As we went to press, the country—and to some extent, the world—was reeling from US Treasury Secretary Henry Paulson's proposed $700 billion Wall Street bailout. In appealing for support, Paulson stressed this was a crisis. 

This sense of urgency is reminiscent of the way millions of Americans without health insurance cope with medical problems—in the emergency room, because they have no access to routine and preventive care. 

And just as the cost of shoring up the financial sector would not be so astronomical if we had started treating the condition before it became life-threatening, much less would be spent on emergency care if everyone had access to routine checkups. A visit to the emergency room costs three times as much as a visit to a physician's office.

  And of course, when treatment is delayed, patient outcomes are much worse. 

In 2006, we spent more than $2 trillion on healthcare in this country. That's $7,026 per person, nearly twice the per capita spend in France and Germany.

 Yet the results are unimpressive. The United States ranks 41st in infant mortality, just behind Cuba, and 46th in life expectancy.

  And, of course, 45 million Americans remain uninsured.

Americans wonder whether we can afford to insure everyone. But lack of insurance is not cheap either. The uninsured pay about 35% of their own medical bills. The remaining costs of uncompensated (charity) care are mostly covered by taxpayers through subsidies to hospitals and clinics that total about $50 billion a year.

  As former Tennessee Senator Bill Frist put it, "We are already paying for a lot of care for the uninsured in a very indirect, untransparent, inefficient way."

 it cost to insure everyone? A 2002 Institute of Medicine (IOM) study estimated the costs at $34–$69 billion per year for the additional healthcare that would be used by the uninsured if they had coverage, plus $26 billion to cover out-of-pocket costs the uninsured currently pay by themselves.

That makes the total about $60–$95 billion. 

 insuring everyone? Using a "health capital" model, covering factors like lost productivity, the IOM study estimates that poorer health resulting from lack of insurance costs between $65 and $130 billion annually. So according to the IOM's figures, the net cost of insuring everyone could be as high as $35 billion, or, surprisingly, could provide a net gain of up to $40 billion. 

It is also important to consider how much is spent in our complex system because of its inefficiency. One study found that administrative waste consumes 31% of health spending in the US, double the proportion in Canada (16.7%).

Regardless of the numbers, however, we should be reminded of the moral imperative to provide healthcare to all. In a developed country, no patient should go untreated.  

The current financial crisis has left us all feeling a bit at risk. It's a stark reminder of how unprotected America's uninsured already were before the current crisis—and will continue to be afterward, unless we get serious about changing the situation. 

 1. Mitchiner JC, Schultz DS. The cost of nonurgent care for Medicaid patients in the emergency department and two community health clinics. Abstr Book Assoc Health Serv Res Meet. 1999;16:203. 

 2. Wilson, KB. Health Care Costs 101. 2008 edition. Oakland, CA: California HealthCare Foundation. 2008. 

 3. The Central Intelligence Agency. The 2008 World Factbook. Washington, DC. CIA. 2008 Sept. 

 4. DeNavas-Walt C, Proctor BD, Smith JC. US Census Bureau. Current Population Reports, P60-235, Income, Poverty, and Health Insurance. Coverage in the United States: 2007.  

  Washington, DC: US Govt Printing Office. 2008. 

 5. Institute of Medicine. Insuring America's Health. Washington, DC: National Academy of Sciences. 2004. 

 6. Baker CD, Caplan A, Davis K, Dentzer S, Epstein AM, Frist B, et al. Health of the nation—coverage for all Americans. N Engl J Med. 2008 Aug 21;359(8):777–80. 

 7. IOM. Hidden Costs, Value Lost. Uninsurance in America. Washington, DC: National Academy of Sciences. 2002. 

 8. Woolhandler S, Campbell T, Himmelstein, DU. Costs of health care administration in the United States and Canada. N Engl J Med 2003;349:768-75. 

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The country is reeling from US Treasury Secretary Henry Paulson's proposed $700 billion Wall Street bailout. In appealing for support, Paulson stressed this was a crisis. This sense of urgency is reminiscent of the way millions of Americans without health insurance cope with medical problems-in the emergency room, because they have no access to routine and preventive care.

Sick Economy, Sick Healthcare System

The year 2007 witnessed the approval of 15 biopharmaceuticals in the United States and/or European Union (EU). The 15 approvals included six erythropoietin (EPO)-based products, three antibodies, and two hormones, as well as a one therapeutic enzyme, one recombinant vaccine, one growth factor, and a fusion product (Table 1).  

 The target indications included anemia (six products) hereditary genetic conditions (four products), cancer prevention or treatment (two products), and neovascular macular degeneration, rheumatoid arthritis, and infertility (one product each). 

Only nine of the 15 products were genuinely new to the market in 2007. The other six, although approved in one region last year, had gained approval before 2007 in another world region (Table 1). 

Table 1.  Biopharmaceuticals (defined as recombinant protein, monoclonal antibody, and nucleic acid-based products) approved in the United States or European Union in  2007. Biosimilars are in shaded rows.  

In terms of expression systems used, 11 of the 15 approved biopharmaceuticals are produced using mammalian cell lines; two in 

; and notably, one in a baculovirus/insect cell-based system. Overall, this trend confirms the prominence of mammalian-based expression systems in the biopharmaceutical sector. On the other hand, Cervarix's approval is particularly noteworthy as it is the first biopharmaceutical approved for human use that is produced using an insect-cell–based expression system.  

A wide range of therapeutic proteins (e.g., tPA, interferon γ, and hepatitis B surface antigen) have been produced at laboratory scale using such systems. A small number of approved veterinary medicines (e.g., Intervet's porcilis pesti subunit vaccine) are commercially manufactured using such systems. The advantages of recombinant insect-cell–based production include high levels of intracellular expression and rapid cell growth on relatively inexpensive media. However, issues including low extracellular expression levels and the exact nature of post-translational modifications achieved have been cited as disadvantages of this system. 

Perhaps the single most notable feature of the 2007 approvals is the number of biosimilar products that entered the market in the EU. Of the 14 products approved for the first time last year in Europe, five are biosimilars (Abseamed, Binocrit, Epoetin alfa Hexal, Retacrit, and Silapo; Table 1). This clearly illustrates that the biosimilar legislative framework developed by the EU works in practice. Another notable fact is that all five products are EPO-based. This is not surprising given that EPO is the single most lucrative biopharmaceutical on the market. EPO-based products represent three of the top 10 blockbuster biopharmaceuticals (Aranesp, Procrit/Eprex, and Epogen)

 , and relevant company annual reports show a cumulative annual market value in excess of $10 billion for these three products. The approval of biosimilar EPOs also confirms the practical feasibility of illustrating comparability of a glycosylated biosimilar to its reference medicine.    

