The document discusses generic drugs and dissolution testing. It notes that some generic products pass dissolution testing using their own methods but fail comparative dissolution testing against innovator products in different pH mediums. Proper dissolution method development is important to demonstrate a method's ability to detect manufacturing variations. The document emphasizes that generic drugs should show similar dissolution profiles to innovator products in different pH environments to help ensure similar clinical responses. It also stresses the importance of methods being able to discriminate between formulations and catch impacts of manufacturing changes.

1. GENERIC DRUGS
Comparative Dissolution Profile
&
Discriminative Method for Dissolution
Roohi B. Obaid
Civil Service Officer/Deputy Director
At Drug Regulatory Authority of Pakistan
February 2017
Disclaimer:
It is written and judged in the best of author's professional knowledge, experience and education.
It has nothing to do with the organization or societies to which author is associated, so there is
no obligation to the author's organization or societies on the document. It represents current
thinking of the author on the subject. Within the boundary of good science, critical thinking and
comment with reference will always be respected
Narrowing the Confusions and Promoting Discussions based on Science

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Table of Contents
S. No Title Page No.
A Problem Statement 3
B Potential Hazards Scale 3
C Dissolution Test & Formulation 3
C-1 Background 4
C-2 Surrogate Marker 4
C-3 Dissolution Method and Manufacturing Process 5
C-4 Method Development 5
C-4-1 Method Evaluation 6
C-4-2 Discriminating Power 6
C-4-3 Acceptance Criteria 6
C-5 Common Deficiencies 6
D Way Forward 6
E Project Designing and Regulatory Initiatives 7
F Note 7
G Reference 7
H Key Words 7

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A. Problem Statement:
In some cases generic products lot to lot qualifies dissolution test with manufacturer method and
specification but fail in comparative dissolution profile with innovator in three different extreme
pH mediums narrated from the pH range across the Gastrointestinal Tract (GIT). An attempt is
being made to unfold the cases and bring it under microscope for its resolution as under:
1. They fail on conducting dissolution test when Pharmacopeia method and specifications
are applied mainly due to weak product development practices or/and non-robust
formulation or/and at time of its scale up.
2. They do not qualify the Comparative Dissolution Profile with the Innovator in all the
three mediums in terms of their release pattern, that otherwise must be similar to the
profile of Innovator.
3. They are not capable to demonstrate discriminating power of dissolution method to
detect/catch any variation in the manufacturing process and attribute of quality
parameters.
B. Potential Hazards Scale:
Clinical responses are based on the availability of drug and its release pattern in the biological
system. If clinical response is underlined and carries probability of irreversible damage, then the
hazards can be severe and immeasurable. If clinical response is measureable and carries
probability of irreversible damage, then the hazards can be severe and measureable. In the same
way, potential hazards may elevate the knowledge level to understand the threat on safety of
consumer associated with the quality of drugs.
C. Dissolution Test and Formulation:
Historically, dissolution test was a quality parameter; with the passage of time it has emerged as
a critical quality attribute of the drug product measuring the strength of dosage form. Generic
drugs require data to support product safety and efficacy for which dissolution testing is used as
one of the important tools. It is used both in stability and batch release purposes mainly for oral
solid dosage forms. This dissolution testing reduces regulatory burden for the pharmaceutical
industry and unnecessary human studies. It has emerged as a vital tool for generic industry to
monitor and control manufacturing process.

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C-1 Background:
Critical quality attributes of the drug formulation are focused to control its quality. This is
the way to strengthen the predictability about its clinical performance. Dissolution is one
of the critical quality attribute that explains availability of the drug in GIT for its
permeability and absorption. Clinical responses of a drug depend upon its availability in
blood stream reaching to the site of action. If an "In-Vitro In-Vivo Correlation" (IVIVC)
has been established, it is predicted that the drug will be dissolved and will be available
in the bloodstream for its intended action, otherwise its availability for intended action is
not guaranteed. Solubility of the drug is the fundamental attribute but has potential to be
affected otherwise due to its formulation or/and during manufacturing. Permeability at
GIT depends on behavior of drug in different pH of GIT as well as the physiological
system. Altogether solubility of drug, its dissolution from formulation at extreme range of
GIT pH and permeability are the fundamental components to decide requirement of
bioequivalence study or its waiver upon compliance of comparative dissolution profile
with the innovator.
C-2 Surrogate Marker:
As a matter of good science, every generic drug is not subject to clinical studies.
Availability of drug in the bloodstream with the pattern similar to the innovator is
reasonably sufficient to guarantee its pharmacological actions or dynamics. This
similarity is defined to declare equivalency and subsequent confidence for its
substitution. In some cases, where substitution is not justified, the evidences, clinical
experience are placed to understand the science behind and accordingly concluded. To
determine the similarity, bioequivalence (measurement of drug pattern in bloodstream of
both innovator and generic for comparison) study is required. In drugs where molecule is
highly soluble, formulation is capable to deliver ions of drug in free form and permeable
throughout the diversified extreme GIT pH, bioequivalence study does not add any value
but becomes a bumper in approval process as well as unreasonable exposure of drug to
the healthy volunteers. Science always came with rational and good science creates
balance between absolute and practical working range especially in the field of

