General Introduction PhD Thesis Ali Alsamil extracted for the website of Biosimilars Nederland Utrecht University, 3 November 2022
Quality of Biopharmaceuticals: Comparability Exercise and Post Approval Surveillance
Direct link to full thesis: https://dspace.library.uu.nl/bitstream/handle/1874/423114/ali%20alsamil%20- %206336be7a313a3.pdf?sequence=1
CV Dr. Alsamil: https://www.uu.nl/medewerkers/AMAlsamil/Profiel
Biopharmaceuticals currently dominate the development and approval of new medicines, illustrated by the coronavirus disease 2019 (COVID-19) vaccines [1, 2]. The definition of biopharmaceuticals is still changing with the advancement in knowledge, science, technology, and discoveries. Although there is no consensus among the drug regulatory and health authorities, the definition of biopharmaceuticals is often deduced from the definition of biological medicine (Table 1). The definition of biological medicine covers a broad spectrum of naturally extracted and recombinant products that range from simple polysaccharides (e.g., heparin) and polypeptides (e.g., insulin) to complex monoclonal antibodies (e.g., adalimumab) and advanced gene- and cell-based therapies (e.g., genetically modified autologous T-cells).
However, a more specific definition of “biopharmaceuticals” has been proposed as “pharmaceuticals with active substance inherently biological in nature and manufactured using biotechnology” . This definition is more specific and aligns with the regulatory definitions of biological medicine but distinguishes biopharmaceuticals produced using recombinant deoxyribonucleic acid (DNA) biotechnology from naturally extracted biologicals, such as animal- or human- derived medicine, and from small-molecule drugs produced using chemical synthesis. This biopharmaceutical definition also accommodates biosimilars developed following the expiration of a patent on a reference product for a biopharmaceutical. This thesis focuses on biopharmaceuticals used to treat and cure human diseases.
Table 1: Definitions of biological medicine according to drug regulatory and health authorities.
European Medicines Agency (EMA)
“A medicinal product contains a biological substance that is produced by or extracted from a biological source and that needs for its characterization and the determination of its quality a combination of physicochemical-biological testing, together with the production process and its control.”
Food and Drug Administration (FDA)
“Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources–human, animal, or microorganism–and may be produced by biotechnology methods and other cutting-edge technologies.”
Pharmaceuticals and Medical Devices Agency (PMDA)
“Biological products are drugs, quasi-drugs, cosmetics, or medical devices using materials manufactured from humans or other organisms (excluding plants) as raw materials or packaging materials, which are designated as requiring special precautions in terms of public health and hygiene.”
Discovery and Use of Biopharmaceuticals
Before the introduction of recombinant DNA technology, biologicals used in clinical practice were extracted from biological materials, including humans (e.g., human albumin and clotting factors), animals (e.g., porcine derived heparin), plants (e.g., aspirin), yeasts (e.g., penicillin), and viruses (e.g., vaccines). Vaccines were introduced in the late eighteenth century when Edward Jenner developed and tested the first vaccine for smallpox using the relatively mild cowpox virus. The
discovery and development of biopharmaceuticals could not occur without basic scientific discoveries, including the following:
• unlocking the full arrangement of the amino acid sequence of insulin (i.e., the backbone chain defining the primary structure of a biological molecule) by Frederick Sanger ,
• the DNA structure (i.e., a molecule to provide genetic instructions for organisms and molecules) by Watson and Crick in the 1950s , and
• the mechanistic unraveling of many diseases.
These breakthrough scientific discoveries allow for unlocking the structure of DNA and proteins, enabling healthcare to catch up with the fruits of these discoveries. It allowed introducing a piece of DNA with appropriate elements into living cells, often referred to as recombinant DNA technology, enabling the development of protein drugs that can replace a malfunctioning endogenous counterpart . The first recombinant protein was human insulin, introduced into clinical practice in the 1980s, which significantly decreased the potency variation and immunological complications associated with using animal-derived insulin .
Recombinant DNA technology also reduces the risk of viral transmission associated with human-derived biological materials, such as human plasma to extract coagulation factors for bleeding disorders and human urine to extract gonadotropins for infertility treatments [12-16]. Progressive advancements in recombinant DNA technology have facilitated the production of monoclonal antibodies (mAbs), which can target-specific antigens or receptors, such as tumor necrosis factor-α (TNF-α), providing novel methods of target-specific treatments for many acute and chronic diseases [17, 18].
The development of mAbs requires a thorough understanding of the pathogenesis and biological targets. For example, TNF-α was initially recognized as a major regulator of inflammatory responses where binding to two different receptors initiates signal transduction pathways, including cell survival, differentiation, and proliferation. Excessive activation of TNF-α signaling is associated with chronic inflammation and is involved in the pathogenesis of several autoimmune diseases. Understanding the TNF-α signaling pathway led to developing several TNF-α-i products, including mAbs, such as infliximab, adalimumab, golimumab, and certolizumab and fusion proteins, such as etanercept.
