, grated, or milled) products in 
Level 1 solvent at RT 
 
Evaluate R product.  A potential ANDA applicant should identify the most effective physical 
manipulation for R product at RT.  If the percent of opioid drug substance extracted from R 
product using 240 mL of solvent is greater than or equal to 50 percent at 30 minutes for the 
intact or physically manipulated R product, R product is considered to have no abuse 
deterrence under this tier of testing.  Therefore, no comparative testing of T product to R 
product is needed. 
 
Compare T and R products.  If the maximum percent of opioid drug substance extracted from 
R product in 240 mL of solvent is less than 50 percent in 30 minutes in the level 1 solvent, 
the potential ANDA applicant should compare the maximum percent of opioid drug 
substance extracted from the intact and most effectively physically manipulated T product to 
19  Contains Nonbinding Recommendations 
 
the maximum percent extracted from the intact and most effectively physically manipulated 
R product, respectively.  If the maximum percent of opioid drug substance extracted from T 
product is less than the maximum percent of opioid drug substance extracted from R product 
plus an absolute 10 percent (section VIII), the potential ANDA applicant should conduct 
testing at the next tier. 
 
Tier 2A:  Extraction of intact and manipulated (e.g., cut, grated, or milled) products in 
Level 2 solvents at RT 
 
Evaluate R product.  A potential ANDA applicant should identify the most effective physical 
manipulation for R product at RT.  If the percent of opioid drug substance extracted from R 
using 240 mL of solvent is greater than or equal to 50 percent at 30 minutes in any of the 
level 2 solvents, R product is considered to have no abuse deterrence under this tier of 
testing.  Therefore, no comparative testing of T product to R product is needed.     
 
Compare T and R products.  If the maximum percent of opioid drug substance extracted from 
R product in 240 mL of solvent is less than 50 percent in 30 minutes in all level 2 solvents, 
the potential ANDA applicant should identify conditions (physical and thermal manipulation 
methods) that lead to the extraction of the maximum percent of opioid drug substance from 
intact and physically manipulated T products in all level 2 solvents at RT.  The maximum 
percent of opioid drug substance extracted from T and R products in each solvent should be 
compared.  Extractability of T and R products should be compared as described in section 
VIII and shown in Figure 5 and Table 1. 
Tier 2B:  Extraction of intact and manipulated (e.g., cut, grated, or milled) products in 
Level 1 solvents at ET 
 
As shown in Table 2, the same steps described in Tier 1 (identify the study condition where 
extraction of opioid drug substance from T and R products is maximum, evaluate R product, 
and compare T and R products) should be used for testing T and R products in Tier 2B using 
level 1 solvents at ET. 
 
Tier 3A:  Extraction of intact and manipulated (e.g., cut, grated, or milled) products in 
Level 3 solvents at RT  
 
As shown in Table 2, the same steps described in Tier 2A (identify the study condition where 
extraction of opioid drug substance from T and R products is maximum, evaluate R product, 
and compare T and R products) should be used for testing T and R products in Tier 3A using 
level 3 solvents at RT. 
 
20  Contains Nonbinding Recommendations 
 
Tier 3B:  Extraction of intact and manipulated (e.g., cut, grated, or milled) products in 
Level 2 solvents at ET  
 
As shown in Table 2, the same steps described in Tier 2A (identify the study condition where 
extraction of opioid drug substance from T and R products is maximum in each solvent, 
evaluate R product, and compare T and R products) should be used for testing T and R 
products in Tier 3B using level 2 solvents at ET. 
 
