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Journal of Medical Chemical, Biological and Radiological Defense
J Med CBR Def  |  Volume 7, 2009
Submitted 29 April 2009 | Accepted 22 June 2009 | Revised 13 August 2009 | Published 1 September 2009

AN INTRODUCTION TO SAFETY ISSUES IN BIOSIMILARS/FOLLOW-ON BIOPHARMACEUTICALS

Filiz Hincal

Hacettepe University, Faculty of Pharmacy, Department of Toxicology

Hacettepe Drug and Poison Information Center

Ankara, 06100, TURKEY

Tel: ++90 312 305 1871 | Fax: ++90 312 426 3344 | EMail: fhincal@tr.net

 

Suggested citation: F Hincal (2009), “An Introduction To Safety Issues In Biosimilars/Follow-On Biopharmaceuticals”, JMedCBR 7, 1 September 2009, http://www.jmedcbr.org/issue0701/Hincal/Hincal_09_09.html.

 

 

abstract

Biopharmaceuticals are emerging global healthcare tools, which promise to provide effective treatment of many serious and life-threatening illnesses with their high specificity and activity; they are considered the future of drug therapy. Biopharmaceuticals include a wide-range of products such as vaccines, immunoglobulins, monoclonal antibodies, cell and gene therapy products. The size and complexity of the therapeutic proteins make the production of an exact replica almost impossible; therefore, there are no true generic forms of these proteins, biogenerics, but these are rather “biosimilars” or “follow-on biopharmaceuticals”. Verification of the similarity of biosimilars to innovator medicines remains a key challenge. Whereas marketing authorization for generic versions of classical drugs can be achieved by showing that the generic is chemically identical and the bioequivalent of the innovator drug, registration of biosimilars requires more stringent evaluations. Since the immunogenicity of biopharmaceuticals may have serious clinical consequences, potential immunogenicity, as well as general safety, are the key issues for biosimilars. Stability and safety are critical in the development, storage, and stockpiling of biopharmaceuticals, particularly for when used and stored in field conditions where temperature control may be problematic.

 

INTRODUCTION

“Biopharmaceuticals” are biological medicinal products that are developed by means of one or more of the following biotechnology practices: recombinant DNA, controlled gene transfer/expression, and monoclonal antibody production. In spite of the undoubted promise of nucleic acid therapeutics, thus far most approved biopharmaceuticals are protein-based therapeutics, such as, recombinant hormones, growth factors, blood products, monoclonal antibody-based products, recombinant vaccines, and advanced technology products, including gene and cell therapy biologicals. Biopharmaceuticals have become part of clinical practice and important therapeutic options for a variety of indications, including cancer, diabetes, anemia, rheumatoid arthritis, multiple sclerosis, as well as various rare diseases [Dudzinski and Kesselheim, 2008]. Since the approval of first biological, recombinant insulin, in 1982, regulatory authorities in USA and in EU have approved more than 250 products, and, these have been given to an estimated 350 million individuals worldwide [Giezen, 2008]. Well in excess of 500 candidate biopharmaceuticals are at the pipeline [Walsh, 2005]. Between 2003 and 2006, biologicals represented 24% and 22% of all new chemical entities approved by US and EU regulatory authorities, respectively [Walsh, 2006]. Their market growth is twice that of classical drugs and by the year 2010, almost 50% of newly approved drugs are expected to be biopharmaceuticals [Walsh, 2005]. Though only one of the top 200 prescribed drugs of 2006 was a recombinant protein (on the basis of prescription volume) [Grabowski 2006], according to the forecasting firm EvaluatePharma® , the first six of the top ten drugs in 2014 will be biologics, and five of these will be monocolonal antibodies. Further, EvaluatePharma® estimates that biotechnology products will account for 50% of the top 100 drugs in 2014 [EvaluatePharma, 2009; Fierce Biotech, 2009a]

