APR May/June 2022 - 24

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ROUNDTABLE
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course, new products or excipients that reduce or eliminate legacy
limitations are always welcome.
Jim Huang, PhD, CEO, Ascendia Pharmaceuticals: Pharmaceutical
companies developing Controlled Release (CR) products want to
increase the success rate of CR at the preclinical and clinical stages,
as well as during commercialization and life cycle management.
Formulation robustness is important in-vitro and in-vivo but also to
establish IVIVR/IVIVC to reduce the biostudy burden in case of minor
changes in formulation, process and other SUPAC changes. They are
also looking to partner with a CDMO who can help create IP to further
strengthen their marketing position and life cycle management.
Tiwari: Drug products including controlled release products are
produced in a manner that ensures their identity, safety, strength,
quality and purity. This requires consideration of the quality of all
ingredients in a drug product, including excipients. Excipients in a
drug product can impact drug substance solubility and permeability,
stability, release rate, and absorption. Variability in excipients,
especially controlled release excipients, therefore need to be part
of the formulation risk assessment. Working with excipient supplier
can facilitate the understanding of the impact of excipient variability
on drug product performance and identification of critical material
attributes for defining subsequent control strategy.
Collaboration
with Active Pharmaceutical Ingredient (API) and excipient suppliers
is the key to avoid future challenges with material supply as the
specifications for incoming raw materials need to be set based on
the manufacturing capabilities and control strategies used by the
supplier's operations teams and not based on the sole assessment of
pharmaceutical companies developing the products.
More recently US FDA has been mandating nitrosamine impurities risk
assessment of all marketed products and those products with pending
applications both for APIs and drug products. Such a risk assessment
necessitates collaboration with suppliers of API, excipients, and
packaging components so that information can be collected, and risk
analysis performed for the finished product and if the risk is identified
then control strategies are put in place to avoid costly recall scenarios.
BASF as an innovator excipient company had taken an early lead in this
area and made nitrosamine risk assessments available for its excipient
products for use by the pharmaceutical companies.
Moody: Modern pharmaceutical companies are looking for more than
a 'pair of hands' when it comes to development and manufacturing
of modified release products. As a leading development partner for
such companies, Catalent has, over many years, encountered a wide
range of product challenges and has acquired significant knowledge
in how to overcome them. Pharmaceutical company customers rightly
expect to be able to leverage that experience to streamline their
own product development programs. We also recognize that in the
current environment, where redundancy of supply is so important,
the modified release products that we develop at one site may have
to be manufactured at multiple other locations around the world.
So increasingly, our customers are looking for product and process
design data for a robust package as well as information pertaining
to raw materials and excipients that may impact product quality and
manufacturability. Finally, there is an increasing expectation among
pharmaceutical companies that their development partner use PBPK
modeling to guide modified release product development decisions.
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| May/June 2022
This often starts with in silico feasibility analysis to inform whether
modified release is the right strategy. Once established, a robust model
can be used to set specifications, analyze prototypes, and streamline
final form selection.
Chatterjee: One area where there is sustained interest in controlled
release solutions is the area of complex generics. Complex generics
must demonstrate bioequivalence with the innovator product, just as
any generic must do, but for drug formulators this is easier said than
done. Small changes in pharmaco-chemical characteristics can manifest
differently therapeutically. Complicating the picture is the need
to do a bridging study for any modified or controlled release drug formulation
since you cannot compare systemic bioequivalency directly.
These types of studies are larger and more costly than standard bioequivalency
studies. So, it is paramount that the drug sponsor have
confidence that their formulation will be comparable based upon
characterization and testing before embarking upon a costly and potentially
lengthy bridging study. Suppliers have not historically shared
the details of their full formulations or manufacturing processes, leaving
drug sponsors to design their processes based upon a very limited
level window of the possible material variation they could encounter.
As the industry begins to seriously consider the merits of continuous
manufacturing for finished drug products a supplier's ability to provide
information relating to their formulation, raw material characterization
and in-process tests will be essential to drug sponsors' ability to
consistently manufacture conforming product.
Kelly: Excipients with consistent quality and physical characteristics
play an integral role in drug release from controlled release products.
Drug release profiles may be affected by several factors including
polymer type and level, drug particle size, dose and solubility, ratio of
polymer to the drug, filler type and level, and ratio of polymer to filler.
To ensure reproducible batch-to-batch consistency it is important to
understand how any variability in these factors and the manufacturing
process could influence the release performance if inconsistency
occurs. A Quality by Design (QbD) approach is typically used to
identify and characterize the impact of varying process parameters
and determine the Critical Material Attributes (CMA) for the excipients
and rate-controlling polymers.
Using the right technology and choice of excipients, it is possible to
develop a stable formulation with reduced complexity and excellent
reproducibility. Partnership with suppliers of ingredients and
equipment is critical during the development phase to ensure that
the formulation and process parameters used during development
are transferable to commercial-scale equipment. Similarly, to avoid
future supply issues, formulators should discuss with suppliers before
putting in place any limiting specifications for ingredients.
Hayden Skalski, Lead Product Application Specialist - Biodetection,
Sievers Analytical Instruments: Companies developing controlled
release products, along with parenteral drug companies, will often
request data from suppliers or service providers to help them make
a decision on whether or not they will choose that particular supplier.
These companies want to make sure the product from the provider
works, that it is safe to use, and most importantly that it is compliant.
From my experience, the data that these companies want to see is data
to demonstrate how their specific product will work on the supplier/
APR May/June 2022

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