About Author: DEDAKIYA ARJUN S.*, BANDHIYA HEMANT M., VIPUL P. PATEL, TUSHAR R. DESAI2
1. Assistant professor, Department of pharmaceutics, R. K. College of Pharmacy, Kasturbadham,Rajkot.
2. Principal, Department of pharmacology, R. K. College of Pharmacy, Kasturbadham,Rajkot.
3. Research Scholar, R. K. College of Pharmacy, Kasturbadham, Rajkot
Reference ID: PHARMATUTOR-ART-1061
Abstract
This article provides a basic view of what defines biological medicinal Products, often called biologicals, and how they differ from chemical products. In entering into this thought process, let us remember that proteins range in size from small amino acid chains up to macromolecules of hundreds of kilodaltons in size. In addition, in order to appreciate the science behind the regulations, an understanding of organic chemistry is necessary, and preferably knowledge of molecular cell biology and how proteins are created in cells via the DNA expression mechanisms. Although the details are inevitably complex and specialist as a result, we will look at some basic concepts pertinent to biologicals so that a regulatory generalist can be effective in dealing with such products.
Introduction
Biotechnology is a new technology capable of much good for humankind. Although it should not be feared, biotechnology is still unfamiliar, even frightening to some. One thoughtful commentator views the risk of product liability as potentially greater for biotech products than for conventional products. We believe that ample policy reasons exist for not exposing biotech products to a greater risk of product liability and that fears about such products are unfounded. In this article, we address the question of product liability for biotech drugs. We examine a path-breaking recent decision of the Supreme Court of California that limits strict product liability for a conventionally produced drug.
and conclude that it should apply with equal force to biotech drugs. Part I illustrates two hypothetical
situations involving biotech products that raise product liability issues which could be confronted by emerging companies. Part II presents an introduction to biotechnology as applied to pharmaceutical products. A better understanding of the technology itself should help one to understand why products manufactured with this technology will ordinarily not have any greater product liability risk than products manufactured conventionally in the pharmaceutical industry. Part III summarizes briefly the federal regulatory structure for biotech drugs and identifies issues excluded from this article because of extensive analysis elsewhere. With the foregoing background, Part IV reviews the most recent statement of product liability law in California, Brown v. Superior Court, to test how issues involving biotech manufactured products might be resolved. Finally Part V examines several emerging product liability issues for pharmaceuticals made using biotechnological processes and discusses the role of courts in addressing these issues. [1]
GLOSSARY OF TERMS
Antibiotic-resistance marker gene: A gene that produces a protein that allows only plants containing that gene to grow in the presence of a specific antibiotic.
Backcross: A technique used to eliminate an undesirable genetic trait from a newly developed hybrid plant. The hybrid plant is bred with a closely related plant that does not have the undesirable trait with the goal of eliminating the trait in the offspring plant. Generally, backcrossing requires multiple generations of breeding because newly developed hybrids may carry many undesirable traits.
Base: A component of DNA made up of nitrogen and carbon atoms in a ring structure. There are two classes of bases: purines (adenine and guanine) and pyrimidines (cytosine and thymine). The bases pair in the DNA double helix.
Biotechnology: The application of living organisms to develop new products.
DNA: Deoxyribonucleic acid, a compound of deoxyribose (a sugar), phosphoric acid and nitrogen bases. Each DNA molecule consists of two strands in the shape of a double helix. DNA is responsible for the transfer of genetic information from one generation to the next.
Chromosome: Microscopic rod shaped elements in the nucleus of the cell. Chromosomes, composed of DNA, contain the complete genetic information of the organism.
Fungicide: A chemical used to control fungi that cause plant disease
Gene: A portion of a chromosome that contains the hereditary information for the production of a protein.
Genetic modification or genetic engineering: The technique of removing, modifying or adding genes to a living organism.
Herbicide: A substance used to kill plants especially weeds.
Hybrid: A plant resulting from a cross between parents that are related, but not genetically identical or the offspring of two different species.
Hybridisation: The process of breeding hybrid plants.
Insecticide: A substance used to control certain populations of insects.
No-till: A method of farming without tillage.
Outcrossing: The unintentional breeding of a domestic crop with a related species.
Pesticide: A substance used to control pests, such as insects, weeds or microorganisms.
Plant biotechnology: The addition of selected traits to plants to develop new plant varieties.
Plasmid: A small piece of DNA found outside the chromosome in bacteria. Plasmids can be used as a tool to insert new genetic material into microorganisms or plants.
Proteins: Polymers of amino acids. The uniqueness of proteins is a function of the length of the polymer and the sequence of amino acids within the polymers.
Restriction enzymes: Enzymes that can cut a gene out of a piece of DNA
Tillage: Cultivation using hoeing and ploughing
Virus: A microorganism that consists of protein and nucleic acid. [2]
What is a biological?
In the EU, a medicinal product is defined in Article 1 of Directive 2001/083/ EC (consolidated)1 as: “Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or any substance or combination of substances which
may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.” Thus a medicinal product is defined by its action.
However the definition of a biological medicinal product appears in the Annex to Directive 2001/83/EC, published in Directive 2003/63/ EC2 as follows:
Section 3.2.1.1: A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physicochemicalbiological testing, together with the production process and its control.
The following shall be considered as biological medicinal products:
Immunological medicinal products
Medicinal products derived from human blood and human plasma as defined, respectively, in paragraphs (4) and (10) of Article 1
Medicinal products falling within the scope of Part A of the Annex to Regulation (EEC) No 2309/933
Advanced therapy medicinal products as defined in Part IV of this Annex. In
all cases, a biological medicinal product is defined by what it is, and usually by its source.
In the US, where the term is a ‘biological product’ or ‘biologic’, the legal definition is provided in 21 CFR 600 Biological Products General, Subpart A – General Provisions, Sec.600.3 Definitions:4 “(h) Biological
product means any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man.” In practice, as stated on the CBER website,5 “Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic
proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources – human, animal, or microorganism – and may be produced by biotechnology methods and other cutting-edge technologies...” Again, the definition of the product by what it is rather than its mode of action is true.[3]
Why are biologicals different?
