Non-biological Complex Drugs Research Articles

Rock-to-Pharma: Characterization of Shale Oil-Based Nonbiological Complex Drugs along the Production Process by High-Resolution Mass Spectrometry.

Antibiotic resistance has become a primary concern in medicine because of the overuse and misuse of classical pharmaceuticals. Recently, nonbiological complex drugs (NBCDs) have gained interest for their complex pharmacological profiles. Bituminosulfonates, which have lately been tentatively allocated toward NBCDs, are pharmacologically well-studied and show low potential in resistance development. However, molecular composition knowledge is limited. With this work, we present a comprehensive approach to investigate the manufacturing process of complex pharmaceuticals like bituminosulfonates on a molecular level via Fourier-transform ion cyclotron resonance mass spectrometry. The application of various hyphenations and ionization techniques comprehensively covers the entire mass and polarity range of the matrix, and the high sensitivity enables the identification of significant and minor chemical alterations caused by the multistep manufacturing process. The distillation of the shale crude oil eliminates highly aromatic PAH and PASH constituents. ESI(-) revealed strong PAH- and PASH-sulfonate formation after reacting the shale oil distillate with sulfuric acid. Increasing alkylation reduced the sulfonation yield, instead causing oligomerization side reactions, as observed by APPI analysis. Furthermore, multidimensional gas chromatography coupled with high-resolution mass spectrometry verified core structural motifs. With this work, we demonstrate the high potential of FT-ICR MS in NBCD process analysis. The results also give valuable information for future pharmacological investigations focusing on specific compound classes or properties.

Exploiting Pharma 4.0 Technologies in the Non-Biological Complex Drugs Manufacturing: Innovations and Implications.

The pharmaceutical industry has entered an era of transformation with the emergence of Pharma 4.0, which leverages cutting-edge technologies in manufacturing processes. These hold tremendous potential for enhancing the overall efficiency, safety, and quality of non-biological complex drugs (NBCDs), a category of pharmaceutical products that pose unique challenges due to their intricate composition and complex manufacturing requirements. This review attempts to provide insight into the application of select Pharma 4.0 technologies, namely machine learning, in silico modeling, and 3D printing, in the manufacturing process of NBCDs. Specifically, it reviews the impact of these tools on NBCDs such as liposomes, polymeric micelles, glatiramer acetate, iron carbohydrate complexes, and nanocrystals. It also addresses regulatory challenges associated with the implementation of these technologies and presents potential future perspectives, highlighting the incorporation of digital twins in this field of research as it seems to be a very promising approach, namely for the optimization of NBCDs manufacturing processes.

A place for biosimilars in the changing multiple sclerosis treatment landscape.

The treatment paradigm for multiple sclerosis (MS), particularly relapsing-remitting MS, is heavily reliant on biologic disease-modifying therapies (DMTs). However, the current cost of treatment acts as a significant barrier to access for patients. Over the next few years exclusivity periods for key biologic medicines used in MS are likely to end, opening the door for biosimilar medicines to enter the market. In this review, we discuss what biosimilar medicines are, and how the existing experience with biosimilar medicines across multiple therapy areas can inform the assimilation of biosimilar medicines into the MS treatment landscape in Europe and the US. There is currently a lack of knowledge and awareness around the distinctions and similarities between small molecules, non-biological complex drugs, and biological medicines, as well as the different categories of follow-on successor medicines. These include biosimilar medicines that offer a matching efficacy and safety profile to the reference biologic. Understanding and recognition of the stringency of the approval pathways required for drug categories such as biosimilars are key in building confidence in treatment outcomes. For example, biosimilar medicines are sometimes perceived only as 'copies' of their reference biologic despite undergoing an extensive approval process requiring that no clinically meaningful differences are observed between the biosimilar medicine and the reference medicine. For MS, introduction of biosimilar medicines in the future will enable more people with MS to receive effective treatment, and also expand access to biologic DMTs in MS. Experiences from the use of biosimilars in multiple therapy areas have shown us that this can result in cost-saving benefits for a healthcare system. Introduction of biosimilar medicines in other therapy areas has also demonstrated the importance of appropriate, accurate education and information for their successful integration into clinical practice. In order to realize optimized treatment outcomes in MS in coming years and to find the appropriate place for biosimilar medicines in the changing MS landscape, it is essential that clinicians and people with MS understand the fundamentals of biosimilars, their potential benefits and consistency of treatment provided by a biosimilar medicine, given the matching efficacy and safety profile to its reference medicine. As evidenced in other therapy areas, biosimilar medicines may reduce key barriers to access by providing a cost-effective alternative to the MS treatment arsenal, while providing the same treatment outcomes as reference biologics.