While the biopharmaceutical market is thus growing very fast, the initiating phase of the first generation of biologicals is now coming to an end. The patents are beginning to expire and this opens the market to generic brand products. However, these new products are not defined as generics or biogenerics, but are called “biosimilars” in Europe, “follow-on pharmaceuticals” in the USA and Japan, and “subsequent entry biologics” in Canada. Due to the size and complexity of the protein structure, production of biosimilars is complex and sensitive to even slight changes in the manufacturing and storage processes, thus, heterogeneity between the same proteins from different manufacturers and even between batches from the same manufacturing process cannot be avoided [Chirino and Mire-Sluis, 2004; Crommelin, 2003b; Schellekens, 2004]. These differences may arise from separate manufacturing processes and variations in master cell line, processing and purification, inert ingredients, and packaging. Even small and seemingly insignificant manufacturing changes could theoretically contribute to differences in protein folding, aggregates, and glycosylation, which might manifest clinically as decreased efficacy, altered pharmacokinetics, or increased immunogenicity. Therefore biosimilars are biological products “similar”, but not “identical”, to their reference products. The classical generic approaches do not work with protein drugs, because the term generic implies an exact copy of the original product with the exact pharmaceutical actions.

Furthermore, it is difficult to establish therapeutic equivalence of biosimilars with reference products without clinical trials; therefore, their market approval is more complicated [Locatelli and Roger, 2006]. In fact, registration of biosimilars requires more stringent evaluation than is required for conventional generics, and, applications for marketing authorization must be accompanied by detailed comparability studies to demonstrate the similarity of the proposed biosimilar to the reference product with respect to quality, safety and efficacy.

 

GENERIC versus BIOSIMILAR

Generic drugs are chemical medicinal products, which have the same qualitative and quantitative composition in terms of drug substance(s), the same pharmaceutical form, and are bioequivalent to an approved originator product. Generic drugs are approved with reference to the toxicological and clinical data submitted by the innovator and are marketed after the patent/data protection of the originator product has expired. Thus, a generic drug is a product that is shown to be the same as an innovative drug, generally designated as therapeutically interchangeable with the originator product and does not need clinical trials except for bioequivalence studies in healthy subjects. There are no requirements for therapeutic equivalence evaluations or establishment of safety and efficacy for generics. While having the same efficacy and safety, they may cost as much as 80% less and that is why generics are widely prescribed, well accepted by the public as safe and effective, generally viewed as clinical and economic success, and preferentially reimbursed. In fact, generics account for ~55% of the total US prescription, but only 13% of the dollars spent [Morrison, 2007].

Biopharmaceuticals are products derived from biological (living) sources (with their attendant potential variability); they have much larger and more complicated structures, as well as complex modes and multiple targets of action. See for example [Figure 1]. Most are recombinant proteins with complex three-dimensional structures that cannot be completely defined with reference to physical and chemical parameters. They are produced by genetically modified cells, which are highly variable and synthesize and secrete large numbers of proteins, in addition to the desired active substances. The products may have different isomeric forms, variable glycosylation patterns and other post-translational modifications.

The production of recombinant protein molecules involves the use of ‘‘biotechnology’’, often defined as ‘‘all lines of work by which products are produced from raw materials with the aid of living things’’. Each stage of the production process is an area of intensive research and investigation, from the choice of the expression vector, host cell line, purification protocols, quality control assessments, through to the final product formulation. Production steps starts with insertion of gene encoding the protein of interest, growth of cells is accomplished with proper conditions for optimal growth (temp, pH, oxygen, feeds, etc.), cell culture and fermentation can take weeks, complex purification steps are required, and finally safe product with desired potency is obtained. Production and purification of biologicals are, thus, complicated processes; and process conditions and in-process controls determine the product composition. As shown in [Table 1], while less than 100 product quality tests are normally required for a small molecule pharmaceutical, typically more than 2,000 tests are required in the manufacturing process of a biological. Small differences in starting materials and manufacturing processes can alter clinical effects, for example, by causing different glycosylation and folding patterns, ratios of impurities and aggregation of subunits result in heterogeneous products. Furthermore, the majority of biological manufacturers patent the production process rather than the biological compound itself, thus guarding the production methods as “intellectual property” secrets. Accordingly, the process of development and approval of biosimilar products is difficult and making exact replicas of biopharmaceutical products is almost impossible. Thus, there are no true biogenerics, but rather biosimilars.