 
Tier 1: intact and manipulated T and R 
products using 240 mL level 1 solvent at 
RT
YES Is % opioid extraction  NO Is % opioid extraction  YES
T fails the test 
of R  50% in 30 min? of T  (R+10%) in 30 min?
Proceed with 
syringeability study                  NO             
(Appendix 3)
Tier 2A: intact and manipulated T and R  Tier 2B: intact and manipulated T and R 
products using 240 mL level 2 solvent at  products using 240 mL level 1 solvent at 
RT T fails the test  ET T fails the test 
YES YES
YES Is % opioid extraction  NO Is % opioid extraction  YES Is % opioid extraction  NO Is % opioid extraction 
of R  50% in 30 min? of T  (R+10%) in 30 min? of R  50% in 30 min? of T  (R+10%) in 30 min?
Proceed with  NO Proceed with  NO
syringeability study  syringeability study 
(Appendix 3) (Appendix 3)
Tier 3A: intact and manipulated T and R  Tier 3B: intact and manipulated T and R 
products using 240 mL level 3 solvent at  products using 240 mL level 2 solvent at 
RT T fails the test  ET T fails the test 
YES
YES
YES Is % opioid extraction  NO Is % opioid extraction  YES Is % opioid extraction  NO Is % opioid extraction 
of R  50% in 30 min? of T  (R+10%) in 30 min? of R  50% in 30 min? of T  (R+10%) in 30 min?
Proceed with  NO Proceed with  NO
syringeability study  syringeability study 
(Appendix 3) (Appendix 3)
Proceed with  Proceed with 
syringeability study  syringeability study 
(Appendix 3) (Appendix 3)
Figure 5: Decision Tree for Determining Extractability of Opioid Drug Substance (each 
dotted box represents one tier)
21  Contains Nonbinding Recommendations 
 
Table 1: Statistical Evaluation of Extractability  
Study Conditions 
TIER  240 mL all solvents within the tier 
Extraction Duration 30 min 
Ha: R < 50% in 30 min versus H0:  R  50% in 30 min  
If  R < 50% in 30 min  If  R  50% in 30 min 
Identify  Conclude that less than 50% of opioid drug substance can be extracted from R product  Conclude that equal or more 
extraction study condition   than 50% of opioid drug 
  substance can be extracted 
from R product;  
  no further comparative testing 
Ha: T < R+10% in 30 min versus H0: T  R+10% in 30 min 
If  T < R+10% in 30 min    If  T  R+10% in 30 min 
   
Conclude that T product is no worse than R  Conclude that T product is worse than R product 
product by an amount < 10%; T product passes  by an amount  10%; T product fails the study 
Evaluate  
the study under this tier  under this tier 
T vs R  STOP  
   
at study conditions  no further testing 
CONTINUE    
identified in this tier 
to the next tier  STOP 
or   no further testing 
STOP 
no further testing, if this is the last tier 
 
 
Note: The measure used to evaluate extractability is the % opioid drug substance extraction, determined as follows: (CONC*V/ labeled 
strength of R product) *100, where CONC is the concentration of opioid drug substance in the solution, and V is the volume of the 
solution.  10% is applied as an absolute margin. 
22  Contains Nonbinding Recommendations 
 
APPENDIX 2:  ABUSE BY INGESTION (ORAL ROUTE) 
Abuse by ingestion may involve orally ingesting physically manipulated (e.g., cut, grated, or 
milled) or chewed drug products.  FDA recommends an oral PK study be conducted on 
physically manipulated or chewed products if the summary in section 9.2 of the RLD 
labeling indicates that FDA has concluded that the product has properties that are expected to 
deter abuse by the oral route (i.e., Drug X is expected to reduce  . . . oral abuse when 
chewed.) or FDA otherwise recommends such a study in product-specific guidance.   
FDA recommends a potential ANDA applicant first conduct comparative extractability 
studies as described in Appendix 1 to assess the particular vulnerabilities of the T and R 
products to inform the comparison of their abuse deterrence.  If the potential ANDA 
applicant conducts a PK study, the study should compare the rate and extent of absorption of 
orally administered T and R products that are physically manipulated or chewed.  The 
strength(s) selected for the PK study should be based on the strength(s) used to evaluate the 
R products abuse deterrence.  If the upper 95 percent confidence bound of the T/R ratio for 
the rate and extent of oral absorption of the opioid drug substance is less than 125 percent, 
then T product passes the test.  For agonist/antagonist combination products, T product 
passes the test if the lower 95 percent confidence bound of the T/R ratio for the rate and 
extent of oral absorption of the antagonist is greater than 80 percent.  Section VII.A. outlines 
general recommendations for conducting oral PK studies.  Alternatively, the potential ANDA 
applicant may rely on data from in vitro testing if such methods and data are adequate to 
compare the rate and extent of absorption of orally administered T and R products to evaluate 
whether T product is no less abuse deterrent than R product for the oral route. 
 
