The FDA and European Medicines Agency (EMA) have indicated that the clinical testing requirements for a biosimilar drug can
be reduced if it can be demonstrated that the biosimilar candidate does not meaningfully differ from the innovator drug (45,
46). Currently developed biosimilars, such as human growth hormone, insulin, and erythropoietin, are chemically far simpler
than mAbs. It is unlikely that blood or plasma-derived products or complex vaccines will be acceptable as biosimilars in the
US or Europe due to their complexity (47). However, eight categories of biosimilar molecules have been manufactured in India,
including monoclonal antibodies and recombinant hepatitis B vaccine (48). The first monoclonal antibodies that will lose patent
protection in Europe and the US were made using more stringent impurity level targets than exist now because the technology
is more mature and the safety and efficacy is well established. For example, early mAbs had levels of high molecular weight
species below 0.5% (49). It is possible that mAbs in the future will target levels below 5% (50).
A new purification challenge will be to produce antibodies with product quality attributes that match the innovator antibodies.
This may be carried out with a host cell and/or purification process that differs from the innovators. A biosimilar antibody
can have different levels of impurity or product variant species than the innovator, if it can be justified. The biosimilar
manufacturer will determine the amount of clinical and characterization data that will be used to justify differences to the
agencies. Therefore each biosimilar manufacturer must balance the development costs required to match innovator antibody characteristics
against the costs of justifying differences. During development of biosimilar recombinant human growth hormone, higher levels
of host cell proteins lead to increased levels of antibodies to both host cell proteins and growth hormone. This necessitated
modifications to the purification process, which eventually allowed demonstration of comparability to the innovator and approval
by the EMA (51). The success of a biosimilar development program will benefit from robust, selective, and efficient purification
processes that require minimal development time and material.
IMPLEMENTING QUALITY BY DESIGN
The past decade has witnessed an increasing emphasis—by both industry and regulatory agencies—on implementing Quality by Design
(QbD) principles. In 2008, the FDA's Office of Biotechnology Products invited companies to participate in a pilot program
involving the submission of quality information for biotechnology products in an Expanded Change Protocol (52,53). The purpose
of the pilot program is "to gain more information on and facilitate agency review of QbD, risk-based approaches for manufacturing
biotechnology products". These approaches link "attributes and processes to product performance, safety and efficacy". The
concept of a design space has been introduced, which is defined as the multidimensional combination and interaction of input
variables and process parameters that have been shown to provide assurance of quality (54). The underlying principles of QbD
and risk management are contained in ICH Q8 (R2), Q9, and Q10 (50, 54–56).
A comprehensive case study of the application of QbD principles to the development of a mAb product (A-mAb) has recently been
published that describes extensive use of scale-down models to gain process and product knowledge (50). However, significant
data from scale-down models could be used to define the design space. In addition, data from triplicate studies performed
at pilot or commercial scale using center-point conditions could ensure that product quality and process performance were
not impacted by the process change.
Significant questions and challenges remain in implementing QbD. While there is agreement on the value of process and product
understanding, there is often debate within most biopharmaceutical companies on the extent of QbD investment and underlying
cost implications. Several technical hurdles need to be overcome to define methodologies to describe a design space and control
strategy. Quality systems need to be developed that will enable the movement within a design space. Furthermore, as different
regulatory agencies embrace QbD along different timelines, how will that affect a global submission? Finally how will QbD
apply to more challenging large molecules such as vaccines? People involved in process development will be involved in the
effort required to resolve many of these questions.
Biopharmaceutical development and manufacturing have evolved significantly in the past 25 years. Clinical and commercial pipelines
have evolved from replacement proteins and other therapeutic proteins/hormones to mAbs. Technological advances in bioprocessing
have led to tremendous increases in product and cell mass that in turn have posed several challenges to downstream process
development of mAbs. Novel approaches to downstream processing, such as development of highly efficient platforms, HTS tools,
and reduction in the number of unit operations have helped to address these challenges. In the future, mAbs may represent
a smaller percentage of the pipelines and the challenges to downstream processing will likely have a different focus. Most
product portfolios will likely include other complex biomolecules, such as conjugated proteins and vaccines, a variety of
biosimilar protein therapeutics, and novel scaffolds such as fusion proteins, nanobodies, etc. Future expression systems may
include microbial, yeast, and others in addition to high cell density mammalian systems. The diversity of scaffolds and expression
systems will pose unique challenges for downstream development. Novel tools, approaches and/or platforms may need to be applied
to enable rapid development. Furthermore, there is a need to develop paradigms to apply QbD not only to mAbs but also to other
BERNARD N. VIOLAND is a research fellow, GLEN R. BOLTON is senior principal scientist, RICHARD S. WRIGHT is senior principal scientist, SHUJUN SUN is senior principal scientist, KHURRAM M. SUNASARA is senior principal scientist, KATHLEEN WATSON is associate director, JONATHAN L. COFFMAN is associate research fellow, CHRISTOPHER GALLO is associate research fellow, and RANGA GODAVARTI* is senior director, all from Pfizer.