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Biopharmaceuticals are defined as 'pharmaceuticals consisting of proteins along with/without nucleic acids. They are produced by means of various biotechnological principles. They have specific characteristics with respect to the molecular properties, therapeutic uses and formulation. However, during the recent years their development rate has decreased due to various factors. The present study is carried out to overview specific characteristics of biopharmaceuticals. The present study also overviews the major obstacles in their development.
One of the main setbacks for the development of biopharmaceuticals has been the extensive financial requirements for the same. Several hundreds of biopharmaceuticals are under clinical studies. Another important reason for their setback is that the success rate of taking biopharmaceuticals from the research laboratories to clinical studies and then to the market is very low. The present study has also been carried out to review the economic aspects with respect to the manufacturing of biopharmaceuticals
Biopharmaceuticals are defined as pharmaceuticals consisting of proteins and/or nucleic acids. They are produced through various biotechnological principles. They make up only a small fraction of the market today. However, the growth of these medicines is much faster as compared to the conventional medicines. Recent statistics show that the FDA approved various biotechnology derived protein medicines and vaccines. Currently, hundreds of biopharmaceuticals are in clinical trials. The present study is carried out to overview the development process of a biopharmaceutical product, the associated characteristics, and economic considerations and also highlights the main hindrances in its development.
Specific characteristics of biopharmaceuticals:
Biopharmaceuticals deserves special attention because of their specific characteristics that sets them apart from the conventional medicines. Their specific characteristics include:
1. Molecular characteristics:
2. Pharmacological/therapeutic uses:
Severe fatal diseases.
b) Rate controlled delivery.
1. Molecular characteristics:
Biopharmaceuticals differ from the conventional pharmaceuticals in size, structure and molecular weight. Biopharmaceuticals mainly consist of proteins and nucleic acids. The building blocks for these molecules are amino acids and various sugar molecules. They form three-dimensional structures in space. Such special structures do not exist in low molecular weight drug molecules. Apart from these, different areas in protein drug molecules have different functions. For instance, in a monoclonal IgG type antibody different parts clearly have different functions. A diagram of a monoclonal antibody is depicted in Fig. 1.
Fig.1 A diagram of a monoclonal IgG type antibody
The antigen binding site (responsible for site specific docking on the antigen) is located at the beta-pleated N-terminal ends. Small molecules do not possess such sophisticated structures harboring several different functions on one molecule.
2. Pharmacology/therapeutic use:
Table 1 shows a list of biopharmaceuticals marketed in the USA.
a) Severe fatal diseases:
The biopharmaceuticals were introduced to treat severe and life threatening diseases. They may include: biological response modifiers to stimulate cell growth; monoclonal antibodies for immune modulation and treatment of cancer; hormones such as insulin and human growth hormone; enzymes such as alteplase to remove blood clots; and a number of vaccines.
Table1.List of some biopharmaceutical products
Antihemophilic factor VIII
Growth hormone releasing hormone
Hepatitis B vaccine
Interferon Alfa con
Legend: MAb: monoclonal antibody;
HGF: hematopoietic growth factor;
BRM: biological response modifier.
b) Safety/clinical testing:
Species specificity :
Various drug safety programs are conducted on the new chemical entities before it subjected to clinical studies. It is an intrinsic part of a dossier that is submitted to the regulatory authorities. For biopharmaceuticals there are various reasons to reconsider the use of a standard protocol. 1) Some biopharmaceuticals are species specific. Interferons are an example of a class of biopharmaceuticals well known for its species specificity in terms of pharmacological action.
Human interferon does not show the same pharmacological effects as mouse interferon in mice. It may even lack all activity in animals.
2) Unlike low molecular weight drugs, biopharmaceuticals rarely yield metabolites that are pharmacologically or toxicologically active; they are simply degraded to non-active products.
3) Human biopharmaceuticals may readily induce immune reactions in animals.
ii) Dosing schedules:
Most of the biopharmaceuticals are administered parenterally. In spite of tireless efforts of a number of groups, oral delivery of proteins and peptides never became a success. Fractions of (intact) peptide and protein absorbed in the GI tract just remain very low and not easy to reproduce. Bell-shaped dose response curves often occur in animal studies with biopharmaceuticals, in particular with cytokines. These curves have been encountered in clinical settings as well. The pharmacological action of cytokines is pleiotropic. These substances affect different processes of the immune response. Dose increase may thus lead to a full disappearance of the desired effect, because of down-regulation of key receptors, or a signal transduction mechanism where the cells become refractory to subsequent receptor mediated augmentation. Dose finding for drugs with a proven bell-shaped dose response relationship in animals increases the level of uncertainty when starting a clinical trial, in particular when long-term therapeutic effects are defined (e.g. in tumor therapy) and reliable therapeutic markers are difficult to identify.