23  Contains Nonbinding Recommendations 
 
APPENDIX 3:  ABUSE BY INJECTION (PARENTERAL ROUTE) 
Abuse by injection usually involves extraction of opioid drug substance from intact or 
physically manipulated (e.g., cut, grated, or milled) opioid drug products at RT and ET in 
small volumes of water followed by injection using a syringe.  To evaluate abuse deterrence 
for the parenteral route, a potential ANDA applicant should measure the amount of opioid 
drug substance available for injection after evaluating whether or not the solvent used can be 
parenterally administered in humans or evaporated for reconstitution.  The amount is 
determined by the opioid drug substance concentration in a solvent such as water 
(extractability), the volume that can be drawn into a syringe, and the volume that can be 
expelled from the syringes needle (syringeability). 
The potential ANDA applicant should note that comparative extractability and syringeability 
testing should be conducted with intact and physically manipulated (e.g., cut, grated, or 
milled) drug products.  To evaluate whether T product is no less abuse deterrent than R 
product for the parenteral route of abuse, the intact and physically manipulated T products 
should be compared with intact and physically manipulated R products, respectively, under 
each applicable study condition, as described below. 
The measure considered meaningful for evaluating the abuse deterrence relevant to abuse by 
injection is the percent of opioid drug substance extraction determined as follows:  
(CONC*V/labeled strength of the R product) *100, where CONC is the concentration of 
opioid drug substance in the sample that can be expelled from the syringe needle, and V is 
the volume of the solution expelled.  If R product is an agonist/antagonist combination, the 
ratio of the percent of opioid drug substance extraction of agonist to antagonist should be 
determined.  
Study conditions 
Syringeability testing should be conducted on the intact and manipulated T and R products in 
a small volume (10 mL) of each of the solvents in the relevant tier as described in Figure 6 if 
the maximum extraction of opioid drug substance from R product in 240 mL of solvent is 
equal or more than 50 percent in 30 minutes in a tier or T product successfully passes the 
large volume (240 mL) extraction study in all tiers (Figure 5).  If the opioid drug substance 
can be extracted from R product in a large volume of solvent, the potential applicant should 
conduct comparative syringeability testing in a small volume of the same solvent.  In general, 
FDA recommends conducting syringeability testing using a single unit of each T product and 
R product.  If single-unit syringeability testing cannot accurately characterize the 
syringeability of R product, the potential ANDA applicant should conduct multiple-unit 
syringeability tests and justify that the number of tablets or capsules used in syringeability 
tests can sufficiently discriminate the comparative syringeability of T and R products.  
Appendix 1 describes some of the ways in which solid oral opioid drug products can be 
physically manipulated.  For each manipulation likely to be used by abusers, T and R 
products should be statistically compared, as described in section VIII. 
Following physical manipulation (e.g., cutting, grating, or milling), further testing of 
syringeability is recommended under the following range of study conditions:  solvents used 
24  Contains Nonbinding Recommendations 
 
in the tier, volume 10 mL, temperature RT or ET, duration 5 to 60 minutes, and needle gauge 
21 or finer.  The study conditions, including extraction time, syringing time, needle gauge 
number, and filtering of particles, should be specified in the ANDA. 
Evaluate solvents.  If the solvent cannot be parenterally administered in humans or 
evaporated for reconstitution, no comparative syringeability testing of T product to R product 
is needed using that solvent.  If the solvent can be administered in humans or evaporated for 
reconstitution, the potential ANDA applicant should compare T and R products. 
 
