#238 
 
Guidance for Industry 
 
Modified Release Veterinary Parenteral Dosage 
Forms:  Development, Evaluation, and 
Establishment of Specifications 
 
Submit comments on this guidance at any time.  Submit electronic comments to 
http://www.regulations.gov.  Submit written comments to the Division of Dockets Management 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 
20852.  All comments should be identified with the docket number FDA-2015-N-4563. 
 
For further information regarding this document, contact AskCVM@fda.hhs.gov. 
 
Additional copies of this guidance document may be requested from the Policy and Regulations 
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish 
Place, Rockville, MD 20855, and may be viewed on the Internet at 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/d
efault.htm or http://www.regulations.gov. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
June 2016 
   
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION .................................................................................................................. 3 
II.  BACKGROUND ................................................................................................................. 3 
III.  SCOPE ................................................................................................................................. 4 
IV.  GENERAL CONSIDERATIONS FOR THE DEVELOPMENT OF A DRUG 
RELEASE METHOD ................................................................................................................... 5 
V.  IN VITRO DRUG RELEASE TEST METHOD PARAMETERS: ................................ 6 
VI.  THE ROLE OF THE IVIVC/R IN A PRODUCT APPLICATION: ............................. 8 
VII.  DEFINING AN IVIVC OR IVIVR .............................................................................. 10 
VIII.  ESTABLISHING DRUG RELEASE SPECIFICATIONS ....................................... 12 
IX.  FILING INFORMATION FOR CMC SUBMISSIONS ............................................... 12 
A.  Early Information ............................................................................................................ 12 
B.  Protocol ........................................................................................................................... 13 
C.  Pharmaceutical Development Reports (PDRs) ............................................................... 13 
D.  Other Information ............................................................................................................ 14 
X.  GLOSSARY....................................................................................................................... 15 
XI.  BIBLIOGRAPHY ............................................................................................................. 17 
 
   
2  Contains Nonbinding Recommendations 
Guidance for Industry 
 
Modified Release Veterinary Parenteral Dosage Forms: 
Development, Evaluation, and Establishment of Specifications 
 
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 provides recommendations on the submission of chemistry, manufacturing, and 
controls (CMC) and pharmacokinetic information, as well as procedures to follow, to support the 
approval of modified release parenteral drug products intended for use in veterinary species.  
This information should be filed with the Center for Veterinary Medicine (CVM) to support a 
new animal drug application (NADA) or an abbreviated new animal drug application 
(ANADA).1 
 
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 
 
The evolution of parenteral modified release technology provides an opportunity to develop new 
therapeutic options that were impracticable using traditional tablet or parenteral product 
platforms.  For example, these novel formulations provide a mechanism to deliver a drug over a 
period of months to years.  With some formulations, multi-phasic in vivo release characteristics 
can be achieved such that a single injection provides controlled changes in the drug release 
characteristics over time.  Other formulations allow for drug delivery directly to the site of 
action, minimizing the adverse effects that accompany systemic drug exposure.  But, with these 
benefits comes the need to establish product specifications to ensure that every batch results in 
the therapeutic benefits purported on the product label.  And for parenteral products intended for 
use in food-producing animals, these specifications must ensure that violative residues will not 
occur at the FDA-approved withdrawal time.  See the Federal Food, Drug, and Cosmetic Act 
(FD&C Act), Section 512(d)(1)(F). 
                                          
1Due to the potential complexities of these modified release formulations, each sponsor should discuss whether its proposed 
product is appropriate for consideration as a generic.  In those situations where CVM determines that a product can be filed as a 
generic drug application, the same development and CMC information that is requested for new drug applications must be 
submitted.  See FD&C Act, Section 512(n)(1)(G). 
3  Contains Nonbinding Recommendations 
 
In vitro drug-release testing methods provide the information necessary for (1) assuring the 
adequacy of the proposed process and quality controls; (2) determining stable release 
characteristics of the product over the proposed product shelf-life; and (3) facilitating an 
assessment of product modifications (e.g., absence of effect of minor formulation changes, 
change in manufacturing site or process on product performance).  These approaches are detailed 
in the FDA Center for Drug Evaluation and Research (CDER) and Center for Biologics 
Evaluation and Research (CBER) Guidance for Industry (GFI), Q8(R2) Pharmaceutical 
Development (International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use [ICH]) Q8(R2)) (November 2009).i  Product 
specifications are linked directly to the in vitro release test method. 
 
