dx.doi.org/10.14227/DT220415P46
Meeting Report:
Profiling of Drug Dissolution,
Pharmacokinetics and Pharmacodynamics
Vivian A. Gray1 and Kim Huynh-Ba2
1Dissolution
Technologies, Hockessin, DE, USA
Newark, DE, USA
2Pharmalytik,
T
he AAPS In Vitro Release and Dissolution Testing
Focus Group cosponsored, along with the PROTEMP
Group, a two-day workshop on Profiling of Drug
Dissolution, Pharmacokinetics, and Pharmacodynamics,
held in Kuala Lumpur, Malaysia, on September 2–3, 2015.
The organizing institutions were the Non-Destructive
Biomedical and Pharmaceutical Research Centre,
iPROMISE, Universiti Teknologi MARA, and the University
of Bath, UK. The goals and objectives of the workshop
were:
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•
•
•
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Share knowledge on critical relationships
between dissolution, pharmacokinetics (PK),
pharmacodynamics (PD), and in vitro–in vivo
relationship analysis.
Present Malaysia research activities and
collaborations in dissolution, PK, and PD
topics.
Network for research collaboration,
knowledge sharing, education, and
industry exchange in dissolution, PK,
and PD topics.
Disseminate Malaysian regulatory
information for dissolution testing.
Provide information on dissolution method
development, cGMP, and product stability
issues.
Members of the Program Committee were Wong Tin Wui
(Universiti Teknologi MARA), Nikoletta Fotaki (University
of Bath), and Denise Ang (PROTEMP Group).
In their opening remarks, Nikoletta Fotaki and Wong
Tin Wui reiterated the goals of the workshop and set the
stage for the first session.
Sumitha Ganasegaram gave the first talk, titled
“Regulatory Control of Generic Pharmaceuticals in
Malaysia.” She began by discussing the regulatory
framework in Malaysia. The Control of Drugs and Cosmetic
Regulation (CDCR) was established with Drug Control
Authority (DCA) to regulate the pharmaceutical industry.
The DCA is the executive committee responsible for
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e-mail: vagray@rcn.com
product registration and licensing activities. The National
Pharmaceutical Control Bureau (NPCB) carries out these
activities. The Drug Registration Guidance Document
(DRGD) is the parent guidance document to implement
Malaysian regulatory requirements. She mentioned the
Pharmaceutical Product Working Group established under
the Association of Southeast Asian Nations (ASEAN) that
has established many harmonization guidances adapted
from the International Conference of Harmonization
(ICH). She went on to describe the data requirements for
generic pharmaceuticals. The efficacy data requirements
include bioequivalence studies that follow two guidelines,
the ASEAN Guideline for the Conduct of Bioavailability
and Bioequivalence Studies and the FDA Guidance on the
Biopharmaceutics Classification System. She described
the challenges with generic approvals that include
issues with comparators, biowaivers, and grandfathered
products. She recommended an open dialogue and
engagement with NPCB.
Sandra Klein (University of Greifswald) spoke on “Basic
Principles of Compendial Dissolution Testing.” She began
by stating that dissolution testing is a very important
tool in drug development and quality control. According
to the United States Pharmacopeia, dissolution testing is
required for all non-solution oral, including sublingual,
pharmacopeial dosage forms in which absorption of the
drug is necessary for the product to exert the desired
therapeutic effect. Compendial dissolution testing
should be conducted on equipment that conforms to
pharmacopeial requirements. The choice of apparatus
should be based on knowledge of the formulation and
actual dosage form performance in the in vitro test
system. This presentation gave detailed information on
how to select the right test equipment, how to calibrate
it, and how to avoid typical mistakes in routine dissolution
testing.
The next speaker was Vivian Gray (V. A. Gray Consulting),
whose talk was titled “Method Development and Setting
Clinically Relevant Dissolution Specifications, Including
Quality by Design.” Her talk gave principles needed to
develop a meaningful dissolution test, one that follows
the concepts of QbD. The emphasis was on understanding
the product release mechanism and knowing the critical
quality attributes, leading to clinically relevant dissolution
specifications. The important aspects of method
development were discussed in detail, including selection
of filters, media, time points, volumes, apparatus, and
other aspects of method development. The use of
surfactants, sinkers, deaeration, and infinity points was
discussed. An introduction to the attributes of a clinically
relevant method along with design of experiments (DOE)
was provided. The role of variability was discussed, and
ways to minimize it were explored.
The afternoon session began with Vivian Gray giving an
overview of the America Association of Pharmaceutical
Scientists (AAPS), the U.S. organization that cosponsored
the event. She highlighted the availability of e-membership
for Malaysian scientists and the resources that AAPS
offers.
The next speaker, Sandra Klein, spoke on “Designing
Predictive Dissolution Test Methods for ImmediateRelease Formulations.” She first asked if simulation of
gastrointestinal conditions is essential to adequately
predict the in vivo behavior of drug formulations. To
reduce the size and number of human studies required
to identify a drug product with appropriate performance,
it would be advantageous to be able to prescreen
formulations in vitro. For this purpose, the choice of both
appropriate media and instrumental settings are crucial to
forecast the in vivo performance of the test formulation.