A biological is a combination of the drug substance, its product-related impurities and process-related impurities (see ICH Q6B). 6 In contrast to most drugs that are chemically synthesised and their structure is known, most biologicals are complex mixtures that are not easily identified or cannot be finitely characterised. An arsenal of analytical methods is required, looking at the different levels of protein structures in orthogonal ways. As in the Indian fable, where six blind men were asked to describe an elephant, but each was limited to touching only one part of the animal’s anatomy, so each analytical method tells us one aspect of the protein’s characteristics – together they provide the overall structure and characterisation. It is not possible to define the impurity profile on the basis of the starting materials alone – cellular systems create impurities that are undefined. This has led to statements along the lines of ‘the process defines the product’, and provides the basic thought processes that have driven the acceptability (or not!) of post-approval changes to biological products, and ultimately the barriers to the biosimilar concept. It also drives the need to provide extensive information in the quality dossier on the process and control of starting materials, both in terms of quality and safety. There is also the need to monitor potency/biological activity as this determines the functionality of the medicinal product. A potency bioassay needs to be developed, usually based on an animal model, but later using a cell-based assay where possible. Often a reference standard must be defined in parallel (where an international reference standard may not exist) and the unit of biological activity must be defined, and justified. Although susceptible to microbial contamination, whether from the process or adventitiously, biological drug products are usually restricted to parenterals; as terminal sterilisation is not possible (biological products are generally heat sensitive), it is necessary to use aseptic principles in the earlier manufacturing steps. Stabilisation of biological drug products also has to take into account their sensitivity to variations in pH or even to shaking. Nonclinical testing requires a modified approach to take into account the species specificity of biological products, and that the choice of a relevant animal species model needs to be demonstrated. Not only may the biological product be of limited activity in animals, but its clearance may be modified by immune-mediated clearance mechanisms. Standard toxicology programmes are generally inappropriate and a prediction of immunogenicity is necessary, especially for immune-modulating products. Clinical pharmacokinetics of biologicals differ from those of new chemical entities (NCEs). Distribution is impacted by the compartmentalisation of proteins by bilipid membranes and limited by the need for active transport mechanisms. Clearance mechanisms are different and may be impacted by glycosylation. Most regulatory professionals are aware that immunogenicity is a key issue, particularly following the high profile case of TeGenero’s immunomodulatory compound, TGN 1412, in 2006. The impact can be either neutralising through induction of antibodies after repeated administration or stimulating where the product is immunostimulating. There is a risk that immunogenicity can knock out endogenous function, as widely reported for the Eprex (epoetin alfa) cases of Pure Red Cell Aplasia. Therefore, clinical development strategies should take into account the limitation of the nonclinical studies, including toxicology studies, as well as the impact on clinical efficacy.[3]
Field
1. Academic and government groups which produce publicly available tools and databases, some of which are quite comprehensive and sophisticated.Examples are the many tools and databases maintained by the NCBI, including GenBank. Appendix B at the end of this report contains a partial list of availablebiological databases, many of which arepublic free-access databases. Below is a schematic of NCBI’s Entrez database browser system:Source: NCBI Commercial Bioinformatics10
2. Genomic and pharmacogenomic companies that offer databases and services to outside customers, as well as for their own internal use. This includes companies like Incyte, Celera, CuraGen and GeneLogic. We would also include biotech instrumentation companies like PE
Biosystems in this category.Instrumentation products usually include data management and analysis tools of varying utility.
3. Large pharma, biotech and agbio companies which develop their own inhouse databases and bioinformatics expertise. As discussed above, some of the largest pharmaceutical companies have well-developed bioinformatics infrastructures, and thus are difficult for outside providers to penetrate. The situation is much more favorable in midsize to smaller companies, however these firms often cannot justify extremely large expenditures on infrastructure unless it addresses a core research focus.
4. Traditional computer, electronictechnology and IT services companies
that offer products and services for the bioinformatics market. This includes companies like Compaq, Sun Microsystems, Silicon Graphics, IBM and Agilent Technologies. For the most part, these companies have taken the complementary approach of providing infrastucture that supports various solutions by specialized bioinformatics providers. We expect these companies to be an increasingly important competitive force in genomics and bioinformatics. For instance, Compaq has a major strategic alliance with Celera to provide integrated bioinformatics hardware, software, networking and service solutions. IBM is conducting research into high value data mining and protein structure determination methods. IBM offers a variety of enterprise-wide ITsolutions for the life science market, and recently initiated a collaboration with NetGenics. Through its partnership with Rosetta Inpharmatics, Agilent offers an enterprise-wide gene expression analysis solution that software and hardware and is a rival to Affymetrix’s GeneChip system.
5. More or less “pure play” bioinformatics companies that offer products and services to external customers. Some of these companies are trying to leverage their bioinformatics expertise toward in-house efforts like drug discovery, and are thus somewhat like traditional genomics companies (see category #2 in this list). Most of these are private companies, but we would not be surprised to see a number of the more mature players go public in the next 12 months. Some, but by no means all, of the prominent companies in this space are listed in Appendix A of this report, and the market outlook for this segment is discussed in more detail below. [4]
Advantages of Biotechnology
Biotechnology permits the large-scale production of proteins that have beneficial uses but occur in only minute quantities in nature. In addition, the production of protein pharmaceuticals by biotechnological processes may have other significant advantages over preparations of such products that are obtained from natural sources. As the following discussion illustrates, in some situations, products of biotechnology may actually be safer than equivalent products made using conventional technology. Conventional vaccines, for example, carry the risk of causing the disease in some people because the vaccines are made of killed or attenuated (weakened) viruses or bacteria that cause the disease. Conventional vaccines are designed so that, theoretically, enough activity remains to stimulate the immune system to make antibodies to the disease, but not enough activity remains to cause the disease. In fact, however, there is a risk that sufficient virulence remains in the virus or bacteria to cause the disease. The same risk does not exist for vaccines produced via recombinant DNA techniques. Using those techniques, only the portion of the viruses or bacteria that stimulates the immune system is produced, not the portion that would be infectious By way of analogy, imagine the design of a vaccine against being shot. A conventional vaccine would have been produced by inoculating the patient with a small amount of loaded gun in which the firing pins were either removed or bent so as to be inoperative. But sometimes a production worker misses a gun so that an operative gun is included in the vaccine. With recombinant DNA techniques, a loaded gun is not used at all. Instead a metallic shape is made that looks like a gun but is not. Thus, there is no way the recombinant gun can fire, even though the body's immune system identifies it as a gun and accordingly produces the appropriate antibodies. The HIV virus is recognized as such by the immune system because of a particular three-dimensional structure on the surface of the virus. A recombinant DNA vaccine would produce only that portion of the virus but no other. The vaccine would not contain either killed or attenuated virus, hence obviating the risk that it could cause AIDS. The potential advantage of recombinant DNA techniques over conventional processes finds apt illustration in the following actual case. One conventional technique for producing a pharmaceutical involves purifying a substance obtained from human tissue. For many years human growth hormone ('hGH'), used to treat pituitary dwarfs, was obtained by purification of material obtained from the pituitary glands of cadavers. In the mid-1980's it was discovered that some children so treated had contracted a disease known as Creutzfeldt- Jakob's Disease ('CJD'). CJD is caused by a so-called slow virus that attacks the nervous system but is undetectable for 10 or 15 years after exposure. By the time symptoms appear, the disease has advanced so far that the brain is said to look like Swiss cheese. It turned out that the process of purifying hGH failed to eliminate the virus particle that causes CJD, which had evidently infected some of the individuals from whom pituitary glands were obtained Thus, some batches of therapeutic hGH contained the CJD causing virus. The production of recombinant hGH without using human pituitary glands precludes such a contamination from adventitious viruses or bacteria. [1]
Does Biotechnology Present Unusual Risks?