Further analysis of the nine products entering the market for the first time last year provides additional insights. The five biosimilar products contain only two different active ingredients: The active ingredient in Abseamed, Binocrit, and Epoetin alfa Hexal (recombinant human erythropoietin alfa) is identical in each case, while Retacrit and Silapo also share an identical active substance (epoetin zeta). Furthermore, Mircera is a PEGylated version of a product already on the market (Neorecormon) and the twin active substances in Pergoveris are already marketed as individual products (Gonal F and Luveris). 

The remainder of this article focuses on individual products approved for the first time in 2007, with product information detailed in a monograph format. The information was drawn from regulatory sources and the web sites of sponsoring companies.

 Monographs detailing the products listed in Table 1 that had gained prior approval in some world region were included in previous articles.

  Therefore, they are not considered below.  

 (recombinant human erythropoietin alfa) is a recombinant form of human erythropoietin (EPO) produced in a Chinese hamster ovary (CHO) cell line. Native human EPO is a 165 amino acid, 36 kDa glycoprotein housing three N-linked and one O-linked glycosylation sites. It is synthesized almost exclusively in the kidney and is primarily responsible for stimulating and regulating erythropoiesis (red blood cell production). Abseamed is a biosimilar product, with Janssen-Cilag's erythropoietin Eprex/Erypo having served as reference medicine. The product is identical to both reference and native EPO in amino-acid sequence, but does differ in exact glycosylation detail. Compared to Eprex it displays somewhat higher sialylation levels, particularly associated with its O-linked glycan chain. The biosimilar product also displays higher levels of mannose-6-phosphate containing glycans associated with the Asn 24 N-linked glycosylation site. However, these specific glycans display only weak binding affinity for the mannose-6-phosphate receptor, and therefore are unlikely to trigger rapid product uptake from circulation. 

Abseamed gained approval in the EU in August 2007. It is indicated for the treatment of anemia associated with chronic renal failure and for anemia accompanying chemotherapy of certain cancer types. It also can be used to reduce exposure of patients undergoing major orthopedic surgery to blood transfusions if transfusion related complications are anticipated. 

The product is manufactured by batch cell culture in media supplemented with recombinant human insulin. After recovery from the cell media, the product is purified to homogeneity by a combination of standard chromatographic techniques. Downstream processing also incorporates a nanofiltration-based viral-removal step. 

Glycine, sodium chloride, polysorbate 80, and phosphate buffer components are added as excipients, and the final product is filter sterilized, followed by aseptic filling into presterile syringes. The product is commercially available at two active ingredient concentrations, 16.8 μg/mL and 84 μg/mL, equating to 2,000 and 10,000 IU/mL, respectively.  

The exact administration regime of Abseamed will depend on the indication being treated and will also be tailored to the individual patient. Product comparability to the reference medicine was established primarily by a double- blind, randomized, parallel group multicenter study involving 479 patients displaying anemia associated with chronic kidney disease. The primary endpoint measured was the mean absolute change in hemoglobin levels. A second study comparing the effects of Abseamed to Eprex in 114 cancer patients undergoing chemotherapy also was reported, with both studies confirming product comparability to Eprex. The most common adverse effect associated with product administration was an increase in blood pressure.  

Abseamed's active ingredient is manufactured by Rentschler Biotechnologie GmbH (Laupheim, Germany). Germany-based Medice Arzneimittel Putter GmbH markets the product. 

 This product, along with its indications and all other characteristics, is identical to Abseamed. It differs only in the tradename used and in that Sandoz GmbH (Kundl, Austria), holds marketing authorization throughout the EU.  

 (Papillomavirus, human, types 16,18) is a divalent vaccine containing the purified recombinant (C-terminally truncated) major caspid L1 proteins of human papillomavirus (HPV) types 16 and 18. The L1 proteins are produced separately using a recombinant baculovirus expression system coupled with an insect cell line derived from 

. It is the first recombinant biopharmaceutical approved anywhere for human use that is produced using a baculovirus-based expression system. The product gained approval in the EU in September 2007 and is indicated for the prevention of cervical cancer and high-grade cervical intraepithelial neoplasia causally related to HPV types 16 and 18. High-grade cervical intraepithelial neoplasia refers to precancerous abnormal cervical cellular growth with a high probability of progression to cancer if left untreated. Over 100 genotypes of these double-stranded DNA-based enveloped viruses have been identified. Of these 100, 16 strains are regarded as highly oncogenic, with strains 16 and 18 believed responsible for over 70% of all cervical cancers. 

Cervarix manufacture requires separate recombinant production of the major caspid (L1) proteins of HPV strains 16 and 18. Subsequent to upstream processing the caspid proteins are released from the cultured insect cells by osmotic shock. This is followed by multiple chromatographic purification steps, and nanofiltration. The purified L1 protein antigens are then adsorbed separately onto aluminium hydroxide. An adjuvant material,  monophosphoryl lipid A (MPL), is also separately adsorbed onto an additional aluminium hydroxide. MPL is a detoxified derivative of the lipopolysaccharide moiety of the gram negative bacterium 

. The final vaccine product is then produced by mixing defined amounts of all three adsorbed species, along with sodium chloride and phosphate buffer components as excipients. The final vaccine suspension is filled into either vials or syringes. Each dose contains 20 μg of both HPV type 16 and type 18 L1 caspid proteins.  

Product administration (to girls and women 10 years and older) is by intramuscular injection and a typical administration schedule entails follow-on doses one and six months after administrating the initial dose. Clinical trials assessing product safety and efficacy involved more than 21,000 females between the ages of 10 and 25, and clearly illustrated a protective effect. The most common side effects noted were headache, muscle pain, and injection site reactions. The product is manufactured and marketed by GlaxoSmithKline Biologicals (London, UK).  

. This product, along with its indications and all other characteristics, is identical to Abseamed and Binocrit. It differs only in the tradename used and in that Hexal biotech Forschungs GmbH, Germany, holds marketing authorization throughout the EU. 

(methoxy polyethylene glycol epoetin beta) is a PEGylated recombinant form of human EPO. The erythropoietin used to generate Mircera is the active substance of Neorecormon (epoetin beta; Roche's recombinant EPO first approved for general medical use in the EU in 1996). The PEG moiety used is methoxypolyethylene glycol–succinimidyl butanoic acid (PEG–SBA), a 30 kDa linear chemically activated PEG. When co-incubated under appropriate conditions, the PEG–SBA spontaneously forms amide linkages with either EPO's N-terminal amino group or with the ε-amino group of an accessible surface lysine residue (Lys 45 or Lys 52). The final product generated is a 60 kDa monopegylated product.  