Product in vitro drug release specifications provide a metric for confirming that the in vivo drug 
release characteristics will be consistent with the intended therapeutic objectives.  Empirical 
(minimal) approaches base product specifications on batch data at the time of registration, and 
these specifications then serve as the primary means of product control.  In this approach, the 
prognostic potential of the drug-release method is constrained by the limits of the information 
about which the specifications can be based.  In contrast, the systematic (enhanced) quality-by-
design (QbD) approach incorporates product specifications as a component of the overall 
quality-control (QC) strategy.  The QbD approach establishes specifications based upon the 
design space. 
 
A greater understanding of the product and its manufacturing process may create a basis for 
flexible and innovative regulatory approaches.  But the scope of that flexibility will depend, in 
part, on the relevant scientific knowledge provided in the registration application.  It is the 
knowledge gained and submitted to the authorities that forms the basis for science- and risk-
based submissions and regulatory evaluations. 
 
III.  SCOPE 
 
This document provides: 
 
  Suggestions for development of an in vitro drug release test method 
  A discussion of the components of a drug release method 
  The role of an in vivo/in vitro correlation (IVIVC) or an in vivo/in vitro relationship 
(IVIVR) in a product application.  Throughout this document, we use the term 
IVIVC/R to denote text pertaining to IVIVC and/or IVIVR. 
  Methods for establishing IVIVC/R for a parenteral product 
  Suggestions for establishing clinically relevant in vitro drug release specifications 
  Methods for using in vitro product specifications for setting expiry and for supporting 
batch release 
  Recommendations for filing information for in vitro drug release methods and data as 
well as material for the Pharmaceutical Development Report, and Chemistry, 
Manufacturing, and Controls technical section for modified-release parenteral dosage 
forms. 
 
4  Contains Nonbinding Recommendations 
This guidance does not describe post-approval changes of in vitro methods or development of 
suitable correlation for oral modified release dosage forms and nanotechnology products. 
 
IV.  GENERAL CONSIDERATIONS FOR THE DEVELOPMENT OF A DRUG 
RELEASE METHOD 
 
Accelerated in vitro test conditions are necessary if these methods are to serve as a product QC 
tool; months-long timeframes are generally not practical.  Whenever possible, specifications 
should be established on the basis of a single in vitro test method.  Because modified release 
parenteral products are formulated to release drug over a period of days, weeks, or months, the 
development of a discriminating in vitro test method that achieves total drug release within a 
period of hours or days is challenging.  Nevertheless, the in vitro method should be sensitive to 
changes in those drug product quality attributes that can influence in vivo product performance.  
To be an effective prognostic tool, the shape of the in vitro profile should be determined by the 
same rate-limiting factor that determines the in vivo drug release profile.  This underscores the 
need to achieve product and process understanding during formulation development. 
 
The in vitro drug release test method should be established during the early phases of product 
development so that it can be used to characterize the preliminary formulations, the formulations 
used in the Target Animal Safety and Effectiveness studies,ii and to provide the assessment of 
the stability lots.  The establishment of product release specifications should be based upon in 
vitro performance of those lots used during the pivotal studies used to demonstrate drug product 
safety and effectiveness.  However, a widening of the specifications may be deemed acceptable 
based upon additional in vivo and in vitro data gathered during product development. 
 
Prior to proceeding with development of the drug release method, the following information 
should be considered and discussed with CVM: 
 
  Formulation development, including assessment of the need for an initial burst release 
(loading dose) and rate and duration of drug release 
  Assessment of the excipient(s) or dosage form that may impact the rate and duration of 
drug release 
  Development of an in vitro test that adequately describes the formulation attributes 
  Evaluation of the method as a QC test to support batch release at the initial time point and 
ensure product performance throughout expiry 
  Evaluation of the impact of manufacturing process changes on product performance 
  Evaluation of the impact of changes in supplier of the active pharmaceutical ingredient 
and critical excipients 
  Substantiation of CMC-associated label claims (such as product drug release 
characteristics). 
   
5  Contains Nonbinding Recommendations 
V.  IN VITRO DRUG RELEASE TEST METHOD PARAMETERS: 
 
The in vitro drug release method should be capable of identifying formulation differences that 
affect in vivo product performance.  This necessitates that the method is sensitive to the rate 
limiting factor impacting in vivo drug release.iii  Method sensitivity can be confirmed during the 
formulation screening stage.  Often, this evaluation compares the results provided across several 
in vitro release methods.  Once a sponsor develops a discriminating system, a consistent set of 
testing conditions should be maintained across all formulations and manufacturing lots used 
during target animal safety and clinical effectiveness trials. 
 
In most circumstances, the in vitro method should employ sink conditions to reflect the 
relationship between product formulation and the rate and extent of drug release.  In those rare 
situations where sink conditions cannot be achieved, justification for an assay that does not 
achieve sink conditions should be submitted in a protocol or with the application. 
 
