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5.3.5.3 Host Cell Protein and Residual DNA
Analytical Assessment
When developing a new biological product, determining the acceptable limits of HCP (host cell
proteins) and residual DNA involves demonstrating the feasibility of reducing this adverse attribute,
evaluating the relative safety risk of the specic products, and monitoring these attributes. Both HCP
and residual DNA are dependent on organism strain, so even if developers use the same expression
system, replicating the originator’s exact strain is impossible. Since HCP and residual DNA are
strain- specic, directly comparing the relative safety of a proposed biosimilar product is only feasible through comprehensive safety studies assessing these attributes. Regulatory agencies necessitate a critical analysis of HCP and residual DNA, acknowledging that these might differ from those
in the originator product. A 2D SDS resolution is also recommended to address these components
for both the test and reference products. Claiming similarity between HCP and residual DNA in
the test and originator product is challenging. While it is true that the HCP and residual DNA in
a proposed biosimilar product may not match those in the reference product, if the same expression system (e.g., E. coli) is used, there is a high likelihood that safety will be proportional to the
quantity of these components, despite any specic activity associated with a particular component.
Consequently, it is plausible for the test product to demonstrate non- inferiority through an equivalence range approach.
5.3.6 lot- to- lot vaRiability
Observed lot- to- lot variability may stem from manufacturing conditions and analytical assay
differences. Factors contributing to variability between lots in the production of a protein product
include the origin of specic raw materials (such as growth medium, resins, or separation materials)
and distinct manufacturing sites. Hence, it is crucial in the comparative analytical assessment to
adequately characterize lot- to- lot variability of the reference product and a proposed biosimilar
product.
In certain instances, modications to the manufacturing process of a proposed biosimilar
product may be necessary to address differences observed in the comparative analytical assessment.
Data demonstrating resolution of observed differences through manufacturing changes should be
provided, along with evidence that other quality attributes were not signicantly impacted. If other
attributes were affected by the manufacturing change, data should illustrate evaluation and mitigation of the change’s impact.
5.3.7 PRoduct- oR PRocess- Related substances
Advances in analytical sciences— both physicochemical and biological— have signicantly
enhanced the characterization of various protein products in terms of their physicochemical and
biological properties. These analytical procedures have markedly improved the capability to identify and characterize the intended product, as well as product- related substances and impurities
associated with the product and its manufacturing process.
The terminology “product- related substances” and “product- and process- related impurities”
aligns with the usage and signicance outlined in the ICH Q6B guidelines. A product- related substance refers to a variant of the targeted substance exhibiting at least 80% of the activity of the active
target drug substance. Impurities can either be active or inactive.
It is imperative to identify, appropriately characterize, quantify, and compare the product- related
impurities and substances using multiple lots of both the proposed biosimilar product and the reference product. This comparison, to the extent feasible and relevant, forms a crucial part of assessing
potential impacts on the safety, purity, and potency of the product.
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5.3.8 Method sensitivity
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Regulatory agencies advocate for the utilization of state- of- the- art technology. Developers should
employ analytical methodologies with adequate sensitivity and specicity to discern differences
between a proposed biosimilar product and the reference product.
Advancements in manufacturing science and production methods have increased the likelihood
of demonstrating similarity between a proposed biosimilar product and the reference product, especially by targeting the physicochemical and functional properties of the reference product. However,
despite advances in analytical sciences, some differences between protein products may be detected
that might not be clinically relevant. Nevertheless, employing highly sensitive methods that demonstrate similarity provides increased condence and reduces the need for additional studies.
Despite improvements in analytical techniques, the current methodology may not identify all
relevant structural and functional differences between the two protein products. Understanding the
limitations of each analytical method is crucial for developers to identify residual uncertainties
and plan subsequent testing. Additionally, there might be an incomplete understanding of how a
product’s structural attributes correlate with its clinical performance.