A Comparative Study on Approval of Follow-on Version of Sevelamer Carbonate and Glatiramer Acetate (GA) in US, EU

Abstract: Many non-biological drugs, different in terms of their structure and mode of action, pharmacological classification, and therapeutic indication, have a common factor of structural complexity and are grouped as non-biological complex drugs (NBCDs). When an innovator drug nears the time of off-patent, different manufacturers attempt to produce its subsequent version, so the patients will have a cost-effective therapeutic equivalent. Since the innovator molecule is complex, its follow-on drug can be called its true generic version, if its bioavailability, bioequivalence and therapeutic equivalence to the innovator drug are demonstrated. However, it is observed that a case-to-case basis approach is implemented by European Medicines Agency (EMA) and Food and Drug Administration, US (USFDA) in the approval of such drugs and there is no uniformity observed between the two. : In this study, an attempt is made to study the complexity of molecules compare and understand the data requirements, and procedures adopted for the review and approval of such complex products. Therefore, drug sevelamer carbonate and glatiramer acetate are selected for the study. A methodical approach was followed. European assessment reports and drug approvals available in the orange book database of the former two regulatory agencies were studied. It is observed that the generic version of glatiramer acetate is approved as an abbreviated new drug application (ANDA) by Food and Drug Administration whereas the same was approved as the hybrid application by European Medicines Agency requiring the applicant to generate and submit more data. Thus, harmonization of the regulatory requirements for the approval of follow-on versions of such complex drugs is essential for better understanding, predictability of the regulatory process, and acceleration of the drug approval process, in the interest of patients. This will help the faster access of the drugs to the patients and allow interchangeability of the innovator drugs with its cost-effective generic version.

Regulatory considerations for generic products of non-biological complex drugs.

The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs.

Mass spectrometry-based methods to characterize highly heterogeneous biopharmaceuticals, vaccines, and nonbiological complex drugs at the intact-mass level.

The intact-mass MS measurements are becoming increasingly popular in characterization of a range of biopolymers, especially those of interest to biopharmaceutical industry. However, as the complexity of protein therapeutics and other macromolecular medicines increases, the new challenges arise, one of which is the high levels of structural heterogeneity that are frequently exhibited by such products. The very notion of the molecular mass measurement loses its clear and intuitive meaning when applied to an extremely heterogenous system that cannot be characterized by a unique mass, but instead requires that a mass distribution be considered. Furthermore, convoluted mass distributions frequently give rise to unresolved ionic signal in mass spectra, from which little-to-none meaningful information can be extracted using standard approaches that work well for homogeneous systems. However, a range of technological advances made in the last decade, such as the hyphenation of intact-mass MS measurements with front-end separations, better integration of ion mobility in MS workflows, development of an impressive arsenal of gas-phase ion chemistry tools to supplement MS methods, as well as the revival of the charge detection MS and its triumphant entry into the field of bioanalysis already made impressive contributions towards addressing the structural heterogeneity challenge. An overview of these techniques is accompanied by critical analysis of the strengths and weaknesses of different approaches, and a brief overview of their applications to specific classes of biopharmaceutical products, vaccines, and nonbiological complex drugs.

Addressing a future pandemic: how can non-biological complex drugs prepare us for antimicrobial resistance threats?

Loss of effective antibiotics through antimicrobial resistance (AMR) is one of the greatest threats to human health. By 2050, the annual death rate resulting from AMR infections is predicted to have climbed from 1.27 million per annum in 2019, up to 10 million per annum. It is therefore imperative to preserve the effectiveness of both existing and future antibiotics, such that they continue to save lives. One way to conserve the use of existing antibiotics and build further contingency against resistant strains is to develop alternatives. Non-biological complex drugs (NBCDs) are an emerging class of therapeutics that show multi-mechanistic antimicrobial activity and hold great promise as next generation antimicrobial agents. We critically outline the focal advancements for each key material class, including antimicrobial polymer materials, carbon nanomaterials, and inorganic nanomaterials, and highlight the potential for the development of antimicrobial resistance against each class. Finally, we outline remaining challenges for their clinical translation, including the need for specific regulatory pathways to be established in order to allow for more efficient clinical approval and adoption of these new technologies.

The Identification of Quality Risk Factors for Non-biological Complex Drugs and Epilepsy Drugs Using Statistical Analysis of Formulation-Based Recalls in the USA.