In the first decade of the 2000s, new modalities to treat patients emerged from the advance therapeutic medicinal products, including modified genes and engineered cells, to intervene with human biology, providing breakthrough therapies for complex diseases with high unmet medical needs . Biopharmaceutical innovation is expected to continue with the rapid advancement in science and technology [20, 21].
However, these valuable innovations are highly expensive originator biopharmaceuticals. The discovery and development of biopharmaceuticals are time-consuming and costly and could reach $2.6 billion according to the 2016 Tuft center estimation [22, 23]. According to a recent IQVIA report, biologicals, including biopharmaceuticals, accounted for $277 billion in the global pharmaceutical market sales in 2017 and are projected to reach $452 billion in
sales by 2022 . Global spending on medicine has been growing at 3% to 5% per year and is expected to reach around $1.6 trillion by 2025. Most of this growth derives from biopharmaceuticals representing eight of the top 10 selling medicines in 2018. Although biopharmaceuticals have found their way into clinical practice, their high cost has placed economic pressure on the healthcare budget and limits patient access, challenging the regulatory system to develop a balanced solution.
The expiration of patents and exclusivity rights for some originator biopharmaceuticals has allowed the introduction of biosimilars since 2006 in the European Union (EU), providing alternative and more affordable treatment options to alleviate the pressure on healthcare budgets and improve patient access to important biopharmaceuticals. Today, the number of approved biological medicines (primarily biopharmaceuticals) has more than doubled from less than 200 in 2000 to more than 400 in 2020. Currently, this number represents approximately half of the newly launched active (chemical and biological) entities authorized in the EU and the United States (US) [1, 24].
Unique Features and the Biopharmaceutical Production Process
Biopharmaceuticals, whether originators or biosimilars, exhibit distinct molecular and production features compared to the chemically synthesized small-molecule pharmaceuticals (Table 2) . The primary distinctions between biopharmaceuticals and small molecules are their size and the structural and functional complexity of the molecules. The size of biopharmaceuticals is defined by the molecular weight and ranges from 3.7 to 150 kDa, which is larger than small-molecule pharmaceuticals (<1 kDa). Biopharmaceuticals are often proteins made of long ribbons of amino acids (i.e., primary structure) that twist into complicated knots (i.e., higher-order structure). Knowing the shape of a protein knot can reveal how the protein works, which is crucial for understanding how diseases occur and developing new drugs. The structure of a biopharmaceutical is critical for mediating (multiple) functions, which are often triggered by replacing a malfunctioning protein or a specific or nonspecific binding to a receptor or target. Unlike small molecules, biopharmaceuticals might be immunogenic by inducing the formation of an anti-drug antibody, which often has no clinical effects but, in some cases, could lead to adverse events, such as immune-mediated reactions and reduced product efficacy. Immunogenicity is the process through which a protein is recognized by the human immune system as a foreign antigen, forming an anti-drug antibody against the therapeutic protein. Several factors can induce immunogenicity, including product-related factors, such as structural attributes, formulations, impurities, administration routes, and patient-related factors [27, 28].
Table 2: Characteristics of biopharmaceuticals versus small-molecule pharmaceuticals .
A paramount distinction between biopharmaceuticals and small-molecule pharmaceuticals is the production process, which is far more complicated for biopharmaceuticals. Biopharmaceuticals are produced using living systems and involve numerous biological and chemical materials and steps . The typical production process for a biopharmaceutical can be divided into upstream and downstream processes to produce the drug substance (DS) and drug product (DP) [30, 31]. The upstream process starts with the cloning and expression of a cell line, followed by a cell culture under predefined growth conditions (e.g., media materials, temperature, and pH). The downstream process starts with various
harvesting and purification steps involving centrifugation, chromatography, and exposure to various solution conditions and filtration to extract and purify the DS from the cell culture and remove process and product-related impurities. Then, the DS undergoes formulation (by adding excipients), concentration, and sterile filtration steps and sometimes lyophilization through freeze-drying cycles to create the liquid (and sometimes a powder) dosage form of DP that fills the primary packaging (e.g., vials and prefilled syringes) . The DP is stored and transported under proper conditions to ensure product quality and stability during the entire chain from manufacturing to patient administration [33, 34].
Figure 1: Typical manufacturing process and steps affecting biopharmaceutical quality attributes (from ).