Contrary to routine quality control assays, tests utilized for characterizing the product do not
necessarily need validation. However, they should be scientically sound, suitable for their intended
purpose, and capable of producing reproducible and reliable results. Selection of these tests should
consider the characteristics of the protein product, including known and potential impurities.
Information on a method’s ability to discern pertinent differences between a proposed biosimilar
product and the reference product should be included in the comparison. The methods should demonstrate appropriate sensitivity and specicity to provide meaningful insights into the similarity
between the two products.
5.3.9 coMPaRative testing
In contrast to the standalone testing conducted for a new drug to establish its characteristics, the
development of biosimilars doesn’t necessitate such independent testing for safety or efcacy.
Instead, all testing is carried out comparatively, emphasizing a pivotal difference in establishing test
methods, protocols, and their scopes for comparison, not characterization.
Comparative analytical data serve as the cornerstone for developing a proposed biosimilar
product, inuencing decisions about the necessary type and quantity of animal and clinical data
to support demonstrating biosimilarity. Comprehensive and robust comparative physicochemical
and functional studies, which may include biological assays, binding assays, and enzyme kinetics,
should be performed to evaluate a proposed biosimilar product against the reference product.
A comprehensive comparative analytical assessment relies signicantly on the capabilities of stateof- the- art analytical assays. These assays determine various factors such as the protein’s molecular
weight, complexity (including higher- order structure and post- translational modications), degree
of heterogeneity, functional properties, impurity proles, and degradation proles, all of which indicate stability. Developers must detail the capabilities and limitations of the methods employed in
these analytical assessments. Alternative analytical study methods offer distinct perspectives on
quality attributes without redundantly testing the same attribute or utilizing a method that does not
offer a unique viewpoint. It is imperative not to disregard a failed test based solely on orthogonal
testing.
In conducting comparative analytical assessments, risk ranking and data analysis evaluate
numerous attributes, often utilizing multiple orthogonal assays. Regulatory agencies assess the
entirety of the analytical data. Failure to meet specic criteria in a particular assay alone does not
necessarily negate the demonstration of similarity. If differences between products arise during the
comparative analytical assessment (even within components not initially part of the risk ranking),
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developers may provide additional scientic information (such as risk assessment and supplementary data) along with justication for why these differences do not hinder demonstrating similarity
between the products.
5.3.10 side- by- side testing
For a proposed biosimilar product, developers should conduct comparative testing through sideby- side analyses of an appropriate number of lots of both the proposed biosimilar product and the
reference product. Where available and suitable, comparison with an internal reference standard for
relevant attributes (e.g., potency) should also be included. Evaluating multiple lots of both the reference and proposed biosimilar products allows for estimating variability across different lots. The
required number of lots may vary case by case, and developers should provide a scientic rationale
for their choice.
The emphasis on side- by- side testing is crucial in resolving variability in test methods, especially those that cannot be entirely validated. Conducting tests simultaneously helps resolve most,
if not all, differences in test method reliability. Consequently, any published data concerning reference product quality attributes cannot be used for comparison with a proposed biosimilar product.
Similarly, using a reference standard to match attributes between a proposed biosimilar product
and the reference product is not valid. These limitations apply even to established attributes such as
molecular weight, sequence, or other xed attributes.
5.3.11 heteRogeneity
Therapeutic proteins, being produced in living systems, naturally exhibit variability in certain quality
attributes. This variability can arise from various sources and signicantly impact the anticipated
clinical performance of a protein product. Errors during replication in the DNA encoding the protein sequence and misincorporation of amino acids might occur during translation, although these
errors typically remain at low levels. Furthermore, most protein products undergo post- translational
modications that can modify the protein’s functions by attaching additional biochemical groups
like phosphate, lipids, carbohydrates, undergoing proteolytic cleavage after translation, changing the
chemical nature of an amino acid (e.g., formylation), or through numerous other mechanisms. These
modications may result from intracellular activities during cell culture or intentional modications
of the protein (e.g., PEGylation). Additionally, manufacturing process operations might lead to other
post- translational modications; for instance, glycation may occur due to the product’s exposure
to reducing sugars. Certain storage conditions could also facilitate or impede specic degradation
pathways like oxidation, deamidation, or aggregation. These various product- related variants have
the potential to alter the biological properties of the expressed recombinant protein. Therefore, it’s
crucial to include the identication and determination of these variants’ relative levels in comparative analytical characterization studies.