Conventional drugs have fewer molecular ingredients, and most small molecules can be completely characterized on the basis of their chemical structure. For full identification a limited set of analytical assays can be used. Different pharmacopoeial sources describe this in detail. Assays to describe impurity profiles can also be found in the same sources. Typically, 98 to >100% purity is required and suppliers are able to reach that quality level consistently. By contrast, biotechnology products have many molecular ingredients and often are not fully characterized using evaluative tools alone. [Table 2], taken from Crommelin et al., [Crommelin, 2003] lists analytical techniques to characterize the structure or functions of proteins, and shows the diversity and the complexity of analytical approaches need to be used. However, none of these techniques can fully define a protein’s 3-dimentional structure and folding pattern. Only by combining the different pieces of evidence can the picture of the protein be built. Moreover, the analytical tools for biologics are 100-1000 times less sensitive than for classical drugs.

Biopharmaceuticals have revolutionized the treatment of many serious and life-threatening illnesses such as cancer, multiple sclerosis, diabetes, HIV/AIDS, and many serious rare diseases, they hold enormous clinical promise and are considered to be the future of drug therapy [Mellstedt, 2008]. As this market is hugely profitable, the difficulties posed by strict regulations and requirements do not generally deter the producers.

As biological medicinal products come off patent, there is a growing trend for developing biosimilars. Various countries want to extend the approval process used for generic (small molecule) drugs to biological/biotechnological products and to create an abbreviated application process for follow-on products, relying in part on the safety and efficacy data generated and filed by the innovator. However, because of the unique characteristics of biologicals compared to small molecule conventional pharmaceuticals, it is not appropriate to apply the generic drug paradigm to biosimilars. In contrast to generics and because of the difficulty in reproducing a follow-on pharmaceutical or biosimilar, there will certainly not be substantial price reductions occasioned by the entry of biosimilars into the market. Treatment with biopharmaceuticals is very expensive for individual patients and for the whole health care system. They cost anywhere from $15,000 to $150,000 per year, prices that are far in excess of those charged for traditional small-molecule products [Simon, 2006], and, they have an especially high value per dose. Vectibix®, e.g., for metastatic colorectal cancer, costs $4000 per infusion and $100,000 per treatment [Morrison, 2007]. Due to these high individual costs, however, a price reduction of 25% compared to the original biopharmaceutical will lead to massive cost reductions. The rapid penetration of novel biologics and the gradual expiry of their patents will create significant market opportunities for biosimilar developers through to 2016. In the short term, biosimilar market growth will be driven by drug classes, including erythropoietin, filgrastim, human growth hormone (hGH) and insulin [FierceBiotech, 2009b].

 

LEGAL FRAMEWORK- GLOBAL SITUATION

The EU has already established a legal pathway for the approval of biosimilars; European Medicines Agency (EMEA) has developed regulatory guidelines, and in April 2006, the European Commission granted approval for the first ever biosimilar drug, a biosimilar recombinant human growth hormone product. Currently, no formal regulatory process exists in the USA. While discussions on a pathway enabling the approval of biosimilars through an abbreviated regulatory process are underway, Congress is examining proposed legislation to create an approval pathway for follow-on biologicals [Gottlieb, 2008].

Copy versions of innovator biologicals are available in many countries, where licensing has been based on reduced data packages, in the absence of a clear regulatory pathway and complicated by various other problems, such as, different terminology, definitions and data requirements. The need for international guidance on biosimilars has been identified and regulatory expectations, at a global level, were defined in an informal consultation held on 19-20 April 2007 at the WHO. The WHO’s objectives were to discuss the current status of biosimilars and to review regulatory pathways and challenges in evaluating the quality, safety and efficacy of these products [Joung, 2008].

 

EUROPEAN UNION GUIDELINES

In the EU, guidance is issued through open procedures with participation by expert committees, national authorities, the scientific community and industry. The term “biosimilar product”, “biosimilar”, or “biosimilarity” was introduced in EU legislation in June 2003, and further elaborated with the adoption of the EU-Pharmaceutical Review in April 2004 [European Parliament and Council, 2004]. This notion allows a manufacturer to submit an application and receive an authorization for a product claimed to be similar to another biological medicine, the “reference product”. According to basic provisions for biosimilars, the manufacturer will have to demonstrate or justify that the new and original/reference products have similar profiles in terms of quality, safety, and efficacy; and the data will be judged on a case-by-case bases. For all products, preclinical and clinical testing, special attention to immunogenicity, post-market testing, and surveillance are required. Thus, in the EU the specially-adopted approval is based on a thorough demonstration of "comparability" of the similar product to an existing approved product.