Mircera was approved for general medical use in both the EU and the USA in 2007. The approved indication in both regions is restricted to the treatment of chronic kidney disease, and the label explicitly states that the product's safety and efficacy in the context of other indications has not been established. In fact, one dose-ranging clinical study aimed at assessing the product for treating chemotherapy-induced anemia was terminated prematurely because of a significantly greater death rate amongst patients receiving the product.  

The recombinant EPO is manufactured by initial cell culture of the producer CHO cell line in serum-free media. Purification entails five sequential chromatography steps (dye affinity, hydrophobic interaction, and hydroxyapatite chromatographies, followed by a reverse phase HPLC step and finally an ion-exchange step). The purified EPO is then co-incubated with the chemically activated PEG, followed by chromatographic separation of the PEG–EPO conjugate from unreacted monomers or reaction by products. Phosphate buffer constituents, mannitol, poloxamer 188, sodium sulphate, and methionine are added as excipients and the filter-sterilized product is filled into glass vials or prefilled syringes.  

 studies indicated that the PEGylated EPO has a lower affinity for the EPO receptor compared to unmodified EPO. However, 

 studies (using both mouse and dog models, and echoed in clinical studies) showed the PEGylated product to be a more potent stimulator of erythropoiesis in terms of magnitude and, in particular, duration of response. These effects are likely indirect, being linked to reduced product-tissue penetration and retardation of product elimination. Although exact dosage regimes are tailored to individual patients, typical regimes entail product administration once every 2–4 weeks. Neorecormon, in contrast, is administered at least once weekly. The most common adverse reaction associated with Mircera administration is hypertension. The product is manufactured and marketed by Roche (Basel, Switzerland).  

 (follitropin alfa/lutropin alfa) contains twin active substances—recombinant human follicle stimulating hormone (FSH; follitropin alfa) and recombinant human luteinizing hormone (LH; lutropin alfa). Both are separately produced using an engineered CHO cell line. Both active ingredients are already approved individually for general medical use as stand-alone products (tradenames Gonal F and Luveris, respectively).  

Both of these gonadotropic hormones are dimeric glycoproteins, consisting of identical 92 amino acid α subunits and a distinct β subunit (111 amino acids in the case of FSH; 121 amino acids in the case of LH). The distinct β subunit confers biological specificity on these hormones. Both subunits are glycosylated. 

Pergoveris was approved for general medical use in the EU in June 2007. It is indicated for stimulating follicular development in women with severe LH and FSH deficiency (and who are therefore usually infertile). FSH naturally stimulates follicular development with subsequent rupture, and hence, egg release being largely under the influence of LH. 

Manufacturing the active substances entails separate cell culture of the anchorage-dependent producer CHO cells in microcarrier -containing bioreactors. The products are subsequently purified by multiple chromatographic steps and are then combined in a fixed concentration. The final product is filled into vials and lyophilized. Each vial contains 11 μg (150 IU) FSH and 3 μg (75 IU) LH. 

Pergoveris is typically administered once daily until the recipient has developed a suitably matured follicle. This may take up to five weeks. 

Some clinical data generated during previous studies of the individual active ingredients were presented in support of safety and efficacy. Additional studies of the combination product, including bioequivalence studies, were also conducted. The most common side effects noted were headaches, injection site reactions, and ovarian cysts. The product is manufactured and marketed by Serono (Geneva, Switzerland). 

 (epoetin zeta) is a recombinant form of human erythropoietin produced in a CHO cell line. It is a biosimilar product with Janssen-Cilag's EPO Eprex/Erypo having served as reference medicine.  

The product is identical to both reference and native EPO in amino-acid sequence. A combination of HPLC, NMR, and Mass spectrometry-based analysis indicated the molecule's overall glycocomponent to be substantially similar to the reference EPO. The number of glycoforms devoid of the O-linked glycan chain was slightly higher although the level of sialylation was similar. Overall, the product's carbohydrate content was judged to be free of any unusual or potentially immunogenic structures or epitopes.   

Retacrit gained approval in the EU in December 2007. Its approved indications are similar to those of Abseamed, Binocrit, and Epoetin alfa Hexal. Specifically, it is indicated for the treatment of anemia associated with chronic renal failure and for anemia accompanying the chemotherapy of certain cancer types. It also can be used to increase the yield of autologous blood from patients in a predonation program. 

The upstream element of product manufacture is based on a feed-batch cell-culture process. The cell-culture media is proteins, insulin, and free of antibiotics, and is also devoid of ingredients derived from human or animal origin. After initial recovery, the product is purified by a combination of chromatographic techniques, and downstream processing also incorporates a nanofiltration-based virus-removal step. The excipients added include phosphate buffer components, calcium, and sodium chloride, polysorbate 20, and several amino acids (glutamic acid, glycine, isoleucine, leucine, phenylalanine, and threonine). The final product is filter sterilized and aseptically filled into presterile syringes. The product is commercially available at active ingredient potency levels ranging from 3,333 IU/mL to 40,000 IU/mL.  

Retacrit's exact dosage regime will be tailored to the individual patient. The product can be administered subcutaneously to patients receiving chemotherapy and intravenously for other indications.  

Product comparability to the reference medicine was established primarily by two studies involving a total of 922 patients displaying anemia associated with chronic kidney disease, as well as a third study in which the product was administered to 261 cancer patients receiving chemotherapy. Primary endpoints measured were invariably generation and maintenance of blood hemoglobin levels. The most common adverse effect associated with product administration was an increase in blood pressure.   

Retacrit's active ingredient is manufactured by Norbitec GmbH (Uetersen, Germany). Netherlands-based Hospira enterprises B.V., markets the product. 

This product, along with its indications and all other characteristics, is identical to Retacrit above. It differs only in the tradename used and in that Germany-based STADA Arzneimittel AG, holds marketing authorization throughout the EU. 

(eculizumab) is a 148 kDa humanized IgG2/4 kappa antibody produced by recombinant means in an NS0 murine myeloma cell line. The antibody is composed of two 448 amino acid heavy chains and two 214 amino acid light chains, and displays a characteristic IgG oligosaccharide attached to Asn 298 of the heavy antibody chains. The product, which binds to the human C5 complement protein, was approved in 2007, both in the EU and the US, and is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH), to reduce hemolysis. It has orphan status. 