5.3.12 stRuctuRe confiRMation
The three- dimensional conformation of a protein signicantly inuences its biological function.
Proteins typically display intricate three- dimensional conformations (tertiary structure and, occasionally, quaternary structure) owing to their size and the rotational traits of protein alpha carbons,
among other factors. This inherent exibility allows for dynamic yet subtle changes in protein conformation over time, some of which may be necessary for functional activity. These rotations are
frequently reliant on low- energy interactions, such as hydrogen bonds and van der Waals forces,
which can be highly sensitive to environmental conditions. Present analytical technology is capable
of assessing the three- dimensional structure of numerous proteins. Utilizing multiple, pertinent,
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cutting- edge methods can aid in dening tertiary protein structure and, to varying degrees, quaternary structure, thereby contributing to the information supporting biosimilarity. However, precisely
dening a protein’s three- dimensional conformation with current physicochemical analytical technology can pose challenges. Any disparities in higher- order structure between a proposed biosimilar
product and the reference product should be scrutinized regarding potential impacts on protein
function and stability. Consequently, functional assays are essential tools for evaluating the integrity
of higher- order structures.
5.3.13 accePtance cRiteRia
The acceptance criteria for each test are established by initially conducting exploratory tests on
both the reference product and the proposed biosimilar product. This approach leads to dening
specications and acceptance criteria. A formal study, necessitating a specic number of lots
determined by statistical calculations, compares the proposed biosimilar product with the reference product. Agencies encourage developers to consult with them to ensure the evaluation of an
appropriate number of lots. Specic lots of the reference products used in comparative analytical
studies, including expiration dates, analysis time frames, and their utilization in nonclinical or clinical studies, must be identied. This information substantiates acceptance criteria, ensuring product
consistency, and supporting the comparative analytical assessment between the proposed biosimilar
product and the reference product.
However, the acceptance criteria should not solely rely on the observed range of product
attributes of the reference product. Instead, they should be based on comprehensive analytical data
evidence. Certain product attributes interact, collectively inuencing a product’s safety, purity,
and potency prole. Hence, their potential interactions should be considered when establishing
specications. For instance, in some glycoproteins, the content and distribution of tetra- antennary
and N- acetylglucosamine repeats can collectively affect in vivo potency, and their evaluation should
not occur independently.
Furthermore, data obtained from lots used in nonclinical and clinical studies, along with pertinent
information on attribute- drug product performance relationships, can aid in establishing acceptance
criteria. Refer to the ICH guidance for industry Q8(R2) Pharmaceutical Development (November
2009) for more details.
5.3.14 oRthogonal testing
To comprehensively address physicochemical properties or biological activities, multiple analytical procedures are often necessary for evaluating the same quality attribute. Methods using diverse
physicochemical or biological principles to assess the same attribute are particularly valuable as
they offer independent data supporting that attribute (e.g., employing orthogonal methods to assess
aggregation). Utilizing complementary analytical techniques in sequence, such as combining peptide mapping or capillary electrophoresis with mass spectrometry of separated molecules, offers a
meaningful and sensitive approach to compare products.
Extensive analytical characterization may reveal differences between the reference product
and a proposed biosimilar product, particularly when employing techniques capable of discerning
qualitative or quantitative attribute variations. Prioritize the development of orthogonal quantitative
methods to denitively identify any differences in product attributes. However, an orthogonal test
should offer an alternative perspective on the quality attribute, or in cases where the validity of a
test might be questioned. For instance, using both UV absorbance and HPLC to determine protein
content could be considered. Nevertheless, the specication must always be denitive, leaving no
ambiguity in the choice of testing method.
