Maintaining consistent quality and clinical performance of biopharmaceuticals

ABSTRACT

Introduction: Biopharmaceuticals are large protein based drugs which are heterogeneous by nature due to post translational modifications resulting from cellular production, processing and storage. Changes in the abundance of different variants over time are inherent to biopharmaceuticals due to their sensitivity to subtle process differences and the necessity for regular manufacturing changes. Product variability must thus be carefully controlled to ensure that it does not result in changes in safety or efficacy.

Areas covered: The focus of this manuscript is to provide improved understanding of the science and strategies used to maintain the quality and clinical performance of biopharmaceuticals, including biosimilars, throughout their lifecycle. This review summarizes rare historical instances where clinically relevant changes have occurred, defined here as clinical drift, and discusses modern tools used to prevent such changes, including improved analytics, quality systems and regulatory frameworks.

Expert opinion: Despite their size complexity and heterogeneity, modern analytics, manufacturing quality systems and comparability requirements for the evaluation of manufacturing changes cumulatively help to ensure the consistent quality and clinical performance of biopharmaceuticals throughout their product lifecycle. Physicians and patients can expect the same safety and efficacy from biopharmaceuticals and their respective biosimilars irrespective of batch or production history.

KEYWORDS:

• Biopharmaceutical
• biosimilar
• consistency
• drift
• equivalence
• manufacturing

1. Introduction

Biopharmaceuticals are a broad class of drugs produced from native biological tissue or using living cells [1]. The vast majority of biopharmaceuticals are protein based drugs that are manufactured by use of recombinant DNA technology and the term biopharmaceuticals in this manuscript will be used to describe exclusively these recombinant protein therapeutics. The first biopharmaceutical to be produced in this manner was insulin, which was approved for treatment of type 1 diabetes by the US Food and Drug Administration (FDA) in 1982 [1,2]. In the years since, the number of protein therapeutics has expanded dramatically with over 260 unique biopharmaceutical products approved in the US and Europe to date, including cytokines, hormones, enzymes, monoclonal antibodies, and fusion proteins (see Supplementary Table 1) [2–5]. The ability of different protein therapeutics to elicit complex, specific, and well-tolerated biological responses has made them some of the most effective treatments for a broad array of ailments including metabolic disorders, autoimmune diseases, and cancer [2].

Biopharmaceuticals include a growing group of follow-on products referred to as biosimilars that are designed to match protein drugs for which patents and exclusivity have expired. Stringent regulatory requirements dictate that biosimilars and their corresponding reference medicine must contain a matching active ingredient and exhibit equivalence upon extensive physicochemical and biological evaluation and comparative phase I and phase III clinical studies [6–8]. In the EU, a regulatory pathway for biosimilars was established in 2004 and the first biosimilar, a follow-on version of the human growth hormone somatropin, was approved in 2006 [9]. In the US, the legal basis for a biosimilar was not signed into law until 2010 and the first biosimilar, a follow-on version of human granulocyte colony stimulating factor filgrastim, was licensed in 2015 [10]. To date, 27 distinct biosimilars to 10 different reference product biopharmaceuticals have been approved in the EU and 7 distinct biosimilars are licensed in the US to 5 different reference product biopharmaceuticals, with expectations for a dramatic increase in this product class over the next decade [11,12]. Importantly, while biosimilars and originator biopharmaceuticals receive initial regulatory approval based on different regulatory frameworks, they are held to the same high quality standards. Furthermore, both product classes are regulated according to the same guidelines post approval to ensure that equivalent safety and efficacy are maintained throughout their life cycle.

Biopharmaceuticals are large and complex molecules and subject to diverse and heterogeneous posttranslational modifications whose type and abundance can vary depending on production cell type, culture conditions, purification strategy, formulation, and storage device format [13,14]. Maintaining the consistent quality of a protein-based therapeutic over time requires stringent manufacturing and regulatory controls as well as an extensive understanding of product quality attributes and their impact on safety and efficacy. The term quality in this context refers to the suitability of the product for its intended use, that is, its clinical performance [15]. The consistent clinical performance of a biopharmaceutical therefore requires consistent quality, meaning that the variability of the quality attributes, such as differing abundance of posttranslational modifications, must stay within acceptable limits to ensure equivalent safety and efficacy over time.