Proper protein formulation development is crucial for the optimal therapeutic performance of biopharmaceuticals. Immunogenicity is in some way related to the presence of aggregates and contaminants. As all systemically active proteins are administered parenterally, sterility and non-pyrogenicity are standard requirements for these products. Removal of viruses and other contaminants should be an integral part of the downstream process. To reach the desired shelf life of two years for biopharmaceuticals, a number of specific challenges have to be met such as stability and rate controlled release.
On storage, proteins are exposed to a number of different chemical degradation pathways. Apart from chemical degradation, physical degradation can occur in the form of changes in secondary or tertiary structure, and aggregate formation, which can ultimately lead to precipitation. Formulation design should be geared to avoid degradation. Proper selection of excipients, physical state and storage conditions are critical to avoid loss of therapeutic value and induction of immune responses.
Rate controlled delivery:
Biopharmaceuticals often have to be administered frequently, a number of times daily or a few times per week. To improve patient friendliness several different approaches can be chosen. Modification of the protein is one option. With NESP (darpoeitin) a hypersialylated erythropoeitin is used. At two N-glycosylation sites of the protein that do not interact with the receptor, carbohydrates with terminal sialic acid groups are attached. This modification increases the t1/2 in blood from 9 to 21 h. Similar effects have been described for PEGylation of biopharmaceuticals. PEG-G-CSF (pegfilgrastim, a long circulating form of G-CSF) has recently been approved. Six milligrams pegfilgrastim in one injection proved to be therapeutically equivalent to five daily doses of filgrastim (Pegfilgrastim). Many years ago, different formulations of insulin were developed that provide controlled release patterns. Zinc or protamine interactions with insulin lead to the preferred blood level of insulin. And a span of duration of action between 6 hrs for soluble insulin to 28 h for 'ultralente extended insulin zinc suspension' can be achieved. For low molecular weight drugs, release duration may be extended to a few days or to a few weeks by using oil suspensions or solutions (with antipsychotics or hormones). Biodegradable microparticle systems based on polylactic-coglycolic acid (PLGA) have also been described. PLGA in the form of a rods or microspheres has been successfully used for the sustained release (up to six months) of small peptide drugs (e.g. LHRH analogs such as leuprolide). Only if the drug molecule is highly potent with a daily required dose of <1 mg and if prolonged release for over 1 week is required, does this PLGA technology (or other prolonged release technologies) offer advantages. But, PLGA technology suffers from a number of disadvantages: (a) strong burst effects are regularly observed; (b) several reports show that inside the device a substantial pH drop occurs during degradation of the PLGA, affecting the integrity of the PLGA-device associated protein; (c) standard microsphere preparation technology involves a w/o emulsification step, while the protein is dissolved in the aqueous phase. As proteins readily denature at w/o interfaces this process may not be optimal. There is a clear need for more protein friendly technologies without burst effects. Several hydrogel technologies for controlled release of biopharmaceuticals have been described over the last few years.
Growing obstacles in the development of biopharmaceuticals:
Since the launch of Eli Lilly's (Indianapolis, IN) recombinant human insulin-the first marketed biotechnology product-in 1982, the number of biopharmaceuticals reaching the market has increased steadily (Fig. 2)
Fig.2. Development of biopharmaceuticals from 1982-2000
By the beginning of the year 2000, a total of 77 biopharmaceutical products (excluding vaccines) were available in the global marketplace. Although these products did not fully compensate for the decline in the output of (new chemical entities) NCEs-which has been ongoing since the mid-1980s-biotechnology has been an invaluable source of new medicines.
Biopharmaceuticals have also had much shorter development times than NCEs. Between 1982 and 1989, the mean time for the development of a product from the "bench" through to its first market launch was 5.9 years for a biopharmaceutical compared with 11.0 years for an NCE (Fig.3).
FIG.3.Mean development time (three-year moving average) for biopharmaceuticals and NCEs launched on their first world market between 1985 and 2000.