Although the techniques of biotechnology are new, many of its products have a long history. Insulin and human growth hormone have been produced for years using conventional technology. Moreover, the pharmaceutical industry, which markets these products, is closely regulated and must comply with elaborate standards of quality control. Indeed, vaccines produced by biotechnology should prove their superiority to conventional vaccines by minimizing the risk of causing disease. Although some apprehension persists about the new whiz kid on the block, [FN39] there should be little reason today to fear dangerous 'mutations.' As for contamination in drug manufacturing processes, it is an old problem.
III. ISSUES EXCLUDED FROM THIS ARTICLE BECAUSE OF EXTENSIVE ANALYSIS
ELSEWHERE
In the text and footnotes of section A of this part, we will identify the several agencies that regulate various aspects of biotechnology. Because these topics are treated extensively elsewhere we will not discuss them in detail. In Section B, we will discuss briefly the possibility that product liability law for agricultural products may not necessarily develop in the same way as for human pharmaceutical products.
A. Federal Regulation of Drugs
Federal statutes, regulations, and administrative agencies govern various aspects of biotechnology. These agencies have articulated a Coordinated Framework for the Regulation of BiotechnologyDrugs produced by biotechnology are regulated by the FDA (Food and Drug Administration) under the Food, Drug & Cosmetic Act and regulations thereunder. FDA has issued a general policy statement governing its regulatory practices. Ordinarily, it takes 5-10 years from the beginning of clinical research to premarketing, to obtain approval of human drugs Since the emerging issues relate essentially to prescription drugs and vaccines, we exclude from the scope of this article over-the-counter drugs and products for which package inserts must be given directly to the patient.
B. Agricultural Products
The development of product liability law for genetically engineered agricultural products is a subject that deserves separate treatment. In some aspects, this area of the law may develop in a way parallel to that governing human pharmaceuticals. In others, there may be significant contrasts. For example, the public health and social utility reasons that led the court in the Brown case, to insulate prescription drug manufacturers from strict liability, provided the drug are properly prepared and accompanied by adequate warnings, may not extend to agricultural pesticides or genetically engineered plants. Moreover, there are differences in the regulatory structure. For example, with human pharmaceuticals, the manufacturing process occurs in a closely contained system and does not involve releases of organisms into the environment. There are substantial regulations governing manufacture of pharmaceuticals that are not paralleled in the regulation of agricultural products. More agencies govern agricultural products because they are much more diverse and include transplants, pesticides, herbicides, and fertilizers. To focus discussion on human pharmaceuticals, we exclude agricultural products from the scope of this article.
IV. PRODUCT LIABILITY FOR A BIOTECH DRUG UNDER BROWN V. SUPERIOR
COURT
In a crucial new case, the Supreme Court of California concluded that 'a drug manufacturer's liability for a defectively designed drug should not be measured by the standards of strict liability' and that 'because of the public interest in the development, availability, and reasonable price of drugs, the appropriate test for determining responsibility is the test stated in comment k' to section 402A of the Restatement (Second) of Torts. In section A of this part, we review the Brown decision and its application of comment k. In section B, we analyze the policy considerations underlying the Brown decision and their applicability to biotech drugs.
A. The Brown Decision
The Brown case did not deal with a prescription drug produced by recombinant DNA technology. It involved claims by numerous plaintiffs that the defendant manufacturers of DES (diethylstilbestrol) made a drug that 'was unsafe for use in preventing miscarriage and resulted in severe injury' to each plaintiff in utero when her mother ingested it. In Brown, the California Supreme Court upheld the trial court's pretrial ruling that the manufacturers 'could not be held strictly liable for the alleged defect in DES but only for their failure to warn of known or knowable side effects of the drug.' Comment k, on which the court relied, provides:
k. Unavoidably unsafe products. There are some products which, in the present state of human knowledge, are quite incapable of being made safe for their intended and ordinary use. These are especially common in the field of drugs. An outstanding example is the vaccine for the Pasteur treatment of rabies, which not uncommonly leads to very serious and damaging consequences when it is injected. Since the disease itself invariably leads to a dreadful death, both the marketing and use of the vaccine are fully justified, notwithstanding the unavoidable high degree of risk which they involve. Such a product, properly prepared, and accompanied by proper directions and warning, is not defective, nor is it unreasonably dangerous. The same is true of many other drugs, vaccines, and the like, many of which for this very reason cannot legally be sold except to physicians, or under the prescription of a physician. It is also true in particular of many new or experimental drugs as to which, because of lack of time and opportunity for sufficient medical experience, there can be no assurance of safety, or perhaps even of purity of ingredients, but such experience as there is justifies the marketing and use of the drug not withstanding a medically recognizable risk. The seller of such products, again with the qualification that they are properly prepared and marketed, and proper warning is given, where the situation calls for it, is not to be heldto strict liability for unfortunate consequences attending their use, merely because he has undertaken to supplythe public with an apparently useful and desirable product, attended with a known but apparently reasonable risk. The court noted that '[w]hile there is some disagreement as to [the] scope and meaning' of comment k, 'there is a general consensus that, although it purports to explain the strict liability doctrine, in fact the principle it states is based on negligence. Comment k has been adopted in the overwhelming majority of jurisdictions that have considered the matter. In applying comment k, the court discussed the underlying policy considerations for and against strict liability and concluded (1) strict liability should not apply to design defects in prescription drugs, (2) strict liability should not apply to a failure to warn of the risk of side effects inherent in a drug if the risk was unknown and could not have been known despite the application of scientific knowledge available at the time of distribution of the drug, and (3) elimination of strict liability for a drug does not require a preliminary judicial determination that the drug is unavoidably dangerous.
B. Policy Considerations Underlying the Brown Decision Although only the issue of conventional drugs was before the court, the policies articulated in the decision apply equally well to biotech drugs. In this section, we review the court's treatment of the following issues: design defects and the rejection of the 'benefit v. risk' test; failure to warn; rejection of case-by-case judicial determinations; and rejection of the 'consumer expectation' test. Then, we discuss the applicability of the court's reasoning to biotech drugs.
1. DESIGN DEFECTS; REJECTION OF BENEFIT V. RISK TEST.
a. Brown Decision. The court articulated the following six policy issues in deciding that strict liability should not apply to design defects in drugs:
(1) Prescription drugs may be necessary to alleviate pain and suffering or to sustain life. They are distinct from other products, such as construction machinery, which are used to make work easier or to provide pleasure.