The inherent variability of biopharmaceuticals can be further compounded by the necessity for manufacturing process changes which are often regularly required for various reasons such as production equipment discontinuation, manufacturing improvements, or production site transfers [16–18]. Because manufacturing changes are not transparently communicated in many countries, it is difficult to accurately assess their type, impact, and frequency; however, a recent study reported over 400 reported changes for 29 evaluated biopharmaceuticals marketed in the EU, ~5% of which were designated as ‘high risk’ for impacting product quality or safety [19].

Despite the inherent batch-to-batch variability of protein therapeutics and the frequent need to modify manufacturing processes, examples where quality and regulatory systems have failed to prevent clinical drift from occurring, that is, differences in clinical safety or effectiveness over time, are exceptionally rare. The primary focus of this manuscript is to discuss key elements of modern manufacturing quality systems and regulatory strategies for maintaining consistent quality and equivalent clinical performance of biopharmaceuticals over the course of their often decades long product life cycle.

2. Rare reported cases of clinical drift

The greatest testament to the ability of manufacturing and regulatory controls to maintain the consistency and clinical performance of biopharmaceuticals is the paucity of cases where the safety or effectiveness of a biopharmaceutical have changed over time, referred to in this manuscript as clinical drift. In the 35 years since the approval of the first biopharmaceutical, over 260 biopharmaceuticals have been marketed in the US and Europe while only 3 cases of clinical drift have been reported (see Supplementary Table 1). Although the examples of clinical drift described below are in some cases anecdotal or the result of complex product modifications which today would no longer be permitted without an extensive comparability investigation according to current international guidance [20], they are a reminder that quality systems must be continually evaluated and improved for robust maintenance of biopharmaceutical quality.

2.1. Cetuximab

Cetuximab is a monoclonal antibody which binds and inhibits epidermal growth factor receptor activation and is effective for the prevention of neoplastic proliferation in specific cancer types [21]. Initial approval was granted in the US and EU in 2004. Historically, commercial manufacturing of cetuximab for the US and Europe occurred in different facilities by different companies [22,23]. Clinically relevant differences between US and EU manufactured material were reported in 2011 by the FDA who uncovered a 22% higher pharmacokinetic exposure in patients receiving US material after applying population pharmacokinetic analysis to compare clinical trials with slightly different designs and using exclusively EU or US manufactured cetuximab [22,24].

While a difference in pharmacokinetic exposure does not necessarily impact drug safety or efficacy, there is a risk that higher exposure results in clinical differences, which is problematic if regionally distinct material is used to support global clinical programs to extend or modify the label. These concerns were initially addressed in 2011 using a limited clinical comparison of US and EU material [22,24]. To further resolve the risk associated with these country specific differences, the FDA requested a larger post-marketing head to head follow-up trial for comparing the safety of cetuximab manufactured in the EU and US in patients with head and neck squamous cell carcinoma receiving concomitant treatment with platinum-based chemotherapy [24]. Results from this trial were recently published and reveal no difference in treatment emergent adverse events or clinical efficacy [25], nonetheless, the difference in pharmacokinetic exposure between US and EU manufactured cetuximab is indicated in the US prescribing information [22].

2.2. Interferon beta 1a

Interferon beta 1a is a naturally occurring cytokine with a wide range of anti-inflammatory properties [26]. The first marketed version of interferon beta 1a as a biopharmaceutical was Avonex, which was approved for intramuscular injection in the US in 1996 and a year later in Europe for the prevention of relapse in multiple sclerosis patients [27–29]. At approximately the same time, a second drug form of interferon beta 1a was independently developed by another company and marketed under the trade name Rebif for the same prophylactic treatment of multiple sclerosis patients via subcutaneous administration [30,31]. Interestingly, although both Avonex and Rebif were both developed to contain the same amino acid sequence and share the same international nonproprietary name, these products were not developed to be comparable or biosimilar to one another and thus likely exhibit differences in type or abundance of clinically relevant variants, glycosylation or impurities [32]. These putative quality differences, together with differences in dose and route of administration, may be the cause of observed variance in the immunogenicity of these products, manifesting in a higher prevalence of neutralizing antibodies in patients administered with Rebif [32,33].