PNH is a rare genetic condition in which patients harbour a mutant gene coding for CD 59, a complement inhibitory protein normally found on the surface of red blood cells. As its name suggests, this protein serves to inhibit the formation of a complement complex (i.e., the membrane attack complex) on the red blood cell (RBC) surface, thereby preventing RBC destruction (hemolysis). This RBC protective mechanism is absent in PNH sufferers and the predominant clinical manifestation of the condition is intravascular hemolysis. Patients typically have a 15-year median survival period from diagnosis. The treatment approaches are largely palliative, with transfusion therapy often used to maintain RBC levels. By binding to the C5 complement protein, the antibody effectively inhibits final activation of the complement system, hence preventing complement-mediated hemolysis. 

Antibody manufacture entails an initial cell-culture step using a 5,000-L bioreactor. The product is subsequently purified by a combination of chromatographic steps, and downstream processing also incorporates viral inactivation (low pH) and virus-removal (nanofiltration) steps. The excipients added include phosphate buffer components, sodium chloride, and polysorbate 80. The final product is filter sterilized and presented in vials as a concentrate (30 mL of a 10 mg/mL solution) destined for IV infusion after dilution to 5 mg/mL. A typical dosage regime entails initial infusion of 600 mg of product weekly for four weeks, a 900-mg infusion at week five, followed by 900-mg infusions every second week thereafter.  

Product safety and efficacy were primarily investigated by one main study involving 87 PNH patients. All had received at least four blood transfusions for anemia in the previous year. By the 26-week endpoint, 49% of treated patients displayed stabilized hemoglobin levels, as opposed to none in the untreated group. Likewise, 51% of the treated group had avoided the necessity for a blood transfusion while all of the nontreated group required transfusions. The most commonly reported side effects included headaches, urinary tract infections, and nasopharyngitis. The most significant adverse reaction experienced was meningococcal infections. As a result, patients should be vaccinated against meningitis caused by 

 The active ingredient in Soliris is manufactured by Lonza Biologics (Newington, New Hampshire). The product is marketed in the United States and EU by Alexion (Cheshire, CT).

, is an associate professor in the Industrial Biochemistry Program at the  University of Limerick, Limerick City, Ireland, +353.61.202664, 

 1. Lawrence S. Billion dollar babies– biotech drugs as blockbusters. Nature Biotechnol. 2007;25:380–382. 

Features

The year 2007 witnessed the approval of fifteen biopharmaceuticals in the United States and European Union.

Biopharmaceuticals: Approval Trends in 2007

Monoclonal-antibody (MAb) manufacture presents substantial current and upcoming challenges to the biopharmaceutical industry. This is true both from an economic point of view and from a technical perspective. The goal of producing sufficient quantities of high-dose antibodies, and the concurrent pressure to reduce cost-per-treatment, is culminating in a vigorous public debate. Recent presentations and publications suggest that manufacturing costs are particularly critical for  scientists and engineers. So, where is the biopharmaceutical industry heading? 

Multiton scale manufacturing is on the horizon. Or is it? There's considerable doomsday talk about future demands in downstream processing and the industry's lack of preparedness. Yet industry trends suggest a need for reduced, rather than increased, production scales. 

In a recent case study of large-scale MAb manufacturing, Kelley investigated a single-branded product need of up to 10,000 kgs per year.

  He concluded that such production is possible with current technology. In addition, he saw little need to turn to unproven alternatives simply for cost reasons. Indeed, in his analysis, cost was not a major driver away from current technology. The caveat with Kelley's study may be that he assumed access to a facility planned and built for the production in question, and clearly not everyone has such access. He also assumed that downstream processing technology would make some evolutionary progress (e.g., in capacity) before such a hypothetical case would become reality, yet large-scale MAb manufacturing is already taking place. Finally, Kelley concluded that it was unlikely that this scale of production would ever be required.  

It is important to note that Kelley was undertaking a case study to make a point. He was not intending to create a blueprint for the biopharmaceutical industry.  

A study conducted by GE Healthcare BioSciences began by examining the production scale of currently marketed biopharmaceuticals (Figure 1). Investigators identified four general trends that could reduce the average production scale for novel protein drugs. These trends are: diminished likelihood of discovering blockbuster drugs, increased competition, dosage reductions, and diagnostic improvements. 

Diminished Likelihood of Finding Blockbuster Indications

The chances of finding blockbuster indications are not improving. Many major medical indications are already served by several protein drugs, and more drugs are coming through the pipeline. Rheumatoid arthritis is one example; anemia and diabetes also fall in this group. 

Perhaps more important than the diminished need for blockbuster drugs is the issue of competition. Competition in the biopharmaceutical industry has increased significantly over the past decade. For example, in the early days of the industry, the first competitor to a first-to-market drug appeared, on average, eight to 10 years after the drug's market introduction.

  Today, the first competitor typically appears much sooner—within 1.5 years. As a result, few individual branded biopharmaceuticals are likely to enjoy high market shares. 

MAb-based medicines are high-dose drugs, and intensive research is underway to reduce dosages. This is being done to minimize patient risks and reduce drug manufacturing costs. Examples of this include the targeted manipulation of glycosylation patterns and the replacement of MAbs with smaller proteins (such as antibody fragments), with the desired effect of improved efficacy (for example, an enhanced ability to penetrate solid tumors). 

Evolving improvements in diagnostic tools are expected to lead to disease prevention, as well as earlier treatment, with less need for medication. One aspect of this evolution is the earlier identification of patients who are not likely to respond to treatment, and of patients who may experience severe side effects. Thus, such individuals would not be treated at all with the drug in question.  

LOWER-SCALE PRODUCTION APPROACHES ARE NEEDED

For MAbs specifically, the current spectrum of marketed protein drugs (shown in Figure 1) indicates that production scales for a few of these have already reached ton levels. One example is Rituximab, a MAb used for treating B-cell non-Hodgkin's lymphoma, B-cell leukemias, and some autoimmune disorders. Rituximab is marketed as Rituxan by Genentech and as MabThera by Roche. For most MAbs, the scale of production ranges from 50 and 100 kgs to several hundred kilograms. An example of this would be Adalimumab, a drug marketed by Abbott under the name Humira for treating rheumatoid, psoriatic, and juvenile idiopathic arthritis, as well as Crohn's disease and chronic psoriasis. In addition, most recombinant proteins other than antibodies are manufactured at relatively small scales—as low as a few hundred grams per year, and rarely more than 10 kgs per year. The exception to this would be the various insulins, which are individually manufactured at lower-ton scales but which, as a group, may reach 10 tons of production annually. 