(2) 'Moreover, unlike other important medical products (wheel-chairs, for example), harm to some users from prescription drugs is unavoidable.
(3) The delay involved in withholding a drug from the market 'until scientific skill and knowledge advanced to the point at which additional dangerous side effects would be revealed,' when added to the delay required for approval from the FDA, 'would not serve the public welfare. Public policy favors the development and marketing of beneficial new drugs, even though some risks, perhaps serious ones, might accompany their introduction, because drugs can save lives and reduce pain and suffering.
(4) 'If drug manufacturers were subject to strict liability, they might be reluctant to undertake research programs to develop some pharmaceuticals that would prove beneficial or to distribute others that are available to be marketed, because of the fear of large adverse monetary judgments.
(5) 'Further, the additional expense of insuring against such liability—assuming insurance would be available--and of research programs to reveal possible dangers not detectable by available scientific methods could place the cost of medication beyond the reach of those who need it most.
(6) The court referred to several examples of products that have greatly increased in price or been withdrawn or withheld from the market 'because of the fear that their producers would be held liable for large judgments:' Bendectin; a new vaccine for influenza; diptheria-tetanus-pertussis vaccine; and a new drug for the treatment of vision problems. [FN64] For the foregoing reasons, the court rejected the 'Benefit v. Risk' test for determining whether a product's design is defective. In so ruling, the court departed from a major California precedent.
b. Applicability to Biotech Drugs. The Brown decision did not involve a biotech drug. However, the definition of the term 'drug' does not depend on what technology is used to produce it. Biotech drugs must undergo the same FDA approval process as conventional drugs. In order to determine how Brown might be applied to situations like those described earlier, it is necessary to examine how well the Brown court's policy considerations apply to biotech drugs. The court's first policy consideration, the necessity of alleviating pain and suffering or sustaining life, seems equally applicable to a bias a conventional drug. A biotech drug is certainly not akin to construction machinery; it is not intended to make work easier or to provide pleasure. The AIDS vaccine in the first illustrative case was intended to prevent a disease which leads to death. The cholesterol dissolving drug in the second illustrative case was intended to avoid death due to blocked arteries. Thus, both drugs were intended 'to sustain life.' The court's second policy consideration, the unavoidability of harm to some users, also seems applicable to biotech drugs. Common experience tells us that any substance, whether a drug or sugar water, has the potential for harm in some set of users. Harm in some users of drugs, biotech or conventional, is unavoidable because the drug must have some activity in the human body in order for it to have any efficacy. Because there is such a wide range of human susceptibilities to side effects, it is unavoidable that the very activity which is generally beneficial may be deleterious to certain individuals. Even if the manufacturing process influences what particular harm some specific set of users may experience, the principle remains the same-- drugs, however made, carry the inevitable risk of harm for some. Both the hypothetical AIDS vaccine and the cholesterol dissolving drug carried a risk of side effects. Perhaps, if the vaccine had been tested for two or three times as many years, the harmful side effect would have been detected. Even so, the only change might have been in the warnings. Not all users suffered the side effect, and there might not have been any way to change the vaccine to avoid the side effect. If that were the case, the practical consequences of the additional testing would have been delayed approval and additional cost. Although the vaccine created some risk for a small percentage of the population, it eventually would have been approved because of its great potential benefits. A similar argument can be made with respect to the cholesterol dissolving drug. In that case, the risk of harm was an unusual risk, known to the Army but not to Sponsor. The side effect which caused the injury in that case was associated with only a relatively small subset of the people for whom the drug was potentially beneficial. The court's third policy consideration was that beneficial new drugs should be made available without undue delay, despite serious risks. As discussed in the preceding paragraph, this policy consideration applies to all safe and efficacious drugs, regardless of the manufacturing process employed. The public good that would result from the availability of either the AIDS vaccine or the cholesterol dissolving drug could well justify the risk of harm to some. Both drugs were intended to address serious public health problems. In the vaccine case, a panel of medical and scientific experts, at the request of the FDA, specifically found that the incidence of AIDS constituted a critical public health hazard. The decision to approve the marketing of a new drug involves a governmental balancing of risk versus benefit. Benefit is a function both of the seriousness of the disease and the efficacy of the drug in treating it. AIDS and cholesterol are severe problems in that they can lead to suffering and death in a significant proportion of the population. Under these circumstances, a certain amount of risk is surely justified. The test results available to Manufacturer and Sponsor indicated that their products were apparently safe. A balancing of risk and benefit on these facts supports both the conclusion that FDA marketing approvalbwas warranted and that strict liability would be inappropriate. The court's fourth, fifth and sixth policy considerations dealt with the likelihood that a manufacturer would be reluctant to develop new drugs in the face of strict products liability, that insurance would be expensive and difficult to obtain, and that as a result of these costs, drugs would become very expensive or unavailable. These last three considerations provide no basis for distinguishing between biotech drugs and conventional drugs.
In fact, since biotech companies are generally smaller than conventional pharmaceutical companies today, they are more likely to be anxious about product liability risks than conventional companies. In short, the policies articulated in the Brown case apply to biotech companies not because they utilize biotechnology but because they are pharmaceutical companies in need of the same incentives and protections as those pharmaceutical companies utilizing conventional technologies.
2. FAILURE TO WARN.
A central issue in product liability cases and under comment k is whether the manufacturer's warning is adequate. This issue is acute in drug cases because of the extensive federal regulation of warnings. We expect that the warning issue is likely to be as significant in biotech drug cases as in conventional drug cases, hence the pertinence of the Brown court's treatment of this issue. a. Brown Decision The issue of warning, a crucial one, is also addressed by the Brown case. Ordinarily, a product manufacturer is not strictly liable for failure to warn of dangers that the manufacturer neither knew nor could have known given the state of the art at the time the product was manufactured. The Brown court adopted Professor Wade'ssuggestion that a manufacturer's knowledge should be measured at the time a drug is distributed. It ruled that liability for failure to warn 'is conditioned on the actual or constructive knowledge of the risk by the manufacturer as of the time the product was sold or distributed. This rule is consistent with comment j to section 402A of the Restatement (Second) of Torts, which 'confines the duty to warn to a situation in which the seller has knowledge or by the application The rationale for the majority rule, as expressed in Brown and implicit in the Restatement, is that public interest favors the 'development of new and improved drugs to combat disease. The court was concerned that strict liability would discourage this development. Although the court did not address the potential conflict between extensive and pervasive federal regulations of warnings and state tort law warning requirements, we note that this issue is percolating in the courts in conventional drug casesand will very likely arise in biotech drug cases.