Between 2005 and 2007, a new bovine serum-free and human serum albumin-free formulation was developed for Rebif and found to reduce the degree of neutralizing antibodies [34]. In 2014, a brief communication was published in the New England Journal of Medicine reporting an increase in the number of spontaneous reports of thrombic microangiopathy in a small number of patients treated with Rebif following the formulation change [35]. Importantly, due to the low number of reported incidents and lack of a controlled clinical investigation, the association of the Rebif reformulation and thrombotic microangiopathy remains anecdotal. More recent global evaluations of Rebif adverse event case reports reveal no apparent correlation between the Rebif formulation change and thrombotic microangiopathy [36]. However, true causal relationships between product changes and rare adverse events are very difficult to definitively establish due to patient variability and reporting inconsistencies [35,36]. Thus, as a precaution, regulators have requested the addition of a warning to the Rebif product information to assure that patients and health-care providers are informed of this potential risk [30,31].

2.3. Erythropoietin

Erythropoietin is a hormone produced primarily by the kidney and is responsible for the induction of erythropoiesis in the bone marrow and subsequent production of circulating erythrocytes which distribute oxygen in the body [37]. Erythropoietin can be administered to patients to treat anemia resulting from various conditions including chronic kidney disease, cancer, and chemotherapy [38]. The first recombinant erythropoietin to become available for human use was Eprex (epoetin alpha), which received regulatory approval in Europe 1988 and is marketed exclusively outside of the United States. In 1998, a second epoetin alpha biopharmaceutical was independently developed and marketed as Epogen® exclusively within the US [38].

Following initial approval, the Eprex brand in Europe underwent a number of changes including the adoption of subcutaneous administration in the early 1990s, the introduction of syringes with uncoated rubber stoppers in 1994, and the replacement of human serum albumin with polysorbate 80 in 1998 [38–40]. Beginning in 1998, there was a dramatic increase in patients outside the US developing pure red blood cell aplasia (PRCA), a dangerous autoimmune reaction toward erythropoietin resulting in severe anemia [37–40]. Subsequent investigations revealed that the increased incidence of PRCA in Eprex-treated patients was associated with the formulation change which also resulted in the extraction of high levels of leachate impurities from uncoated rubber syringe stoppers by the new polysorbate 80 formulation [38–40]. In response, and because the increase in PRCA was only associated with the more immune-sensitive subcutaneous route of administration, the subcutaneous application of Eprex was contraindicated between 2002 and 2006 by affected national health authorities. Further, a worldwide replacement of uncoated rubber stopper syringes by those with much more inert coated rubber stoppers was initiated in 2004, practically abolishing the incidence of Eprex-associated PRCA to baseline levels [38,41,42]. Although the exact mechanism by which the formulation change and potential leachate impurities resulted in increased Eprex immunogenicity remains unresolved, this case report demonstrates how iterative product changes, such as administration route, device, and formulation, that are not sufficiently evaluated using modern comparability assessment standards, can culminate in clinical changes with dangerous adverse consequences.

3. Quality systems and regulatory requirements used to monitor product consistency and maintain clinical performance

Although examples of clinical drift in biopharmaceuticals since their entrance onto the market 35 years ago remain extremely rare, concerns regarding the maintenance of quality and clinical performance have resurfaced due to the emergence of biosimilars products, which implicitly will apply unique manufacturing processes to match the reference product quality. While originator biopharmaceuticals and biosimilars utilize distinct regulatory frameworks for initial product approval, the same regulatory concepts and quality strategies are applied to both product classes post-approval to maintain product safety and efficacy. The following section will discuss tools and strategies important for maintaining consistent product quality, including state of the art analytics and their contribution to understanding and monitoring quality attributes critical for biopharmaceutical safety and efficacy. Further we will discuss how increasing knowledge of biopharmaceuticals is leveraged in modern quality systems to maintain product consistency. Last, we will discuss the concept of comparability and how the application of this regulatory requirement is used maintain the equivalent clinical performance of a biopharmaceutical throughout its life cycle.