Figure 1.  Production volume and revenue map, 2006 data 

The spectrum of marketed protein drugs includes the plasma proteins human albumin and intravenous immunoglobulin. Interestingly, these first-generation biopharmaceutical proteins are, as a group, manufactured at multiton scales—up to 500 tons per year for global albumin. Chromatographic purification has been used to manufacture some of these proteins since the 1970s,

 and it is expanding in this sector as a means of improving the manufacturing, purity, and safety of these drugs.

  This approach is feasible and economical because members of the plasma fractionation industry are among the most mature and financially pressured players. These companies are probably on a level with insulin manufacturers because insulins are typically manufactured using multiple chromatographic purification steps. Together, these two categories of biopharmaceuticals provide additional proof that today's technology can provide for patients' needs. 

In the future, successful antibody manufacturing companies will have fewer ton-scale proteins (perhaps five to seven brands at the most), and will find economical ways to produce their much lower-scale antibody products (those of between 50 and 500 kgs per year, and rarely approaching 1,000 kgs per year). Although there will probably be few technical hindrances, a number of practical matters will require attention. One of these matters will be using existing facilities for product manufacture. Most of the first generation and many of the second generation facilities have been built with little flexibility to accommodate additional processes with different design or at different scale. Another will be much greater economic pressure resulting from two factors: pressure from healthcare systems to reduce reimbursement levels, and competition with biosimilars that reduce the margins of the most profitable protein drugs.  

NEW PRODUCTS REQUIRE FLEXIBLE MANUFACTURING 

Fortunately, there is still a very dynamic pipeline of new products in the biopharmaceutical industry. Figure 2 compares this pipeline as recorded by the Pharmaceutical Research and Manufacturers of America (PhRMA), first in 2004 and then in 2006.

  Within two years, antibody-related projects grew from 76 to an impressive 160. The combination of various recombinant proteins—including growth factors, interferons, and interleukins—amounted to 94 projects in 2006, up from 57 in 2004. At an average success rate of 20%, these two parts of the pipeline will lead to more than 50 approved products in the near future. Additional products such as vaccines are likely to be added. 

Figure 2.  Dynamic portfolio driven by monoclonal antibodies 

One conclusion to be drawn from these data is that increased numbers of companies will manufacture more than one protein drug. To achieve this, some companies will use contract manufacturing organizations (CMOs). Others will invest in new manufacturing facilities of their own. And a few will convert existing facilities originally designed for single-product manufacturing. 

As more drugs enter the market, the need for multiproduct manufacturing facilities with sufficient flexibility to match the diverse production schedules of different drugs—both now, and in a dynamic, difficult-to-predict future—will increase. As described above, many of the manufactured proteins will be relatively small-scale products, so the issue of a lack-of-scale advantage will also need to be considered. 

Figure 3 shows the production scenarios that may emerge when companies deal with an increasing number of diverse approved biopharmaceuticals manufactured at widely varying scales. 

Figure 3.   Emerging production scenarios. More companies will have more than one product in production, many of them small in scale. 

TRADITIONAL FACILITIES VERSUS DISPOSABLE SOLUTIONS

The traditional "stainless-steel space" is a facility that includes fixed installations, such as several bioreactors at any scale from 100 to 25,000 L, combined with one or two purification suites with chromatography columns and membrane skids, together with the corresponding buffer and intermediate product storage tanks. For products required at ton scale, this type of manufacturing facility is currently used and will continued to be used in the future. Many mid-scale products are also manufactured in production units with fixed stainless-steel installations. Beginning with facilities owned by CMOs such as Lonza and Boehringer Ingelheim, however, some first-generation sites have been expanded to add capacity, or have been redesigned to become multiproduct facilities. 

On the other hand, the "disposables space" is gaining importance for efficient manufacturing. For some time now, disposable production tools have been used in pilot plants to make material for preclinical trials or product and process characterization. In addition, current practice in clinical trials is to produce product in few batches often at 2,000-L bioreactor scale, within reach for disposable solutions. Disposables enable the manufacturer to be flexible and cost-efficient. No major upfront equipment investment is required and the company can avoid the delays associated with waiting for equipment to be installed and with validating cleaning regimes for operating this equipment in re-use mode. 

However, disposables have some drawbacks. Neither disposable bioreactors nor single-use bags for buffer and product storage are regularly available, and many companies do not find them useful above 1,000 liters. In addition, because of the cost of replacing disposable devices after every production run, many companies limit the use of disposables in regular production to processes that run only a few batches per year. For large batch numbers—that is, for regular manufacturing that uses most of the available facility time—traditional re-use is still considered economically favorable. It is still common practice to make even the few clinical batches for Phase 1 and 2 trials in, for example, a 2,000-L stainless-steel bioreactor, mimicking the full-scale designs envisioned for later development stages. This practice is established because clinical manufacturing serves not only to formulate products for patients, but also to study the processes involved in manufacturing under commercial conditions. 

IMPACT OF INCREASED MAMMALIAN CULTURE PRODUCT TITERS 

One development that will impact production scenarios and may also change common practice is the increasing product titers achieved in mammalian cell culture, the dominant method of biopharmaceutical manufacturing. Because of low product titers of one gram per liter or even less, some protein drugs require large bioreactors and many batches to yield the required quantities. However, many projects currently in the clinic have reached product titers of three to five grams per liter. 

This development opens up two options, both with potentially significant effects on the facility of the future. These options are: producing only a few batches with very large cell-culture volumes, or producing many batches with a reduced scale of operation.  

Few Batches, Very Large Cell-Culture Volumes

A company may decide to manufacture the same product quantities in fewer batches using large cell-culture volumes, producing between 50 and 125 kgs of protein in one batch. This set-up could create facility time in the plant for manufacturing additional products or, in a less positive situation, it could create a problem with unused facility time. In addition, this scenario challenges downstream processing because the batch sizes envisioned here require high-capacity resins for all steps. Although such products are either under development or have only recently become available, the biopharmaceutical industry is concerned about downstream processing becoming a bottleneck.  

Many Batches, Reduced Scale of Operation 

As the second option, a company may reduce the scale of operation and manufacture the product at a 500- to 1,000-L bioreactor scale in many small batches. In principle, this option would allow much of the production to be run on disposable equipment—albeit at the cost of replacing such equipment for every batch. However, such a small-scale operation could be advantageous by requiring relatively low upfront investments and smaller plants, and by allowing more flexibility to add capacity or move production to other sites. 

The classic fixed facility is coming under pressure. No longer is it sufficient for companies to demand that processes be adapted to a facility design that is "cast in steel." To get full value from its facility investment, a company should realize that rethinking its facility design is just as important as carefully creating a process design. In the changing business landscape, technical process improvements are providing new ways of operation.  