CVM recommends the following information to support the proposed drug release method and 
apparatus of choice: 
 
1.  Description of the apparatus used: United States Pharmacopeia (USP) chapters <711>iv 
or <724>v can be referenced if a sponsor uses one of the USP apparatus.  If the sponsor 
selects a different apparatus, the description should include the vessel (shape, 
dimension, and its material, etc.), motor, shaft, collection basket or device, water bath or 
heating device, and how a sponsor performs sampling throughout the duration of the 
test. 
 
2.  Description of physical design and set up conditions of the apparatus.  A picture of the 
equipment and set up with identification of the specific parts of the equipment is 
helpful.  Include the dimensions and tolerances of the specific components and their 
related position to the whole assembly. 
 
3.  Characterization of temperature conditions of the vessel and how they can be 
maintained consistently during the run. 
 
4.  Justification of apparatus suitability: 
 
a.  Determination of the apparatus suitability.  This information should include 
conformance to the measurements (width, length, etc.) and specifications (degree of 
tolerance) of the specific components. 
 
b.  Performance validation and verification of the apparatus: 
 
i.  If the apparatus is a USP apparatus, follow the USP procedure as described in 
<711> or <724> to demonstrate the suitability of the apparatus. 
6  Contains Nonbinding Recommendations 
 
ii.  If the apparatus is not described in the USP, information from the manufacturer 
can be used as a point of reference. 
 
iii.  Acceptable performance of the apparatus assembly should be verified periodically 
and the conditions by which the apparatus is deemed acceptable for use should be 
described. 
 
5.  Description of the type of media and justification for its selection. 
 
6  Description of sample and standard preparation, including storage conditions and any 
precaution in handling and sampling techniques. 
 
7  Description of other assay parameters; i.e., temperatures, mix rates, duration of the test, 
degradation rate, release rate, sampling points and techniques, etc. 
 
8.  Demonstration of sink conditions:  Provide data that defines the volume of fluid 
necessary to insure that the concentration of drug in the medium at 100% release does 
not exceed one-third of the saturation concentration, where saturation concentration is 
defined by the maximum mg/mL of drug that can be solubilized in the release medium. 
 
9.  Specification of timing of measurements:  Ideally, the drug release test should take no 
more than 2 days to perform, thereby expediting the lot release process and minimizing 
the risk of degradation of the in vitro test system.  The test time points, generally four, 
are expressed in hours.  Samples should be withdrawn within a tolerance of 15 
minutes or 2% of the stated times (where criteria used for tolerance are determined on 
the basis of when the sample is taken relative to the duration of the test and may differ 
across the four selected time points).  Deviation from the tolerance will need to be 
justified. 
 
10.  Description of the instrumentation used to quantify drug concentrations used to assay 
sample aliquots collected from the designated time frame.  A description of the 
analytical system should include details, such as the type of chromatography, column, 
detector, mobile phase, etc.  Validation of this type of system typically follows the 
elements and criteria as specified in USP <1225>vi and VICH GL2vii which should 
include measures of specificity, linearity, accuracy, precision, range, limit of detection, 
limit of quantitation, robustness, and system suitability. 
 
11.  Discussion of procedures and criteria for determining discriminative ability of the test.  
The method should allow differentiation in the profile with formulation involving some 
change in the manufacture of the batch used in the safety and effectiveness trials (such 
as composition, process, equipment, excipients) or age of the product (new as compared 
to aged or expired product). 
 
7  Contains Nonbinding Recommendations 
12.  Any additional data analysis or supporting data needed to determine release rate or 
specifications from the batches used to fulfill requirements associated with the Safety 
and Effectiveness technical sections.ii 
 
13.  Detailed calculation of % drug release. 
 
14.  Proposed specifications (time = 0 and t = stability throughout expiry) and justification. 
 
VI.  THE ROLE OF THE IVIVC/R IN A PRODUCT APPLICATION: 
 
An IVIVC describes a quantitative (generally linear) relationship between in vivo and in vitro 
release characteristics while an IVIVR reflects a relationship that can be described by something 
other than that of a straight-line.viii  CVM recommends that at the very least, sponsors 
demonstrate an IVIVR to support the biological relevance of the in vitro release method. 
 
