A biological product is defined as a therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine or any other trivalent organic arsenic compound, applicable to the prevention treatment or cure of a disease or condition of human beings. On the other hand a small molecular drugs also known as new chemical entity (NCE), or new molecular entity (NME), is a drug that which contains no active moiety that is yet to be approved by the Federal Food, Drug, and Cosmetic Act. A moiety that is active is said to be a molecule or ion, exclusive of those attached portions of that molecule that causes that drug to be a salt,ester, or any other non covalent derivative of the molecule, that is responsible for the physiological or pharmacological action of the drug substance. A biological product has a number of differences and similarities to a small molecule drug.
Most small molecule drugs are produced via a pathway that has at least some chemical synthetic steps. Small molecule drugs are also subjected to more rigorous purification and characterization steps which enable the production of substantially pure and objectively characterized compositions containing the active ingredient. Also in most instances small molecule drugs can be produced via multiple pathways all of which end at the same known and objectively characterized composition this capacity of small molecule drug product to be objectively characterized as to its purity and compositional homogeneity is an essential predicate of the regulatory paradigm that governs approval of pioneer and generic small molecule drug products that is active ingredients that have an identical chemical structure. (troy, 2007)
By contrast biological products are generally large complex molecules produced using living organisms. The development of a reliable, consistent manufacturing process based on the use of cell cultures or other living organisms is substantially more demanding than the development and implementation of a suitable manufacturing process for small molecule drugs that is one based on a series of chemical synthesis and purification steps. Biotechnology production processes also at present are incapable of yielding compositions that are homogeneous and objectively characterized that is where constituents of the identity of a biological product and the clinical assessment of its safety and effectiveness are inherently linked to the process by which it has been produced. (troy, 2007)
Throughout the manufacturing process of a biopharmaceutical product, these changes greatly affect the product quality. As a result of new therapeutic monoclonal antibodies being formulated at high concentrations, usually there is a concern regarding aggregates and a potential for immunogenicity. This changes may alter the purity of the products or post translational modifications which result in production of antibodies in humans this antibodies that bind to the products normally affect both pharmacokinetic and pharmacodynamics parameters. In order to counter these changes a number of changes have to be made in the manufacturing process these changes are introduced upon carrying out the analytical tests and biological assays. Some of these tests include the measurements of biological activity both in vitro and in vivo and carrying out analytical release testing with the possibility of including secondary and tertiary structure and carbohydrate analysis. (Schiff, 2004)
Safety is a very important when developing any biopharmaceutical product. One very important clinical measure is pre clinical testing. once a candidate biopharmaceutical product has been identified it is subjected to extensive pre clinical testing to identify toxicity .But because most biologics are expressly designed to manipulate a native human biological mechanism or cellular target the investigations of these products can prove challenging and often present toxicity issues distinct from screening of chemical compounds. For example a biologic may mimic a natural substance or trigger events in the body that occur naturally in healthy individuals. The consequences of manipulating these endogenous pathways are not well understood but can alter the benefit/risk profile by contrast toxicology screening of small molecule drugs typically focuses on identification of toxic metabolites that are produced once the active ingredient has been ingested. Those screens can be conducted on laboratory animals as surrogates for humans as the toxicity effects are generally macroscopic and easily measurable for example liver failure.
Another important safety measure is seen in the case of the design of the clinical studies. In cases where the pre clinical testing is found to be positive a biological candidate just like a small molecule drug enters to the clinical studies referred to as clinical trials. These Clinical trials that are conducted for both biologics and small molecule drugs they generally consist of three phases. The first phase referred to as Phase 1 studies involve administering the compound to a small number of healthy subjects to obtain initial data on metabolism, pharmacologic action and side effects. The second phase referred to as Phase 2 studies normally may involve several hundred subjects and is normally directed to the side effects effectiveness and optimal dosing. In cases where the preliminary evidence indicates that the biological product or drug is safe and effective, then phase 3 trials are conducted with up to several thousand patients. Phase 3 trials are intended to provide a safety and effectiveness data to meet with the FDA’s approval standards. (WHO, 2009)
Safety measures are also carried out in the development of the manufacturing process. Due to the fact that in many cases the ability to identify clinically active components of any complex biological product, these products are in many cases identified by their manufacturing processes. The various changes in the manufacturing process, equipment or facilities could result in changes in the biological product itself and sometimes require additional clinical studies to demonstrate the products safety, identity, purity and potency. The production is monitored by the agency from the early stages to make sure the final product turns out fine. (Albano, 2008)
After the manufacture of a pharmaceutical product quality control is performed. It is one element of the overall quality assurance process and refers to the testing of samples of all pharmaceutical products against some specific set standards the main objective being to evaluate the continuous compliance of the products with the manufacturer’s requirements and specifications. This testing is conducted by systematically drawing samples of each pharmaceutical batch. These samples are then randomly subjected to quality control testing in selected laboratories. The tests normally conducted are those that show deterioration of the product. If the tests conducted are not acceptable the product is returned to the manufacturer to find an alternative product to procure and replace the product. (Daviaud, 2007)