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5.3.15 accountability of lots
Analytical Assessment
The developer must ensure inclusion and characterization of all acquired reference product lots.
The application should encompass data and information from all evaluated reference products and
proposed biosimilar product lots across various studies: physicochemical, functional, animal, and
clinical. Justication for the selection or exclusion of specic lots in analytical studies should be
provided. The application should contain the dates of analytical testing and product expiration.
Generally, expired reference product lots should not be included in the comparative analytical
assessment due to potential deviations from typical observations in unexpired lots, leading to
overestimated variability. Testing expired lots may be acceptable under certain storage conditions,
such as long- term frozen storage at − 80°C. The developer should submit data conrming that storage
conditions do not compromise product quality.
Similar information and data gathered for reference product lots should also be provided for each
manufactured drug substance and product lot of the proposed biosimilar.
All reference and proposed biosimilar product lots used in clinical studies (e.g., PK and PD
studies, if applicable, similarity and comparative clinical study) must be included in the comparative
analytical assessment.
Combining data from two reference products in testing is prohibited as it may lead to broader
similarity acceptance criteria than relying solely on data from one reference product, potentially
enlarging the range.
If the drug substance is extracted from the reference product for analytical studies, the developers
should detail the extraction procedure. They must demonstrate that the procedure itself does not alter
relevant product quality attributes, including impurities and product- related substances. Appropriate
controls should ensure that the extraction procedure does not signicantly modify the relevant
characteristics of the protein.
5.3.16 cRitical Quality attRibutes
When conducting the comparative analytical assessment to establish biosimilarity, developers
should consider all factors impacting the safety and efcacy of the proposed biosimilar product.
Critical quality attributes pertinent to analytical similarity can be categorized as inherent and
legacy attributes. Inherent attributes include variable properties intrinsic to the manufacturing process, resulting in lot- to- lot variability. This classication covers both process- and product- related
factors, such as post- translational modications in cytokines and antibodies. Legacy attributes
are xed characteristics not subject to lot- to- lot variation, including the total mass of a protein (in
some cytokines but not monoclonal antibodies), amino acid sequence, and other reported properties
like disulde bond positions. These characteristics are documented in protein databases, patents,
publications, and pharmacopeias. Another category of legacy attributes encompasses labeled
specications of inactive ingredients and product characteristics such as pH, and osmolality.
While legacy attribute specications signicantly characterize the reference product, a proposed
biosimilar product still requires testing against reference product lots. This is because the reference
product isn’t obligated to comply with any legacy attributes. Moreover, conducting side- by-
side tests helps mitigate the impact of test method variability in identifying clinically meaningful
differences between a proposed biosimilar product and the reference product. However, the release
specications for various quality attributes can be established independently based on established
principles ensuring the product’s efcacy. For example, protein content (e.g., ±3%), bioactivity
(e.g., ±15%), post- translational modications (e.g., ±10%), subvisible particles (USP specication),
physical properties (e.g., pH, osmolality, density, etc., ±10%), aggregates (e.g., ±10% of the average
from multiple lots of RP), ll volume (USP specication), impurities (e.g., no more than 3%, no
single impurity more than 1%, and no unidentied impurity). Developers may propose other limits
based on multiple analyses of reference product lots. The core principle in establishing analytical
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TABLE 5.1
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Common Critical Quality Attributes
Quality Attribute Criticality Potential Impact Suggested Analytical Methods
Amino acid sequence Very high Efcacy, safety Peptide mapping, MS, Edelman degradation
Glycan structure and content Very high Efcacy, safety Glycan wnalysis
Biological activity Very high Efcacy, safety Bioassay
Immunochemical identity Very high Efcacy, safety SDS- PAGE+ immunoblotting, immunoassay
Higher- order structure High Efcacy, safety Spectrophotometric, thermodynamic Methods
Isoform distribution High Efcacy Isoelectric focusing
Insoluble aggregates High Safety Light obscuration
