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78
Trends in Recombinant Proteins Manufacturing
FIGURE 4.5 A continuous manufacturing system for the production of therapeutic proteins
Source: FDA
the protein is secreted into the culture medium. This process helps improve the yield of labile
proteins and prevents inconsistent post- translational modications while maintaining cells at higher
viabilities, which is a critical factor. Apart from material costs, it reduces the need for testing, adding
signicant cost and time savings (Figures 4.4 and 4.5).
The quest for a CM process has been in research for several years1; however, it was in March
2023 when the FDA released its rst guidance on CM addressing the scientic and legal issues that
arise during the creation, installation, operation, and lifecycle management of CM for chemical and
biological drugs. Figure 4.5 shows a owchart for manufacturing in a CM for a therapeutic protein.
The FDA also identies other guidelines that control CM.
The setup consists of unit operations such as a bioreactor compatible with a perfusion culture
system, continuous capture chromatography, virus ltration, virus inactivation, and buffer exchange
and concentration through TFF chromatography columns. Each unit operation is integrated with
adjacent unit operations, a surge line, or a tank connecting unit operations. Diversion points D1
and PAT (T1) are located after chromatography (Chrom #1). Using a surge line or tank allows
continuous operations to accommodate differences in mass ow rates or process dynamics. Unit
operations can be integrated as necessary.
The CM process continuously feeds input materials into, transforming in- process materials
within, and simultaneously removing output materials from a manufacturing process in an
integrated system involving two or more unit operations, regardless of their nature. The batch size
produced by CM is dened as the quantity of the output material, the quantity of the input material,
and run time (minimum or maximum) at a dened mass ow rate. In CM processes, a single thaw
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Trends in Recombinant Proteins Manufacturing
79
of one or multiple vials from the same cell bank may result in single or numerous harvests. The
number or range of cell bank vials used to produce the specied drug substance batches should be
dened. The cell bank vials should be traceable to the output drug substance batches. The FDA
guidance also details how the electronic Common Technical Document (eCTD) ling should be
managed for the CM process, making it possible for biosimilar developers to plan the process
change properly. This technology can be applied to proteins that are secreted or made to secrete
using E. coli (Table 4.6).
CM of chemical and biological products has long been a goal to optimize the cost of manufacturing; however, the cGMP compliance issues had pushed it back until March 2023, when the
FDA released the rst guideline to advise how to develop and adopt CM, particularly the biological
products. CM requires a perfusion system, and it can be designed to use E. coli, which will be a
better choice over CHO cells because of a much shorter batch cycle, generally a few hours than
weeks for the CHO cells. In E. coli, the proteins can be directed to the cytoplasm, periplasm, or
secreted directly into the culture media, offering several choices on routing the recombinant protein
exploiting the features of each cellular compartment and the protein produced.
The quest for a CM process has been in research for several years.2 While the FDA is yet to
approve a biological product manufactured in a continuous system, it anticipates much interest.
Consequently, in March 2023, the FDA released its rst guidance on CM3 addressing the scientic and regulatory issues, including the eCTD ling structure, which arose during the designing,
installation, operation, and lifecycle management of CM for chemical and biological drugs. This
guideline has opened the path to continuous systems over batch systems, which will signicantly
inuence the development and production cost and the stability of proteins and cause a signicant
reduction in the size of the bioreactors. The FDA also identies other guidelines that control CM.
The recombinant protein technology executed as a batch process is the industry standard. However,
proteins can also be produced in a vessel, from which the yield is continuously removed, provided
the protein is secreted into the culture medium. It helps to improve the yield of labile proteins and
prevents inconsistent post- translational modications while maintaining cells at higher viabilities,
which is a critical factor. Apart from material costs, it reduces the need for reduced testing, adding
signicant cost and time savings.