Because biopharmaceuticals are produced using living systems and biological materials and involve a complex manufacturing process, biopharmaceuticals are inherently variable (Figure 1). In other words, the manufacturing process determines the DP, and intentional or unintentional changes in the manufacturing process can lead to changes in the DP with or without clinical consequences. This inherent variability is illustrated by post-translational modifications, such as glycosylation, which are heterogeneous and differ between a) cell lines (e.g., Escherichia coli and Chinese hamster ovary), b) different clones from the same
cell line, c) biopharmaceuticals produced from the same cell line, and d) even batches from the same process.
Furthermore, biopharmaceuticals are highly susceptible to physical and chemical degradation due to environmental factors, such as temperature, humidity, light, and mechanical stress. Careful control and monitoring of the manufacturing process and post-production activities, including storage, transportation, and pharmacy and patient handling, are required to maintain the quality of biopharmaceuticals. Therefore, biopharmaceuticals are subjected to high regulatory and quality standards that are more stringent than those for most small molecules to ensure patients can use safe and effective products.
Quality of Biopharmaceuticals
The quality of a biopharmaceutical can best be described by the physical, chemical, biological, and microbiological properties that define the structure and functions, known as quality attributes (QAs). The International Conference on Harmonization (ICH) defined QAs as “A molecular or product characteristic that is selected for its ability to help indicate the quality of the product. Collectively, the quality attributes define identity, purity, potency and stability of the product, and safety with respect to adventitious agents.” In the same guideline, the ICH divided QAs into various types related to structural and functional attributes (Table 3). The QAs of biopharmaceuticals are more complex than the QAs of small-molecule pharmaceuticals and require a higher number of analytical tests, deploying several techniques or assays to generate complementary information on a single QA. For example, several tests may be necessary to define protein purity using different chromatography and electrophoresis techniques, including the SEC‐HPLC test for detecting aggregates, a CEX‐HPLC test for detecting charge variants, and RP‐HPLC or CE‐SDS for detecting misfolded variants. The type and extent of QAs can vary between biopharmaceuticals and highly depend on the molecule of interest and the manufacturing process. For biopharmaceuticals, the QAs of the DS and DP are generally identical, except that QAs related to process impurities can be measured at the DS level, whereas QAs related to the final formulation (e.g., pH, appearance, volume, osmolality, particulate matter, sterility, endotoxins, microbial limits, and excipients) are typically measured at the DP level.
A subset of QAs for biopharmaceuticals is known as critical QAs (CQAs) because a slight variation in these beyond the acceptable range or limit may have direct or indirect influences on product quality and functions, including biological, immunochemical, and pharmacological activities (pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcomes (i.e., safety and efficacy). The ICH defines CQAs as “physical, chemical, biological or microbiological attributes that must be within appropriate limits, range or distribution to ensure the desired product quality.” Prior knowledge of the structural and functional attributes of a molecule is the foundation of identifying which QAs are critical and noncritical based on a risk assessment. Risk assessment evaluates the risk probability, severity, and potential consequences for clinical outcomes. Different quality risk
assessment tools (e.g., risk ranking, primary hazard analysis, and safety assessment decision tree) can assess the criticality and determine a list of potential CQAs, which can be refined based on a continue knowledge about the QAs and understanding of the product and process.
For example, c-terminal lysine was thought to affect the bioavailability of mAbs and was considered a CQA. However, a large body of knowledge and laboratory studies have revealed that c-terminal lysine is rapidly removed after administration in human serum within 2 h with no effect on the potency and PK profiles of mAbs, indicating that c-terminal lysin does not affect bioavailability and should be considered a noncritical QA [35-41]. Knowledge of CQAs is crucial for predicting the influence on clinical outcomes. Because CQAs are potentially clinically relevant and bridge the gap between the quality and clinical outcomes, they are strictly controlled within acceptable ranges and limits to maintain the efficacy-safety profile. Although pharmacopoeias have been established to set standards for QAs to ensure medicinal quality, information on CQAs and their acceptable limits for biopharmaceuticals is often not specified in pharmacopoeias . Modern and still-advancing techniques have high precision and low detection or quantification limits and can increasingly detect smaller differences. However, a considerable unknown is which (measurable) differences in CQAs are clinically meaningful.
Table 3: Definition of common types of quality attributes (QAs) for biopharmaceuticals.