Generally, an estimation of in vivo drug product release characteristics is based upon blood level 
profiles.  When establishing the blood level profile that will be used to support the generation of 
an IVIVC/R, the intended in vivo release characteristics of the proposed product need to be 
considered.  For example, early concentrations (i.e., blood captured within the first 1-8 hours 
after drug administration) may be needed to characterize an initial burst of drug release, 
irrespective of whether or not such a burst in drug release is intended. Profiles for products 
targeting zero order release characteristics should allow for a determination of the duration of 
that zero order release.  Characterization of the in vivo profile generated for products that exhibit 
multiple peaks throughout the dosing interval may need more frequent blood samples, where the 
definition of frequent will be based upon the rate at which these bursts are observed and/or the 
proposed duration of drug release.  Therefore, the blood sampling profile used when establishing 
the IVIVC/R needs to be tailored to the intended product. 
 
In some instances, an IVIVC/R has been developed with only a single formulation in order to 
predict blood level profiles generated within that formulation.  For example, DSouza and 
DeLuca (2005)ix and Rawat et al (2012)x demonstrated that accelerated in vitro test conditions 
can be developed that adequately describe complex, multi-phasic in vivo drug release patterns.  
However, from the perspective of using in vitro data to extrapolate across formulations (i.e., to 
enable the in vitro release test results to substitute for an in vivo bioequivalence study), CVM 
believes that the IVIVC/R needs to be established on the basis of data generated across at least 
three formulations exhibiting differences in their respective rates of in vivo drug release.  While 
describing the in vivo release characteristics across these formulations, the same blood sampling 
schedules should be employed in order to define the relationship between in vitro and in vivo 
product performance. 
 
For the in vitro component of the IVIVC/R, no fewer than 12 replicates for each of the 3 
different formulations should be tested.  Due to unique attributes of modified release 
formulations, 12 replicates could, for example, reflect 1) 12 individuals units, such as 12 
individual implants from a given production batch; 2) 12 replications of an aliquot from a 
production batch of a liquid formulation, such as a suspension and in situ gels; or 3) 12 
replications of multiple unit products, such as implantable pellets.  In the latter situation, separate 
8  Contains Nonbinding Recommendations 
tests of 12 replicates each should be performed when with pellets are designed to exhibit 
different in vivo release characteristics and the modifications necessary to establish the IVIVC/R 
should provide a test of product critical quality attributes (CQAs) without altering the 
mechanism controlling drug release. 
 
Depending upon the nature of the information generated during product development (i.e., the 
ability to establish an IVIVC or an IVIVR) and the purpose of subsequent in vitro release test 
data (e.g., its use in supporting pre- or post-market changes versus development of product 
quality release specifications), once a target in vitro profile has been established (based upon the 
lots used in the clinical field trial) and product specifications have been established, subsequent 
profiles may be evaluated on the basis of: 
 
  The ability of a subsequent profile (i.e., multiple time point release specification) to meet 
established product specifications.  This information should be used to support batch 
release and product stability (see VIII.  Establishing Drug Release Specifications). 
 
  The ability to demonstrate comparability to the target profile based upon use of the f  
2
criterion where an f  value between 50 and 100 suggests that 2 profiles are similar (see 
2
the glossary and the FDA CDER GFI, SUPAC-MR: Modified Release Solid Oral 
Dosage Forms (September 1997)xi for definition).  For profile comparability (as defined 
by f ) to support a waiver of in vivo relative bioavailability study requirements, the 
2
magnitude of formulation change that can be supported by in vitro release data depends 
upon several factors: 
 
  If the change has the potential to alter what constitutes the rate-limiting factor,2 
o
then an in vivo relative bioavailability study will be necessary to support the 
safety and effectiveness of the new formulation. 
 
  If the proposed formulation change falls within SUPAC Level 1 changes or if the 
o
change in product composition or manufacturing is unlikely to alter in vivo 
product performance (e.g., a change in ingredient supplier or substitution between 
two similar excipients), then the f  test can be applied to support the biowaiver as 
2
long as an IVIVR has been established. 
 
  If a major change in formulation occurs (for example, a deletion or addition of 
o
ingredients that may be critical to the in vivo release characteristics of the 
formulation), then CVM can only render a decision of product bioequivalence if 
an IVIVC has been established. 
 