TABLE 4.6
Therapeutic Proteins Secreted in Escherichia coli
Adiponectin receptor
Adiponectin
Alpha- amylase
Amylase
Antibacterial peptides
Antibodies
Antithrombin III
Bone morphogenetic protein (BMP)
Chimeric antigen receptor (CAR)
Cholecystokinin (CCK)
Chymosin (rennin)
Ciliary neurotrophic factor (CNTF)
Coagulation factor VIII
Colony- stimulating factor 1 (CSF- 1)
Connective tissue growth factor (CTGF)
(continued)
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Trends in Recombinant Proteins Manufacturing
TABLE 4.6 (Continued)
Therapeutic Proteins Secreted in Escherichia coli
Epidermal growth factor (EGF)
Erythropoietin (EPO)
Erythropoietin receptor (EPOR)
Factor IX
Factor VII
Factor VIII
Fibrinolytic enzymes
Fibroblast growth factor (FGF)
Follicle- stimulating hormone (FSH)
Glucagon- like peptide- 1 (GLP- 1)
Glucagon
Glucocerebrosidase
Glucokinase
Glutathione S- transferase (GST)
Granulocyte colony- stimulating factor (G- CSF)
Granulocyte colony- stimulating factor receptor (G- CSF receptor)
Granulocyte- macrophage colony- stimulating factor (GM- CSF)
Green uorescent protein (GFP)
Growth hormone (GH)
Hepatitis B surface antigen (HBsAg)
Hepatitis B surface antigen (HBsAg)
Human calcitonin
Human growth factor- 1 (HGF- 1)
Human growth hormone receptor antagonist (GHR antagonist)
Insulin- like growth factor 1 (IGF- 1)
Insulin- like growth factor 2 (IGF- 2)
Insulin- like growth factor- binding protein (IGFBP)
Insulin
Interferon alpha- 2b
Interferon beta- 1a
Interferon gamma (IFN- γ)
Interferon- alpha (IFN- α)
Interferon- beta (IFN- β)
Interferon- gamma (IFN- γ)
Interferon- lambda (IFN- λ)
Interleukin- 1 receptor antagonist (IL- 1RA)
Interleukin- 10 (IL- 10)
Interleukin- 11 (IL- 11)
Interleukin- 12 (IL- 12)
Interleukin- 13 (IL- 13)
Interleukin- 15 (IL- 15)
Interleukin- 17 (IL- 17)
Interleukin- 18 (IL- 18)
Interleukin- 2 (IL- 2)
Interleukin- 2 (IL- 2)
Interleukin- 4 (IL- 4)
Interleukin- 5 (IL- 5)
Interleukin- 6 (IL- 6)
Lactoferrin
Leptin
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Trends in Recombinant Proteins Manufacturing
TABLE 4.6 (Continued)
Therapeutic Proteins Secreted in Escherichia coli
Lipase
Matrix metalloproteinases (MMPs)
Nerve growth factor (NGF)
Nerve growth factor beta (NGF- β)
Nerve growth factor receptor (NGF receptor)
Oncolytic viruses
Osteopontin
Parathyroid hormone (PTH)
Platelet- derived growth factor (PDGF)
Relaxin- 2
Relaxin
Serine protease
Somatostatin receptor
Streptavidin
Streptococcal M protein
Streptokinase
Thrombopoietin (TPO)
Tissue plasminogen activator (tPA)
Transforming growth factor- beta (TGF- β)
Vascular endothelial growth factor (VEGF)
81
4.8 SUMMARY
Several regulatory advances include 3D printing of solid dosage forms, continuous batch manufacturing, and online in- process control in place of release testing. The role of articial intelligence and
machine learning will be heavily embedded in all manufacturing operations. SUT will eventually
replace the hard- lined systems once the regulatory agencies begin approving products manufactured
through SUT; more particularly, startups will adopt this approach.
NOTES
1 National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Board on
Chemical Sciences and Technology. Continuous Manufacturing for the Modernization of Pharmaceutical
Production: Proceedings of a Workshop. Washington (DC): National Academies Press (US); 2019 Jan 30.
PMID: 30994997.
2 National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Board on
Chemical Sciences and Technology. Continuous Manufacturing for the Modernization of Pharmaceutical
Production: Proceedings of a Workshop. Washington (DC): National Academies Press (US); 2019 Jan 30.
PMID: 30994997.