In part, this reflects the nature of biopharmaceuticals, many of which are naturally occurring proteins with specific pharmacological profiles and defined physiological mechanisms of action. For these reasons, the clinical evaluation of a biopharmaceutical can be less prone to trial and error than the evaluation of an NCE, and less time is spent demonstrating clinical efficiency. However, the present study has revealed that the mean development times for biopharmaceuticals rose dramatically during the 1990s (Fig. 3). Using three-year moving averages, it is clear that the mean development times for biopharmaceuticals and NCEs have been converging since 1996. Data collected as part of CMR International's benchmarking program-which measures the time taken between key milestones in the development process-suggests that the development times of biopharmaceuticals and NCEs will be indistinguishable in the future. Hypothetical development profiles, created by adding the average time spent in each key stage of drug development completed between 1997 and 1999, suggest that it will take 9.8 years to bring a biotechnology product to market compared with 10.1 years for an NCE. However, it should be noted that these profiles represent the development of biotechnology products and NCEs within the pharmaceutical industry only; few biotechnology companies are represented in the database. With fewer medicines to concentrate research and development activities on, biotechnology companies may be in a position to drive compounds through development more quickly than large pharmaceutical companies. Explaining why the clinical development times of biopharmaceuticals have slowed in recent years is more problematic. Rolf Werner accounted for the widely varying development times for biotechnology products on the basis of differences in prior knowledge of clinical efficacy and/or pharmacological modes of action. Many of the early biopharmaceuticals were protein replacement therapies and/or recombinant versions of natural proteins for which therapeutic benefits had already been established. The transition from the selection of these "easy" drug targets of established therapeutic/pharmacological actions to those with a less well-established therapeutic profile has surely contributed to the prolongation of development times for biopharmaceuticals.
More recent data suggest, however, that the difference between the success rates for biopharmaceuticals and NCEs is narrowing. Based on the progress of new molecular entities through clinical development between 1994 and 1999, Lobo calculated that the clinical success rate for biopharmaceuticals and gene therapies was 35% compared with 23% for NCEs. There continues to be a much greater likelihood that a biopharmaceutical will successfully complete early clinical development (phase I and 2) compared with an NCE, but much of this advantage is lost during phase 3 when biotechnology products show a higher failure rate than NCEs.
During the period 1982 to 1990, biopharmaceuticals achieved international marketing status over a year more quickly than did NCEs. The speed at which a product is made available on international markets is often considered to be a surrogate marker of their innovative value, on the assumption that a drug offering advantages over existing therapies will be widely and swiftly adopted. Not surprisingly, the trends in time taken to achieve international launch correspond very closely to trends in time taken to submit marketing authorization applications in two of the three ICH regions. However, this difference has narrowed and, during the 1990s, 32% of NCEs attained international marketing status compared with 23% of biopharmaceuticals, and companies were launching both types of products with similar alacrity (fig.4.)
Fig.4. The time to international launch (in two out of the three ICH regions) for biopharmaceuticals and NCEs.
One of the main setbacks for the development of biopharmaceuticals has been the extensive financial requirements for the same. Several hundreds of biopharmaceuticals are under clinical studies. Another important reason for their setback is that the success rate of biopharmaceuticals from the research laboratories to clinical studies to the market is very low.
Given the prospective high number of monoclonal antibodies under clinical development in 2010, sales of US$ 16 billion are expected assuming a certain probability of success in certain phases of development. As monoclonal antibodies are usually given in high doses over a long period of time, the capacity for manufacturing these products in mammalian cell cultures will be a challenge. It has been forecasted that from 2010 onwards, there will be a shortage of capacity for products derived from mammalian cell cultures, although major investments are being made, especially by big pharma. In order to overcome this capacity shortage and to create ï¬‚exibility in capital investment the regulatory authorities accept a cGMP pilot plant facility for the manufacture of Phase III clinical material and for the supply of the market; even different cGMP pilot facilities are accepted for clinical material and market supply and for later scale-up to commercial manufacture. However, the drawback is that it has to be demonstrated that the product remains equivalent and consistent, regardless of the different pilot plant resources and after scale-up to commercial scale. If the numerous protein analytical methods available today are applied, there is a certain risk of differences between products coming from different pilot plants and between those obtained from the pilot plant and from commercial scale. This has to be taken into consideration when selecting the strategy for supplying the market from a pilot plant. This is especially critical if the fermentation technology in the pilot plant is different to that of the commercial system. Since the engineering for such a plant has to start prior to the pre-clinical study in order to meet the timeline required for Phase III clinical material to be produced in the commercial plant, there is a long way from groundbreaking to the validated facility in operation. Depending on the size and type of investment-greenfield or extension to an existing infrastructure-the cost of a 6 Ã- 15,000 L bioreactor plant ranges between $ 300 and $ 500 million. Due to the long development time-frame of a biopharmaceutical and the long time required to realize the investment, the biopharmaceutical business always has to think about 5 years ahead in terms of process improvements, investment and product development, not to mention economic success The timing of technology transfer to a contract manufacturer is critical and should be decided on the basis of the company's own capacity and the process chain from the expression system to commercial supply, without jeopardizing the launch of the product.