Pharmaceutical companies use the quality by design (QbD) approach to build high-quality drug products. A thorough understanding of risk factors is required to successfully employ QbD. In order to better understand risk factors that potentially impact drug product quality and inform future QbD approaches, we hypothesized root causes of drug product recalls based on publicly available data and a retroactive analysis of drug products recalled by the United States Food and Drug Administration (USFDA) from 2012 to 2018. We focused on two categories of drug products that pose unique regulatory challenges and an increased risk of shortage that could hinder the adequate supply of quality medicine to the patient. Knowing the significant risk factors from previous drug product recalls can help inform QbD and avoid future recalls. Quality recall reasons were studied individually to find risk factors associated with each recall category. Logistical regression statistical tests were done in R using a significance level of 0.05 to find correlations between a recalled product and its manufacturing information such as excipients and manufacturing steps. The results showed significant positive and negative correlations, such as products containing magnesium stearate are more likely to be recalled for impurities and degradation. This information could be used in the future to inform the design and manufacturing of drug products, ensuring consumers receive high-quality products with a low risk of recall.

Evaluation of the Physicochemical Properties of the Iron Nanoparticle Drug Products: Brand and Generic Sodium Ferric Gluconate.

Complex iron nanoparticle-based drugs are one of the oldest and most frequently administered classes of nanomedicines. In the US, there are seven FDA-approved iron nanoparticle reference drug products, of which one also has an approved generic drug product (i.e., sodium ferric gluconate (SFG)). These products are indicated for the treatment of iron deficiency anemia and are administered intravenously. On the molecular level, iron nanomedicines are colloids composed of an iron oxide core with a carbohydrate coating. This formulation makes nanomedicines more complex than conventional small molecule drugs. As such, these products are often referred to as nonbiological complex drugs (e.g., by the nonbiological complex drugs (NBCD) working group) or complex drug products (e.g., by the FDA). Herein, we report a comprehensive study of the physiochemical properties of the iron nanoparticle product SFG. SFG is the single drug for which both an innovator (Ferrlecit) and generic product are available in the US, allowing for comparative studies to be performed. Measurements focused on the iron core of SFG included optical spectroscopy, inductively coupled plasma mass spectrometry (ICP-MS), X-ray powder diffraction (XRPD), 57Fe Mössbauer spectroscopy, and X-ray absorbance spectroscopy (XAS). The analysis revealed similar ferric-iron-oxide structures. Measurements focused on the carbohydrate shell comprised of the gluconate ligands included forced acid degradation, dynamic light scattering (DLS), analytical ultracentrifugation (AUC), and gel permeation chromatography (GPC). Such analysis revealed differences in composition for the innovator versus the generic SFG. These studies have the potential to contribute to future quality assessment of iron complex products and will inform on a pharmacokinetic study of two therapeutically equivalent iron gluconate products.

Tackling the challenges of nanomedicines: are we ready?

PurposeThis review provides an overview of the proceedings of the symposium “Tackling the Challenges of Nanomedicines: Are We Ready?” organized by the International Pharmaceutical Federation (FIP) Hospital Pharmacy Section and Non-Biological Complex Drugs (NBCDs) Working Group at the 2019 FIP World Congress of Pharmacy and Pharmaceutical Sciences. Debate centered on reasons underlying the current complex regulatory landscape for nanomedicines and their follow-on products (referred to as nanosimilars) and the pivotal role of hospital pharmacists in selecting, handling, and guiding usage of nanomedicines and nanosimilars.SummaryThe evaluation and use of nanomedicines are recognized among scientific, pharmaceutical, and regulatory bodies as complex. Interchangeability and substitutability of nanomedicines and nanosimilars are confounded by a lack of pharmaceutical and pharmacological equivalence, reflecting the inherent complex nature of these drug products and manufacturing processes. Consequences include implications for clinical safety and efficacy and, ultimately, comparability. Local regulatory approvals of some nanomedicines have occurred, but there is no standard to ensure streamlined evaluation and use of consistent measures of therapeutic equivalence of reference products and their nanosimilars. Hospital pharmacists are expected to be experts in the selection, handling, and substitution of nanomedicines and familiarize themselves with the limitations of current methods of assessing pharmaceutical and clinical equivalence of nanosimilars in order to ensure informed formulary decision-making and eventual patient benefit.ConclusionSupportive guidance for pharmacists focusing on the substitutability and/or interchangeability of nanomedicines and their nanosimilars is needed. Current FIP guidance for pharmacists on therapeutic interchange and substitution should be extended to include nanomedicines and nanosimilars.