                                          
2Examples of rate-limiting steps include: for a lipophilic solution, the rate of partitioning between the lipophilic layer and 
interstitial fluid is a rate-limiting step; for an in situ forming gel or implant, the rate of drug movement through the gel to the 
surface is the rate-limiting step; for a suspension, the rate at which the particles dissolve and the particle size and surface to 
volume ratio is a rate-limiting step.  For more discussion please refer to Martinez M., Rathbone M., Burgess D., Huynh M., 2008.  
In vitro and in vivo considerations associated with parenteral sustained release products: a review based upon information 
presented and points expressed at the 2007 Controlled Release Society Annual Meeting. J Control Release, 129:79-87. 
9  Contains Nonbinding Recommendations 
When systemic drug concentrations are measurable, the in vivo characterization should be based 
upon blood concentration/time profiles.  However, there exist situations where it is not feasible 
to measure drug concentrations in the systemic circulation.  Within the framework of veterinary 
medicine, it may be feasible to establish the IVIVC/R on the basis of an explant study.  When 
explant data are utilized, the method should capture the amount of drug remaining in the 
injection site as a function of time.  Optimally, these data would be collected as a component of 
other ongoing investigations (e.g., as part of the Target Animal Safety study).  Ravivarapu et al. 
(2000) have shown that such explant studies can provide valuable information on the relationship 
between product formulation, in vitro performance and in vivo drug release.xii  Alternatively, for 
safety reasons, there may be times when it is important to evaluate residual drug remaining prior 
to subsequent administrations.  Sponsors should discuss methods for capturing these data with 
CVM as early as possible in drug development. 
 
VII.  DEFINING AN IVIVC OR IVIVR 
 
To demonstrate an IVIVC/R, both internal and external validations are necessary.  The internal 
validation examines the ability of the model to predict in vivo performance using the in vitro data 
that originally went into the model development.  Also needed is an external validation where a 
formulation, with known bioavailability but that was not used in the development of the model, 
is used to evaluate the overall prediction error of the test method. 
 
Four types of correlations have been described (see CDER GFI, Extended Release Oral Dosage 
Forms:  Development, Evaluation, and Application of In vitro/In vivo Correlations (September 
1997)).xiii  The extent to which each of these can be used to support changes in formulation will 
depend both upon the formulation in question, the pharmacokinetics of the active pharmaceutical 
ingredient(s) (API), the therapeutic window for of the API, and the type of correlation that has 
been established.  A helpful description of how these relationships can be established and 
support product development throughout the product development process has been described 
elsewhere.xiv 
 
Level A 
 
The Level A correlation should usually be estimated by a two-stage procedure:  
deconvolution followed by comparison of the fraction of drug absorbed to the fraction of 
drug dissolved.  A correlation of this type is generally linear and represents a point-to-point 
relationship between in vitro drug release rate and the in vivo input rate (e.g., the in vivo 
dissolution of the drug from the dosage form).  Because the rate of drug release from 
parenteral modified release products is accelerated under the in vitro test conditions, the in 
vitro drug release and in vivo input curves would need to be rendered superimposable with a 
scaling factor. 
 
Whatever the method used to establish a Level A IVIVC, the model should predict the entire 
in vivo time course from the in vitro data.  In this context, the model refers to the relationship 
between in vitro dissolution of a modified release dosage form and an in vivo response such 
as plasma drug concentration or amount of drug absorbed.  To generate this level of 
correlation, in vivo pharmacokinetic data should be provided for an immediate release dosage 
10  Contains Nonbinding Recommendations 
form so the clearance and volume of distribution associated with the drug itself can be used 
to facilitate the estimation of absorption rate and fraction absorbed from the formulation.  
Using convolution (or other appropriate modeling techniques), the fastest and slowest 
allowable in vitro release rates should be determined based upon modeled plasma 
concentration time profiles that exhibit a maximal difference of 20% in the predicted C  
max
and AUC values. 
 
With regard to the in vitro dataset, the time points should cover the early, middle, and late 
stages of the dissolution profile.  The last time point should be the time point where at least 
80% of drug has dissolved.  If the maximum amount dissolved is less than 80%, then the last 
time point should be the time where the plateau of the dissolution profile has been reached.  
CVM believes parenteral modified release dosage forms have a greater risk of long-term 
accumulation than oral dosage forms.  For products in which accumulation is potentially a 
concern, CVM may request time points in which the maximum percentage of drug release is 
greater than 80%. 
 
It should be noted that a Level A correlation is extremely difficult to obtain, and is 
particularly difficult when applied to parenteral modified release formulation where a very 
long duration of release and multifunctional absorption characteristics complicate the ability 
to obtain a Level A correlation. 
 
Level B 
 
The Level B relationship is based upon principles of statistical moment analysis.  The mean 
in vitro release time is compared either to the mean residence time or to the mean in vivo 
release time.  Similar to Level A, the Level B uses all of the in vitro and in vivo data.  
However, because it is not a point-to-point correlation, the Level B relationship does not 
uniquely reflect the shape of the in vivo concentration-time profile. 
 