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pharmaceutical regulation. These scientific decisions certainly adopt outcome of clinical
studies and may be termed as surrogate of clinical studies done by the innovator.
C-3 Dissolution Method and Manufacturing Process:
The importance of dissolution method and manufacturing process that impacts on
dissolution are vital and require careful attention. For a generic product it is a prerequisite
to demonstrate release pattern of the formulation similar to the innovator. Sometimes,
generic product does not follow the release pattern completely with the innovator, e.g. it
may release more at some time point while less at the other, however, at the end it
complies with the innovator and is released 80% in 30 min. thus, there is not a uniform
release pattern. This may lead to adverse clinical response in some cases e.g. Bupripion
which resulted in suicide desire/attempt of some patients taking the drug.
It is necessary to keep in mind that all clinical studies have been done by the innovator to
conclude label claims. Direct relation of physiological response with the release pattern
of drug inside the biological system has already been established through stringent review
and evaluation process of innovator's application. Generic needs to undergo competitive
testing of dissolution with innovator product at all extreme pH of GIT. Moreover, release
of every batch of generic drug product requires compliance of dissolution test by the
method sensitive to catch impact of change of any critical quality attribute of substance
and critical processing parameter of manufacturing process. These changes may include
changes in the formulation, in the manufacturing process, the manufacturing site, change
in equipment and the alteration in batch size(s). So, discriminative property of dissolution
method is indispensible. To qualify the dissolution method, ability to visualize change
carrying potential to impact dissolution in diversified pH mediums of GIT is essential.
Expanding knowledge and understanding of dissolution science and mechanism is
gaining attention of both regulatory authority and pharmaceutical industry.
C-4 Method Development:
Dissolution testing is one of the important attributes of formulation to control batch to
batch consistency and conformance with specifications. It supports in explaining the post

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approval variations on ultimate quality features of drug product. This mainly covers role
of process parameters, material attributes and formulation variables.
Components of method development covers method evaluation, discriminating power
and acceptance criteria.
C-4-1 Method Evaluation: Apparatus selection, dissolution media, rotation
speed, solubility profile, selection rational of surfactant are the key attributes for
evaluation of method.
C-4-2 Discriminating Power: Meaningful variations of different formulations
for the most relevant manufacturing variables need to be assessed on the scale of
dissolution method that can differentiate formulations from its release pattern.
C-4-3 Acceptance Criteria: The selection of time points should be the points
where 80% of the drug is dissolved.
C-5 Common Deficiencies:
Information on critical material attributes and process parameters is limited and thus
proposed method of dissolution is not able to demonstrate its discriminative power.
Lacking of substantial data to support acceptance criteria. Assumption of delivering
promised clinical response (based on compliance of dissolution test by using a method
that is not capable to demonstrate its discriminating power and/or without conducting
comparative dissolution profile) is a matter of risk and its severity depends on the nature
of drug under question. Use of a 6 station dissolution apparatus instead of a 12 station, for
conducting comparative dissolution profile may have tendency to give variance in results.
D. Way Forward:
Classification of drug products with logical setting of priority to conduct comparative dissolution
profile with innovator is the first step. Subsequently, innovator brands also require comparative
dissolution profile if formulation development is done or/and reference is manufactured at any
other site.

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Sensitivity of dissolution test to discriminate among the formulations need to be assessed so that
its application in end product testing of every batch be safe guarded for the intended purpose.
E. Project Designing and Regulatory Initiatives:
A balanced approach and efficient tools may be identified and designed to move in a trustworthy,
transparent, result oriented, knowledge based manner.
F. Note:
A drug is considered rapidly dissolving when 85% or more than 85% of the labeled amount
dissolves within 30 minutes while using a USP Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm
in a volume of 900 ml or less of each medium.
a) 0.1 N HCl or simulated gastric fluid USP without enzymes
b) a pH 4.5 buffer
c) a pH 6.8 buffer or simulated intestinal fluid USP without enzymes
G: Reference:
Nothing extracted from anywhere but compiled from the knowledge gained during scientific
discussions, regulatory practice and extensive reading of materials on the subject.
H. Key Words:
Gastrointestinal Tract (GIT), Comparative Dissolution Profile (CDP), Bioequivalence (BE),
Bioavailability (BA), United States Pharmacopeia (USP).