Another Major issue in developing a safe, cell culture-based biological product has been viral contamination. There are several routes that viral contaminants can be introduced during production maybe through, Cell substrate, Contamination during cell and culture medium handling and maybe and maybe Use of contaminated biological reagents such as animal serum components. Manufacturers therefore design and implement screening strategies that ensure freedom from potential viral contamination. The most important being that of viral clearance evaluation. When performing the earlier clinical trials, viral clearance studies are designed to eliminate endogenous retrovirus and other relevant viruses depending on the manufacturing process. The manufacturing changes normally occur at the early stages of manufacture and clinical trials. These changes may result in altered levels of endogenous retrovirus like properties and thereby alter results of previous viral clearance studies. (Schiff, 2004)
The clinical trial design consists of three main phases; Phase I Phase II and phase III. Each phase is more complex, time consuming and resource intensive than the preceding one. In phase one the initial testing of new therapeutics in humans is carried out. The objectives of this phase are the determination of initial safety and pharmacokinetic and pharmacodynamics profiles for the product for example reported adverse effects, highest tolerated dose and the rates of absorption metabolism and distribution of product in the body after various doses. The testing may be carried out in either volunteers or volunteers. If the product performs well in phase one then phase II studies are conducted to determine product efficacy in patients and to provide additional safety information. Data from these pilot studies are used to design the pivotal phase III studies, which provide precise measurements of safety and efficacy of the product in a targeted patient population. The exact indication the food and drug administration (FDA) or other regulatory agency will consider for approval is determined by the phase III study data. (E Jatto, 2002)
Phase I and phase II clinical trial studies show great difference in objectives, the patient population, controls and blinding, duration the dose and entry criteria. Phase 1 which includes the initial introduction of an investigational new drug into humans. The Phase 1 studies are normally closely monitored and may be conducted in patients or normal subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug’s pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80. Phase 1 studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. (CDISC., 2003)
In cases where phase 1 studies of a product have succeed then Phase 2 is carried out. This phase consists of well Controlled clinical studies that are conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects
In phase 1 and phase 3 different endpoints and different analysis methods are used. Because phase one is carried out on fewer subjects then the data obtained is subjected to very thorough analysis they mostly employ statistical models that usually make assumptions abut the data or the form of treatment effect. In phase 3 due to the involvement of very many subjects employ simple crude methods are used. In cases of end points time to disease progression is an endpoint that is employed in phase 1 because it requires a measure of disease severity or that od disease progression on the other hand the phase 3 employs surrogate endpoints because it is a clinically relevant end point. (CHMP, 2006)
When conducting the quality control testing of a biologic product the essential elements considered are Identity, Purity, Potency, Strength, Safety and Stability. All this elements have their own challenges of assay development. in the case of stability testing the major challenges encountered are the size of sample that would be required and test intervals fro each attribute tested and also the storage conditions for the samples that are retained for testing may not be suitable enough giving wrong conclusions on matters of a stability. Yet it is a given fact that failure to conduct a proper stability testing can be very time consuming and costly for companies, and damaging to their reputation. (WBG, 2007)
Potency which is the quantitative measure of biological activity based on the attribute of the product that is linked to the relevant biological properties. The challenges that are encountered for proper potency assay development is the complexity of the biologic product, the inherent variability of starting materials for product development and there is limited material for testing and the lack of appropriate reference standards. A good example of an analytical method is the Non-biological analytical assays.
In the elements of safety the challenges encountered for a proper assay development is the limited stability of a biological product a good example being the viability of cellular products. Another fact also that affects safety is the lack of appropriate reference standards. In the case of strength the challenges encountered for proper assay development is due to the existence of multiple active ingredients in the product examples being heterogeneous mixtures of peptide pulsed tumor and multiple vectors used in combination. (WHO, 2009)
The determination of absolute and relative purity presents a number of analytical challenges because the results are highly dependent of the method. The main challenge encountered in assay development is the in vivo fate of product. This is seen in the case of migration from site of administration which may facilitate impurities in the product. Another case is that of viral or cellular replication. A good analytical method to use in matters of purity is by combination of analytical procedures such as the analysis of the process related impurities using clearance studies such as spiking experiments at the laboratory scale to demonstrate the removal of cell substrate derived impurities like nucleic acids.
An identity test is normally conducted highly specifically for each drug substance and is based on unique aspects of its molecular structure and other specific properties. More than one test may be necessary to establish identity the main challenges encountered in assay development is the potential for an interference or synergy between active ingredients. This is seen in the fact that multiple genes expressed by the same vector and multiple cell types in autologous and allogeneic cell preparations. A good analytical method includes PH and osmolarity. (Janice M. Reichert, 2003)
A company is developing a monoclonal antibody for the treatment of cancer. The development groups have selected the commercial cell line, finalized development for increasing the bioreactor scale from 1000L to the 10,000L commercial scale and made several changes to downstream resins. The liquid drug product was initially supplied as a liquid in vials but the firm plans to introduce the commercial product in pre-filled syringes. Key degradation products have been isolated and shown to be an oxidized form of a methionine residue found at the active site. This protein is also prone to aggregation.