Compare T and R products.  The potential ANDA applicant should test the intact and 
manipulated T product and compare the abuse deterrence of T product to intact and 
manipulated R product, respectively.  Then, the maximum percent of opioid drug substance 
extracted from T product should be evaluated to determine whether it is greater than or equal 
to R plus an absolute 10 percent in 30 minutes. 
 
Figure 6 illustrates the tier-based approach for evaluating the syringeability of opioids for 
abuse by injection, as described above. 
 
Manipulate T and R  products using 10 
mL solvent used in the previous 
extraction study (Appendix 1)
Can the solvent be parenterally  Yes Yes
Is % opioid extraction 
administered or evaporated for  T fails the test 
of T  (R+10%) in 30 min?
reconsitution?
No                 No             
T passes the test T passes the test
 
Figure 6: Decision Tree for Determining the Syringeability of Opioid to Evaluate Abuse-
Deterrence Potential (abuse by injection) 
25  Contains Nonbinding Recommendations 
 
APPENDIX 4: ABUSE BY INSUFFLATION (NASAL ROUTE) 
Abuse by insufflation generally involves the snorting of manipulated solid oral opioid drug 
products.  The known approaches to deterring insufflation include reducing bioavailability 
and reducing human abuse potential (e.g., likability or take-drug-again) of the abused 
product.  Thus, to evaluate abuse deterrence for the nasal route of abuse, a potential ANDA 
applicant should test T product for reduced bioavailability and/or reduced human abuse 
potential. 
The measure considered meaningful for in vitro evaluation of reduced bioavailability is the 
mass percent of fine particles (<500 micrometers (m)) available for insufflation.   
Reduced Bioavailability 
Reducing the opioid drug substance available for insufflation may be accomplished by 
inclusion of excipients that impart hardness to the formulation and make it difficult to 
manipulate, retard the rate of release of the opioid drug substance from the manipulated 
product, or increase the size of the drug product, thereby increasing the amount of 
manipulated powder and proportionally decreasing the amount of opioid drug substance to be 
insufflated. 
Consequently, the amount of opioid drug substance available following insufflation of 
manipulated T and R products is a function of several factors, including, but not limited to, 
the ease of manipulation of the drug product, the amount of manipulated product available 
for insufflation, the degree of effort needed for manipulation, and the rate of release of opioid 
drug substance from the manipulated product.  Therefore, evaluation of a products 
bioavailability includes measuring the size and amount of particles available for insufflation 
and measuring the rate and extent of absorption of manipulated T and R products following 
nasal administration.  
The tier-based approach to the comparative studies for evaluating bioavailability of opioid 
drug substance when abused through the nasal route is based on the progressively more 
complex studies moving from in vitro studies in Tier 1 to a PK study in Tier 2.  The potential 
ANDA applicant can propose alternative in vitro evaluation methods to assess the abuse 
deterrence of T products to avoid conducting a PK study if the methods provide reliable and 
predictive information on the PK behavior and performance of manipulated opioid drug 
products following insufflation. 
Tier 1:  Evaluation of manipulated T and R products 
 
Identify study condition.  Appendix 1 describes some of the ways in which solid oral opioid 
drug products can be physically manipulated.  If T and R products cannot be pulverized into 
fine particles (<500 m) after 5 minutes of manipulation (with or without thermal 
pretreatment), alternative approaches such as crushing, hammering, or grating after thermal 
pretreatment can be used to generate particles of size less than 500 m.  
26  Contains Nonbinding Recommendations 
 