Level C 
 
Level C relationships do not reflect the complete shape of the plasma concentration time 
curve and often use less than the full complement of in vitro release data.  Rather, the Level 
C relationship describes a single point relationship between a dissolution parameterfor 
example, the percent dissolved in 4 hoursand a pharmacokinetic parameter (e.g., time to 
50% AUC).  This one time point may be used to establish the specification such that there is 
not more than a 20% difference in the predicted AUC and C .  At other time points, the 
max
maximum recommended range at any dissolution time point specification should be within  
10% of label claim deviation from the mean dissolution profile obtained from the 
clinical/bioavailability lots.  Reasonable deviations from this  10% standard may be 
acceptable if the range at any time point does not exceed 25%. 
 
Multiple Level C 
 
A multiple Level C relationship relates one or several pharmacokinetic parameters of interest 
to the amount of drug dissolved at several time points of the dissolution profile. 
11  Contains Nonbinding Recommendations 
VIII.  ESTABLISHING DRUG RELEASE SPECIFICATIONS 
 
To maximize the relevance of the outcome of in vitro drug release tests, CVM prefers at least 
four time points with associated specification limits within a drug release profile.  Future 
reduction of time points for routine in vitro release testing will be evaluated post-approval.  Any 
justification for a different number of points should be based on the complexity of the 
pharmacokinetic and in vitro release profiles for the formulation. 
 
Setting Drug Release Test Specifications with an IVIVC/R 
 
An IVIVC/R adds in vivo relevance to in vitro product release specifications and can be used 
as more than a tool for batch-to-batch QC.  The in vitro drug release test is used as a 
meaningful predictor of in vivo performance of the formulation, and the release specifications 
may be used to minimize the possibility of releasing lots that have different in vivo 
performance.  It can also influence expiry if product release characteristics change over time. 
 
One of the challenges associated with establishing the in vivo relevance of the in vitro release 
test is that these data are generated under conditions that markedly accelerate the rate of in 
vitro drug release.  Therefore, a confirmation of the relationship can be obtained through the 
generation of in vivo and in vitro data across a range of formulations (e.g., variation in curing 
time, different source of excipients, and differing composition).  To achieve this, CVM 
recommends that the sponsor submit information generated throughout the period of 
formulation development (thereby eliminating the need to purposefully generate inequivalent 
drug products).  Confirmation of an IVIVC/R allows the use of the in vitro test method for 
establishing clinically-relevant release specifications and for setting product expiry. 
 
Setting Drug Release Test Specifications without an IVIVC/R 
 
Without an IVIVC/R, the in vitro drug release test is applicable solely for QC purposes; in 
vivo bioequivalence cannot be determined on the basis of in vitro drug release tests.  In the 
absence of an IVIVC/R, CVM may accept proposals for in vitro release specifications based 
on averages of drug release results from lots used for clinical studies.  When the in vitro test 
is used as a QC test without any in vivo significance, we recommend drug release percentage 
limits that at all time points are no more lenient than the average release  2 standard 
deviations.  Exceptions may be considered based on evidence that proposed ranges represent 
those of safe and effective lots.  Widening specifications based on scale-up, stability, or lots 
for which bioequivalence would be difficult to support without information about in vivo 
effects of this greater variability. 
 
IX.  FILING INFORMATION FOR CMC SUBMISSIONS 
 
A.  Early Information 
 
Sponsors developing a drug release method or considering the establishment of an 
IVIVC/R may wish to consider the submission of background information or early study 
information as part of an early information submission.  The submission of early 
12  Contains Nonbinding Recommendations 
information is an additional tool that allows CVM an opportunity to have discussions with 
sponsors earlier in the process. 
 
B.  Protocol 
 
CVM recommends that sponsors submit a method protocol before finalizing the in vitro 
drug release test method and prior to conducting the pivotal target animal safety and 
effectiveness studies so both CVM and sponsor may agree on expectations for the method.  
Likewise, CVM recommends that a sponsor wishes to pursue an IVIVC/R, a protocol 
covering both in vivo and in vitro components should be submitted for CVM concurrence.  
In so doing, the conditions associated with the in vitro method will be defined prior to 
manufacture of the safety and effectiveness study batches; agreement obtained on the 
information needed to support product specifications based upon study batch(es); and 
concurrence reached on the corresponding analysis of those data for generating in vitro 
product specifications.  Sponsors may also request a meeting to discuss the development 
of early and final formulations and to gain CVMs current thinking on the proposed 
dosage form and formulation. 
 