High- molecular- weight aggregates High Safety SE- HPLC, AUC, SDS- PAGE
Protein content High Efcacy UV; use HPLC as an orthogonal method
Host cell proteins High Safety SPR spectroscopy, cell- based assay
Receptor binding High Efcacy SPR, cell- based assay
Truncated forms Low Efcacy Reference product HPLC, other chromatography
Deamidation, oxidation Low Efcacy Chromatography
Notes: AUC, analytical ultracentrifugation; HPLC, high- performance liquid chromatography; MS, mass spectroscopy;
SDS- PAGE, sodium sulfate polyacrylamide gel electrophoresis; SE, sedimentation equilibrium; SPR, surface
plasmon resonance; UV, ultraviolet
similarity and release specications for drug substance and drug product is to eliminate uncertainties
that could potentially impact safety and subsequently efcacy. For example, protein content (e.g.,
±3%), bioactivity (e.g., ±15%), post- translational modications (e.g., ±10%), subvisible particles
(USP specication), physical properties (e.g., pH, osmolality, density, etc., ±10%), aggregates (e.g.,
±10% of the average from multiple lots of RP), ll volume (USP specication), impurities (e.g., no
more than 3%, no single impurity more than 1%, and no unidentied impurity). Developers may
propose other limits based on multiple analyses of reference product lots. The core principle in
establishing analytical similarity and release specications for drug substance and drug product is to
eliminate uncertainties that could potentially impact safety and subsequently efcacy.
Critical quality attributes are identied based on their impact on the product’s safety and efcacy.
Table 5.1 provides a non- exhaustive list of various attributes and their classication. The choice of
the test method depends on the criticality of the attribute.
5.3.17 RefeRence standaRd
Using a proposed biosimilar product in comparison with a publicly available standard, such as
a pharmacopeia monograph or a reference standard, is not permitted for conducting comparative
testing to establish biosimilarity. It is crucial to emphasize that any specications from a pharmacopeia monograph or a reference standard provided by third parties are not deemed suitable to establish biosimilarity.
Pharmacopoeia reference standards are unsuitable for conducting comparative studies; their
usage is restricted solely to test method qualication. A qualied reference standard should be
internally developed by the developer, based on its thoroughly characterized batch.
While a physicochemical and functional comparison of a proposed biosimilar product with a
suitable, publicly available, and well- established reference standard for the protein might offer
valuable insights, studies with such a reference standard alone are insufcient to demonstrate the
biosimilarity of the proposed biosimilar product to the reference product. For instance, if there exists
an international standard for calibrating potency, it is necessary to compare the relative potency of a
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proposed biosimilar product with this potency standard. According to the recommendations outlined
in ICH Q6B, in- house reference standard(s) must always be qualied and employed to control both
the manufacturing process and the product.
Typically, an in- house reference standard is developed from early development lots or lots used
in clinical studies. Additional reference standards may be qualied later in the development process
and for submission. Ideally, developers will establish and properly qualify primary and working
reference standards representative of proposed biosimilar product lots used in supporting clinical
studies.
When developing a proposed biosimilar product, the reference product lot usually undergoes qualication as an initial reference standard. After manufacturing clinical lots of a proposed
biosimilar product, one of these lots is expected to be appropriately qualied (including bridging to
previous reference standards) for use as a reference standard for release, stability, and comparative
analytical testing. Ideally, once an in- house reference standard is fully qualied, sufcient quantities
should be available for use throughout the proposed biosimilar product’s development. All reference
standard lots used during the development should be suitably qualied. Additionally, the qualication protocol for reference standards should encompass all analytical methods reporting results
relative to the reference standard.
For all methods reporting results relative to the reference standard, the assignment of potency at
100% should incorporate a narrow acceptable potency range to ensure control over product drift. For
example, developers should consider utilizing a predetermined two- sided condence interval (CI) of
the mean of the replicates, where the mean relative potency and the 95% CI fall within a sufciently
narrow range (e.g., 90%– 110%). An evaluation across multiple reference standard qualications
should be conducted to address potential drift over the history of qualication.