Whether homemade or contracted, the custom engineering of production plants suffers from a lack of standardization in both hardware and automation. Wheels are re-invented, and available standard solutions are ignored. This situation often exists because, in making short-term decisions related to costs, companies ignore the long-term savings of standardization. The results are facilities that are adequate but too specific; thus, cost issues arise when a new process must be accommodated or a site transfer takes place between two facilities. Moreover, in a maturing biopharmaceutical industry that faces significant economic challenges, both the cost and time for completing an entirely new plant or a major reconstruction are viewed as heavy burdens. 

What, therefore, has the biopharmaceutical industry achieved in performance and in manufacturing? Figure 4 summarizes a "best-in-class performance" study conducted at GE Healthcare BioSciences during the last two years. When this information is compared with GE Healthcare BioSciences' own performance-related data, the conclusion is that most companies can further improve their technical frameworks. Few companies have achieved full success. Those that have succeeded have multiple products in their facilities already and can look back on a decade of successful large-scale antibody manufacturing. 

An analysis of current and upcoming industry challenges.

Where is Biopharmaceutical Manufacturing Heading?

Chinese hamster ovary (CHO) cell substrates are widely used for manufacturing biologics, such as recombinant proteins and monoclonal antibodies, used as human therapeutic and diagnostic agents. These cells are free of infectious endogenous viruses and have proven to be relatively resistant to contamination by adventitious viruses derived from the environment, manufacturing staff, and raw materials used in the processes.

  The few viral contaminants that have been detected with some frequency include the mouse parvovirus (mouse minute virus), the respiratory/enteric virus reovirus, and the 

  We describe the detection of CVV in biologics manufactured in CHO cells over a 10-year period. 

From 1996 through 2006, we performed viral safety testing of a variety of biologics manufactured in CHO cells in both bioreactor and large-scale monolayer culture processes. A major component of such testing, the 

 virus screen, is required by the US Food and Drug Administration for each manufactured lot of a biologic.

  The assay consists of inoculating the biologic bulk harvest samples (taken before purification) onto monolayer cultures of three or more detector cell lines. Cache Valley virus causes a striking and characteristic response in this assay. It produces an unusually rapid lytic infection of the detector cells, but does not produce hemadsorption or hemagglutination of red blood cells. At high viral loads (>10

 tissue culture infectious doses/mL), cytopathic effects are observed in the detector cells within 48–72 hours of inoculation. Total cell lysis rapidly follows initial observation of cytopathic effects, typically within 24 hours. 

At least three separate encounters with CVV were documented at BioReliance. A biologic was found to be contaminated in the year 2000. Cache Valley contamination of a cluster of five samples from one client was detected in the year 2003. In 2004, a separate cluster of four samples from one client was contaminated. The viral infection in each case manifested itself as the manufacturing process progressed (before collecting samples for viral safety testing). The manifestations included the absence of cell sheets in the monolayer processes, and perturbations in parameters (oxygen and base consumption) indicative of death of the cells in the bioreactor processes. 

Figure 1.  Transmission electron micrograph of Vero cells infected with the year-2000 Cache Valley virus isolate (V, a particle apparently budding from the plasma or vesicle membrane; S, external spikes on a viral particle). 99,800x magnification.  Reproduced from reference 14, with permission. 

Transmission electron microscopic evaluations of cells infected with the year-2000 isolate, the five year-2003 isolates, and two of the year-2004 isolates were performed during the course of the contaminant identification process. Average viral particle size, structure, and location in the infected cells were recorded. Viral particles were typically observed in vesicles in the cell or were observed extracellularly. The electron micrograph of the year-2000 isolate displayed particles with characteristic external spikes, including one particle apparently budding from a plasma or vesicle membrane (V in Figure 1). The particle sizes for the year-2000 isolate were in the 80–100 nm range. Viral particle sizes for the isolates from the years 2003 and 2004 ranged from 70–90 nm (Table 1). A micrograph of one of the year-2003 isolates displays numerous 74–86 nm particles located extracellularly (Figure 2). 

Table 1. Transmission electron microscopic findings for Cache Valley virus isolated from biologicals 

In each case, the contaminant was ultimately identified as CVV by means of reverse transcriptase–polymerase chain reaction (RT–PCR) assays using bunyavirus-specific primer sets targeting the S- or M-segment G1 envelope glycoprotein genes, followed by nucleotide sequencing of the resulting amplicons. Species level identity was obtained by comparing  the sequences obtained for the amplicons to published viral sequence data (GenBank) using basic local alignment search tool (BLAST) searches. For the year-2000 isolate, 100% sequence identity was obtained for a 198 base-pair amplicon sequence and sequences posted for CVV (GenBank accession numbers X73465.1, DQ315775.1). For one of the isolates obtained in 2003, a 98% sequence identity was obtained for a 493 base-pair amplicon sequence and sequences posted for CVV (GenBank accession numbers AF186242, AF231119, AF231113). A concensus region of 167 base pairs was obtained between the four isolates detected in 2004. There was 99% sequence identity between the determined consensus sequence and sequences posted for CVV (GenBank accession numbers X73465, DQ315775). For each BLAST search, the other close matches were all members of the Bunyamwera serotype. 

Figure 2.  Transmission electron micrograph of Vero cells infected with a year-2003 Cache Valley virus isolate (arrow points to one of a cluster of viral particles). 90,700x magnification. 

Cache Valley virus is a mosquito-borne arbovirus that is a member of the family 

, serogroup Bunyamwera. The virus is widely distributed throughout North America.

  Neutralizing antibodies to the virus have been detected in deer, sheep, horses, cattle, and in humans.

  Cache Valley virus has been reported to cause disease in humans on at least two occasions. A case of encephalitis and multiorgan failure leading to death of a human was reported in 1997 to be attributed to CVV infection.

  More recently, a case of acute meningitis in a patient was attributed to CVV.

  The CVV isolated from the encephalitis patient in 1997 was found by thin-section electron microscopic analysis of infected Vero cells to contain enveloped viral particles of 55 to 84 nm (average 70 nm) size in intracellular vacuoles of smooth cytoplasmic membranes.

  In the case of the meningitis patient in 2006, evaluation of negative-stained concentrated cell culture supernatants revealed viral particle sizes ranging from 60–80 nm.

  Although the 80–100 nm particle size observed for the year-2000 isolate in the present study was in the nominal range (80–120 nm) expected for a 

  the isolates from 2003 and 2004 displayed particle sizes in the mid-70 to mid-80 nm range, substantially smaller than expected but similar to those noted in the human cases.