3 FDA. Q13 Continuous Manufacturing of Drug Substances and Drug Products www.fda.gov/ media/ 165 775/
downl oad
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Analytical Assessment of a
5
Biosimilar
5.1 INTRODUCTION
Analytical assessment of biosimilar candidates is the primary determinant of biosimilarity. Figure 5.1
shows the original Food and Drug Administration (FDA) pyramid that classied the tiers of development; in 2020, the FDA modied regulations to show a bigger role of analytical assessment,
yet it became obsolete when, in 2023, the US Congress amended the BPCIA and removed the
term “animal toxicology” and grouped it under nonclinical testing. Another major change was also
established in 2023 when the FDA agreed that no efcacy testing in patients is needed for molecules
that exhibit pharmacodynamic parameters (Figure 5.1).
Advancements in analytical instrumentation and a better understanding of proteins structure and
functional relationships have established analytical assessment as the most robust tool for comparing critical quality attributes with the reference product.
These quality attributes stem from both the product and the process, identiable and analyzable
now with methods millions of times more sensitive. Product- related attributes pertain to the inherent
expression property, often challenging or impossible to alter. Process- related attributes, on the other
hand, are linked to the entire manufacturing process, spanning from upstream and downstream to ll
and nish stages. These criteria, determined by the manufacturing process, become integral in the
release specication, ensuring compliance. Dening acceptance criteria for these quality attributes
can leverage requirements gleaned from testing the reference product. These criteria might be rooted
in legacy values, established injectable product practices, or a blend of both. However, a limitation arises when using pharmacopeial specications. The FDA prohibits their utilization for Drug
Substance (DS) or Drug Product (DP), despite their applicability in pharmacopeial methods, which
only necessitate verication without validation.
Proteins, in general, can manifest differences in three primary ways: (1) primary amino acid
sequence; (2) modications to amino acids, such as glycosylation or other side chain modications;
and (3) higher- order structure encompassing protein folding and interactions between proteins.
Amino acid alterations can introduce heterogeneity, posing challenges for control. Environmental
factors like light, temperature, moisture, packaging materials, container closure systems, and
delivery device materials can inuence protein modications and higher- order structure. Moreover,
process and product- related impurities might escalate the probability and severity of an immune
response to a protein product. Certain excipients could hinder comprehensive characterization of
the protein product.
Regulatory guidelines outline the assessment of analytical attributes required to demonstrate
a proposed biosimilar product’s eligibility for a marketing application submission. While these
guidelines specically target therapeutic protein products, the foundational scientic principles
82
DOI: 10.1201/9781003392026-5
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83
FIGURE 5.1 Methodologies for analytical assessment. Nupur N, Joshi S, Gulliarme D, Rathore AS.
(2022) Analytical similarity assessment of biosimilars: global regulatory landscape, recent studies and major
advancements in orthogonal platforms. Front Bioeng Biotechnol. 10: 832059. www.fron tier sin.org/ arti cle/
10.3389/ fbioe.2022.832 059. DOI: 10.3389/ fbioe.2022.832059
could extend to the development of other protein products, including in vivo protein diagnostic
products.
If the reference product lacks adequate characterization for pertinent analytical attributes,
developers might be unable to le a marketing authorization application.
As part of a comprehensive CMC data submission, an application must include analytical
studies showcasing the similarity of the proposed biosimilar product to the reference product. The
rationale behind the comparative analytical assessment should be clearly articulated, considering the
characteristics, known mechanism(s) of action, and function of the reference product.
The studies on physicochemical and functional characterization need to sufciently establish
the pertinent quality attributes, which encompass the dening elements of a product: its identity,
quantity, safety, purity, and potency. By analyzing the outcomes of analytical studies that evaluate
functional and physicochemical characteristics— such as higher- order structure, post- translational
modications, impurity, and degradation proles— developers can establish a scientically sound
basis for a targeted approach in subsequent animal and clinical studies to validate biosimilarity.
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Analytical Assessment
Employing a meaningful ngerprint- like analysis algorithm that encompasses various product
attributes and their combinations through highly sensitive orthogonal methods can aid in comparing
differences in quality attributes between a proposed biosimilar product and the reference product.