3.1. State-of-the-art analytics for detection and control of critical quality attributes

Essential for the maintenance of product quality is an in-depth understanding of protein modifications, impurities, and contaminants which impact product safety or efficacy. While general improvements in analytical instrumentation and strategies have been achieved over the past few decades [14], the ability to detect and characterize variants and impurities in biopharmaceuticals has been facilitated to a large degree by advancements in mass spectrometry, with current instruments achieving high resolution detection of peptides in the femtomolar and attomolar range [43,44]. This technology is being leveraged to allow improved detection of functionally relevant glycans on therapeutic proteins [45–47], as well as the assessment of minor product variants potentially relevant to protein structure or function, such as sequence variants, truncations, incorrect disulfide bridge structures, and other amino acid modifications [48–54]. Further, mass spectrometry has become an orthogonal tool in the monitoring of process impurities such as host cell proteins (HCPs), providing improved assessment of the type and amount of these impurities and their potential impact on product stability and immunogenicity [55,56]. As shown in Figure 1(a), mass spectrometers are able to detect and monitor specific HCPs down to a single part per million (ppm).

Figure 1. The analytical capability of mass spectrometry. (a) The detection of a specific host cell protein at 1 ppm using a modern electrospray ionization source mass spectrometer. The extracted ion chromatograms of three fragment ions used for characterization and quantitation are shown in green, orange and blue. The doted lines indicate the range for integration and relative quantitation. (b) Analysis of polyethylene glycol (PEG)-filgrastim using a matrix assisted light desorption (MALDI) source mass spectrometer in the 1990s (upper panel) and analysis of PEG-filgrastim using a modern electrospray ionization source mass spectrometer showing resolution of individual PEG extension units and associated variants (lower panel). A representative model of PEG-filgrastim shows the protein therapeutic component and its associated PEG chain.

In addition to improvements in sensitivity, advances in the resolution of mass spectrometers have allowed novel capabilities in characterizing variants in large complex biopharmaceuticals. For example, pegfilgrastim, a pegylated biopharmaceutical whose heterogeneity was previously impervious to detailed characterization, can now be directly characterized down to site-specific amino acid modifications and individual peg-extension units (see Figure 1(b)) [57,58]. Further, progress in the ability of mass spectrometers to analyze large intact proteins is increasing the utility of this technology for identifying and monitoring functionally relevant product variants. Example include strategies for top down elucidation of site-specific variants as well as additional capabilities for characterizing variants and their impact on protein interactions in intact molecules under native conditions [59–64].

The ability of mass spectrometry to quickly, sensitively, and accurately detect a plethora of protein variants in a single analysis provides the potential of this technology to replace more conventional analytical applications and to broaden its use beyond development to quality control and product release. Although challenges remain for the standardization of the complex software and analytical functions associated with these instruments, strategies for the integration of mass spectrometry into the highly regulated quality control environment have been published [65]. Taken together, mass spectrometry has become an effective tool in manufacturing process development, in particular for generating product and process understanding to inform control strategies ensuring product consistency and safety.

3.2. Manufacturing quality systems for monitoring product consistency

Product consistency is a core expectation of health authorities world wide and multiple laws and regulations have been established toward ensuring consistent biopharmaceutical manufacturing . The International Conference of Harmonization (ICH, since 2015 International Council for Harmonization), was established in 1990 to generate and harmonize regulatory guidelines for pharmaceutical development and manufacturing between the European Union, US, and Japan. Meanwhile many more countries have joined this initiative and adopted the ICH guidelines, which include regulations for ensuring product consistency.

ICH Q7 describes Good Manufacturing Practices (GMPs) which comprehensively cover requirements for a vast array of quality control measures including: personnel, building and facilities, process equipment, documentation and records, materials management, production and in-process controls, packaging, storage and distribution, laboratory controls, equipment qualification and process validation, change control, and the handling of product complaints and recalls [66].