Individiual QA examples
Determining physical and chemical protein properties
Molecular weight, protein content, color, solubility, optical activity, and pH
Linear sequence of amino acids in a polypeptide chain
Amino acid sequence, disulfide bridges, and N- and C-terminal sequences
One or more polypeptides twisted into a three- dimensional shape forming a protein
Secondary, tertiary, and quaternary structures
Adding or subtracting chemical groups to or from proteins after translating from RNA via an enzymatic or chemical reaction—
Glycosylation, deamidation, and oxidation
important for protein functions, localization, and stability
Purity and impurities
Determining the absolute and relative purity of the drug substance and product and quantitively and qualitatively measuring product- and process-related impurities and contaminants
Size and charge variants, host-cell proteins, host-cell DNA, and adventitious viral and microbial species
The ability or capacity of a product to perform a function to achieve the defined biological and clinical effects using various potency assays
binding affinity, and
The ability and affinity of binding to specific receptors to mediate effector functions and pharmacological activities of monoclonal antibodies and fusion proteins
Binding to a) complement 1q (C1q), b) neonatal Fc receptors (FcRn), and c) Fc-gamma receptors (FcγRs)
Regulation of Biopharmaceuticals
The establishment of regulatory authorities has been driven by several safety tragedies, including deaths associated with using contaminated diphtheria antitoxin in the first decade of the 1900s, several side effects related to using the liquid formulation of sulfanilamide elixir in the 1930s , and the thalidomide tragedy in 1960s, where more than 10 thousand babies were born with phocomelia and other deformities to mothers who had taken thalidomide . In the aftermath of the thalidomide tragedy, regulatory authorities have been created worldwide, and governments established regulatory systems to facilitate assessment, licensing, inspection, and post-approval surveillance and monitoring. These core regulatory activities are mandated by regional and national regulatory authorities, such as the Food and Drug Administration (FDA) in the US and the European Medicines Agency (EMA) in the EU, based on government legislation and directives. These legislations and directives were the basis for developing regulatory guidelines, which are later harmonized by the ICH to ensure that medicines are globally approved according to the same requirements. These guidelines minimized the unnecessary repetition/duplication of testing, experiments, and trials to help the industry reduce the development time and resources and, most importantly, benefit the patient.
Like all other medicines, biopharmaceuticals must obtain regulatory approval before reaching the market to ensure that patients and healthcare professionals (HCPs) can use these treatments in clinical practice with a positive benefit-risk profile. Evidence must be generated to obtain regulatory approval, comprising the three main pillars of quality, safety, and efficacy. Each pillar must be ensured at the time of approval and be monitored throughout the life cycle of (bio)pharmaceuticals.
Regulatory authorities, such as the EMA and FDA, have established several regulatory pathways for biopharmaceuticals, differentiating between reference products and biosimilars. The reference product is an originator biopharmaceutical containing a new active biological substance approved by regulatory authorities based on its stand-alone quality and nonclinical and clinical data. The biosimilar is a follow-on biopharmaceutical containing an active biological substance highly similar to an already authorized reference product and approved based on its stand-alone quality data and comparability exercises against the reference product.
For the reference product, regulators require stand-alone quality, safety, and efficacy data demonstrating that the manufacturing process (inputs) produces a product with consistent and stable QAs under predefined storage conditions (outputs) with proof that the benefits outweigh the risks (i.e., benefit-risk balance) based on clinical trials. The regulatory decision on the approval of the reference product is primarily derived from the assessment of (randomized) clinical trials (Phases I, II, and III) designed to demonstrate safety and efficacy in treating the claimed therapeutic indications in the studied population.
For biosimilars, regulators demand stand-alone quality data and comparability exercises demonstrating the biosimilarity to the reference product for QAs, safety, and efficacy. The biosimilar pathway was created because the existing generic pathway for small molecules was considered insufficient to demonstrate the biosimilarity1 of biopharmaceuticals. During the last decades, regulatory guidelines of biosimilars have been developed and revised, reflecting the evolution of biosimilar regulations based on scientific progress and experience with the approved biosimilars. Pioneered by the EMA (2004), regulators have issued an extensive set of guidelines for biosimilars to facilitate the development and regulatory assessment of biosimilars. These guidelines were generally adopted by other health and regulatory authorities, including the World Health Organization (WHO, 2009), Health Canada (2010), and the FDA (2015) [46-50]. The EMA has developed multidisciplinary scientific guidelines for biosimilars, ranging from addressing general principles to guidelines that cover quality, nonclinical and clinical issues, and specific product class (e.g., somatotropin, filgrastim, epoetin, insulin, follitropin, interferon alpha and beta, and monoclonal antibodies) guidelines .
1 The term “biosimilarity” first appeared in the literature in 1977 in the Journal of Biorheology and was used by Hunter Roues to compare biomechanical properties between different species, becoming a principle of biosimilar development and approval decades later .