Non-biological Complex Drugs (NBCDs): Complex Pharmaceuticals in Need of Individual Robust Clinical Assessment Before Any Therapeutic Equivalence Decision.

Non-Biological Complex Drugs (NBCDs) are complex non-biological drugs comprised of large high molecular weight molecules and, often, nanoparticular structures (including liposomes and block-copolymer micelles). In the case of NBCDs, the entire complex is the active pharmaceutical ingredient and its properties cannot be fully characterized by physicochemical analysis. Moreover, the manufacturing process is fundamental in creating the correct originator product. The same is true for generic versions of the product. A recent appraisal of approval procedures for NBCDs “follow-on products” approved in Europe shows a diversity of regulatory pathways. In fact, three different abridged application procedures, under European legislation, were used: the generic application procedure of Article 10(1), the hybrid application procedure of Article 10(3), and the biosimilar application procedure of Article 10(4). Three informed consent applications via Article 10(c) from innovator companies of glatiramer acetate and sevelamer carbonate were submitted shortly after the approval of the first follow-on products. Furthermore, a number of “well-established use” applications [via Article 10(a)] were approved for iron sucrose and iron dextran complexes. In order to protect patients from the increased risks of NBCD products and NBCD follow-on products, two complementary approaches should be considered: (i) improving the regulatory procedures and their guidance documents within the pre-registration phase, and (ii) not considering interchangeability whenever clinical data is not available. With regards to the latter, the need for adequate safety and efficacy data might also include risk management programmes within post-approval pharmacovigilance actions. This, however, would depend on a risk appraisal that must be considered for individual medicinal products, based on the nature of the submitted relevant set of safety/efficacy data.

Medication practice in hospitals: are nanosimilars evaluated and substituted correctly?

Introduction: This study investigates the drug selection and dispensing behaviour of hospital pharmacists of intravenous iron products including iron sucrose and iron sucrose similar, with special emphasis on substitution and interchangeability in France and Spain. Iron– carbohydrate complex drugs represent different available intravenous iron drugs and are part of the non-biological complex drug (NBCD) class, an expanding drug class with up to 30 brands available in intravenous pharmacotherapy and over 50 in clinical development. Follow-on versions of iron sucrose have appeared in some markets such as France and Spain, which were authorised by the generic approval pathway. However, differences in clinical efficacy and safety of iron sucrose similars compared with the reference originator drug Venofer have been observed, putting a question mark on their equivalence as assessed for authorisation and consequently their substitutability and interchangeability. Method: 70 French and 70 Spanish hospital pharmacists were surveyed via an online questionnaire on their formulary selection and dispensing behaviour of intravenous iron medicines. Results: There is little awareness about the characteristics of this class of drugs and the reported differences in safety and efficacy between iron sucrose and iron sucrose similars. In approximately 85% of cases the intravenous iron is chosen according to the hospital formulary. In 30% (France) and 34% (Spain) of cases an iron sucrose similar was dispensed because the formulary requires dispensing an alternative lower cost drug when available. In 26% (France) and 52% (Spain) of cases the physician is not informed on such a medication change using a similar product. Conclusions: Evaluation of NBCD similars for substitution and interchange by hospital pharmacists is rarely based on scientific and clinical criteria but rather on cost aspects only, which does not ensure safe, efficacious and cost-effective use of such drugs.

Contributions of the Japanese Pharmacopoeia to the Quality of Generic Pharmaceuticals

The rapid increase in the use of ethical generic pharmaceutical formulations in Japan emphasizes the importance of measures to ensure the quality of pharmaceutical distribution. This short review discusses the contributions of the Japanese Pharmacopoeia (JP) to pharmaceutical quality control. Numerous monographs have defined specifications and tests for multiple active pharmaceutical ingredients and excipients. Standardized methods of performing general tests and reference standards allow efficient, reliable evaluation of pharmaceutical quality during development processes and commercial manufacturing. Some new methods of characterizing the structure and performance of nonbiological complex drugs have been included in recent editions. An introduction to general tests and general information regarding the control of impurities in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines should significantly reduce the safety risks of pharmaceuticals.

Evaluation of Therapeutic Equivalence for the Follow-On Version of Intravenously Administered Non-Biological Complex Drugs.