With the beginning of the 21st century, regulatory agencies started to enhance and modernize the regulation of pharmaceutical manufacturing and product quality [67]. This undertaking fostered risk- and science-based approaches to pharmaceutical quality, resulted in the modern requirements for a Pharmaceutical Quality System (PQS) [68], and introduced the concept of quality by design to the development of pharmaceutical products [15]. The core objectives of a PQS are (i) to consistently achieve the realization of a safe and effective medicine, (ii) to establish and maintain a state of product control, and (iii) to facilitate continual improvement of the product and process to mitigate quality risks [68]. A PQS builds on and complements current GMP and additional international quality guidance which requires that manufacturing processes be designed and controlled such that pharmaceutical products meet predetermined quality requirements in a consistent manner [15,66,69,70]. The PQS covers the entire life cycle of a pharmaceutical product, from early process development to commercial manufacturing, to facilitate that product consistency is already built into the process design, that is, to limit the variability in manufacturing and prevent aberrant manufacturing changes already by default. Consequently international PQS guidance also describes the management responsibilities in overseeing quality assurance measures [68]. Compliance to these measures as well to GMP and all other regulatory commitments is verified by on-site inspections by the responsible health authorities prior to product approval and routinely thereafter at regular intervals.

Quality by Design is an improved systematic approach to the development of pharmaceuticals which emphasizes product and process understanding, established by extensive product and process characterization exercises. The outcome is a process design where the sources of variability within the manufacturing process are identified and correlated with specific product quality attributes [15]. The acquired product and process knowledge is the basis for establishing an integrated control strategy that assures process performance and product quality using control elements such as raw material controls, process design, in-process testing, control of process parameters, and release testing.

An important feature of the control strategy are specifications, which are tests and acceptance criteria for the product to be considered safe and fit for purpose. Since specifications are developed based on batches that were evaluated in controlled pivotal clinical trials prior to initial approval, continued adherence to these specifications over the life cycle of the product provides a direct link to the clinical experience with the product [71]. In the event that either product specifications or in-process monitoring detect changes in a critical quality attribute beyond the acceptable range, affected batches cannot be released for human use and are discarded. GMP also requires an investigation to identify the cause and to initiate measures to prevent such cases in the future.

Process validation is another layer of control which aims to ensure consistent product quality. This quality confirming measure establishes the scientific evidence that the commercial manufacturing process is capable of consistently delivering product quality within predetermined specifications [70]. Scientific evaluation of process development data, together with the assessment of an appropriate number of production batches are typically used to verify that the commercial process performs according to process design expectations before the pharmaceutical product can be commercially distributed. Importantly, product and process data need to be continually collected and analyzed in order to detect any undesired variability or trends early on and to allow for the prevention of product inconsistency well before the product does not meet its specifications. This strategy of continued process verification leverages assessment of production data to support identification of outliers or trends [68,72,73]. As shown in Figure 2, continued process verification mediates objective assessment of process variability, allowing corrective or preventive actions to be implemented before specifications or safety and efficacy limits are breached. In the case of any deviation from the approved manufacturing process, GMP requires that an investigation is undertaken to identify the cause and to undertake corrective and preventive actions.

Figure 2. Strategic overview of continued process verification. Continued process verification helps to ensure process consistency by allowing fast and objective identification of outliers or trends in production data. Statistical process control limits, in general three standard deviations above the mean (3s) are used to define out of expectation (OOE) data, allowing preventive or corrective action to be taken before outlies approach specification limits and are out of specification (OOS). Specification limits are set based clinical data and manufacturing capability and prevent the release of batches with differences in safety or efficacy.

Product consistency is therefore maintained by the combination of many tools at different layers throughout the product life cycle. In addition, detailed improvements are encouraged to further reduce the risk of inconsistency. For example, to verify that analytical test results are consistent over time, a two-tiered reference standard strategy has been proposed by regulators and has been quickly adopted by industry [74]. As shown in Figure 3, this two-tiered approach dictates that any official or ‘in house’ reference standard for routine testing must be qualified or calibrated against a single primary reference standard, and subsequently tested at regular intervals against the primary standard to detect any drift of the reference standards. This strategy is another feature to maintain consistent analytical test results and preserve a reliable link between analytical data and clinical studies throughout the product life cycle.

