How are we doing and what's left to do?
Interest in smaller biotech companies has accelerated because of a decline in the number of big pharma blockbuster drugs and the fact that many of the latter have gone off patent or will soon do so. (1) Traditionally, the two industries were distinct from each other based on their approach to drug discovery and the materials they use. Pharmaceutical companies typically employ combinatorial chemistry and informatics to develop small molecule drugs (new chemical entities [NCEs]), from chemically defined raw materials, whereas the biotech companies use genetically engineered biological systems to produce large-molecule therapeutics/new biological entities (NBEs) (Table I). The distinction between the types of companies that produce pharmaceuticals (small molecules) and biopharmaceuticals (large molecules), however, is blurring rapidly. Members of both industries have come to realize that they need each other to succeed. (2)
The impetus for pharma companies to combine into one entity producing both small- and large-molecule therapeutics, stems from biotech firms' need for the expertise and manpower of big drug companies in bringing drugs to approval and in marketing them thereafter. For their part, the large pharmaceutical enterprises have noted that the success rate in FDA approval is now higher in the biotech sector compared with nonbiotech products. The Tufts Center for the Study of Drug Development analysed average approval rates from 1993 to 2004 for investigational drugs first tested in humans. The 32% success rate for biotech molecules was substantially higher than the 13% approval rate observed for the small molecule therapeutics. Of the large molecules, monoclonal antibodies comprised the largest group (47%). (3)
Furthermore, annual sales of biopharmaceuticals, which are presently estimated to be approximately $100 billion, are expected to grow two to three times faster than conventional small-molecule compounds during the next 5 years. (4) The impetus for both types of companies to converge is fueled even further by the fact that major advances in cell line development, bioreactor design and purification techniques have led to a 7-fold increase in global protein output from mammalian cell cultures alone from 2000 to 2005 (500 kg versus 3600 kg). (5)
Current and Future Safety of Biopharmaceutical Products
Safety Record to Date
Advances in genetic engineering and the impressive ability to produce new therapeutic proteins in large quantities are tempered by well-founded safety concerns. Biopharmaceuticals have an elevated degree of heterogeneity and structural complexity (Table I). They are produced using living organisms and may be augmented with reagents (for example, serum, transferrin, growth factors) derived from those and other animate systems (Table II).
Consequently, contamination with endogenous and adventitious viruses may occur via raw materials used in production, purification reagents, viral load associated with the cell line or as a result of flaws in the manufacturing process (breach of good manufacturing practices [GMP]). Furthermore, the production of biopharmaceuticals often requires a minimum of 10 stages in their manufacture. All told, these stages could necessitate the use of 18-30 unit operations associated with hundreds of process parameters; it is, therefore, necessary, to identify what constitutes a critical process parameter (CPP) as a change in any one of them could affect any or all of the downstream operations. (6)
The combination of these factors requires the use of unique approaches to achieve an acceptable purity-to-impurity ratio (that is, risk-benefit analysis) because analytical techniques used for characterizing chemically synthesized drugs are not directly applicable to biopharmaceuticals. Nevertheless, regulatory agencies mandate the same level of quality andsafety assurance for both types of therapeutic agents
From their inception, biopharmaceuticals have had an excellent safety record despite the attendant risks; for example, there have been no reports of iatrogenic pathogenic virus transmission through administration of biopharmaceuticals derived from recombinant cell lines. (6) The record, however, is not flawless--Genzyme experienced an occurrence of viral bioreactor contamination in June of 2009. (7) Product inventories were insufficient to meet projected demand for Cerezyme, resulting in significant patient morbidity and loss of revenue for the company. Such occurrences also raise regulatory and legal concerns, as well as requiring the shutdown of the facility or, at minimum, the production process. There have been other reports of safety breaches affecting bulk harvests because of the inadvertent introduction of adventitious viruses; these were, however, detected during in-process testing and did not affect patient safety. (6)
Complete elimination of risk in any situation with multiple interacting systems is impossible to achieve. For biopharmaceuticals, zero risk would translate into absolute absence of residual pathogenicity and extraneous agents. Limitations in detection methods preclude the possibility of proving total clearance of viruses. The excellent safety record in biopharmaceuticals production has been achieved by using several overlapping processes directed at eliminating or inactivating viruses and other adventitious agents. Each process is mandated per regulatory guidelines to operate by a different mechanism of action to help ensure virological safety of biotherapeutics.
Overall, safety is commonly approached with the principle of achieving a level of risk that is as low as is reasonably practicable (ALARP). Accordingly, a level is set below which risk is judged to be tolerable. The principle of the ALARP approach is used on a case-by-case basis; for example, low concentrations of infectious virus in plasma products are not tolerated, nor are virus-contaminated source materials. High levels of endogenous retrovirus, however, are judged to be acceptable in certain cell lines, such as Chinese hamster ovary (CHO) cells because they are noninfectious and safety concerns are chiefly theoretical. (8)
Determining how much risk is acceptable requires negotiation of a complex decision tree. Compared with their small-molecule counterparts, assessment of causality and management approaches are significantly different for biopharmaceuticals. Benefit-risk assessment for a drug (NCE) typically involves collating a body of data in search of evidence beyond a reasonable doubt that an adverse event is/is not attributable to the drug. In contrast, with biotherapeutics, each discrete reported case of potential virus transmission must be viewed as a possible indicator of an infectious batch, and carries with it some level of probability that the disease may be transmitted to large numbers of patients. (8)
The Safety Triad
The continued and improved safety of biopharmaceuticals will probably be achieved by the current and continually evolving three-step process:
* appropriate sourcing
* documentation of virus clearance (virus validation studies) by steps in the downstream purification process
* in-process testing.