Recently, EMEA, the decentralized body of the EU, released final guidelines containing details of clinical, nonclinical and quality expectations for biosimilar protein therapeutics [EMEA, 2005; EMEA, 2006a; EMEA, 2006b]. In a more recent document issued in October 2008, EMEA has pointed out that “biosimilar and biological reference medicines are used in general at the same dose to treat the same disease... since biosimilar and biological reference medicines are similar but not identical, the decision to treat a patient with a reference or a biosimilar medicine should be taken following the opinion of a qualified healthcare professional” [EMEA, 2008]. These suggestions emphasize that biosimilars are biopharmaceuticals, which are considered similar in composition to an innovator product, but not necessarily clinically interchangeable.

In fact, fifteen countries across Europe have published new regulations to prevent automatic substitution of biological medicines by biosimilars [Kane, 2008]. Furthermore, the name, appearance and packaging of a biosimilar medicine must differ from those of the biological reference medicine because biosimilars will be approved as safe and efficacious agents by the authority, but they will be inherently different from innovator products. As a result, switching or substitution between innovator products and biosimilars should be viewed as a change in clinical management.

 

QUALITY, SAFETY AND EFFICACY

For any medicine to be marketed in the EU quality, safety, and efficacy of the product must be approved by the relevant regulatory body. All manufacturers of medicinal products have to demonstrate that the product is of a specific and reproducible quality, safe for patients to take (i.e., the risk of potential side effects is considered acceptable when compared to the benefits), and guaranteed to produce the desired clinically beneficial effect (efficacy). In order to obtain a marketing authorization, companies are required to supply the data supporting all these areas. These data are evaluated by the EMEA and its experts, which includes staff from EU national agencies. If all these data are assessed as being satisfactory, then the medicine will be approved and will receive a marketing authorization from the European Commission that will allow the company to launch and market the product in Europe.

In the case of biosimilars, studies comparing the two medicines have to be carried out a step-by-step process with a comparison of the quality, consistency of the product and its manufacturing process, and safety and efficacy [Wiecek and Mikhail, 2006; Rossert, 2007; Schellekens, 2009]. The information required in a dossier of a biosimilar to be submitted to the EMEA, the so-called “Marketing Authorization Application” is as follows:

  1. Quality data: A full quality dossier is required along with the demonstration of comparability using state-of-the-art analytical methods to characterize both the similar and the reference product. The manufacturing process should be well developed.
  2. NonClinical data: Data is generated through an abbreviated programme of in vitro and in vivo tests prior to clinical studies. In vitro receptor-binding or cell-based [binding] assays should normally be done. At least one repeat-dose toxicity study should be conducted. Toxicokinetics should include antibody titers, cross reactivity and neutralizing capacity. Other routine types of toxicity studies are not normally required.
  3. Clinical data: Covers the results of abbreviated (when appropriate) clinical trials conducted in healthy volunteers and patients. Clinical comparability is done in stages, much like a traditional program and includes:
    1. Clinical equivalance (pharmakinetic (PK) studies for all routes of administration applied for, absorption and elimination rates, clinically relevant pharmacodynamic (PD) marker(s) and usually a combined PK/PD study, etc)
    2. Safety
    3. Immunogenicity
    4. Pharmacovigilance

As seen from this brief description, the requirements for marketing authorization of a biosimilar are somewhat less then the originator product, but it is still not comparable to a generic of a conventional pharmaceutical where only identical chemistry and bioequivalence data are required.

 

CLINICAL SAFETY AND PHARMACOVIGILANCE

Safety data are required to be obtained from a number of patients sufficient to address the adverse effect profiles of the test and the reference product. The data from pre-approval studies are insufficient to identify all differences in safety due to the constraints in the sample size and in the design of randomized controlled trials. Therefore, safety monitoring after approval is mandatory. Pharmacovigilance pertains to the detection, assessment, understanding and prevention of adverse effects after a product is available on the market; and, pharmacovigilance permits controlled monitoring of patient safety in a large population [EMEA, 2006b].