b. Applicability to Biotech Drugs. In our opinion, biotech drug manufacturers are as adverse to being 'virtual insurers' as conventional drug manufacturers. There is no reason to suppose that the Brown court would apply its policy considerations any differently to biotech drugs than to conventional drugs. However, the AIDS vaccine illustration suggests a related problem. The manufacturer must warn of side effects known at the time of distribution. In that illustration, Manufacturer may not have distributed all the vaccine at one time. It probably manufactured and distributed periodically. Did the court intend to test a pharmaceutical company's knowledge at each distribution time or only at the time it commenced distribution? If the former, the manufacturer presumably must change the warnings when it discovers relevant information. However, the FDA must approve any label change, something it may or may not do. A further related question arises as to the vaccine still in the hands of the hospitals and others who were to actually administer the vaccine. Had that material been 'distributed'? One reading, perhaps the most likely, is that the court was referring to distribution by the manufacturer. Another reading, however, might be that the drug is not distributed until actually administered to the patient. Biotech companies may have a greater risk in this area than conventional companies. If young biotech companies have a greater research focus than conventional companies, then they may be more likely to learn new information about their drugs faster than conventional companies. From the flood of newspaper announcements in recent years, it appears that the pace of development and understanding of biotechnology and biology is accelerating. Today's scientific beliefs may turn out to be incorrect when reexamined in light of tomorrow's knowledge and with the benefit of future scientific tools. In such circumstances, the application of the Brown opinion's duty to warn of everything known or reasonably knowable at the time of distribution may result in biotech drugs becoming a rapidly moving target for product liability suits.
3. REJECTION OF CASE BY CASE JUDICIAL DETERMINATIONS.
a. Brown Decision Prior to the Brown decision, the leading California case on drug product liability was Kearl v. Lederle Laboratories .The Kearl test attempts to separate products that meet the description of 'unavoidably dangerous' from those that do not. If the product is 'unavoidably dangerous' under the Kearl test, 'the liability of the manufacturer is tested by comment k; otherwise, strict liability is the applicable test. The Brown court rejected the Kearl test for the following reasons:
(1) It is not feasible at the front end to distinguish clearly between drugs that will prove useful to mankind (e.g., penicillin) and those that will prove clearly harmful (e.g., thalidomide).
(2) The process of attempting to make this distinction impairs the public interest in the development and marketing of new drugs.
(3) 'A manufacturer's incentive to develop what it might consider a superior product would be diminished if it
might be held strictly liable for harmful side effects because a trial judge could decide, perhaps many years later, that in fact another product which was available on the market would have accomplished the same result (4) The superiority of one drug over another would have to be decided not in the abstract but in reference to the plaintiff; however, 'in one case the drug that injured the plaintiff might be the better choice, while this would not be true as to another user.
(5) Different trial judges might reach different conclusions about the same drug.
(6) The findings of the judge and the jury may be inconsistent.
(7) Establishing the Kearl test is costly and requires the drug to 'survive two risk/benefit challenges, first by the judge and then by the jury. In order to vindicate the public's interest in the availability and affordability of prescription drugs, a manufacturer must have a greater assurance that his products will not be measured by the strict liability standard that is provided by the test stated in Kearl.
b. Applicability to Biotech Drugs Each of the policy considerations articulated in Brown applies equally whether the manufacturer uses biotechnology or conventional methods. Biotech pharmaceutical companies compete in the same markets as do conventional pharmaceutical companies. They both conduct clinical trials in the same hospitals and respond to many of the same incentives and concerns. The public policy consideration which favors development of new drugs is especially relevant to biotechnologically produced pharmaceuticals because biotechnology is a powerful new science which promises new therapies for major diseases. Public policy should encourage biotech companies to develop and produce new therapies in responsible ways. Because many are relatively young and small, they are particularly vulnerable tthe costs, both financial and human, of product liability litigation.
4. REJECTION OF CONSUMER EXPECTATION TEST
a. Brown Decision The court rejected the 'Consumer Expectation Test' on the following ground: while the 'ordinary consumer' may have a reasonable expectation that a product he purchases, such as a machine, will operate safely when used as intended, a patient's expectations regarding the effects of such a drug are those related to him by his physician, to whom the manufacturer directs the warnings regarding the drug's properties.
b. Applicability to Biotech Drugs Although the Brown court's reasoning seems plainly applicable to prescription drugs produced by biotechnology, some cautionary notes are in order. '[W]hen technology produces a substitute for a conventional drug and the substitute exhibits a risk different from that of the original version, can the substitute assert that its danger is unavoidable? Although that argument may prove persuasive to some, we think it more likely that the technology encouraged by the comment k principles and the Brown case will be favored and that the courts will not impede innovative biotechnology or create a preferred status for conventional drugs. A contrary result would require an improved version of an existing drug to be completely free of defects in order to have the benefit of comment k and avoid strict liability.
A 'zero defects' standard would, in our judgment, be a significant disincentive to pharmaceutical companies to invest in improving drugs already on the market. It would be difficult to be certain that the improved version would not have a risk different from the original. In fact, there is some indication in the court's opinion, and in comment k, that the policy justifications for insulating prescription drug manufacturers from strict liability are most compelling in the case of new or experimental drugs. The new biotech drugs are likely to meet even this narrower standard, at least during the early stages of marketing and distribution. Whether the insulation afforded by the Brown case will extend to prescription drugs that are no longer new or experimental or whether the requirement of adequate warning will be augmented in such cases (perhaps after the initial 'honeymoon' period) are questions that remain open after Brown. Brown is a path-breaking case that departs from the judiciary's usual case-by-case approach. We expect that it will gradually gain acceptance in other jurisdictions and may be resisted in some.
V. EMERGING ISSUES FOR BIOTECH DRUGS
A. Will the Liability of a Manufacturer of a Genetically Engineered Vaccine Be Measured by the Standards of Strict Liability? The policies underlying comment k and the Brown case would seem to apply with equal or greater force to vaccines. The principal exception, discussed below, would appear to be the court's reliance on physicians relating the effects of a prescription drug to their patients. There is widespread concern that if manufacturers are held strictly liable for vaccines, they will be deterred from manufacturing products necessary for public health. Indeed, the Brown court stated that '[d]rug manufacturers refused to supply a newly discovered vaccine for influenza on the ground that mass inoculation would subject them to enormous liability. Such concerns led, for example, to the National Childhood Vaccine Injury Act of 1986. To encourage manufacturers to produce vaccines, such as an AIDS vaccine, it seems likely that the courts would invoke the Brown case and measure the liability of a manufacturer of a genetically engineered vaccine by the same basic standards applicable to the manufacturer of prescription drugs. The court's rejection of the 'hindsight' and case-by-case approaches to strict liability would lead to comment k protection of the manufacturer in the hypothetical vaccine case discussed at the beginning of this article. Both the Brown case and the hypothetical vcase involve products where more is known about the risks now than when they were first approved. Thus, the products would be made differently, contain new warnings, or not be marketed depending on the circumstances. Nonetheless, the policy of encouraging much needed innovation precludes adoption of a 'hindsight' test. The vaccine case may more strongly warrant relaxed standards of strict liability of manufacturers than the prescription drug case. 'Vaccines offer the classic case of an externality, in that my vaccination reduces your risk of contracting the disease . . . Some individuals might consider it wise to avoid vaccination while supporting a program for vaccinating everyone else. (In AIDS cases, an individual's reluctance to be vaccinated may be greater than in flu or childhood disease cases because the AIDS virus is not perceived to be transmitted as easily.) Therefore, 'it is not surprising that vaccinations have traditionally been provided either directly or indirectly subsidized by the government. If the government is unwilling to provide compensation, subsidize, or enter the insurance market (or some combination of these approaches), and private insurance is unavailable or insufficient to cover the potential compensatory costs of victims, it may be especially onerous and counter-productive to impose the compensation burden solely on manufacturers. Although we expect the Brown case to be applied to vaccines, it is important to examine whether the distribution of vaccines via mass inoculation rather than via individual prescriptions from physicians requires a different result.