Figure 3. Strategic overview for the generation of a two tiered reference standard. A strategic overview for the generation and maintenance of a two tiered reference standard over the course of biopharmaceutical development to commercialization. A large scale phase III or pivotal trial drug substance batch produced under cGMP conditions is used for generating the in house primary reference standard. All working standard batches used to release commercial material must first be compared to the primary reference and comply with primary reference standard specifications prior to use, ensuring a consistent standard throughout the lifecycle of the product.

Overall, the requirements for a PQS, for GMP, for process design & validation and the control strategy are identical for all biopharmaceuticals, including biosimilars and their reference products. Both must consistently deliver a product with clinically established performance according to the label claim.

3.3. The application of comparability to maintain clinical performance

Quality systems have evolved to maintain biopharmaceutical consistency despite product heterogeneity. Nonetheless, due to the sensitivity of biopharmaceutical composition to even small variations in production conditions, shifts in the abundance of quality attributes can be observed in conjunction with manufacturing changes [16,75]. Manufacturing changes are commonly required in biopharmaceutical production for a variety of reasons, for example, to maintain state-of-the-art production facilities or to adapt to changing demand on a global scale. However public information on post-approval manufacturing changes is limited, preventing direct correlations between production changes and shifts in quality attributes [18,19]. Despite this lack of transparency, biopharmaceutical quality attribute shifts are increasingly reported in the literature and can be assumed to be associated with changes in the manufacturing process. Such shifts in product quality attributes are a consequence of intended process changes and are distinct from gradual and unintended product changes over time which should be controlled by stringent process controls and quality systems described above. One of the most notable examples of a process-related shift involved glycosylation changes in darbepoetin alfa, which corresponded chronologically with the establishment of a new production cell line [76]. Other recent examples biopharmaceutical quality attribute shifts include in vitro potency in recent Enbrel batches [54], and shifts in the glycosylation and antibody-dependent cell-mediated cytotoxicity activity of Herceptin, Rituxan, and MabThera [17,77].

While documented changes in the abundance of quality attributes such as critical glycans or potency can appear concerning at first glance, it is important to understand that such shifts are implicit to biopharmaceutical production and that the equivalent safety and efficacy of a product, before and after a process change, must always be established using a comparability exercise [20]. Comparability is a regulatory requirement ensuring that the quality, safety, and efficacy of product are not impacted by changes in the manufacturing process. The requirements for a comparability exercise will vary depending on the associated risk and severity of the manufacturing change, ranging from a purely analytical comparison to the inclusion of a comparative phase III clinical trial [20,78,79].

Despite decades of experience establishing the ability of comparability exercises to maintain equivalent clinical performance over countless manufacturing changes in hundreds of biopharmaceuticals [18,19], concerns have been expressed that multiple manufacturing changes carry the potential to result in clinically relevant changes over time, in particular between a biosimilar and its reference product as these products are manufactured by independent entities [75]. However, this concern ignores the fact that products resulting from a manufacturing process change must always be assessed by suitable comparability testing which includes review and approval from the responsible health authorities. Upon successful completion of the comparability assessment, a product manufactured after the process change is presumed to have safety and efficacy comparable to the material manufactured prior to the process change.

To maintain consistent clinical performance following manufacturing changes, it is important that analytical and functional comparability assessments focus on quality attributes that are known or that are suspected to have a high likelihood of impacting clinical efficacy or safety, including immunogenicity. There are some quality attributes that always need to be considered, such as potency and aggregates. Each unique protein will also contain additional product-specific quality attributes that can impact efficacy or safety. These may be known from the literature or from a manufacturer’s experience over time with the product. Manufacturers should take care to include comparisons of these attributes when assessing the impact of manufacturing process changes.