This presentation focused on how to develop predictive in
vitro studies for oral IR formulations and gave an outlook
on how to further improve the predictability of the in vivo
performance of oral drug formulations with particular
respect to various population subgroups.
Nikoletta Fotaki continued the program with “Designing
Predictive Dissolution Test Methods for Modified-Release
Formulations.” She began by stating that the prediction of
in vivo performance of oral modified-release (MR) dosage
forms based on in vitro release testing is challenging. An
in vitro release test based on physiological parameters
and properties of the API and the MR dosage form can
be used as a surrogate for the in vivo performance of
the dosage form. The characteristics of release and the
rationale on designing predictive in vitro release tests for
MR formulations were discussed. Several case studies
were presented.
Johannes Krämer (PHAST) presented the last talk
of the session, “Interchangeability of Multisource
Products—How to Use In Vitro Methodology.” This talk
began with several definitions such as interchangeability,
pharmaceutical equivalence, bioavailability, drug product
performance, and bioequivalence. The experimental
design of dissolution testing for product comparison
was provided. In the case of BCS Class 2 and sometimes
Class 4 drugs, dissolution may be considered the ratelimiting step for the bioavailability of the drug. Hence,
a relationship between in vitro performance (i.e.,
dissolution) and in vivo performance may be established.
In principle, this relationship is only valid for one particular
product and one defined in vitro dissolution method
including its specifications. This is commonly expressed
as an in vitro–in vivo correlation (IVIVC). An example of in
vitro and in vivo performance was discussed. He went on
to show that BCS is linked to dissolution and absorption
factors Dn, D0, and An. The challenge is to extend it to
a group of products with generic properties. When the
drug substance, its content, and the dosage form are
equivalent, it is likely that the IVIVC can be extrapolated to
more than one product. In those cases when the dosage
forms are designed with different release-controlling
mechanisms, the likelihood of a successful extrapolation is
low. This applies to the so-called modified-release dosage
forms, including delayed- and extended-release (in the
EU: prolonged-release) dosage forms. He concluded
by instructing that the USP General Chapter <1092>
Dissolution Method Development and Validation as well
as <1088> In Vitro and In Vivo Evaluation of Dosage Forms
provide guidance for pharmaceutical development.
On the second day, Johannes Krämer started the
workshop with a presentation entitled “IVIVC According
to USP General Chapter <1088> In Vitro and In Vivo
Evaluation of Dosage Forms.” Since the days of Gerhard
Levy in the early 1960s, a relationship between in vitro
performance and the corresponding in vivo performance
of oral drug products for systemic action has been
established in pharmaceutical science. In vitro dissolution
has been considered a quality control tool to ascertain
a required manufacturing quality. Johannes indicated
that in vitro dissolution may also provide meaningful
results on the in vivo performance of a certain product.
This characteristic can be related to its bioavailability. As
in clinical bioequivalence testing, in vitro performance
testing may only prove similarity provided it has
discriminatory power.
Nikoletta Fotaki gave the next talk on “Prediction
of In Vivo Performance from In Vitro Dissolution
Using In Silico Models.” She noted that during drug
development, approximately 40% of new compounds fail
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in the late clinical phases because of pharmacokinetics
problems. Therefore, the successful prediction of
human pharmacokinetics during preclinical research is
of great importance. Recently, a physiologically based
pharmacokinetic modeling (PBPK) approach has been
used as a mechanistic quantitative platform for prediction
of potential human absorption/bioavailability and for
formulation development. Nikoletta discussed the use
of biorelevant in vitro data within a physiologically based
pharmacokinetic (PBPK) model environment for the
prediction of in vivo performance and presented several
case studies to demonstrate the predictability of the
developed models.
Lo Yoke Lin (Universiti Malaya, Malaysia) presented the
“Application of Population Pharmacokinetic Modeling
in Clinical Trials.” The study of pharmacokinetic
and pharmacy–dynamic properties of a drug is an
essential ingredient in the development of a drug and
its clinical use. Plasma drug concentration variability
among subjects when standard dosage regimens are
administered is an important aspect in drug treatment.
Population pharmacokinetics modeling and simulation
assess the within-subject and between-subject
pharmacokinetics variability. This population approach
also helps to identify and quantify factors affecting the
pharmacokinetics processes in a target population. The
population-modeling approach has become a useful tool
in all phases of clinical trials during drug development
(Phase I, II, and III) as well as in clinical studies of patient
populations where intensive blood sampling may be an
issue; for instance, in young children including premature
neonates. Indeed, a well-designed, executed, and
evaluated population pharmacokinetics model can be
used to save time and money by pooling and integrating
all information collected from various clinical trials on the
drug of interest.