  This initially confounded the identification of the viral contaminant for these episodes, because it led us incorrectly in the direction of alphaviruses and togaviruses and appeared to rule out the bunyaviruses. The smaller viral particle sizes observed for CVV in many of these cases do not appear to be an artifact of the method used to size the particles (i.e., thin–section versus negative staining of viral pellets). 

The contamination of biologics manufacturing processes with CVV has been attributed to the large volumes of non-gamma-irradiated fetal bovine serum (FBS) used as a cell growth medium component. Although the FBS is tested for viral contaminants before use, the lots of serum involved are large, and potential viral contaminants are likely to be nonhomogenously distributed among the individual bottles comprising each lot. Modeling of CVV growth in CHO cells under the conditions used in biologics production has suggested that very low levels of the CVV in the FBS used during cell expansion can cause the manufacturing failures observed.

  The rapid lytic infections resulting from introduction of CVV into CHO-cell processes typically manifest themselves through aberrations in process parameters that are monitored during the production runs. Therefore, the presence of the virus typically leads to premature termination of the manufacturing processes, and the investigatory testing that is required leads rapidly to identification of CVV as the root cause of the failed production runs.  

Because CVV is relatively large (80–120 nm) and contains a lipid envelope, it is highly susceptible to inactivation by a variety of physical (gamma-irradiation) and chemical (detergent, solvent) means.

  The viral inactivation and removal processes that must be included in the downstream processing of biologics derived from CHO-cells should readily inactivate or remove any low level CVV infections escaping detection in the viral screening assays performed on the unprocessed bulk samples.

Fortunately, the risk of introducing CVV to patients through contaminated biologics should be very low because of: 1) the rarity of the contamination events; 2) the facility with which the infections are detected during production through in process monitoring and 

 virus screening; 3) the fact that known contaminated lots of product are discarded; and 4) the relatively high susceptibility of any undetected CVV to physical and chemical inactivation strategies used during product purification. 

At the time when this article was written, 

, was a senior scientist, all at BioReliance, Rockville, MD. 

 was a senior scientist, all at BioReliance UK, Glasgow, Scotland, UK. Corresponding author Nims currently is at Amgen, Longmont, CO, 303.401.2354, 

 1. Hojman F, et al. Biological and molecular characterization of an endogenous retrovirus present in CHO/HBs—A Chinese hamster cell line. Dev Biol Stand. 1989;70:195–202. 

 2. Dinowitz M, et al. Recent studies on retrovirus-like particles in Chinese hamster ovary cells. Dev Biol Stand. 1992;76:210–207. 

 3. Garnick RL. Experience with viral contamination in cell culture. Dev Biol Stand. 1996;88:49–6. 

 4. Nims RW. Detection of adventitious viruses in biologicals—A rare occurrence. Dev Biol. 2006;123:153–164. 

 5. US FDA. Points to consider in the characterization of cell lines used to produce biologicals. FDA/CBER, 1993. 

 6. US FDA. Points to consider in the manufacture and testing of monoclonal antibody products for human use. FDA/CBER, 1997. 

 7. Gonzalez-Scarano F, Nathanson N. Bunyaviridae. In: Fields BN, Knipe DM, Howley PM, editors. Fields Virology, 3rd edition, Philadelphia, PA: Lippincott-Raven; 1996. p.1473–1504. 

 8. Blackmore CG, Grimstad PR. Cache Valley and Potosi viruses (Bunyaviridae) in white-tailed deer (Odocoileus virginianus): experimental infections and antibody prevalence in natural populations. Am J Trop Med Hyg. 1998;59:704–709. 

 9. Sahu SP, et al. Serologic survey of cattle in the northeastern and north central United States, Virginia, Alaska, and Hawaii for antibodies to Cache Valley and antigenically related viruses. Am J Trop Med Hyg. 2002;67:119–122. 

 10. McLean RG, Calisher CH, Parham GL. Isolation of Cache Valley virus and detection of antibody for selected arboviruses in Michigan horses in 1980. Am J Vet Res 1987;48:1039–1041. 

 11. Buescher EL, et al. Cache Valley virus in the Del Mar Va Peninsula. I. Virologic and serologic evidence of infection. Am J Trop Med Hyg. 1970;19:493–502. 

 12. Sexton DJ, et al. Life-threatening Cache Valley virus infection. N Engl J Med. 1997;336:547–550. 

 13. Campbell GL, et al. Second human case of Cache Valley virus disease. Emerg Infect Dis. 2006;12:854–856. 

 14. Nims R, et al. Adventitious agents: Concerns and testing for biopharmaceuticals.  In: Rathore AS, Sofer G, editors. Process validation in manufacturing of biopharmaceuticals: guidelines, current practices, and industrial case studies. Boca Raton, FL: CRC Press/Francis Informa; 2005. p. 143–67. 

Avoid manufacturing failures by effective viral inactivation.

Detection of Cache Valley Virus in Biologics Manufactured in CHO Cells

As upstream productivity continues to increase, downstream processing threatens to become a bottleneck. In an effort to overcome this challenge, companies analyze where the best solution lies: streamlining operations, exploring emerging technologies, or using disposables.  

Surprisingly for an industry that has historically been recalcitrant to change, disposables dominate current discussions about best practices. On the surface, disposables offer easy solutions. However, what may appear to be a no-brainer on casual inspection belies the need for a complex decision-making process. Many variables must be taken into account, and this means there is no "one size fits all" solution. What makes sense for one process may be completely unsuitable for another because of differences in the product, the production scale, the development phase, or the user's business model.  

The trend toward disposable manufacturing reflects the pressure on companies to increase capacity without exposure to excessive investment risk. Most biomanufacturing processes are driven by fixed costs and the only way to circumvent this dependence is to shift resources from upfront capital investment into variable costs, i.e., consumables actually used in the production train and not solely as part of the expensive infrastructure. This is, of course, more easily said than done, and the question remains—for what unit operations should disposability be applied? 

For every process scenario, there is an optimum level of disposable technology. Some operations should always be disposable, e.g., sterile filtration as well as steps to effectively remove viruses. Here, re-use is inadvisable, to minimize the risk of contamination and carry over. Hence, disposables dominate the final steps of downstream processing and—more recently—front-end purification with encapsulated single-use devices for cell removal and clarification. 

But apart from clear-cut cases like those, what is wrong with reusable equipment if there is minimal risk associated with long-term use? It makes little sense to  use disposables at any cost. Today's minimum requirements are that process technology should be scalable following clear design principles. In addition, all unit operations should be available in two formats, with either a reusable or a disposable flow path and an identical controlling periphery. The decision about the most appropriate process train assembly must balance economic and technical considerations and can be based on tools for process simulations and cost modeling, which are becoming more readily available.  