The pharmacovigilance plan must be approved prior to authorization, and the systems must be in place to conduct monitoring when authorization is granted. In the EU, pharmaceutical companies are legally required to monitor the use and effects of all their products. Each pharmaceutical company must provide a detailed description of their pharmacovigilance system in the marketing authorization application for every new medicine, including biosimilar products, and a Risk Management Plan (RMP) must be submitted and agreed to by the EMEA. The RMP describes what is known about the safety of the medicine, and outlines how the manufacturer will further monitor and fill any gaps in the knowledge of any measures needed to minimize any risk from the medicine.

 

IMMUNOGENICITY

Immunogenicity is the capability of a specific substance to induce the production of antibodies in the human body. Potential immunogenicity is a key issue for biosimilars and may have serious clinical consequences. In fact, all biopharmaceuticals, in contrast to conventional drugs, demonstrate a greater capacity to induce antibodies and to elicit immune reactions. While foreign therapeutic proteins, such as streptokinase, induce antibodies by a classical vaccine-type immune reaction (reaction to neo-antigen), most therapeutic proteins that are human homologues, e.g., interferon, interleukin-2 and many others, that induce antibodies by breaking B-cell tolerance. In many patients, such a response does not lead to any clinical consequence. However, the potential exists for general immune reactions to produce allergy, serum sickness and life threatening anaphylaxis, as well as to reduce the efficacy of the drug or rarely enhance its activity [Schellekens, 2003; Schellekens, 2009].

Immunogenicity may be influenced by factors related to the biopharmaceutical itself, such as manufacturing process, formulation, aggregates, contaminants and impurities, and also by factors related to the patient, the type of disease, dose and length of treatment, the route of administration or depressed immune response in cancer patients [Crommelin, 2003b; Sharma, 2007a; Schellekens, 2003].

The relative immunogenicity of therapeutic proteins can only be evaluated in clinical studies. Sufficient pre-licensing immunogenicity data are required to exclude markedly increased immunogenicity [EMEA, 2007]. Data should be collected from a sufficient number of patients to characterize the variability in antibody response, and antibody testing should be considered as part of all clinical trials. The methods used to detect antibodies must be sufficiently sensitive to detect low-titer, low-affinity antibodies; standard methods should be used when possible. If aberrant results are detected or if antibody-related safety problems have been encountered with products of the same class, the RMP must specifically address these during pre-approval. A pharmacovigilance plan addressing safety, including immunogenicity is to be submitted with marketing authorization application.


STABILITY IN RELATION TO IMMUNOGENICITY

Stability is particularly important with larger protein molecules. Because their in vivo effects depends upon their structural integrity, and any factor causing physical or chemical instability alters the three-dimentional structure and folding pattern of the protein [Crommelin, 2003a; Crommelin, 2003b].

Chemical instability is caused mainly by deamidation, oxidation and numerous other chemical reactions. Physical instability may be induced during storage and handling by factors such as temperature, pH, interaction with organic solvents, solution shear, surfactants, interactions at interface, freeze/thaw cycle and agitation during transportation, as well as by freeze-drying or pasteurization during the production and purification phases. Minimizing physical instability is possible with careful attention to storage and handling, e.g., by maintaining a suitable storage temperature, without excessive heating or freezing; optimizing the pH to achieve a stable aqueous solution [Sharma, 2007a; Sharma, 2007b; Sharma, 2007c]. One of the most important interfaces is between a protein solution and air, and for that reason, aqueous solutions of innovator biologicals or biosimilars should be stirred but not shaken [Crommelin, 2003a]. Even transport of biopharmaceuticals must be done carefully, something not always possible, especially when normal controlled commercial transportation cannot be used to deliver supplies in militarily or disaster challenged areas or in undeveloped regions.