1. THE 'LEARNED INTERMEDIARY' DOCTRINE
Manufacturers of prescription drugs frequently defend against failure-to-warn claims on the ground that they provide adequate information and warnings to 'learned intermediaries,' i.e. physicians, who can be relied on to explain the pros and cons of the drugs to their patients. 'As a learned intermediary, the physician has a duty to know the product he prescribes, to evaluate the needs of the patient, and to assess the benefits and risks of alternative courses of treatment. He is also under a duty to judiciously administer or prescribe pharmaceutical products which he is in the best position to supervise, but only after obtaining the patient's informed consent.There are significant exceptions to the learned intermediary defense. It has been held unavailable for vaccines administered in mass immunization programs.It may not even be available when the vaccination, though in a doctor's office, is administered more in the manner of a county health clinic than of a private physician. It may not be available under certain other circumstances: for example, such drugs as birth control pills or tranquilizers may be prescribed at a single patient visit, though intended tobe used for a long period of time, without frequent or even any return visits to see the physician. The 'learned intermediary' defense may depend on assumptions about the education and knowledge, the 'learnedness,' of physicians that are not necessarily reliable. Moreover, it may divert attention from the fundamental public policy concerns developed in comment k and the Brown case. Finally, at least until physicians become better educated and informed about biotechnology, the defense may need refinement. One commentator, Lewis Thomas, has admonished that 'medicine will always tend to lag behind the rest of biology, because any comprehension of the underlying mechanisms of disease must always await a deep understanding of the normal processes of life. Although physicians may experience difficulty keeping current with technical developments, they are still likely, by reason of training and exposure, to be much more knowledgeable than their typical patients. For the same reason, they are more likely to understand the information, including warnings, provided by pharmaceutical manufacturers with their new drugs. Moreover, it is reasonable to expect physicians to know their patients' particular conditions and to assess the warnings accordingly.
2. THE 'LEARNED INTERMEDIARY' DOCTRINE IN LIGHT OF THE BROWN CASE
In Brown, the California Supreme Court stated that the consumer of prescription drugs is not the patient 'but the physician who prescribes the drug.A physician appreciates the fact that all prescription drugs involve inherent risks, known and unknown, and he does not expect that the drug is without such risks . . .. [A] patient's expectations regarding the effects of such a drug are those related to him by his physician, to whom the manufacturer directs the warnings regarding the drug's properties. The court referred to the 'well-established' rule that 'a manufacturer fulfills its duty to warn if it provides adequate warning to the physician.
The foregoing reasoning does not apply directly to vaccines except perhaps to the limited extent that they are administered individually by physicians rather than on a mass-inoculation basis. However, from the patient's perspective, there may still be an element of strong reliance on professionals other than the manufacturer, e.g., the public health officials responsible for an inoculation program. In the case of mass inoculations, the medical community at large or the government or both have decided that a vaccine is necessary. An emerging issue, however, is whether the distinction between vaccines and prescription drugs will persuade the court to distinguish the Brown case and impose strict liability or whether the courts will learn from the hard lessons of the polio vaccine litigation and apply the basic policy of encouraging manufacturers by limiting strict liability. It is likely that the courts, at least in jurisdictions sympathetic to the comment k approach, will apply these basic policies and not rely on a rationale that makes limited liability under comment k depend on a physician's prescription. It bears emphasis, moreover, that one of the key examples referred to in comment k involves a vaccine. The decision should turn, not on the presence or absence of a 'learned intermediary' or the availability of a malpractice action against a doctor, but on the fundamental policies of Brown and comment k. In the hypothetical AIDS vaccine case set forth, it is likely that a court would afford comment k protection to the manufacturer notwithstanding the absence of a learned intermediary in many instances. Issues of negligence, adequacy of warning, and regulatory compliance remain in the case. The Brown case does not excuse manufacturers from other grounds of liability or preclude compensation to victims on such grounds.
B. What will be the Effect of a Manufacturer's Compliance with Applicable Regulations?
We anticipate that in biotech drug cases, as in conventional drug cases, plaintiffs may urge that failure to comply with applicable FDA regulations may be negligence per se. Such failure may also preclude a manufacturer from urging that its product was 'properly prepared' and hence eligible for protection under comment k and Brown. In general, courts have rejected the argument that compliance with FDA regulations constitutes a defense to strict liability. [Given expanded product development but limited regulatory resources, there is a question whether courts will hold generally that regulatory compliance is a defense to liability. In particular cases, however, a defense of regulatory compliance may be upheld. For example, in a recent California case, Collins v. Ortho Pharmaceutical Corp. summary judgment for the manufacturer of an IUD device was upheld on appeal. The court held that: [w]hen the product which allegedly caused a plaintiff's injury is a prescription product, which is distributed with the approval of the FDA provided the manufacturer accompany the product with warnings of foreseeable risks, we conclude the product must be considered unavoidably unsafe as a matter of law and thus outside the parameters of strict liability for defective design. Moreover, as courts reexamine the law of punitive damages, it seems quite possible that regulatory compliance will become a defense against claims for punitive damages. In appropriate cases, establishing such a defense as a matter of law might be possible, perhaps on a motion for summary judgment. State statutes are beginning to provide that a drug manufacturer is not liable for punitive damages if the drug is manufactured and vlabeled in accordance with federal law.