The interchangeability evaluation for generic drugs formulated as intravenous injections normally only requires assessments of pharmaceutical equivalence (PE) when the medicinal products are simple small-molecule drugs. However, intravenously administered non-biological complex drugs (NBCDs), such as liposomes, microsphere suspension, or fat emulsion, have inherent passive disposition selectivity due to their special formulations, thereby the in vivo drug performances are improved. Because of the complexity in formulation, the in vitro pharmaceutical investigations of follow-on NBCDs are more complicated than those required for generic small-molecule drugs. In addition to qualitative and quantitative sameness of the active and inactive ingredients, it is required to comparatively study the static and kinetic microscopic particle-related physiochemical properties of the follow-on NBCDs versus the reference products. Moreover, for complex formulations that have a significant impact on the biodistribution of the drug compound, an in vivo bioequivalence (BE) study is also important. Since NBCDs that demonstrated bioequivalence through the conventional BE approach have been found inequivalent in efficacy or safety to the reference products, pivotal BE studies for follow-on NBCDs are required to take both encapsulated/total drug and free drug as the analytes to address release kinetics and biodistribution of the active pharmacological ingredient in the body. This manuscript reviews the 26 U.S. FDA published product-specific guidelines for intravenous injections. In general, these NBCDs can be stratified into four groups according to their release kinetics and ability of bio-membrane penetration. Group 1 consists of seven small-molecule, non-complex drugs; group 2 included four NBCDs with either microscale particle size or rapid dissolution property; group 3 include five loosely packed NBCDs (fat emulsions) and one quickly released ophthalmic liposomal drug; and the last group contains four cytotoxic liposomal or protein-bound NBCDs and five iron carbohydrate complexes. The requirements of the corresponding guidelines range from simple proof of PE between the test and thereference products, to a collection of studies that demonstrate the key manufacturing process (e.g. liposome loading), the particle- or vehicle-wise static and kinetic physiological characterizations, the dissolution test, and BEevaluation of both total/encapsulated drug form and free drug form between the follow-on NBCDs and their reference products. Such studies are challenging in implementation. Therefore, a variety of alternative approaches are proposed in this article.

Application of 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate derivatization for enhanced peptide mapping analysis of non-biological complex drug glatiramer acetate using liquid chromatography/electrospray ionization collision-induced dissociation high-resolution mass spectrometry.

Glatiramer acetate (GA) (Copaxone®) is a non-biological complex drug (NBCD) comprising random-sequence polymer chains of four amino acids (MW ~ 5-9 kDa) with unknown structure. The characterization of NBCDs by reversed-phase liquid chromatography/mass spectrometry (RPLC/MS) peptide mapping is often impeded by insufficient separation and/or low sensitivity. To overcome this issue, pre-column derivatization of GA peptide digest was used to improve RPLC/MS detectability and to generate a comprehensive peptide profile. Amino groups of peptides generated by trypsin digestion of GA were derivatized using 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) reagent. The derivatized mixture of random-sequence peptides was analyzed by liquid chromatography/positive-mode electrospray ionization collision-induced dissociation high-resolution mass spectrometry (RPLC/ESI-CID-HRMS/MS). Data-independent LC/MSE mode was used for data acquisition. The derivatization of the GA peptide mixture increased the detectability of RPLC/ESI-CID-HRMS/MS analysis. The efficacy of the procedure was demonstrated by using selected peptides related to different polymeric chain origins. The resultant peptides were derivatized in a predictable manner giving a minimum of side products. The reproducibility of the developed method was demonstrated by comparing peptide elution profiles derived from six Copaxone® lots. Application of the AQC pre-column derivatization provides a framework that could be used as an attractive approach for monitoring the quality and characterization of NBCD products in the pharmaceutical industry.

Complex Generic Products: Insight of Current Regulatory Frameworks in US, EU and Canada and the Need of Harmonisation.

The regulatory agencies all over the world have defined the pathway and regulations for the approval of simple small-molecule generics. In addition, the agencies are striving to form perspicuous regulatory frameworks for the approval of biosimilars. In this view, there are no defined regulations for the approval of complex generics, also known as non-biological complex drugs (NBCDs). Complex drugs are large, highly complex and synthetic moieties and are made of complex active substances but are different from biologics product. Regulatory frameworks being adopted for complex generics today are questionable and ambiguous. The market for complex generics is huge and there are fewer generic competitors in this area. In addition, the cost of bringing such generics into the market is high. Since the complex generics are largely used for chronic and life-threatening diseases and the competition is less, generic players show high interest in this segment. Thus, there is a need for a well-defined pathway and guidance documents for the authorization of generic versions of complex drug products. The article focuses on the regulatory frameworks currently adopted by US, EU and Canada for bringing complex generics into the market. It also describes on the regulatory disparities existing among the three agencies in the light of complex generics.