Physical instability of the proteins may result in denaturation, aggregation, precipitation or adsorption. Denaturation renders the protein more susceptible to degradation reactions, and if it can be reduced, aggregation and precipitation may be prevented. The most important consequence of protein degradation and/or unfolding is aggregation, because aggregates can enhance immunogenicity. Proteins usually aggregate from partially unfolded molecules, which can be part of the native state ensembles of molecules, thus, therapeutic proteins can directly form significant amounts of covalent aggregates, particularly when the shelf-life is exceeded or under stressed conditions. Therefore for unwanted immunogenicity, all those before-mentioned factors should be considered as a whole for biopharmaceuticals, as well as for biosimilars. Futhermore, protein particles, visible or subvisible can be generated from protein alone or from heterogenous nucleation on foreign micro and nanoparticles, for instance, from filling pumps or product container and closures [Carpenter, 2008]. Strict storage and handling conditions are therefore essential for maintaining product integrity and stability, and thus to guarantee efficacy and minimize adverse effects from products formed when stored for long times or at higher temperatures. Timely and effective stability/shelf-life testing in stockpiling is thus essential for maintaining product integrity and stability, and hence efficacy and safety.

 

STOCKPILING AND STORAGE

Biopharmaceuticals are considered as the future of the drug therapy, and they are also indispensable part of biodefense stockpiles. Critical biodefense biopharmaceuticals include mainly vaccines, immunoglobulins and monoclonal antibodies, and their development and availability is increasing. The concern and awareness of the use of bacteria and viruses as bioweapons has increased interest in developing, producing and stockpiling new vaccines and other countermeasures against these potentially lethal pathogens. As noted earlier, more than 50% of newly approved medicines will be biopharmaceuticals, and beginning in 2010, a number of major biotech medicines will be coming off patent in USA and technically facing biosimilar competition, although it has already started in EU [O’Donnell, 2009]. Thus, emergence of biosimilar drugs will accelerate and expand the number and type of those products requiring special storage conditions. These products include bacterial and viral vaccines, allergenic extracts, plasma derivatives, and other products requiring refrigeration or frozen storage. Most refrigerated vaccines are relatively stable at room temperature for limited periods of time, although certain vaccines are temperature-sensitive. The "How Supplied/Storage and Handling" section of the product label may be consulted for information, as well as the websites of the CDC and the FDA [CDC, 2009; FDA, 2008]. For instance, during a power outage, for vaccines requiring freezer storage, removing them from the freezer after one day (if the power outage continues) and packing them in dry ice should be considered. If the vaccines are not cold to the touch, upon removal from the freezer, the vaccine should be discarded [FDA, 2008]. All these indicate that stability for military and disaster field use, where temperature, humidity and other storage conditions are not likely to be easily controlled, is a critical issue, and shows the need to develop more stable biopharmaceuticals!

 

SAFETY RELATED REGULATORY ACTIONS

Safety issues and regulatory actions have occurred with biopharmaceutical products, even before the introduction of biosimilars. According to an article published in the October 22/29 (2008) issue of JAMA, approximately 25% of biopharmaceuticals that US and EU authorities have approved since 1995 have had at least one regulatory action issued due to safety within 10 years after approval [Giesen, 2008]. On the order of 11% of these products (including antibody, enzyme, and insulin) have even received "black box" warnings, which indicate the possibility of serious side effects. Warnings often related to the immunomodulatory effect, including infections and infestations, immune system disorders and benign or malignant neoplasms.

During that 12.5-year period, a total of 174 biologicals were approved in the US (136) and in the EU (105) or both regions (67). Eighty-two safety-related regulatory actions were issued for 41 of the 174 biologicals (23.6%) between January 1995 and June 2008. These warnings consisted of 46 written communications to health care professionals in the USA, 17 direct healthcare professional communications in the EU, and 19 “black box” warnings. However, none of the biologicals were withdrawn because of safety reasons. On average it took about 3.7 years before a safety-related regulatory action was issued, and almost 71% of these actions were issued within five years after the medicine's approval. If a biological was the first to be approved in its chemical, pharmacological, and therapeutic subgroup, it was more likely that a safety-related regulatory action was issued compared with products in the same subgroup that were approved later.

The conclusion of the journal’s editorial was that "given the current imperfect process for approval and the flawed post marketing surveillance system, the drug and device regulation process is at best an inexact and incomplete science. Until these deficiencies in the system are remedied, some patients inevitably will continue to experience harm from the use of newly marketed products as well as from use of other approved medications” [DeAngelis and Fontanarosa, 2008].