By leveraging product and process knowledge to address specific process changes, analytical and functional assays are generally sufficient to ensure equivalent clinical performance, preventing the necessity of phase III clinical trials following each change in the manufacturing process. Thus, the safety and efficacy of the drug is therefore established only once, at the time of initial approval, with all subsequent manufacturing changes bridged to the initial material [80]. As shown in Figure 4, although it is plausible that the abundance of individual quality attributes may diverge over time, the demonstration of comparability as an integral part of each manufacturing change ensures that any such divergence is not clinically meaningful. As noted earlier, biosimilars and their respective reference products are regulated post-approval under the same criteria – that of an approved biological drug. The comparability concept and its practical application in conjunction with manufacturing changes, ensures that equivalent clinical safety and efficacy are maintained throughout the life cycle of a biopharmaceutical, irrespective of the frequency of manufacturing changes and regardless of whether the product is an originator or a biosimilar.

Figure 4. Demonstration of comparability following manufacturing changes allows maintenance of clinical performance. An example diagram showing the theoretical impact of manufacturing changes on a measurable property of a biosimilar product and reference product (Ref.) over time. While multiple changes over time may result in divergent abundance of a measurable property, the comparability exercise establishes that there are no clinically meaningful difference in the products and allows bridging to the original safety and efficacy established upon product approval. It should be noted that the concept illustrated in this Figure applies equally to the life-cycle management of originator and biosimilar drugs as well as to products known in the US as ‘interchangeable biologics’ (biosimilars that can be substituted by a pharmacist without first obtaining approval from the prescribing physician).

While often unavailable to the public due to proprietary concerns, the evaluation of long-term production data provides the most transparent means by which to assess and understand the ability of quality systems to maintain product consistency. An opportunity to assess such data is provided by the filgrastim biosimilar Zarzio¹, which has been on the EU market since 2009 and subjected to multiple manufacturing changes including process up-scales and adaptions. The relative amount of the most abundant single product variant is ideal as a model for assessing the long-term manufacturing consistency of filgrastim as this critical quality attribute tracks multiple process sensitive variants, reporting always the most abundant of these variants using a single consistent method. As shown in Figure 5, the relative amount of the most abundant single product variant remained largely within three standard deviations of the mean (3s) and all data points align well below the established specification of <2% throughout the product life cycle. A brief excursion of the 3s limits was observed toward the end of 2014 which was addressed by a process adaption to restore process consistency. While filgrastim represents a relatively simple biopharmaceutical due to the smaller size of the protein (~18.8 kDa) and its lack of glycosylation, long-term process consistency has also been published for the biopharmaceutical Humira, a large monoclonal antibody (~150 kDa) with glycan modifications [81]. Taken together, these examples are useful in demonstrating that diverse quality attributes associated with both simple and complex biopharmaceuticals are appropriately controlled across long periods of time and multiple manufacturing changes using established quality systems.

Figure 5. Long term large scale production data for a representative product variant in filgrastim.

The most abundant single product variant is a critical quality attribute describing multiple process sensitive variants in filgrastim detected using a single reverse phase chromatography method. The relative amount of the most abundant variant in a batch is reported. The most abundant single product variant batch release values from the Sandoz filgrastim biosimlar *Zarzio® are reported from 2009 to 2017. Process control limits of three standard deviations above the mean (3s) are indicated by dashed black lines and the mean is indicated by a green line. The release specification of less than 2.0% is indicated by dashed red line. Manufacturing up-scales and process adaptions are specified.

*Zarzio® (filgrastim) was licensed in the European Union in 2009.

The same drug was approved in the US in 2015 as Zarxio® (filgrastim-sndz).

4. Conclusion

Despite their inherent size, heterogeneity, and complexity, current analytical technology, modern GMP-based manufacturing quality systems, and requirements for comparability evaluation following manufacturing changes can be considered appropriate to monitor biopharmaceutical quality and maintain clinical performance. Overall, these tools, systems, and strategies help to ensure that the safety and efficacy of biopharmaceuticals and their respective biosimilars remain consistent, irrespective of batch or production history.