In terms of source materials, the value of starting production with the highest quality ingredients is self-evident and certain continuous cell lines, such as CHO cell lines, the workhorse of the industry for production of monoclonal antibodies and other recombinant proteins, are well characterized. (8)
Validation and In-Process Testing
Source materials contaminated with pathogenic infectious virus cannot be used. Yet, because of limitations associated with virus detection, the steps that comprise the manufacturing process must be capable of removing/ inactivating any theoretical viral load. There are several orthogonal processes (that is, operating by independent mechanisms) that are known to reduce viral threat. These processes include both inactivation (heat, detergents, low pH inactivation) and removal steps (chromatography, filtration for virus removal), which are part of the biologics manufacturing process. The results of each step are evaluated (validated) using worse-case conditions, which theoretically demonstrates the minimum clearance or inactivation the given process can provide.
Optimally, viral validation studies confirm the operating conditions selected, as well as document their efficacy in achieving the expected performance of the processes used. Validation studies only achieve an approximation of the true situation, but they serve to isolate critical process parameters (CPP) regarding viral clearance and help to establish a design space that can be used for setting operational limits and worst-case scenarios. Although conducting validations at both extremes of the process may be preferable, this approach is rarely used because of its cost and the lengthy amount of time required for testing. (9)
Virus clearance studies are a key component of the overall approach recommended to establish the safety of biopharmaceuticals. The ultimate bioclearance claim is related to robust study design, relevant testing regimens and the correct interpretation of the data. Safety validation of production and virus clearance processes coexists with, and is supplementary to, in-process testing. Aside from fulfilling a regulatory requirement, validation studies minimize production failures by providing assurance of the product's consistency and safety. By extension, validation studies also help to maximize production.
Once the overall procedure used to manufacture the biopharmaceutical has been shown (validated) to achieve required safety and efficacy standards, changes in production procedures cannot be made following regulatory approval. Typically, separately evaluating each of the steps and then summing the amount of clearance seen for the whole process establishes adequate viral safety of the end product. Although this technique has limitations, it is currently the only practical means of addressing a complex situation. (9) Safety assurance is extended through time by testing each batch before releasing it for use by patients (also referred to as in-process testing).
Careful risk assessment, followed by rigorous application of the safety triad processes has proven to be a viable means of manufacturing biopharmaceuticals with acceptable risk-benefit ratios. Although it may be a complex procedure, therein lies its strength. Its intricacy and redundancy provide the flexibility that will be needed to encompass the production of the increasing number and complexity of future biopharmaceuticals.
The lack of any cases, to date, of iatrogenic transmission of pathogenic virus in recombinant therapeutics should by no means generate feelings of complacency. It does, however, provide some indication that the current encompassing approach to biopharmaceutical safety, with the customized risk-benefit evaluation, is a viable approach.
In addition, virus safety assurance of biologicals is far from being a stagnant field of endeavour. Clearance and inactivation methods are evolving at an increasing pace. By 2020, 90% of biopharmaceuticals available today will be off patent, but indicators of the accelerating development and approval of biopharmaceuticals strongly suggest that there will be a robust production of many newer biotherapeutics that will be on patent by that time. (4) Advances in safety procedures will proceed in lockstep with the continuing development of biopharmaceuticals.
Such an effort will be necessary because newer biopharmaceuticals are likely to change in character and be associated with different sets of risks, particularly as new contaminants are likely to be discovered. Of an estimated 150,000 viruses, only 5000 have been detected to date, and viruses are constantly evolving.10 In addition, new blood-borne virus infections are being reported and each will need to be addressed in safety analyses and purification processes.
The unrelenting potential for the appearance of new viruses is enhanced by the dissolution of global boundaries. Pathogens can now travel to locations that were not previously considered indigenous to them. Because of this globalization and the many viruses still undiscovered, vigilance and the ability to clear even the viruses we cannot yet detect must remain high. Ultimately, patient protection is paramount. Current indications are that as new threats to safety appear, the in-built flexibility and evolutionary nature of risk management strategies will be able to continue to ensure the safety of biopharmaceuticals.
(3.) J.A. DiMasi, et al., "Trends in Risks Associated with New Drug Development: Success Rates for Investigational drugs," Clin. Pharmacol. Ther. 87, 27-277 (2010).
(8.) H. Aranha, "Virological Safety of Biopharmaceuticals: A RiskBased Approach," Bioprocess Internat. (Suppl), 17-20 (2005).
(10.) P.P. Pastoret, "Human and Animal Vaccine Contaminations," Biologicals, 38(3), 332-433 (2010).
Table 1: Some differences between new chemical entities (small molecules) versus new biological entities (large molecules) New chemical entities New biological entities * Synthesized by controllable, * Derived from/created in proven methods living systems * Synthetic reagents and raw * High level of structural materials complexity * Quality determined by the * Product is defined by both degree to which its specifications and chemical structure and purity the production process specifications are met * Determination of 'absolute' as well as 'relative' purity presents analytical challenges Table II: Source materials and products that must be evaluated for viral safety * Animal blood, plasma or other * Indirectly animal-derived tissues (for example, recombinant insulin, growth factors) * Human blood, plasma or other * Raw materials (for example, tissues serum, transferring, growth factors, hormones * Insect cell lines * Monoclonal antibodies * Mammalian cell lines * Clotting factors * Avian cell lines * Immune system modulators * Transgenic systems (for * Vaccines exmple, goats, cows, sheep) * Polyclonal anitbodies * Excipients--human/animal derived (for example, albumin, gelatin)
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|Date:||Mar 1, 2012|
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