Evaluate T product.  If the mass percent of fine particles (<500 m) of T product is less than 
or equal to 10 percent, then T product is deemed unsuitable for insufflation.  No comparative 
testing of T product to R product is needed. Otherwise, the potential applicant should 
evaluate R product.    
Evaluate R product.  R product is manipulated under the same manipulation condition.  If the 
mass percent of fine particles (<500 m) of R product is less than or equal to 10 percent, then 
R product is deemed more resistant to physical manipulation than T product for insufflation.  
If the mass percent of fine particles (<500 m) of R product is greater than 10 percent, testing 
should proceed to Tier 2. 
If both T and R products can be manipulated into fine particles with the mass percent of fine 
particles (<500 m) being greater than 10 percent, FDA generally recommends conducting a 
comparative PK study (Tier 2) to evaluate whether a proposed generic drug deters abuse by 
the nasal route.  Any exceptions would be provided in product-specific guidance. 
Tier 2: Evaluation of manipulated and insufflated T and R products in a PK study 
Identify manipulation condition.  Approaches to physical manipulation of T product should 
be identified to achieve a particle size range that is considered safe and tolerable for human 
insufflation PK studies (i.e., D >100 m and D <1000 m).  To conduct a comparative 
10 90
nasal PK study, R product should be manipulated into the same particle size range using an 
equal or lesser amount of energy input.  A potential ANDA applicant should characterize the 
particle size distribution of physically manipulated T and R products used in a nasal PK study 
using an appropriate procedure.  
Compare T and R products.  In section VII.A., FDA provides general recommendations for 
conducting nasal PK studies.  The strength(s) selected for a PK study should be based on the 
strength(s) used to evaluate R products abuse deterrence.  If the upper 95 percent confidence 
bound of the T/R ratio for the rate and extent of absorption of the insufflated opioid drug 
substance is less than 125 percent, then T product passes the test.  In addition, for 
agonist/antagonist combination products, T product passes the test if the lower 95 percent 
confidence bound of the T/R ratio for the rate and extent of absorption of the insufflated 
antagonist is greater than 80 percent.  Otherwise, T product is considered to be less abuse 
deterrent than R product. 
The tier-based approach to testing products for nasal bioavailability, as just described, is 
illustrated in Figure 7. 
27  Contains Nonbinding Recommendations 
 
Tier 1: Determine whether or not T and R 
products can be pulverized into particles
Evaluate all physical 
manipulation methods (cutting, 
grating and milling) to pulverize 
T and R products into particles
No
Is % mass of fine particles 
T passes the test
of T (< 500 m) > 10%?
Yes
No
Is % mass of fine particles 
T fails the test 
of R (< 500 m) > 10%?
Yes
Tier 2: Conduct in vivo nasal PK study 
comparing manipulated T and R products
Identify a manipulation 
condition to pulverize T product 
into particles with a size range of 
D10>100 m and D90<1000 m
Can R product be pulverized 
into the above particle size range using  No
T fails the test 
an equal or lesser amount of energy 
input as T product?
Yes
Is the rate and extent of 
No
absorption of opioid from T product 
T fails the test 
statistically equal to or lower than R 
product in a nasal PK study?
Yes
T passes the test
 
Figure 7:  Decision Tree for Evaluation of Abuse Deterrence Potential (abuse by insufflation) 
28  Contains Nonbinding Recommendations 
 
Reduced Human Abuse Potential 
Abuse deterrence by the nasal route may also be accomplished by addition of excipients that 
produce an unpleasant effect if the dosage form is manipulated and insufflated.  These excipients 
(e.g., sodium lauryl sulfate), referred to as aversive agents, are known to cause nasal mucosal 
irritation.  In product-specific guidance, FDA may recommend a potential applicant evaluate 
human abuse potential (e.g., willingness to take the drug again) if R product contains a known 
aversive agent.   
Evaluate R product.  If R product does not contain a known aversive agent in its formulation, 
then no comparative human abuse potential testing of T and R products is needed.  If R product 
contains a known aversive agent, the potential applicant should evaluate T product.  
 
Evaluate T product.  If T product contains a different aversive agent than R product, the potential 
applicant should conduct a comparative pharmacodynamics (PD) study to determine the human 
abuse potential (e.g., willingness to take the drug again) of T product in comparison to R product.  
If T product contains the same aversive agent as R product, the potential applicant should 
compare availability of the aversive agent at the local sites of aversion for manipulated T and R 
products.    
 