According to the International Council for Harmonisation (ICH) Q8(R2), leveraging enhanced
manufacturing science approaches can enable production processes that better align with the
attributes of a reference product (RP). Refer to the ICH guidance documents for industry Q8(R2)
Pharmaceutical Development (November 2009), Q9 Quality Risk Management (June 2006), Q10
Pharmaceutical Quality System (April 2009), and Q11 Development and Manufacture of Drug
Substances (November 2012) for guidance on advanced manufacturing approaches. This strategic
approach could further quantify the overall similarity between two molecules and potentially provide additional grounds for a more targeted and selective approach in subsequent animal and clinical
studies.
5.2 TESTING PLAN
The description and discussion of any differences— whether intentional or observed through comprehensive analytical characterization of multiple manufacturing lots— between a proposed biosimilar
product and the reference product must be clearly outlined. This discussion should encompass the
identication and comparison of pertinent quality attributes from product characterization. If necessary, the potential clinical implications of observed structural and functional differences between a
proposed biosimilar product and the reference product should be evaluated and supported by animal
or clinical studies.
5.3 SOURCES OF VARIATION
Analyzing critical quality attributes requires a comprehensive understanding of the sources of variation between a proposed biosimilar product and the reference product. A primary goal in biosimilar
development is to minimize differences between the proposed biosimilar product and the RP where
feasible. Some efforts towards this end involve modifying the expression system, upstream and
downstream processes, formulation, and manufacturing processes.
5.3.1 exPRession systeM
Therapeutic protein products can be created in various systems: microbial cells (prokaryotic or
eukaryotic), cell lines (such as mammalian, avian, insect, or plant), or tissues derived from animals
or plants. It is anticipated that the expression constructs for a proposed biosimilar product will carry
the same primary amino acid sequence as its reference product. Nevertheless, minor modications,
such as N- or C– terminal truncations (e.g., the heterogeneity of the C- terminal lysine of a monoclonal antibody), are not expected to alter the product performance. Such modications might be
justied and should be explained by the developer. Any potential differences between the selected
expression system (i.e., host cell and the expression construct) of a proposed biosimilar product
and that of the reference product should be carefully considered. This is because the chosen expression system will impact the types of process- and product- related substances, impurities, and
contaminants (including possible adventitious agents) that might exist in the protein product. For
instance, the expression system can signicantly inuence the types and degree of translational and
post- translational modications in a proposed biosimilar product, potentially introducing additional
uncertainties into the demonstration that a proposed biosimilar product is proposed biosimilar to the
reference product.
Minimizing disparities between the expression systems of a proposed biosimilar product and its
reference product to the fullest extent possible can increase the likelihood of producing a biosimilar
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protein product. The use of different expression systems will be assessed case by case. However,
developers should consider the extra testing burden required to validate an alternative expression
system. In the market, surveillance should place more emphasis on demonstrating the product’s
safety.
5.3.2 ManufactuRing PRocess
A comprehensive understanding of all stages in the manufacturing process for a proposed biosimilar
product must be established during product development. As a scientic imperative, characterization
tests, process controls, and specications derived from information gathered during process development must be tailored to a proposed biosimilar product and its manufacturing process. Advanced
pharmaceutical development approaches, combined with quality risk management and efcient
quality systems, will facilitate the consistent manufacture of a high- quality product. For guidance
on enhanced approaches in manufacturing science, refer to the ICH guidance for industry Q8(R2)
Pharmaceutical Development (November 2009), Q9 Quality Risk Management (June 2006), Q10
Pharmaceutical Quality System (April 2009), and Q11 Development and Manufacture of Drug
Substances (November 2012) for guidance on enhanced approaches in manufacturing science.
Developers contemplating manufacturing changes post- initial comparative analytical assessment
or after concluding clinical studies intended to support an application must establish comparability
between the pre- and post- change proposed biosimilar product. Depending on the nature and extent
of the changes, additional studies may be necessary. Comparative analytical studies should encompass a sufcient quantity of a proposed biosimilar product used in clinical studies and a proposed
commercial process if the process used for the clinical studies’ material differs.
Manufacturing processes can modify a protein product, impacting its safety and effectiveness.