Developers should refrain from using a correction factor to compensate for differences in potency
or biological activity between reference standards.
Using a proposed biosimilar product in comparison with a publicly available standard, such as
a pharmacopeia monograph or a reference standard, is not permitted for conducting comparative
testing to establish biosimilarity. It is crucial to emphasize that any specications from a pharmacopeia monograph or a reference standard provided by third parties are not deemed suitable to establish biosimilarity.
5.4 FINISHED DRUG PRODUCT
Product characterization studies for a proposed biosimilar product should focus on the most downstream intermediate that best suits the analytical procedures. The assessed attributes should remain
stable through subsequent processing steps. Consequently, characterization studies are typically
conducted on the drug substance. However, if a drug substance undergoes reformulation and comes
into contact with new materials in the nished dosage form, the effects of these changes must be
considered. Whenever feasible, if the nished drug product is better suited for a particular analysis, developers should analyze the nished drug product. If an analytical method detects specic
attributes in the drug substance more sensitively, but these attributes are critical and susceptible to
change during the manufacture of the nished drug product, a comparative characterization may be
necessary for both the extracted protein and the nished drug product.
Proteins are highly sensitive to their environment. Consequently, differences in excipients or
primary packaging could impact product stability and clinical performance. Discrepancies in formulation and primary packaging between a proposed biosimilar product and the reference product
are factors that could inuence the selective and targeted approach of subsequent clinical studies.
Referencing the ICH guidance for industry Q8(R2) Pharmaceutical Development (November
2009) is advisable. Developers should clearly identify excipients used in a proposed biosimilar
product that differ from those in the reference product. The acceptability of differences in the type,
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nature, and extent of excipients between the nished proposed biosimilar product and the nished
reference product should be evaluated and supported by appropriate data and rationale. Furthermore,
the inclusion of different excipients in a proposed biosimilar product should be substantiated either
by existing toxicology data for the excipient or by additional toxicity studies formulated specically
for the proposed biosimilar product.
After a drug substance has undergone purication through the downstream process, it’s
considered a chemical entity rather than a biological one. Consequently, it becomes subject to all
cGMP requirements applicable to any other chemical drug’s ll and nish process. Nevertheless,
there are exceptional considerations such as proteins desorbing to the lling line, aggregate formation during lling, and concentration changes throughout the process. Cleaning validation of the ll
and nish equipment poses a signicant challenge. To mitigate risks associated with potential contamination of the protein solution by a chemical entity, albeit at a minimal concentration, a preferred
method involves using a dedicated lling head for these operations. Further reduction in contamination risk is achieved by utilizing single- use heads.
5.4.1 exciPients
Proposed biosimilar products may contain different inactive ingredients compared to those
disclosed in the reference product’s prescribing information. This allowance aids developers in overcoming potential patent protections related to formulations extending beyond the biological entity’s
gene patents. However, this alteration introduces additional challenges in demonstrating that the
choice of inactive ingredients doesn’t induce adverse responses in terms of toxicity, pharmacokinetics (including absorption), or product efcacy. Although incidents of toxicities are rare, notable
examples such as pure red cell aplasia (PRCA) caused by changes in erythropoietin formulation and
administration [McKay, J, et al., Epoetin- associated pure red cell aplasia: past, present, and future
considerations. Transfusion, 48(8), July 2008] methods highlight the importance of careful consideration. Early biosimilars faced these challenges when the understanding of biosimilars was in its
infancy. Today, such changes would not be permitted without a thorough investigation to identify
associated risks.
Developers are advised to initially consider the formulation of the reference product as the preferred formulation, relying on the analysis of the reference product. They should establish release
limits for any inactive substances solely based on the prole obtained for the RP. For instance,
surfactants, commonly used in biological drug formulations, may exhibit concentration variations of
30%– 50%. The purity of surfactants is crucial, and in some cases, it is recommended to discard any
remaining surfactant in a new container to avoid potential safety risks to the product.