Compare T and R products with same aversive agent.  If T product contains the same aversive 
agent and the availability of the aversive agent in T product at the local sites of aversion is not 
less than that of R, T product is considered to have similar abuse deterrence as R product and no 
further testing is needed.  The availability of an aversive agent at the local sites of aversion could 
be based on evidence including, but not limited to, qualitative (Q1) and quantitative (Q2) 
formulation sameness between T and R products, in vitro methods that demonstrate equivalent 
performance, and PK studies to measure systemic exposure of the aversive agent.  The potential 
ANDA applicant may propose alternative studies if the applicant can provide justification that 
such study allows for accurate and sensitive comparison of availability of the aversive agent at 
the local sites of aversion between T and R products.  If the above approaches cannot confirm 
that the availability of the aversive agent of T product is not less than that of R product at the 
local sites of aversion, the potential ANDA applicant should conduct a comparative PD study to 
determine the human abuse potential of T product in comparison to R product.  The potential 
ANDA applicant should discuss the study design with the Agency before conducting the study.  
The proposed testing for comparison of T and R products human abuse potential is illustrated in 
Figure 8.  
29  Contains Nonbinding Recommendations 
 
Does R product 
YES NO
contain a known nasal 
aversion agent?
STOP no further testing
Does T product contain 
YES NO
the same aversive agent as 
R product?
Conduct comparative PD 
study 
Is availability of the 
Yes No
aversive agent of manipulated T less 
than that of manipulated R at the 
local site of aversion?
Conduct comparative PD  STOP no further 
study  testing
 
Figure 8:  Evaluation of Reduced Human Abuse Potential (abuse by insufflation) 
30  Contains Nonbinding Recommendations 
 
APPENDIX 5: ABUSE BY SMOKING (INHALATION ROUTE) 
Abuse by smoking involves the sublimation of the active ingredient in an opioid, in its salt or 
free-base form, following ignition.  To evaluate abuse deterrence for the inhalation route, a 
potential ANDA applicant should determine the amount of sublimated opioid salt or free base for 
intact and manipulated drug product.  
The measure used to evaluate abuse by smoking is the percent of opioid sublimation calculated 
as: (sublimed amount/labeled strength of the R product)* 100, where the sublimated amount is 
the amount of drug available for smoking following ignition of the product.  If R product is an 
agonist/antagonist combination product, the ratio of sublimation percent of agonist and 
antagonist should be determined. 
Study conditions  
Appendix 1 describes some of the ways in which solid oral opioid drug products can be 
physically manipulated.  The potential ANDA applicant should use a household coffee grinder or 
other household milling appliance.  The smoking test should be conducted on intact and 
manipulated T and R products at three different temperatures.  The selected temperatures should 
fall within the range of 200C to 300C for 2 to 15 minutes.   
The tier-based approach to comparative sublimation is based on using different methods to 
prepare the product for smoking, starting with direct sublimation of the intact and manipulated 
product in Tier 1, to freebasing the opioid drug substance from the intact and manipulated 
product prior to sublimation of the free base in Tier 2 (Table 2). 
Tier 1:  Sublimation of intact and manipulated products  
Identify study condition.  Appendix 1 describes some of the ways in which solid oral opioid drug 
products can be physically manipulated.  If T or R product cannot be manipulated to generate 
particles of less than 1 mm after attempted manipulation for 5 minutes, alternate approaches such 
as crushing or grating after thermal pretreatment can be used to generate particles of size less 
than 1 mm.  
Evaluate T and R products.  Determine the percent of opioid sublimation of intact and 
manipulated R product by heating at three different temperatures between 200C and 300C 
(selected temperatures should fall within the range of 200C to 300C) for 2 to 15 minutes.  
Using the same conditions and temperatures, determine the percent of opioid sublimation of 
intact and manipulated T product.  
Compare T and R products.  Statistically compare the abuse deterrence of T and R products.  If 
the percent of opioid sublimation of T is greater than R, then T product is less abuse deterrent 
than R product.  If the percent of opioid sublimation of T is less than or equal to R and the opioid 
drug product tested is not a salt, T product is no less abuse deterrent than R and no further 
comparative testing of T product to R product is needed.  If the percent of opioid sublimation of 
T is less than or equal to R and the opioid drug product is a salt, the abuse deterrence of T 
product should be tested further in Tier 2. 
31  Contains Nonbinding Recommendations 
 