Wong Tin Wui continued the workshop by presenting
an interesting talk entitled “Development of Oral ColonSpecific Drug Delivery System—In Vitro Drug Release,
In Vivo Pharmacokinetics and Pharmacodynamics
Studies.” Pectin is a natural heteropolysaccharide made
of 1,4-linked α-D-galactosyluronic acid residues and a
range of neutral sugars such as rhamnose, galactose,
arabinose, and lesser amounts of others. It is available
in the form of free acid, simple salt such as sodium,
potassium, and calcium salts, methyl ester, acetylester,
feruloylester, or amidated polysaccharide. Pectin can
form a gel matrix through pH and cationic cross-linkage
modulation; therefore, it is useful as a colon-specific drug
delivery vehicle. The polymer chains can be selectively
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digested by microflora in the colon to elicit site-specific
drug release. It has the potential to keep the colon
healthy, namely in the prevention of colon cancer. Colon
cancer refers to cancerous growth in colon, rectum, or
cecum. Typical chemotherapy is provided by the injection
route to reduce tumor growth and metastasis. Recent
research investigated the feasibility of oral delivery of
chemotherapeutic agents. In comparison to injection,
oral administration of drugs in the form of a colon-specific
delivery system is expected to increase drug bioavailability
at the target site and reduce drug dose and systemic
adverse effects. He reviewed the physicochemical
attributes of formulation/conjugation needed to retard
drug release from the pectin matrix prior to its arrival at
the colon and evaluated the therapeutic value of pectin in
association with colon cancer. A multi-particulate pectin
matrix is an ideal carrier to orally deliver drugs for the sitespecific treatment of colon cancer. Such a carrier has a
slower transit and a higher contact time for drug action
in the colon than a single-unit dosage form. Tin Wui also
highlighted the recent approach where an in vivo coating
was adopted to equip the multi-particulate pectin
matrix with colon-specific drug release characteristics
and the critical relationship between drug release,
pharmacokinetics, and pharmacodynamics.
In the afternoon, Kim Huynh-Ba (Pharmalytik) discussed
the “Regulatory Requirements of Stability Testing for
Pharmaceutical Products.” Although, the attendees were
mainly clinical professionals, many have encountered GMP
issues as stability data are obtained to determine the shelf
life of the pharmaceutical product as well as establish the
product specifications. Therefore, a sustainable stability
program is critical to new pharmaceutical product
registration. She discussed the ASEAN, WHO, and ICH
stability requirements in designing a global program that
can expedite a new product application. The emphasis
is based on multisource/generic products. She also
discussed climatic-zone, stress-study, and photo-stability
requirements to support establishment of a stability
profile of the product.
Vivian Gray continued the program speaking on “Gelatin
Capsules: Current Issues When Cross-Linking Is Observed
Related to the Addition of Enzyme to Media.” Her
presentation discussed the history behind the allowance
of the use of enzymes in the dissolution testing of gelatin
capsules and gelatin-coated tablets (sometimes known
as Two-Tier testing). The current instructions in the USP
General Chapter <711> Dissolution are not very clear and
pose some challenges; therefore, the chapter is being
revised. The new revision includes the use of enzymes,
pepsin, and surfactants that denature the enzyme. She
also pointed out that this revision may not be harmonized
with the European and Japanese Pharmacopoeia. She
further explained that the USP General Chapter <1094>
Capsules: Dissolution Testing and Related Quality
Attributes became official on August 1, 2014, in the First
Supplement to USP 37. Further changes are anticipated,
and implementation processes will be discussed.
At the close of the workshop, Kim Huynh-Ba presented
“Key Factors to Effectively Comply with Current
Good Manufacturing Practices (GMPs).” GMPs are
mandatory in the manufacturing of pharmaceutical
products. She discussed critical GMP regulations and
key factors to understand current compliance issues in
the pharmaceutical industry. The major focus was on
laboratory issues and related quality systems that can
have a positive or negative effect on an organization.
She introduced selected critical GMP requirements
and discussed issues that are caused by an ineffective
training program. She also gave updates on key issues
with method validation and new initiatives emphasizing
lifecycle management for analytical procedures. She also
discussed documentation system infractions and the
generation and evaluation of data.
Vivian Gray closed the workshop with remarks of
thanks to the Malaysian organizers and speakers and
appreciation for the fine hospitality shown to the AAPS
Focus Group speakers. She remarked on the high quality
of the presentations and thanked the organizers for the
excellent job. The participants were very enthusiastic and
engaged in the discussion, which indicated the workshop
was a success.
There were 63 attendees from nine countries: Malaysia,
Libya, Japan, Singapore, Indonesia, Pakistan, Syria, Yemen,
and Australia. There were 34 delegates from universities,
23 delegates from industry, and 6 from government.
Workshop Attendees
Workshop speakers (left to right): Nikoletta Fotaki,
Kim Huynh-Ba, Sandra Klein, Johannes Krämer,
Vivian Gray, Wong Tin Wui, and Lo Yoke Lin.
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