For instance, variations in biological systems used for protein production can lead to diverse posttranslational modications, inuencing the safety and effectiveness of the nal product. Therefore, when
altering the manufacturing process of a marketed protein product, the applicant must evaluate the effects
of the change. This evaluation necessitates demonstrating, through suitable analytical testing, functional
assays, and in some cases, animal and clinical studies, that the modication does not negatively affect
the product’s identity, potency, quality, purity, or strength concerning its safety or effectiveness.
The ICH guidance for industry Q5E, titled “Comparability of Biotechnological/ Biological
Products Subject to Changes in Their Manufacturing Process,” outlines scientic principles for
assessing manufacturing changes. Establishing the biosimilarity of a proposed biosimilar product
to the reference product typically involves greater complexity compared to assessing the comparability of a product before and after manufacturing changes made by the same manufacturer. This
complexity arises from the extensive knowledge a manufacturer possesses about its manufacturing
process, including established controls and acceptance parameters. By contrast, the manufacturer
of a proposed biosimilar product is likely to employ a different manufacturing process (e.g., distinct cell lines, raw materials, equipment, processes, controls, and criteria) from that of the reference product. Moreover, they lack direct knowledge of the reference product’s manufacturing
process. Consequently, although some scientic principles in ICH Q5E may apply to demonstrating biosimilarity, regulatory agencies expect a greater need for data and information to establish biosimilarity than to demonstrate comparability following a manufacturer’s post- manufacturing
change. Additionally, ICH Q5E does not mandate the use of the reference product, rendering it
unsuitable for initially establishing biosimilarity.
5.3.3 stRuctuRal attRibutes
Structural attributes such as primary, secondary, and tertiary structures are dictated by the nature
of the recombinant expression engine. While a protein’s gene sequence determines its amino acid
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Analytical Assessment
sequence, post- translational modications occurring during quality control in the endoplasmic
reticulum (ER) and passage through the Golgi apparatus determine its nal structure and function.
These processes, specic to species and cells, present challenges to the biopharmaceutical industry
when developing a production platform for generating recombinant biologic therapeutics. Proteins
and glycoproteins (P/ GPs) are susceptible to chemical modications both in vivo and in vitro. The
body tolerates molecular forms of self- molecules, but non- self- variants can trigger an immune
response leading to the production of anti- drug antibodies (ADA). Aggregated forms may exhibit
increased immunogenicity, prompting efforts to avoid or eliminate them. Monoclonal antibody
therapeutics (mAbs) present a unique case because they aim to bind the target, forming immune
complexes (ICs) which represent a specic aggregate form. Phagocytic cells possessing antigenpresenting capacity may eliminate such ICs. These factors make it challenging to mitigate mAbs’
immunogenicity by strictly excluding aggregates from drug products.
Therapeutic antibodies possess various quality attributes, with FcRn binding and related structures
known to signicantly impact the product’s pharmacokinetic prole. Other attributes, such as antigen
binding, glycan structure, and isoelectric point, also potentially inuence the pharmacokinetics.
Validation lots representing the commercial process should be compared for structural variants.
If the primary structure mismatches, the cell line should be discarded, necessitating a fresh start.
Achieving the primary structure often leads to corresponding secondary and tertiary structures. Do
not use any public information data on structural attributes; only what is observed in a side- by- side
comparison with the reference product. At this stage, the analytical methods need only be suitable
and sensitive, not validated. Conducting testing simultaneously and side- by- side nullies any potential impact of the test method. Given minor variations and stringent acceptance criteria, extensive
testing with multiple lots is unnecessary.
If variability in post- translational and other modications arises during testing, developers should
rene the upstream and downstream processes to closely match the prole. However, achieving
an exact match might be unfeasible due to modications moving in opposite directions. The level
of match required depends on the product’s nature. For monoclonal antibodies, any differences
should be justied through additional studies, potentially necessitating clinical efcacy testing.
Post- translational modications serve as release specication attributes and demand multiple lots to
establish a reliable quality range.
5.3.4 functional attRibutes
Among the critical quality attributes of therapeutic antibodies, FcRn binding and related structures signicantly inuence the product’s pharmacokinetic prole. Additional attributes such as antigen binding,
glycan structure, and isoelectric point potentially impact the pharmacokinetic prole as well. However,
these attributes aren’t included in release specications; they are tested once to conrm similarity. As the
testing is done alongside the reference product, the need for method validation is eliminated. An equivalence margin approach, requiring 6– 10 lots (see below), is suggested to establish similarity.