The earlier the process is transferred to the contract manufacturer, the better for time-to-market development of the product, redundancies excluded, as the requirements for process qualification and validation increase with the development of the product in pre-clinical and clinical trials (Fig. 5).
Therefore, it is recommended that a contract manufacturer is selected prior to the pre-clinical stage.
Besides major jump investments, process improvements can make a tremendous contribution to lowering the cost of goods, while saving investments and freeing up capacity for new business. A 10-fold increase in titer and a 30% increase in yield reduce the required number of bioreactors from 31 to 2, assuming that 250 kg protein has to be produced in a 10,000 L plant per year. This will reduce the required capital from $ 1600 to $ 100 million, assuming that one bioreactor including downstream processing and infrastructure will cost $ 50 million. It also lowers the cost of goods from US$ 1600 to US$ 260 gï€1 protein, reï¬‚ecting a reduction in the annual cost of goods from US$ 375 to US$ 65 million (Table 2).
If technology changes are required from laboratory scale to large scale in order to increase the economy of the manufacturing process and to guarantee market supply, it should be borne in mind that there might be differences in the product quality from roller bottle to suspension or from hollow fiber to suspension, from air lift to stirred tank, from batch to fed batch, from fed
Impact of innovation on economics and investments. Assumptions: 10,000 L scale; 250 kg per year, 50K US$ investment per bioreactor
100 mg Lï€1
1000 mg Lï€1
62,000,001 per year
3,400,001 per year
Number of bioreactor
US$ 1600 million
US$ 100 million
CoGs per g
CoGs per year
US$ 375 million
US$ 65 million
batch to perfusion and from perfusion to continuous processes. This can be seen in an example of manufacture of monoclonal antibodies in the hollow fiber system compared with the suspension culture; there are significant differences in diamidation of the molecule in the hollow fiber system, as demonstrated in the isoelectric focusing pattern.
A completely different innovative strategy to improve the economics of both the manufacturing process and patient benefit are second-generation molecules which have a higher affinity for the target, higher efficiency and a longer half-life in the blood. These features were obtained with the TNK-tPA molecule by exchanging specific amino acids, reducing the total dose from a 100 mg infusion to a 40 mg bolus i.v. injection. Besides, the simple administration of this molecule compared with the native tPA molecule, and the advantage of administration in emergency situations with a great patient benefit, this innovation yielded a significant reduction in the cost of goods and therefore freed up capacity for additional business. The productivity of the fermentation process has an impact on the capacity utilization of a bioreactor, ranging from 50 kg per bioreactor to 200 kg per bioreactor depending on whether the titer is 250 mg or 2000 mg Lï€1. It is, therefore, obvious that there is enormous potential to improve the manufacturing processes by innovation. However, the time-frame for significant improvements is about 5 years, the outcome unpredictable. Yet, capital investment in more of the same technology will range from $ 300 to $ 500 million over a time-frame of 5 years and requires well-trained employees, pre-requisite to reliable production startup. Therefore, innovation and capital investment must go hand in hand to maintain leadership, maximize ï¬‚exibility and minimize capital expenditure. For this challenge biopharmaceutical manufacture demands very strong commitment to process: science; including all aspects of genetic engineering; fermentation; down- stream process technology; fill, finish; quality control; quality assurance, if major long term improvements are to be made. Commitment to major investments is also required, while skilled staff have to be hired and trained.
However, with such commitment, the biopharmaceutical industry enjoys above-market growth in sales, while contributing to the improvement of the health of mankind.
Biopharmaceuticals are very different from low molecular weight drugs. The complicated protein production processes and structures ask for a paradigm shift in thinking compared to low molecular weight drugs. No absolute description of drug and drug product is possible with these materials. Our analytical toolbox content and bioassays, including animal testing, are important in ensuring drug quality, efficacy and safety issues in the development phase. But, the biopharmaceuticals rely critically on strict production protocols, clinical expertise and performance monitoring in the clinical situation.