5. Expert opinion

Biopharmaceuticals have a long history of delivering consistently safe and effective treatment over the entire course of their often decades long life cycle. Biosimilars employ the same post-approval regulatory framework and quality systems as originator biopharmaceuticals to maintain quality and clinical performance. Nonetheless, as the number of biosimilars increases, concerns regarding the ability of biosimilar products to maintain equivalent clinical performance with their respective reference product have been disseminated. At the center of these concerns is the misconception that the sheer complexity and heterogeneity of biopharmaceuticals preclude effective monitoring and control of relevant quality attributes which, through intended or unintended process changes, may result in clinically relevant differences to the reference product over time.

As outlined in this manuscript, effective strategies for maintaining product quality and clinical performance are a pivotal regulatory requirement for the production of biopharmaceuticals, including biosimilars. To this end, production quality systems based around the central concept of GMP have been developed to allow consistent production of safe and efficacious biopharmaceuticals over time and worldwide, irrespective of manufacturing process changes. As analytical capabilities and product understanding continually improve, so do the quality systems and strategies used to maintain product consistency and quality. In addition to established aspects of GMP and the PQS, improvements in manufacturing quality systems are discussed in this manuscript, including: (i) the implementation of quality by design strategies to leverage extensive product and manufacturing knowledge to mitigate risk and maintain product consistency, (ii) the use of continued process verification strategies to continually track data and allow early response to risk associated trends, and (iii) the implementation of two-tiered reference standards to ensure the maintenance of consistent acceptance criteria and specifications over time. In addition, this manuscript discusses the concept of comparability and the application of this regulatory requirement to maintain the clinical performance of biopharmaceuticals following process changes.

Overall, despite their inherent complexity and the prevalent necessity for process changes, the challenge of maintaining the quality and clinical performance of biopharmaceuticals has overwhelmingly been met as evidenced by the rarity of clinical drift, with only a single verifiable case in over 260 biopharmaceutical products marketed in the US and Europe over the past 35 years (see Supplementary Table 1). Biosimilars are follow-on biopharmaceuticals which effectively apply the same quality systems and regulatory frameworks to maintain quality and clinical performance, as demonstrated by over a decade of real-world experience in Europe [82]. Despite the demonstrated success and safety of these products, biosimilars have faced significant skepticism, particularly in the US, due in part to the more recent entry of these products onto the US market as well misconceptions with regard to product regulation and quality. To counter these misconceptions, the FDA has published clarifying literature explaining the rigorous nature of the biosimilar pathway, stating that ‘patients and health care professionals are able to rely upon the safety and effectiveness of biosimlar products, in the same manner as for the reference product’ [83].

Attempts to disseminate quality concerns specific to biosimilars lacks scientific and historical basis and contributes to damaging misconceptions of biopharmaceuticals as a whole. The purpose of this manuscript is to provide transparency with regard to the real and perceived risks associated with biopharmaceutical production and the tools in place to maintain their consistency and quality. In our expert opinion, increased transparency regarding the inherent nature of biopharmaceutical variability, as well as the quality systems and controls used to maintain their safety and clinical performance over time, will improve confidence that the same safety and efficacy can indeed be expected from a biopharmaceutical and its respective biosimilar, irrespective of batch or production history.

Article highlights

• Biopharmaceutical heterogeneity and variability are inherent in this product class due to cell based production and the necessity for regular manufacturing process changes

• Biopharmaceutical variability resulting in clinical differences is extremely rare with only a single verifiable case resulting in adverse events in over 35 years and over 260 products

• Analytical capabilities and modern quality systems are continually evolving to ensure consistent biopharmaceutical quality. Recent improvements include: (i) Quality by design (ii) Continued process verification and (iii) Two tiered reference standards.

• Although the abundance of specifc variants may vary, the demonstration of comparability following manufacturing changes ensures equivalent clinical performance throughout the product lifecycle.

• Originator and biosimilar biopharmaceuticals employ identical quality systems and regulatory frameworks to maintain consistent quality and clinical performance.

• Physicians and patients can expect the same safety and efficacy from biopharmaceuticals and their respective biosimilars irrespective of batch or production history.

This box summarizes key points contained in the article.

Declaration of interest

The authors are employees and shareholders of Sandoz, a division of Novartis, which develops, manufactures and markets biopharmaceuticals, including biosimilar products. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

No funding to declare.