5.3.5 PhysicocheMical PRoPeRties
When developers design and conduct characterization studies, addressing the concept of the desired
product (and its variants) as discussed in ICH Q6B becomes crucial. Understanding the heterogeneity between a proposed biosimilar and the reference product, including glycosylation levels,
isoform variability, and post- translational modications, is essential. Refer to the ICH guidance
for industry Q6B Specications: Test Procedures and Acceptance Criteria for Biotechnological/
Biological Products (August 1999).
Analytical methodologies assess specic physicochemical protein characteristics. These methods,
outlined in published documents like scientic literature, regulatory guidelines, and pharmacopeial
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compendia, often provide multifaceted information. Selecting appropriate analytical test methods
depends on the nature of the protein, knowledge about the structure, heterogeneity of the reference product, proposed biosimilar, and critical characteristics for product performance. Appendix 1
presents a representative example of test methods used by proposed biosimilar developers, provided
for reference purposes in applications to the FDA and EMA.
5.3.5.1 Aggregates
Although aggregates are generally considered immunogenic, for monoclonal antibodies,
establishing a range within which all lots must fall is necessary. An equivalence margin approach
is recommended for this release specication attribute, requiring multiple lots for a reliable quality
range. If a proposed biosimilar product exhibits lower aggregates, potential failure within the equivalence margin at the lower end is acceptable. However, it’s crucial to note that reference product
lots undergo time and transportation tests, potentially contributing to total aggregates. A proposed
biosimilar product won’t be considered a “biobetter” solely due to lower aggregates.
5.3.5.2 Impurities
Impurities are categorized as product- related or process- related. Active or inactive, productrelated impurities must be classied based on available literature data. Any impurity not present
in the reference product should be fully characterized regardless of its source due to potential immunogenicity. Developers should prioritize removing such impurities through process
changes rather than justifying their safety, which may necessitate additional nonclinical or clinical studies.
Characterizing, identifying, and quantifying product- related impurities in both the proposed
biosimilar and reference product, to the extent feasible, is essential. If a comparative analysis
reveals similar levels of comparable product- related impurities between the proposed biosimilar
and reference product, additional pharmacological and toxicological studies to characterize specic impurities’ biological effects may be unnecessary. However, if the manufacturing process
introduces different or higher levels of impurities in the proposed biosimilar than in the reference product, further pharmacological, toxicological, or other studies might be necessary. The
terms “product- related” and “process- related” impurities align with their use and meaning in
ICH Q6B.
Relying on purication processes to remove impurities is preferred over establishing a preclinical
testing program for their qualication. (Refer to the ICH guidance for industry S6(R1) Preclinical
Safety Evaluation of Biotechnology- Derived Pharmaceuticals, May 2012, page 2.)
Process- related impurities originating from cell substrates (such as host cell DNA and host cell
proteins), cell culture components (like antibiotics and media components), and downstream processing steps (such as reagents, residual solvents, leachables, endotoxins, and bioburden) require
evaluation. The anticipated process- related impurities in a proposed biosimilar product are not
expected to match those found in the reference product and thus are not encompassed in the comparative analytical assessment. The selected analytical procedures must adequately detect, identify,
and accurately quantify signicant levels of impurities. For reference, consult the ICH guidance
for industry Q2B Validation of Analytical Procedures: Methodology (May 1997). Specically,
immunological methods for detecting host cell proteins depend on assay reagents and cell substrates
used. These assays need validation using the product cell- substrate and orthogonal methodologies
to ensure precision and sensitivity.
As with any biological product, ensuring the safety of a proposed biosimilar product regarding
adventitious agents or endogenous viral contamination necessitates screening critical raw materials
and conrming robust virus removal and inactivation achieved during the manufacturing process.
Refer to the ICH guidance for industry Q5A Viral Safety Evaluation of Biotechnology Products
Derived from Cell Lines of Human or Animal Origin (September 1998).
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