C. To What Extent Will The 'State Of The Art' Defense Be Available?
There may be 'special liability exposure problems for the products being made by means of biotechnology as a substitute for the conventional methods.One such problem concerns the 'state of the art' defense. The defense is inapplicable until the plaintiff has met the burden of establishing either a 'defective product,' for strict liability law, or a failure in the duty of care, for negligence cases. In the strict liability case, the plaintiff asserts that the product was unreasonably dangerous, while in the negligence case the assertion focuses on breach of duty which proximately resulted in harm to the consumer who used that product. Given comment k and Brown, one emerging issue is whether a 'state of the art' defense will become relevant and, if so, when. Under comment k and Brown, strict liability may be avoided if the product is 'properly prepared' and 'accompanied by proper directions and warning. In referring to new and experimental drugs, the Brown court relied on comment k which states that 'there can be no assurance of safety, or perhaps even of purity of ingredients .Thus, the court may have implicitly distinguished 'manufacturing defects' from 'design defects.' Whether a manufacturer of prescription drugs can invoke Brown to avoid strict liability even for manufacturing defects, e.g., impurities, as well as for design defects remains to be seen. In jurisdictions that do not follow comment k and Brown, we envisage manufacturers will invoke the 'state of the art' defense after the plaintiff produces evidence that the product is 'defective.' The major additional issues regarding the 'state of the art' defense for biotechnology products are:
(1) Is 'state of the art' to be 'defined by industry practice or by technological feasibility?
(2) Will courts view the technology realistically or respond to fears that 'biotechnologically derived products can
be less safe or efficacious than the conventional products which they may replace?
(3) Will jury skepticism or 'technology-phobia' about new technology create greater exposure for manufacturers of genetically engineered products?
(4) Will 'state of the art' be tested at the time of design, preparation, treatment of the patient, or trial? The 'time of trial' standard 'makes a defense based on knowledge of the product design virtually impossible.
(5) Can the defense can be established as a practical matter given that '[b]iotechnology research and publications are booming in volume, diversity, and novelty of inquiry? It will be very difficult for defense lawyers in a four-year-old injury case to determine what was the state of the art for monoclonal antibody products on September 18, 1986, because the 1990 state of the art will have advanced so very much.
D. Other New Issues: A Brief Review
There is always the possibility that alternatives to the present tort approach to problems of product liability may be adopted. Such proposals, which we identify but do not attempt to analyze in this article, might include:
(1) A combination of no-fault and negligence, with emphasis on the changing role of health care delivery systems. In a recent, innovative article, the author surveyed the health care industry and suggested that 'the existence of health maintenance organizations ('HMOs') and similar prepaid providers with superior information capacity and total patient care He concluded that: Should large HMOs with near-universal enrollment control future health care delivery, a market mechanism without liability rules could lead to efficient care and consumption decisions with respect to drugs, since the HMO which purchases the drug must pay for the treatment required for any adverse effect it produces. If nonmonetary damages, such as pain and suffering, are to be compensated, a uniform negligence [sic] rule should be applied to the entire health care industry, including drug manufacturers, since organizations will manage both the production of medical goods and the delivery of medical services.
(2) An 'alternative nonfault framework for compensation for certain medical injuries. An alternative framework for compensation would entail the creation of a 'special compensation fund which would utilize separate processes to achieve the compensatory objectives of the program. Compensation awards would be provided to victims according to 'nonfault ‘principles.The fund could be financed by subrogating the fund to the tort claims of accident victims. This suggestion is 'in the service of a moral vision that offers greater inspiration than the competing vision of law and economics scholars.
(3) A federal product liability act. Federal legislation to establish a uniform body of product liability law is now before Congress.
(4) Strict joint and several liability with presumptions favoring plaintiffs.
(5) In vaccine cases, statutory schemes modeled on federal statutes for childhood vaccines or the swine flu vaccine or on the California statute for an AIDS vaccine.
(6) A compromise that would involve strict liability to assure adequate compensation to hapless victims, limits to prevent excessive damages for pain and suffering, preclusion of punitive damages, insistence on rational bases for compensation and sufficient proof of causation, and ceilings on lawyers' and experts' fees in the event of dispute. Perhaps such a compromise would allay manufacturers' concern and promote their reconciliation to strict liability won by such a compromise, particularly in jurisdictions that elect not to follow the Brown case. Some advocates may urge a continuation of the status quo. For example, one commentator has recently concluded that 'it is incorrect to assume thatthe liability associated with existing vaccines will carry over to the HIV [AIDS] vaccine; therefore, it is unnecessary to enact legislation or to modify the common law in order to guarantee that pharmaceutical companies will develop and produce the vaccine. Additional issues are likely to involve causation and joint and several liability. The prospect of government liability for nondiscretionary acts in licensing new drugs and vaccines seems likely to be explored. Moreover, if the government contracts with a private entity to manufacture or distribute a vaccine, issues will arise whether a 'government contractor defense' is available to the private entity, particularly if the ultimate financial liability would fall on the government via indemnity or otherwise. Depending on the circumstances, the hypothetical cases at the beginning of this article could raise such issues. A large question also looms as to whether liability in the case of exported products will be tested by U.S. or foreign standards. [FN142]. Enzyme biotechnology in everyday This list contains some of products of enzyme biotechnology you might use everyday in your own home. In many cases, the commercial processes first exploited naturally occurring enzymes. However, this does not mean the enzyme(s) being used were as efficient as they could be. With time, research, and improved protein engineering methods, many enzymes have been genetically modified to be more effective at the desired temperatures, pH, or under other manufacturing conditions typically inhibitory to enzyme activity (eg. harsh chemicals), making them more suitable and efficient for industrial or home applications.[1]
• StickiesRemoval
Enzymes are used by the pulp and paper industry for the removal of “stickies”, the glues, adhesives and coatings that are introduced to pulp during recycling of paper. Stickies are tacky, hydrophobic, pliable organic materials that not only reduce the quality of the final paper product, but can clog the paper mill machinery and cost hours of downtime. Chemcial methods for removal of stickies have, historically, not been 100% satisfactory.
Stickies are held together by ester bonds, and the use of esterase enzymes in pulp has vastly improved their removal. Esterases cut the stickies into smaller, more water soluble compounds, facilitating their removal from the pulp. Since the early half of this decade, esterases have become a common approach to stickies control. Their limitations are, being enzymes, they are typically only effective at moderate temperature and pH. Also, certain esterases might only be effective against certain types of esters and the presence of other chemicals in the pulp can inhibit their activity. The search is on for new enzymes, and genetic modifications of existing enzymes, to broaden their effective temperature and pH ranges, and substrate capabilities.
• Detergents
Enzymes have been used in many kinds of detergents for over 30 years, since they were first introduced by Novozymes. Traditional use of enzymes in laundry detergents involved those that degrade proteins causing stains, such as those found in grass stains, red wine and soil. Lipases are another useful class of enzymes that can be used to dissolve fat stains and clean grease traps or other fat-based cleaning applications.
Currently, a popular area of research is the investigation of enzymes that can tolerate, or even have higher activities, in hot and cold temperatures. The search for thermotolerant and cryotolerant enzymes has spanned the globe. These enzymes are especially desirable for improving laundry processes in hot water cycles and/or at low temperatures for washing colors and darks. They are also useful for industrial processes where high temperatures are required, or for bioremediation under harsh conditions (eg. in the arctic). Recombinant enzymes (engineered proteins) are being sought using different DNA technologies such as site-directed mutagenesis and DNA shuffling.