The comparability exercise of biopharmaceuticals aims to demonstrate that two batches (pre- versus post-change batches) from either the same manufacturer or two products (a biosimilar versus the reference product) from different manufacturers are comparable with no meaningful differences in quality, safety, and efficacy. The same principles are applied for both scenarios, which the FDA first introduced in 1996 for batches from the same manufacturer, and the EMA extended this in 1998 to cover the possibility of two versions from different manufacturers [51, 52]. Biosimilar development generally begins with an extensive characterization of multiple batches of the reference product to define QAs, determine the variability range or limits for each QA, and establish the quality-target profile, followed by reverse engineering to produce the candidate biosimilar and stepwise comparability exercises (Table 4). The comparability exercise starts by comparing the QAs of the DS between the biosimilar candidate and reference product (i.e., the DS of the reference product can be obtained by extraction, concentration, or deformulation from the reference product batches) to demonstrate high similarity and detect minor differences in QAs. The reference product is used as a comparator for biosimilars because it has been used by patients and has a well-established safety and efficacy record. Publicly available reference standards (e.g., pharmacopoeias) can be employed to calibrate the analytical procedures but cannot be used as a comparator because the reference standards were not developed for clinical use .
The variability in QAs is inherent in all biopharmaceuticals and can occur between and within batches from the same process and between versions from different manufacturers because of the complexity surrounding their molecule and manufacturing processes. However, regulators only accept minor differences if these do not alter clinical outcomes or jeopardize patient care. Schiestl et al. and Planinc et al. reported an example of acceptable minor differences in certain QAs for multiple batches of several reference products of biopharmaceuticals [30, 31]. However, a biosimilar must remain within the variability range of multiple batches of the reference product, and minor differences must not be clinically relevant. Halim et al. illustrated this small variability by analyzing multiple batches of reference products (Eprex® and NeoRecomon®) and biosimilars (Retacrit® and Binocrit®), observing minor differences in epoetin content, isoform profile, and potency between products and within batches of epoetin products. However, these minor differences were not clinically relevant .
Based on the outcome of comparability of QAs (Table 4, Step 3), comparative nonclinical (in vivo animal studies) and clinical exercises have been conducted to rule out the influence of minor differences in QAs on clinical outcomes, including PK/PD, safety, immunogenicity, and efficacy. Comparative nonclinical studies (Table 4, Step 4) have assessed the toxicity. However, their contribution to the comparability exercise is limited because they lack sensitivity to assess the a) influence of minor differences in QAs, b) variability of animal models and assays and c) predictability of safety and immunogenicity in humans,. The later limitation is illustrated by the cytokine storm during the first human trial of anti- CD28 mAb (TGN1412), which could not be predicted from in vivo animal studies [57, 58].
Because of these limitations and to comply with the principle of the three Rs: reduce, refine, and replace, the need for comparative nonclinical exercises is limited to approving quality changes and biosimilars . The comparative clinical exercises (Table 4, Step 5) have been conducted to confirm the comparability in terms of PK/PD, safety, immunogenicity, and efficacy based on various clinical trials (e.g., comparative Phase I in healthy volunteers and Phase III trials in the patient population). Regulators rarely require comparative clinical trials to support the changes in quality of the DS and DP that can be implemented after approval for biopharmaceuticals .
However, comparative clinical trials are required to approve biosimilars, especially those with complex and multifunctional molecules, such as mAbs and fusion proteins. Biosimilars for less complex molecules, such as insulin, (peg)filgrastim, and follitropin alpha, have been approved in recent years without the need for comparative Phase III trials because PD biomarkers are available as a surrogate for efficacy (e.g., the glucose infusion rate in a glucose clamp study for insulin and the absolute neutrophil count for (peg)filgrastim)), and the mechanism of action for these molecules is clearly understood. Furthermore, the accumulated experience with the regulatory evaluation of biosimilars revealed that comparative Phase III trials are less sensitive than comparative PK trials, preferably with a PD marker to assess the influence of minor differences in QAs identified from earlier comparability exercises [60-63]. In response to the ongoing debate on the potential reduction of unnecessary comparative Phase III trials, the EMA initiated a pilot program in 2017 to provide biosimilar developers with tailored scientific advice during biosimilar development.
This initiative has shifted the attention of stakeholders involved in biosimilar regulation, development, and use in clinical practice toward the comparability of QAs, which can detect and assess the influence of minor differences and determine the need for comparative nonclinical and clinical exercises and provide the basis for extrapolating indications. The extrapolation of indications is a well-established scientific and regulatory concept. For a reference product with multiple indications, the biosimilar can be granted all indications based on the outcome of QAs and a comparative clinical trial in one therapeutic indication. This concept has also been applied for long-term reference products when quality changes are introduced after approval, allowing for a reduction or elimination of duplicative and unnecessary clinical trials, which is the main reason biosimilars are cheaper and more accessible than reference products and have a potentially significant effect on patient care.
Table 4: Overview of the stepwise approach to biosimilar development, inspired by the European Medicines Agency guidelines on biosimilars .