C.  Pharmaceutical Development Reports (PDRs) 
 
CVM encourages sponsors to provide PDRs that describe the scientific rationale for the 
chosen manufacturing process(es) and controls for modified release drug products (section 
2.3.P.2 entitled Pharmaceutical Development in CVMs Question-based Review 
format).  A sponsors ability to demonstrate process understanding in this section of the 
drug application can be factored into CVMs risk-based decision making for the Good 
Manufacturing Practice (GMP) component of drug approval.  Suggestions for PDRs can 
be found in CDER/CBER GFI, Q8(R2) Pharmaceutical Development (ICH Q8(R2)).i 
 
Pharmaceutical development of a modified-release parenteral product may include some 
or all of the following elements: 
 
  Defining the quality target product profile as it relates to quality, safety, and 
efficacy.  Considerations for the quality target product profile could include: 
 
  Intended use in clinical setting, route of administration, dosage form, and delivery 
o
systems. 
  Dosage strength(s). 
o
  Container closure system. 
o
  Therapeutic moiety release or delivery attributes affecting pharmacokinetic 
o
characteristics (for example, in vivo release, drug partitioning characteristics, 
potential barriers/obstacles to in vivo drug release and/or target site delivery) 
appropriate to the drug product dosage form being developed. 
  An explanation of why the drug substance may be a good candidate for modified 
o
release dosage forms. 
 
13  Contains Nonbinding Recommendations 
  Drug product quality criteria (for example, sterility, purity, stability, and drug-release) 
appropriate for the intended marketed product. 
  Identifying potential CQAs of the drug product, so that those product 
characteristics that have an impact on product quality can be studied and 
controlled. 
  Determining the CQAs of the drug substance and excipients, and selecting the 
type and amount of excipients to deliver drug product of the desired quality. 
  Selecting an appropriate manufacturing process. 
  Defining a manufacturing control strategy. 
  Optimizing analytical tests, especially the in vitro drug-release test. 
  A description of which excipients in the formulation are release controlling. 
  Experience with similar release-controlling excipients that were not a part of the final 
formulation. 
  Development of a reconstitution vehicle, if appropriate. 
  Physical properties of the formulation, such as partitioning characteristics that may 
affect drug-release rate. 
  Discussion of the effect of particle size on release characteristics, if appropriate. 
  Manufacturing considerations, such as unusual processes or equipment. 
  A comparison to an immediate-release formulation, if one exists. 
  Method development for the drug-release assay, such as buffers and apparatus or new 
release-measurement technology. 
  Risk analyses linking design of manufacturing process to product quality. 
 
D.  Other Information 
 
This section offers an overview of the information that would typically be submitted and 
the corresponding section in CVMs Question-based Review format. 
 
1.  Section 2.3.P.4 Control of Excipients:  If appropriate, references to Type IV master 
files with information about release-controlling excipients may be provided in the 
product quality section pertaining to excipient control. 
 
2.  Section 2.3.P.5 Control of Drug Product: 
 
  The proposed drug release method 
  Appropriate validation for the drug release method 
  Information that describes the IVIVC/R associated with the proposed test 
method. 
  Product expiry; 
o
  Setting product specifications at product release(time = zero) and expiry; 
o
and 
  Changes in specifications beyond the ranges supported by the product 
o
batches used during the safety and effectiveness trials. 
 
3.  Stability:  Justification of the proposed stability specifications.   
14  Contains Nonbinding Recommendations 
X.  GLOSSARY 
 
AUC:  Area Under the Curve; the integral of the plasma concentration vs. time curve. 
 
Batch:  A specific quantity of a drug or other material produced according to a single 
manufacturing order during the same cycle of manufacture and intended to have uniform 
character and quality, within specified limits as per 21 CFR 210.3(b)(2). 
 
C :  Maximum plasma concentration. 
max
 
Critical quality attributes (CQAs):  A physical, chemical, biological or microbiological 
property or characteristic that should be within an appropriate limit, range, or distribution to 
ensure the desired product quality.i 
 
Drug product:  A finished dosage form containing a drug substance, usually, but not 
necessarily, in association with one or more other ingredients as per 21CFR 314.3(b). 
 
Drug Release Test:  An in vitro assay that assesses the percentage of the full dose released from 
a modified-release parenteral product over time.  The performance of drug release tests is 
generally similar to dissolution tests used for solid oral dosage forms, but CVM recognizes that 
the term dissolution is not an adequate description of how many parenteral modified-release 
dosage forms are intended to function. 
 
Explant:  Removal of the tissue at a given time point from the site of injection and subsequent 
assay for remaining active ingredient(s). 
 
f :  A parameter that defines the similarity of two in vitro drug release profiles 
2
 
 
 
where n = number of sampling time points, R = dissolution at time point t of the reference, and T 
= dissolution at time point t of the test.xv 
 
Formulation:  The ingredients and composition of the dosage form. 
 
In vivo/in vitro correlation (IVIVC):  A predictive mathematical model describing the 
relationship between an in vitro property of a modified release dosage form (usually the rate or 
extent of drug release or release) and a relevant in vivo response, e.g., plasma drug concentration 
or amount of drug absorbed. 
 