As a secondary option, developers can consider using a different formulation based on ingredients
generally recognized as safe for parenteral products, avoiding the use of unusual components.
Opting for unique inactive ingredients as the nal choice would necessitate more extensive safety
studies, potentially leaving residual uncertainty about the formulation. Often, it’s not feasible to infer
the toxicity of proteins solely from analytical assessments. One must consider excipient interactions
along with direct toxicities.
5.4.2 stability
As part of an appropriate comparison of the stability prole between a proposed biosimilar product
and the reference product, it’s crucial to conduct accelerated and stress stability studies. Forced
degradation studies should also be employed to establish degradation proles and enable a direct
stability comparison. These comparative studies should encompass multiple stress conditions (e.g.,
high temperature, freeze- thaw cycles, light exposure, and agitation), causing gradual product degradation over a dened period. The results from these studies may uncover product disparities requiring
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further evaluation and help identify conditions necessitating additional controls in manufacturing
and storage. Refer to ICH guidance for industry Q5C Quality of Biotechnological Products: Stability
Testing of Biotechnological/ Biological Products (July 1996) and Q1A(R2) Stability Testing of New
Drug Substances and Products (November 2003). Sufcient real- time, real- condition stability data
from a proposed biosimilar product should validate the proposed shelf life.
Regulatory agencies expect a proposed biosimilar product to undergo side- by- side qualitative and
quantitative testing for degradants’ types and levels. However, challenges arise in sourcing reference products with production dates similar to those of proposed biosimilar products. Additionally,
determining an acceptable deviation from theoretical degradation rates based on declared shelf- life
remains a concern.
Developers must present data from at least three lots, potentially including development lots
placed under stability testing. The stability study should extend for at least six months, aiming to
obtain linear regression coefcients of degradation with high statistical signicance (r2). These
degradation rates’ slopes are then compared with theoretical rates. For instance, if a product has a
36- month shelf- life with a stability limit of no more than 3% degradation, the theoretical slope of the
regression line can be calculated. A proposed biosimilar product should not exhibit a higher degradation rate than predicted theoretically, even if the reference product demonstrates a higher rate that
compromises the projected expiration dating.
Developers must recognize that stability data for proposed biosimilar products are instrumental
in identifying structural differences in the protein structure, along with other factors contributing to
degradation. Forced degradation studies hold particular signicance as they highlight the stability of
ner structures within the molecule.
5.4.3 inteRnational council foR haRMonisation
The regulatory guidance describes considerations for Chemistry, Manufacturing, and Controls
(CMC) information to assess the similarity of a proposed biosimilar product to the reference product.
All product applications must include a complete CMC section providing necessary information
(such as characterization, safety from adventitious agents, process controls, and specications)
to support the consistent delivery of a product with intended quality characteristics. Several ICH
guidelines (Table 5.2) are relevant to presenting this guideline. However, Agencies are not obligated
to accept recommendations from these guidelines.
5.4.4 exaMPles of testing Methods
Developers are advised to create a comprehensive testing protocol based on the product’s nature.
Below is a suggested test list for physicochemical and biological assessment of TNF alpha- blockers
(Table 5.3) and oncology antibodies (Table 5.4).