 

CONCLUSION

As patents of first generation of biopharmaceuticals derived from recombinant DNA are expiring, the development of biosimilars is increasing. In the US alone, patents have already expired on protein therapeutics representing more than $15 billion in costs annually; alternative versions of these products could be available for savings of at least 10 to 30% [Grabowski, 2007]. Reductions in medication costs for patients can also improve adherence to plans of care [Shrank, 2006]. The regulatory authorities are developing and improving approval, pharmacovigilance and post-marketing surveillance systems for biosimilars and this should be considered as a continuous process. Biosimilars are not necessarily clinically interchangeable with an innovator product: switching or substitutions between innovator products and biosimilars is more properly viewed as a change in clinical management. Potential immunogenicity is a critical issue for both biopharmaceuticals and biosimilars and needs to be safeguarded more vigorously. This is especially critical for biopharmaceuticals and biosimilars developed for field use.

Biological products used in defense medicine and stockpiling at present are mainly vaccines, immunoglobul?ns and monoclonal antibodies, predominantly to be used against bioterrorism agents. As the approval and marketing of biosimilars are increasing, they will also be penetrating in these areas, and will be included in public health planning, as well. Since the growth of this category of medicines is much faster and broader than the introduction and growth of conventional low-molecular-weight drug products, safety and efficacy of these products along with proper handling will be challenging issues for the related parties.

 

tables

 

Table 1. Summary of Manufacturing Procedures/Requirements for Biosimilars and Conventional Products [go to text reference]

Process (Metrics/Lot)
Small Molecules
Biopharmaceutical
Number of batch records
>10
>250
Product quality tests
>100
>2000
Critical process steps
>100
>5000
Process data entries
>4000
>60000

 

Table 2. Characterization of Biopharmaceuticals and Techniques for Monitoring Protein Structure [[go to text reference]

PHYSICOCHEMICAL CHARACTERIZATION OF BIOPHARMACEUTICALS
TECHNIQUES FOR MONITORING
PROTEIN STRUCTURE
Structural characterization and confirmation of the drug substance and/or drug product

     Amino acid sequence
     Amino acid composition
     Terminal amino acid sequence
     Peptide map
     Sulfhydryl group(s) and disulfide bridges
     Carbohydrate structure

Evaluation of physicochemical properties of the drug substance and/or drug product

     Molecular weight or size
     Isoform pattern
     Extinction coefficient (or molar absorptivity)
     Electrophoretic patterns
     Liquid chromatographic patterns
     Spectroscopic profiles
UV absorption
Circular dichroism spectroscopy
Fourier transform IR
Fluorescence spectroscopy
NMR spectroscopy
Calorimetric approaches

Bio-assays
Immunochemical assays
     ELISA
     Immunoprecipitation
     Biosensor (SPR, QCM)
Potency testing
  In cell lines
  In animals
Chromatographic techniques
  RP-HPLC
  SEC-HPLC
  Hydrophobic interaction HPLC
  Ion-exchange HPLC
  Peptide mapping
  Electrophoretic techniques
  SDS–PAGE
  IEF
  CZE
Field flow fractionaction
Ultracentifugation
Static and dynamic light scattering
Electron microscopy
X-ray techniques

 

Figures

1a.Figure 1: Histamine production by murine mast cells in response to different stimuli:

1b.1b. Aspirin

1c.1c. Paracetamol,

 

 

Figure 1: Comparison of structures of biopharmaceuticals and of small molecule drugs.

1a. Erythropoetin is typical of a protein made in cell cultures using recombinant DNA. Photo from http://en.wikipedia.org/wiki/File:Erythropoietin.png (August 31, 2009)

1b. Aspirin one of the first drugs made synthetically, photo from http://commons.wikimedia.org/wiki/File:Aspirin-rod-povray.png (August 31, 2009). and

1c. Paracetamol, a synthetic common over the counter drug, photo from http://upload.wikimedia.org/wikipedia/commons/9/92/Paracetamol-rod-povray.png (August 31, 2009) These drawings are not to the same scale, but are included to show how much more complex the biopharmaceuticals are. [go to text reference]

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