In vivo/in vitro relationship (IVIVR):  A relationship between in vivo bioavailability and the in 
vitro release profiles, which can be described by a relationship other than that of a straight line. 
 
15  Contains Nonbinding Recommendations 
Lot:  A batch, or a specific identified portion of a batch, having uniform character and quality 
within specified limits or, in the case of a drug product produced by continuous process, a 
specific identified amount produced in a unit of time or quantity in a manner that assures its 
having uniform character and quality within specified limits as per 21 CFR 210.3(b)(10). 
 
Mean residence time (MRT):  The mean time that the drug resides in the body.  MRT may also 
be the mean transit time.  MRT = AUMC/AUC. 
 
Modified-release parenteral dosage form:  A parenteral dosage form that allows a reduction in 
dosing frequency as compared to that presented by a conventional injectable dosage form. 
 
Non-release-controlling excipient:  An inactive ingredient in the final dosage form that does 
not significantly affect the release of the active drug substance from the dosage form. 
 
Release-controlling excipient:  An inactive ingredient in the final dosage form that functions 
primarily to extend the release of the active drug substance from the dosage form. 
 
Release rate:  Amount of drug released per unit of time as defined by in vitro or in vivo testing. 
 
Sink conditions:  A situation in drug release methods in which the solubility of the drug in the 
dissolution medium does not limit the rate at which the drug may partition to the dissolution 
medium from the dosage form.  This is defined as the volume of fluid necessary to insure that the 
concentration of drug in the medium at 100% release does not exceed one-third of the saturation 
concentration. 
 
Statistical moments:  Parameters that describe the characteristics of the time courses of plasma 
concentration (area, mean residence time, and variance of mean residence time) and urinary 
excretion rate. 
 
T :  time to peak concentration. 
max
   
16  Contains Nonbinding Recommendations 
XI.  BIBLIOGRAPHY 
                                          
i CDER/CBER GFI Q8(R2) Pharmaceutical Development, November 2009. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM073507.pdf 
 
ii CVM GFI #132, Administrative Applications and the Phased Review Process, May 2015. 
http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052532.pdf 
 
iii Shen J, Burgess DJ, 2012.  Accelerated in-vitro release testing methods for extended-release 
parenteral dosage forms. Journal of Pharmacy and Pharmacology 64(7):986-96. 
 
iv United States Pharmacopoeia 38 (2015) Chapter <711> Dissolution. The United States 
Pharmacopeial Convention, Rockville, MD.  http://www.usp.org/ 
 
v United States Pharmacopoeia 38 (2015) Chapter <724> Drug Release. The United States 
Pharmacopeial Convention, Rockville, MD.  http://www.usp.org/ 
 
vi United States Pharmacopoeia 38 (2015) Chapter <1225> Validation of Compendial 
Procedures. The United States Pharmacopeial Convention, Rockville, MD.  http://www.usp.org/ 
 
vii CVM GFI #64/VICH GL2, Validation of Analytical Procedures:  Methodology, July 1999. 
http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/Guidancef
orIndustry/UCM052379.pdf 
 
viii Polli, JE, 2000. IVIVR versus IVIVC. Dissolution Technology 7:6-9. 
 
ix DSouza SS and DeLuca PP, 2005.  Development of a dialysis in vitro release method for 
biodegradable microspheres. AAPS PharmSciTech 6:E323-E328. 
 
x Rawat A, Bhardwaj U, Burgess DJ, 2012. Comparison of in vitro-in vivo release of 
Risperdal() Consta() microspheres. International Journal of Pharmaceutics 434(1-2):115-21. 
 
xi CDER GFI, SUPAC-MR:  Modified Release Solid Oral Dosage Forms, September 1997. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM070640.pdf 
 
xii Ravivarapu HB, Moyer KL, and Dunn RL, 2000.  Sustained suppression of pituitary-gonadal 
axis with an injectable, in situ forming implant of leuprolide acetate. Journal of Pharmaceutical 
Sciences 89:732-741. 
 
xiii CDER GFI, Extended Release Oral Dosage Forms:  Development, Evaluation, and 
Application of In Vitro/In Vivo Correlations, September 1997.  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM070239.pdf 
 
17  Contains Nonbinding Recommendations 
                                                                                                                                      
xiv Emami, J, 2006. In vitro-in vivo correlations:  from theory to applications. Journal of 
Pharmacy and Pharmaceutical Sciences 9:169-189. 
 
xv Tsong, Y, Sathe PM, Hammerstrom T, and Shah VP, 1996.  Statistical assessment of mean 
differences between two dissolution data sets. Drug Information Journal 30:1105-1112. 
18