ADCC: antibody- dependent cell- mediated cytotoxicity; AlphaScreen® and AlphaLISA®
(amplied luminescent proximity homogeneous assay) are bead- based assay technologies used to
study biomolecular interactions in a microplate format; CD: circular dichroism;
CDC: complement- dependent cytotoxicity; CE- SDS: capillary electrophoresis– sodium dodecyl
sulphate; CEX- HPLC: cation exchange– high- performance liquid chromatography; DSC: differential
scanning calorimetry; FcRn: neonatal Fc receptors; FRET: uorescence resonance energy
transfer; Gal: galactosylated glycans; HDX- MS: hydrogen– deuterium mass spectrometry; HILIC-
UPLC: hydrophilic interaction liquid chromatography– ultra- performance liquid chromatography;
HMW: high molecular weight; icIEF: imaging capillary isoelectric focusing; ITF: intrinsic uorescence spectroscopy; LC- ESIMS: liquid chromatography– electrospray ionization– mass spectrometry;
LC/ MS: liquid chromatography– mass spectrometry; LC- ESI- MS/ MS: liquid chromatography–
electrospray ionization– tandem mass spectrometry; PBMCs: peripheral blood mononuclear cells;
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TABLE 5.2
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Pertinent ICH Guidelines for Biosimilars
ICH guidance for industry M4: The CTD — Quality (ICH
M4Q) (August 2001)
ICH guidance for industry Q2(R1) Validation of Analytical
Procedures: Text and Methodology (ICH Q2(R1)
(November 2005)
ICH guidance for industry Q3A(R) Impurities in New Drug
Substances (ICH Q3A(R)) (June 2008)
ICH guidance for industry Q5B Quality of Biotechnological
Products: Analysis of the Expression Construct in Cells
Used for Production of r- DNA- Derived Protein Products
(ICH Q5B) (February 1996)
ICH guidance for industry Q5D Quality of Biotechnological/
Biological Products: Derivation and Characterization of
Cell Substrates Used for Production of Biotechnological/
Biological Products (ICH Q5D) (September 1998)
ICH guidance for industry Q6B Specications: Test
Procedures and Acceptance Criteria for Biotechnological/
Biological Products (ICH Q6B) (August 1999)
ICH guidance for industry Q8(R2) Pharmaceutical
Development (ICH Q8(R2)) (November 2009)
ICH guidance for industry Q10 Pharmaceutical Quality
System (ICH Q10) (April 2009)
ICH guidance for industry S6(R1) Preclinical Safety
Evaluation of Biotechnology- Derived Pharmaceuticals
(ICH S6(R1)) (May 2012)
ICH guidance for industry Q1A(R2) Stability Testing of
New Drug Substances and Products (ICH Q1A(R2))
(November 2003)
ICH guidance for industry Q2B Validation of Analytical
Procedures: Methodology (ICH Q2B) (May 1997)
ICH guidance for industry Q5A Viral Safety Evaluation
of Biotechnology Products Derived from Cell Lines of
Human or Animal Origin (ICH Q5A) (September 1998)
ICH guidance for industry Q5C Quality of
Biotechnological Products: Stability Testing of
Biotechnological/ Biological Products (ICH Q5C) (July
1996)
ICH guidance for industry Q5E Comparability of
Biotechnological/ Biological Products Subject to Changes
in Their Manufacturing Process (ICH Q5E) (June 2005)
ICH guidance for industry Q7 Good Manufacturing
Practice Guidance for Active Pharmaceutical Ingredients
(ICH Q7) (September 2016)
ICH guidance for industry Q9 Quality Risk Management
(ICH Q9) (June 2006)
ICH guidance for industry Q11 Development and
Manufacture of Drug Substances (ICH Q11) (November
2012)
SEC: size exclusion chromatography; SEC- MALLS/ RI: size exclusion chromatography– multi-
angle laser light scattering/ refractive index; SPR: surface plasmon resonance; SV- AUC: sedimentation
velocity analytical ultracentrifugation; UV: ultraviolet; UV/ VIS: ultraviolet visible.
5.4.5 RisK assessMent
Developers are recommended to create a risk assessment tool to evaluate and rank the reference
product’s quality attributes concerning their potential impact on the mechanism(s) of action and
product function. Certain quality evaluations of the reference product (e.g., degradation rates
determined from stability or forced degradation studies) generally should not be part of the risk
ranking. However, these evaluations should still be considered in the comparative analytical
assessment of a proposed biosimilar product and the reference product.
The development of a risk assessment tool should take into account various pertinent factors,
including:
• Potential Impact on Clinical Performance: It is advised that the developer carefully considers
how an attribute may impact activity, PK/ PD, safety, efcacy, and immunogenicity. This
evaluation should draw from publicly available information and the developer’s assessment of
the reference product.
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