In conclusion, a rational decision between single-use and repeated-use technology is based on quality, security of supply, investment risk leverage, total cost of ownership, flexibility, and convenience. In addition, recent discussions about the environmental impact of both disposable and reusable process options underline the need for clear assessments to maximize the use of limited resources.   

No single manufacturing model can fit all products and processes, and there is no value in dogmatically sticking to either disposable or reusable options. Case-by-case evaluations are the safest bet in an industry whose very success depends on a precarious balance between quality and cost. 

is vice president of Purification Technologies at Sartorius Stedim Biotech GmbH, Gottingen, Germany, +49.551.308.2032, 

To achieve the right balance between disposable and reuseable options, companies must consider important technical and economic factors.

Disposable Decisions

The Indian pharmaceutical industry is continuing its high growth rate at 13% for the last six years. From foreign control to domestic grass-roots growth, the Indian pharmaceutical segment has evolved over the last three decades. According to BioPlan Associate's recent report, 

Advances in Biopharmaceutical Technology in India

, the Indian pharmaceutical industry has the potential to reach $25 billion by 2010.  

This rapid growth has yet to translate into a modernization of the Indian distribution system. The main hurdles include the highly fragmented nature of the distribution network, limited advancement in regulatory reforms, and the presence of strong resistance from lobbies of traders involved in the supply chain of pharmaceutical products. 

India's current distribution situation poses greater risks for biotech products, which require careful climate control throughout its transit period. The relative lack of awareness toward the importance of these requirements makes biotherapeutics even more vulnerable to spoilage during distribution. Moreover, the infrastructure for cold-chain management is still developing in India. This situation has forced both pharmaceutical and biotech companies to consider alternate distribution systems. These attempts, however, have faced severe resistance by the lobbies of traders involved in the channel.  

INDIAN DISTRIBUTION SYSTEM: THE CURRENT STATE 

India is a geographically diverse country with extreme climates that make distribution a critical function. The long channel of distribution and high incidence of brand substitution makes it mandatory for a company to make all its stock keeping units (SKUs) available at all levels at all times. In India, most brands have generic versions of drugs and retailers can usually obtain higher margins with generics than for branded products. To reduce risks of substitution, innovator companies must make sure their products are made available to the stockists and retail shops.  

Drug distribution in India has witnessed a paradigm shift. Before 1990, pharmaceutical companies used a different distribution system, in which they established their own depots and warehouses that now have been replaced by clearing and forwarding agents (CFAs). These organizations are part of the distribution chain, and are primarily responsible for maintaining storage (stock) of the company's products and forwarding SKUs to the stockist on request. Most companies keep one to three CFAs in each Indian state. On an average, a company may work with a total of 25–35 CFAs. Unlike a CFA that can handle the stock of one company, a stockist (a regional distributor) can simultaneously handle more than one company (usually, 5–15 depending on the city area), and may go up to even 30–50 different manufacturers. The stockist, in turn, after 30–45 days (a typical credit or time limit) pays for the products directly in the name of the pharmaceutical company. The CFAs are paid by the company yearly, once or twice, on a basis of the percentage of total turnover of products. 

Figure 1 shows how a manufactured product passes through the company-owned central warehouse, which supplies it to the CFA or super stockist. From the CFA the stocks are supplied either to the stockist, substockist, or hospitals. The retail pharmacy obtains products from the stockist or substockist through whom it finally reaches the consumers (patients). Certain small manufacturers directly supply the drugs to the super stockist. 

Figure 1.  Current distribution chain in India 

In 2006, the market size of India's pharmaceutical logistics segment (distribution) was valued at around $200 million and the logistics/distribution industry has been growing at an average annual growth rate of 4% since 2002. According to the Indian Retail Druggists and Chemists Association, in 1978, there were roughly 10,000 distributors and 125,000 retail pharmacies in India. Today, the total number of stockists in India is around 65,000 and the number of pharmacies is about 550,000, an increase of around six- and four-fold, respectively.  

Despite the rapid increase in the number of stockists and pharmacies, there has not been a proportional increase in the volume of prescriptions distributed. Thus, the efficiency of the current system has clearly not been demonstrated. Further, it is estimated that more than three-fifths of Indians still do not have access to modern medicines. This clearly shows that the rural market is largely unattended and untapped. 

Table 1.  Margins at various levels of distribution system 

The prices and the margins of drugs for the wholesaler and retailers are largely decided by the National Pharmaceutical Pricing Authority (NPPA), which varies depending on whether the active constituent of the product is a scheduled drug or a nonscheduled drug. Scheduled drugs are price-controlled whereas nonscheduled drugs are not. The NPPA is an organization of the government of India established to fix or revise prices of controlled bulk drugs and formulations. Companies must keep drug prices affordable to the general public. To keep medicines within reach of the poor population, the government has covered 76 scheduled drugs. 

In addition to the above mentioned margins, wholesalers and retailers are also compensated with additional trade offers. Hospitals and large institutions sometimes directly negotiate with the manufacturing company and get the drugs in their pharmacy at lower costs. Stockists compete with each other in a given city. Generally, hospitals order large quantities and can negotiate with stockists, who provide payment terms, credit periods, and margins.  

Further, retailers and distributors form associations locally and nationally, and manufacturing companies must comply with their terms. For example, in many states when a company launches a new product (either branded or generic), to make that product available in the pharmacy, the company has to pay commissions to the chemist (pharmacy) association. On receiving the commission the association will issue a no-objection certificate, which is mandatory for any company to make their product available in the market. Cipla, a manufacturer of asthma drugs, tried to bypass the supply chain by providing home service for its products. Cipla faced strong resistance from the traders lobby, which stopped stocking Cipla's product. Ultimately, Cipla had to withdraw the scheme. 

THE FUTURE OF INDIA'S DISTRIBUTION SYSTEMS

The rapid growth of the pharmaceutical industry in India is yet to create significant changes in the Indian distribution system.

BioPharm International-10-01-2008

Sick Economy, Sick Healthcare System

Biopharmaceuticals: Approval Trends in 2007

Where is Biopharmaceutical Manufacturing Heading?

Detection of Cache Valley Virus in Biologics Manufactured in CHO Cells

Disposable Decisions

Pharmaceutical Distribution in India

FDA Promotes QbD for Biotech Therapies

Biotech Cruises On Despite a Turbulent Economic Climate

Strengthening the Chain: Addressing Pedigree Challenges Across Outsourced Operations