To date (May 2022), 105 biosimilars of 17 different reference products have obtained regulatory approval from the EMA and FDA. The first wave of approved biosimilars comprised relatively simple proteins that replaced a malfunction of the body, such as growth hormones (e.g., somatotropin, follitropin alfa, and insulin), or enhanced an existing pathway, such as growth factors (e.g., epoetin and filgrastim). The second wave of approved biosimilars included more complex and multifunctional monoclonal antibodies. The first mAb biosimilar to be approved was the TNF-a-i infliximab in 2013, followed by adalimumab and etanercept. Later, the anticancer drugs rituximab, trastuzumab, and bevacizumab entered the market and, most recently (2021), a biosimilar for ranibizumab for eye diseases received market approval. Currently, biosimilars of mAbs and fusion proteins represent half of the approved biosimilars in the EU and US. The number of biosimilars is expected to increase, given that more than 15 candidate biosimilars are currently under evaluation by the EMA and FDA. Furthermore, the imminent expiration of patent and exclusivity rights for several best-selling biopharmaceuticals in the following years could pave the way for other waves of biosimilars .
Although biosimilars have reached the EU and US markets, the uptake and acceptance of biosimilars in clinical practice varies within the European countries and is still low in the US. This variance has been attributed to, among others, budget and reimbursement factors and a lack of understanding, acceptance, or trust in the science behind the biosimilar approval that heavily relies on the comparability of QAs [65, 66]. Previous research on the comparability of QAs by Halim et al. focused on comparing filgrastim and epoetin products and found that certain QAs for products (copies) from less regulated markets differed significantly from the reference products and biosimilars available on the EU market. Although Halim et al. provided insight into the consistency and variability between products and batches, their investigation covers less complex proteins than those available today and did not reflect on the comparability of QAs that should be assessed to support biosimilar approval.
Information on the comparability of QAs for (un)approved biopharmaceuticals is shared through various information sources. These sources include the European Public Assessment Report (EPAR) published by the EMA after the final decision on the marketing authorization application is made by the EC and scientific publications in peer-reviewed journals that can be communicated before or after obtaining regulatory approval. While the EPAR reflects the regulatory assessment, scientific publications communicate what researchers find interesting to share with the scientific community. Previous research has focused on navigating scientific publications to assess the availability of comparability exercises for (intended) biosimilars and found variations in the number of publications per molecule across different therapeutic areas [67-69]. Although these studies demonstrated that comparability exercises might be available in the literature, information on the comparability of QAs for intended biosimilars is scarce.
Furthermore, studies that assessed information on comparability exercises in EPARs are limited to the comparative nonclinical and clinical exercises, which found a substantial variation in the extent of details and type of (non)clinical data between the EPARs on biosimilars [70, 71]. Whether this is also the case for the comparability of QAs is entirely unknown and is addressed in this thesis. Studies that compared how the regulatory and scientific communities share information on biopharmaceuticals are limited to safety and efficacy and report a substantial discord between the two sources, necessitating consulting both sources to obtain a complete picture and make informed clinical decisions. Although it is acknowledged that the two sources have different objectives, little is known about the consistency and complementarity of information on the comparability of QAs described in the regulatory reports and scientific publications for biosimilars.
Post-approval Quality Surveillance and Potential Implications for Patient Care
Drug regulations must ensure the quality, safety, and efficacy of (bio)pharmaceuticals at the time of approval and continuously control and monitor these throughout their life cycle through post-marketing surveillance and pharmacovigilance systems [33, 34]. The establishment of post-approval surveillance and pharmacovigilance systems was prompted by the thalidomide tragedy in the 1960s, resulting in developing pharmacovigilance to further characterize and monitor the safety profile of a (bio)pharmaceutical when knowledge is limited at the time of approval . Today, post-approval surveillance of safety and efficacy is a fundamental part of the drug regulation. The WHO defined pharmacovigilance as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem.”
Post-approval surveillance comprises various pharmacovigilance activities and tools, including routine activities, such as the spontaneous reporting of adverse drug reactions and periodic safety update reports, and proactive activities, such as the risk management plan (RMP) describing additional post-authorization safety or efficacy studies (Table 5). The marketing authorization holder (MAH) provides a periodic safety update report to regulatory authorities at defined time points after approval, which includes further characterizations of all adverse drug reactions reported during the period and a critical assessment of the benefit-risk balance of the product. The MAH mandates submittal of the RMP document, which includes a list of safety concerns for which a distinction is made in the “important identified risks,” “important potential risks,” and “missing information.” The RMP is updated throughout the life cycle to reflect new safety information for a (bio)pharmaceutical. New safety information is assessed, and if considered relevant, risk minimization measures are taken (e.g., via direct healthcare professional communication or letters such as DHPC and DHPLs, black-box warnings, product or batch recalls, and marketing withdrawals issued to inform HCPs and patients).