Tier 2:  Sublimation of precipitated opioid retrieved from intact and manipulated products 
Identify study condition.  Convert the opioid salt in intact and manipulated T and R products to 
precipitated free-base opioid with a household reagent (e.g., baking soda).  Dry the resulting 
mixtures obtained from T and R products at three different temperatures (selected temperatures 
should fall within the range of 200C to 300C) for 2 to 15 minutes. 
      
Evaluate T and R products.  Determine the percent of opioid sublimation of the R product after 
conversion to a free base.  Using the same conditions and temperatures, determine the percent of 
opioid sublimation of T product. 
Compare T and R products.  Statistically compare the abuse deterrence of T and R products.  If 
the percent of opioid sublimation of T is greater than R, T product is less abuse deterrent than R 
product.  If the percent of opioid sublimation of T is less than or equal to R, T product is no less 
abuse deterrent than R product.   
Figure 9 and Table 2 illustrate the tier-based approach for evaluating the sublimation of opioid 
drug substance for abuse by smoking, as described above. 
 
Tier 1: Sublimation study of intact and 
manipulated T and R products
Heat intact and manipulated T and R 
products at three temperatures in 
the range of 200-3000C
YES Is % opioid sublimation of  NO
manipulated T > R?
T fails the test
NO
Is the opioid
a salt?
STOP no further testing YES
Tier 2: Sublimation study of free base retrieved 
from intact and manipulated T and R products
Heat free base at three temperatures in 
the range of 200-3000C
Yes No
Is % opioid sublimation 
of T > R?
T fails the test T passes the test
 
Figure 9: Decision Tree for Evaluation of Abuse Deterrence Potential (abuse by smoking)  
 
32  Contains Nonbinding Recommendations 
 
Table 2. Statistical Evaluation of Sublimation (abuse by smoking) 
 
TIER 1  Study Condition  
Three Temperatures in the Range of 200-300C / Duration of 215 minutes 
Identify  Determine the % of opioid sublimation of the intact and manipulated R product.  
Study  Using the same method, determine the % opioid sublimation of intact and manipulated T product. 
Condition   
H0:  T > R versus Ha:  T  R 
If  T  R and   If  T  R and   If  T > R 
% opioid drug substance is a salt  % opioid drug substance is NOT a salt  Conclude that % opioid sublimation of T 
Conclude that % opioid sublimation of T  Conclude that % opioid sublimation of T  product is greater than R product 
Evaluate the 
product is less than or equal to R product;  product is less than or equal to R product;   
R Sublimation  
T product passes the study under Tier 1  T product passes the study under Tier 1   
versus the  
     
T Sublimation 
CONTINUE   STOP  STOP 
to Tier 2  no further testing  no further testing 
 
 
TIER 2  Study Condition  
Three Temperatures in the Range of 200-300C / Duration of 215 minutes 
Identify 
Convert the opioid salt in intact and manipulated T and R products to free base with a household reagent. Dry the resulting mixtures 
Study 
obtained from the T and R products at three temperatures in the range of 200-300C for 2-15 minutes. 
Condition 
H0:  T > R versus Ha:  T  R 
If  T  R  If  T > R 
Evaluate the  Conclude that % opioid sublimation of T product is  Conclude that % opioid sublimation of T product is greater than  
R Sublimation    less than or equal to R product; T product passes the study   R product; T product fails the study under Tier 2 
versus the   under Tier 2   
T Sublimation     
STOP  STOP 
 no further testing   no further testing 
Note: The measure used to evaluate abuse by smoking is the % of opioid sublimation, determined as follows: (sublimed amount/ labeled 
strength of R product)* 100, where the sublimed amount is the amount of drug available for smoking following ignition of product.  
33