Assessing the Similarity between Random Copolymer Drug Glatiramer Acetate by Using LC-MS Data Coupling with Hypothesis Testing.

The full characterization of nonbiological complex drugs (NBCDs) is not possible, but analytical approaches are of urgent need to evaluate the similarity between different lots and compare with their follow-up versions. Here, we propose a hypothesis testing-based approach to assess the similarity/difference between random amino acid copolymer drugs using liquid chromatography mass spectrometry (LC-MS) analysis. Two glatiramer acetate (GA) drugs, commercially available Copaxone and in-house synthesized SPT, and a negative control were digested by Lys-C and followed by HILIC-MS analysis. After retention time alignment and feature identification, 1627 features matched to m/z values in an elemental composition database were considered as derived from active drug ingredients. A hypothesis testing approach, the sum of squared deviations test, was developed to process high-dimensional data derived from LC-MS spectra. The feasibility of this approach was first demonstrated by testing 5 versus 5 lots of Copaxone and Copaxone versus SPT, which suggested a significant similarity by obtaining the estimated 95th percentile of the distribution of the estimator (ρ̂(95%)) at 0.0056 (p-value = 0.0026) and 0.0026 (p-value < 0.0001), respectively. In contrast, the ρ̂ was 0.036 (p-value = 1.00), while comparing Copaxone and the negative control, implying a lack of similarity. We further synthesized nine stable isotope-labeled peptides to validate the proposed amino acid sequences in the database, demonstrating the correctness in sequence identification. The quantitation variations in our analytical procedures were determined to be 6.8-7.7%. This approach was found to have a great potential for evaluating the similarity between generic NBCDs and listed reference drugs, as well as to monitor the lot-to-lot variation.

A progress report on the 3rd International Symposium on Scientific and Regulatory Advances in Biological and Non-Biological Complex Drugs: A to Z in Bioequivalence

A progress report on the 3rd International Symposium on Scientific and Regulatory Advances in Biological and Non-Biological Complex Drugs: A to Z in Bioequivalence

Comparison of Copaxone® and Synthon's therapeutically equivalent glatiramer acetate.

Glatiramer acetate is indicated for the treatment of patients with relapsing forms of multiple sclerosis (RMS). In 2016, an alternative to the originator product was approved in the EU through the hybrid procedure regulatory pathway. This paper reviews the scientifically rigorous and multifaceted program undertaken to demonstrate the equivalence of this glatiramer acetate follow-on product (GTR) and the reference product Copaxone®, which resulted in the EU approval of GTR 20 mg/mL and 40 mg/mL. Establishing therapeutic equivalence for non-biological complex drugs is not trivial and requires a complex and multidisciplinary effort. Ultimately, there is not a single test or study that establishes therapeutic equivalence of two heterogeneous products. Instead, it requires a good understanding of the synthesis process together with a full set of data that includes comparative physicochemical testing, nonclinical in vitro and in vivo studies, and a comparative clinical study to allow for a valid conclusion that two products are therapeutically equivalent. The detailed understanding of glatiramer's synthesis process and its impact on the characteristics of glatiramer, combined with the results of a scientifically rigorous and multifaceted physicochemical and biological characterization program, and the clinical data from the 794-patient Phase III GATE study, demonstrate that GTR and Copaxone are therapeutically equivalent. The data further demonstrate that Synthon's manufacturing process consistently yields drug substance of the same quality as Copaxone and that switching from Copaxone to GTR is safe and well-tolerated.

Glatiramer acetate: A complex drug beyond biologics

Complex drugs may be either biological, if the active ingredients are derived from a biological source, or non-biological, if obtained by chemical synthesis. In both cases, their quality depends considerably on the manufacturing process. In the case of Non Biological Complex Drugs (NBCDs), complexity may arise either from the active substance, as in the case of glatiramer acetate, or from other sources, such as the formulation, as in the case of liposomes.In this paper, the case of glatiramer acetate (GA) - a NBCD relevant for clinical and economic reasons - is considered and the differences between US and EU regulatory approaches to GA marketing authorization are highlighted. Indeed, though US and EU regulatory agencies have chosen a generic approach integrated with additional data the implementation is different in the two jurisdictions. In the US, the additional data required are listed in a product specific guideline and copies of Copaxone® have been approved as generics. In the EU, instead regulatory agencies followed a hybrid approach requiring an additional comparative study, and interchangeability policies and substitution schemes have been left to national agencies.