The mainstays of post-approval quality surveillance are good manufacturing practice inspections and mandatory lot-release testing, where each manufactured lot is independently tested by the manufacturer and regulators [73, 74]. Lot- release testing is important to ensure the acceptable quality and safety of each lot before reaching the market and patients to obtain confidence in the potency and strength assigned to each lot and assess the validity and accuracy of QA testing performed on that lot by the manufacturer. Thus, the lot-release is a gate- keeper step to ensure the quality and safety of biopharmaceuticals before they reach patients.
However, quality aspects can occur after approval for approved medicines (including biopharmaceuticals), including post-approval changes and defects in the quality of the DS and DP. Post-approval quality changes require regulatory approval or notification through submission of the variation of terms of marketing authorization, whereas post-approval quality defects require regulatory action.
Companies can implement changes for many reasons: compliance with regulatory commitments and standards; maintaining product quality and consistency between batches; and increasing the manufacturing scale, robustness, efficiency, and reliability [75-77]. The regulatory approval of changes in the QAs of the DS and DP can be accessible in post-approval regulatory reports, such EPARs on the EMA public website. Regulatory actions due to quality defects can be communicated through DHPCs and DHPLs, recalls, or marketing withdrawals. Quality-driven tools are generally not publicly communicated, and pharmacovigilance tools are safety and efficacy focused; thus, little is known about the quality aspects of biopharmaceuticals after approval. Therefore, investigating these quality aspects is of primary interest because they could potentially affect clinical outcomes and patient care.
Table 5: Post-approval surveillance tools for biopharmaceuticals.
Moreover, biopharmaceuticals are vulnerable molecules and can be affected by manufacturing, storage, and transportation changes. Vlieland et al. demonstrated this vulnerability by investigating how inadequate compliance with storage recommendations by patients at home could influence certain QAs, such as the formation of aggregates and particles, where the potential risk for clinical outcomes could not be estimated [78-81]. Post-approval changes in the quality of the DS and DP can occur concerning changes in manufacturing, quality control, formulation, packaging, and stability. Such changes can affect CQAs, potentially influencing clinical outcomes and patient care [54, 82].
There are at least two examples of a link between approval changes in the quality and potential implications for clinical outcomes and patient care. The first example is an unpredictable increased rate of pure red cell aplasia in patients treated with Eprex®, which was associated with a post-approval formulation change in 1998, widely known as the Eprex® tragedy . The company replaced human albumin with polysorbate 80 and glycine to decrease the risk of contamination with viral
infections associated with using human plasma. Pure red cell aplasia was attributed to an immunogenic reaction toward some level of protein aggregation in the new formulation, induced by eliciting the formation of epoetin-containing micelles or interacting with leachates released by the uncoated rubber stoppers of prefilled syringes. Since then, protein aggregation has been considered a CQA and must be within the acceptable limits set by regulators. The second example is the shift and drift in glycosylation and potency for several batches of Herceptin®, which was associated with a post-approval change in the manufacturing site and process. Glycosylation and potency are considered CQAs; hence, it raises the question about the potential implications of the shift and drift for clinical outcomes and patient care.
Eprex and Herceptin shifted attention to understanding and exploring post- approval changes in quality, which have been explored in previous studies focused on quantifying and assessing the risk level of the changes in the QAs of biopharmaceuticals [33, 34]. These studies reported a substantial number of changes in quality, often rated at a low or medium risk level (95%), reflecting that the regulatory system has gained experience in how to evaluate post-approval changes and the influence that these changes may have on the quality in general and the CQAs for biopharmaceuticals. Previous studies have reported on post- approval changes in quality focused on reference products of biopharmaceuticals, but information on post-approval changes for biosimilars is lacking in the literature.
When biosimilars are approved, they are considered stand-alone products, which means comparison against the reference product to redemonstrate the biosimilarity is no longer required for biosimilars . Furthermore, little is known about the type of post-approval changes in quality of the DS and DP and whether patterns exist in the timing of implementing post-approval changes. Therefore, the characterization of the nature, including the type, risk level, and timing of post-approval changes in quality, for biopharmaceuticals is relevant to complement the current evidence. The TNF-α-i products, including the reference products and biosimilars of infliximab, adalimumab, and etanercept, were selected as case examples because these biosimilars account for more than half of those approved by the EMA for mAbs and have the longest post-approval history on the EU market [85-88].