Comparability protocol to be used by the company for comparison of First Trial in Humans (FTIH) batches to pivotal clinical trial batches will be based on a number of chemical, physical and biological assays. The Information that was obtained during the process development studies in phase one and phase two would play a very important role in designing an appropriate comparability program. With the exception of minor changes during the manufacture of the antibody, the major comparability testing programs for this companies product would include a combination of analytical testing and biological assays a good example being biological activity measurements both in vitro and in vivo, analytical release testing with the possibility of including secondary and tertiary structure and Pre- and post changes in multiple lots and with reference standard using validated analytical assays when assessing changes during or post completion of pivotal clinical trials. (Seamon K. B., 2008)
The main analytical methodologies that will be used for the evaluation of biochemical and biological properties of the products of the process of comparability and supplies is Bioactivity and blinding. Bioactivity is the assessment of the biological properties. It would be measured by valid biological essay which mainly include Animal based biological assays that measure an organisms biological response to the monoclonal antibody. Also the use of cell culture-based biological assays and biochemical assays that measure biological activity that includes enzymatic reaction rates and the biological responses induced by immunological interactions. On the other hand Blinding is an important means of reducing and minimizing the risk of biased study outcomes. A trial where the treatment assignment is not known by the study participant because of the use of placebo or other methods of masking the intervention is referred to as a single blind study. When the investigator and sponsor staff who are involved in the treatment or clinical evaluation of the subjects and analysis of data are also unaware of the treatment assignments, the study is double blind there is also use of process related impurities analysis. (Stephen Moore, 2003)
In order to determine various physicochemical properties there are a number of method that will be used. For Molecular weight or size, determination would be done using size exclusion chromatography and mass spectrometry. in cases of molar absorptivity would be determined using visible spectrophotometry on a solution of the product having a known product content that is determined using techniques like amino acid compositional analysis. So as to determine Liquid chromatographic patterns they are obtained by size exclusion chromatography or reverse phased liquid chromatography finally in the case of Spectroscopic profiles ultraviolet and visible absorption spectra are determined using procedures of circular dichroism and nuclear magnetic resonance. (John Towns, 2008).
One recent publication on Biosimilars is the one concerned with biosimilar therapeutics the articles summary includes.
Biosimilars can be defined as biological products that are similar, but not identical, to the reference products that are separately submitted for marketing approval that follows patent expiry of these reference products. They are not generic forms of innovator products. The moment bioequivalence and pharmaceutical equivalence have been established then Conventional generics get to be considered as therapeutically equivalent to this reference. Biosimilars have presented new sets of challenges to regulation authorities especially in comparison to conventional generics. In the case of small-molecule generic agent’s demonstration of a pharmacokinetic similarity is sufficient for conventionality, while there are a number of issues that make approval of Biosimilars to be more complicated. There are Documents that have been published by the European Medicines Agency (EMEA) giving the requirements for the market approval of Biosimilars. The EMEA has also approved many be of biosimilar products through a scientific and balanced process. Some issues that are outstanding s include interchangeability of innovator products and Biosimilars, the need of a unique naming system in order to show difference on various biopharmaceutical products, and a more complete labeling that includes relevant clinical data for Biosimilars. (Blackburn, 2008)
Biosimilar products have very complex molecules and, as such, they cannot be given equal treatment to conventional generic drugs. They need to be comprehensively tested in the production process always being compared to an appropriate reference product. Even if there are a variety of assays available, in some cases they may not reliably predict the safety and efficacy of a bio similar product, as such standardization of assays is crucial to the regulation and testing of Biosimilars in future. Regulatory consent of Biosimilars requires more than just demonstration of pharmacokinetic bioequivalence and pharmaceutical equivalence. The immunogenicity of recombinant therapeutic proteins is a significant safety concern especially In the post-PRCA era. This leaves clinical studies and post-authorization pharmacovigilance only as a monitor to potential immunogenicity which provides evidence for product comparability with the innovator product concerning safety and efficacy. The more clinical and manufacturing experience of the first Biosimilars products amasses, the guidelines of EMEA for their market approval needs to be revised so as to include the latest developments. The issues that are outstanding need to be resolved, which includes substitution, naming and labeling. In order to differentiate biopharmaceuticals there is need for unique naming of these products thus facilitating their accurate prescription, dispensation and pharmacovigilance. The labels that are included in EPAR would be of great help to clinicians when making treatment decisions. When the Physicians are aware of the potential differences existing between biopharmaceuticals and Biosimilars then patient safety is ensured because they are able to make more informed treatment choses. (Blackburn, 2008)