Biopharmaceuticals with quality defects can have potential implications for clinical outcomes and pose a risk for patient care. Post-approval quality defects can occur due to unintentional or inattentive errors during manufacturing, storage, transportation, or at any moment throughout the life cycle. When a (new) safety concern or a defect in quality aspects is identified by a manufacturer or reported by HCPs or patients, it is the company’s responsibility to inform regulators as soon as it occurs. In response, regulators investigate the issue and take certain actions to address the potential implications for clinical outcomes that pose a risk to patient care. Regulatory actions often include summary information about the issue (whether safety or efficacy concerns or quality defects) and instructions for HCPs to deal with the issue to protect patients from potential clinical consequences.
An example of regulatory action is the recall of several heparin lots in 2007 because of quality defects concerning contamination with a semi-synthetic over- sulfated chondroitin sulfate, which was associated with serious acute hypersensitivity reactions in patients treated with contaminated batches . As per the regulatory investigation, the over-sulfated chondroitin sulfate is chemically synthesized and similar to heparin in structure and was used to reduce the production process cost. This heparin crisis led the US regulators to require a batch release test for each heparin batch and to revise relevant pharmacopoeia standards to new tests for over-sulfated chondroitin sulfate as an impurity.
Previous studies have focused mostly on regulatory actions issued due to safety and efficacy concerns regarding (bio)pharmaceuticals, revealing that knowledge of the clinical risks and benefits of (bio)pharmaceuticals expands after approval [90-97]. However, studies that have explored regulatory actions due to the quality defects of biopharmaceuticals are scarce. Most previous studies have focused on analyzing recalls for medicines in general, which demonstrated that the number of and reasons for recalls varied between countries and occurred in both less and highly regulated markets [98-104].
Of these studies, only Ebbers et al. reported information on the number and nature of recalls issued in the US between 2003 and 2013 for biopharmaceuticals. Ebbers et al. found that a small fraction of recalls were issued for biopharmaceuticals compared to small-molecule drugs. Recalls of biopharmaceuticals were related to defective devices or containers and packaging or labeling errors, which were unrelated to the complexity of the molecule and manufacturing process. Although the study indicated that none of the recalls for biopharmaceuticals were associated with unexpected risks for clinical outcomes and patient care, the study focused only on a single regulatory action (recalls) and might underestimate the quality defects that could be communicated through different types of regulatory action. Furthermore, the study provided no insight into the product associated with quality defects and, most importantly, how HCPs should act to counter the potential implications of the quality defects for clinical outcomes and patient care.
A few studies have assessed the quality and applicability of instructions for HCPs on clinical and biomarkers monitoring patients in clinical practice, which were often found to be of insufficient quality regarding both the regulatory letters sent to HCPs and the summary of product characteristics [105-107]. However, little is known about the actions required to be taken by HCPs when regulatory actions are issued due to quality defects, which we address in this thesis.
Knowledge Gap and the Rationale Behind this PhD Thesis
Biopharmaceuticals are produced through complex processes using living systems, resulting in molecules with inherent variability and minor differences in QAs even between batches from the same process. Biopharmaceuticals, whether reference products or biosimilars, must have consistent and comparable QAs throughout their life cycle to ensure that patients can use safe and effective treatments. Previous research and PhD theses on biosimilars have focused on requirements for developing regulatory guidelines for biosimilar approval ,
analysis of a selection of QAs to compare the reference product and biosimilars of filgrastim and epoetin obtained from the EU market with copies from emerging markets , market access to biosimilars , barriers to sustainable biosimilar competition and uptake in clinical practice , scientific, legal, and regulatory hurdles for biosimilar development, and interchangeability of biosimilars .
In recent years, the comparability of QAs with more emphasis on CQAs has played a primary role in biosimilar regulation and could dominate biosimilar approval in the future. Knowledge of the comparability of QAs has become increasingly relevant because it is the basis for regulatory decisions for biosimilars and quality changes that can be implemented for biopharmaceuticals after approval.
The quality of biopharmaceuticals must be ensured and maintained throughout the medicine life cycle, which is a prerequisite for safe and effective treatment. Previous research, including PhD theses from our group, has focused on post- marketing regulatory learning for biopharmaceuticals after approval by the characterization of the post-marketing safety and efficacy concerns and the evaluation of regulatory tools available to assess these concerns [108, 111-114]. This research has resulted in several studies that assessed various post-approval regulatory actions and activities related to safety and efficacy for (bio)pharmaceuticals after approval [90-97].
Studies that have assessed the quality of biopharmaceuticals after approval are limited and have focused on the quality of biopharmaceuticals after dispensing to assess patient compliance with storage recommendations and the effect of noncompliance on the quality of the biopharmaceuticals [79-81]. However, specific quality aspects have yet to be explored, including changes and defects that may occur for biopharmaceuticals before dispensing them to patients. These quality aspects require regulatory approval for quality changes and regulatory actions to mitigate the potential risk of quality defects. Insight into these post- approval quality aspects and their potential implications for clinical outcomes and patient care is still lacking.
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