• Textiles
Enzymes are now widely used to prepare the fabrics that your clothing, furniture and other household items are made of. Increasing demands to reduce pollution caused by the textile industry has fueled biotechnological advances that have replaced harsh chemicals with enzymes in nearly all textile manufacturing processes. Enzymes are used to enhance the preparation of cotton for weaving, reduce impurities, minimize “pulls” in fabric, or as pre-treatment before dying to reduce rinsing time and improve colour quality. All of these steps not only make the process less toxic and eco-friendly, they reduce costs associated with the production process, and consumption of natural resources (water, electricity, fuels), while also improving the quality of the final textile product.
• Foods and Beverages
This is the domestic application for enzyme technology that most people are already familiar with. Historically, humans have been using enzymes for centuries, in early biotechnological practices, to produce foods, without really knowing it. It was possible to make wine, beer, vinegar and cheeses, for example, because of the enzymes in the yeasts and bacteria that were utilized.
Biotechnology has made it possible to isolate and characterize the specific enzymes responsible for these processes. It has allowed the development of specialized strains for specific uses that improve the flavour and quality of each product. Enzymes can also be used to make the process cheaper and more predictable, so a quality product is ensured with every batch brewed. Other enzymes reduce the length of time required for aging, help clarify or stabilize the product, or help control alcohol and sugar contents.
For years, enzymes have also been used to turn starch into sugar. Corn and wheat syrups are used throughout the food industry as sweeteners. Using enzyme technology, the production of these sweeteners can be less expensive than using sugarcane sugar. Enzymes have been developed and enhanced using biotechnological methods, for every step of the process. [5]
• WHAT IS FOOD BIOTECHNOLOGY?
• Under its broadest definition, food biotechnology started thousands of years ago when primitive man advanced from hunting and gathering food to farming. For thousands of centuries, plant breeders selected, sowed and harvested seeds to produce enough food to sustain life and to develop desirable traits in their crops such as better taste, richer colour and hardier plants.
• At the beginning of this century, farmers carefully selected plants with beneficial traits and began breeding them together, creating new varieties and hybrids new plants with some of the qualities of each of the parents. They also made traditional ingredients such as yoghurt, vinegar, rice wine, soya sauce and tempeh. Though they did not understand the underlying scientific principles involved, early farmers have been harnessing biotechnology for centuries to make or modify plants and food products.
• Scientists now understand the nature of these biological processes and have developed new techniques to improve on them. Techniques of modern biotechnology allow scientists to improve crops and foods made using traditional methods. In some cases, modern biotechnology makes available products that were non-existent before. [2]
• Benefits of biotechnology
• Biotechnology holds great promise in the fields of medicine, environmental management, food production and agriculture.
• Medicine - A host of biotechnology-based pharmaceuticals are now available to treat diseases. Insulin, for example, is available for the treatment of diabetes and growth hormone is used to treat developmental disorders and to promote wound healing. Biotechnology offers new methods of producing vaccines to help prevent diseases such as Hepatitis B and to help in the detection and diagnosis of viral diseases and inherited disorders.
• Environmental Management - Biotechnology offers new opportunities for the protection of the environment. For example, genetically modified bacteria may be used to convert organic wastes to useful products or to clean up oil spills.
• Food Production - Food production is another area in which biotechnology plays a significant role by standardising the production of large quantities of ingredients, vitamins, starter cultures and enzymes for food processing.
• Agriculture - Scientists are able to improve the appearance of fruits and vegetables, increase the time food can be stored, enhance the nutrient content of plants and foods and produce crops that are resistant to diseases and pests. In the future, biotechnologists hope to produce plants that can withstand unfavourable climatic conditions such as drought, extreme heat or cold, thereby enabling farmers to cultivate land that is currently poorly used. Micropropagation techniques - where plants are grown from single cells or plant segments are used in many plant breeding nurseries to allow for rapid multiplication of identical plants. Genetic modification of ornamental plants, widely used in Asia, allows for the development of unusual colours thereby increasing variety and commercial value. [2]
• PLANT BIOTECHNOLOGY
Traditional plant breeding techniques using the controlled pollination of plants have limitations. Firstly, sexual crosses can only occur within the same or related species. This limits the genetic sources breeders can depend upon to enhance desirable characteristics of plants.
Secondly, when two whole plants are crossed, each having some 100,000 genes or so, all the genes from both plants get jumbled up. This presents a problem as the plant offspring may express both desirable and undesirable traits of the parent plants. Because of this, breeders must spend years "back crossing" the jumbled up plants with the plant they started with, again and again, to slowly breed out the tens of thousands of genes they do not want. Traditional plant breeding takes time, sometimes as long as 10 to 12 years.
Plant biotechnology is an extension of traditional plant breeding with one important difference. Instead of mixing hundreds of thousands of genes to improve a crop plant, modern breeders can use biotechnology to select a specific trait from any plant, microbe or animal and move it into the genetic code of another plant. This is possible because of the similarity of all living things at the DNA level. After the gene has been transferred, the newly modified plant exhibits specific modifications rather than the extensive changes that occur with traditional breeding.[2]
APPLICATIONS OF PLANT BIOTECHNOLOGY
Insect-protected plants
Devastation of crops by insect pests is a major problem for farmers. To fight crop pests, farmers usually spray crops with insecticides. These sprays have limitations as they may degrade in sunlight or be washed away by rain. By introducing a specific gene into the genetic make up of a plant, the plants are able to continuously produce proteins to protect against harmful insects.
This built-in protection offers farmers an alternative to the use of chemical pesticides. When the usage of chemical pesticides is decreased, beneficial bacteria survive and, in turn, help control harmful insect pests.
Other potential benefits of insect-protected plants include:
• Maintenance or improvement of crop yields
• Reduced exposure of farmers to chemical insecticides
• Soil protection
• Less exposure of ground water to chemical insecticides
• Lower levels of fungal toxins spread by insect damage
Herbicide-tolerant plants
Weeds compete with crops for water, nutrients, sunlight and space. They also harbour insect and disease pests, reduce crop quality and deposit weed seeds in crop harvests.
Farmers fight weeds by tilling, using herbicides or through a combination of these methods. Tilling exposes valuable topsoil to wind and water erosion, and has serious long-term consequences for the environment. Environmentally conscious farmers try to reduce tilling and limit the use of chemical herbicides.
By introducing into a plant a gene that confers tolerance to a specific herbicide, a farmer can apply this herbicide in judicious amounts to control weeds without destroying the crop.
This technology allows the grower to apply herbicide only when the presence of weeds requires it, a practice consistent with the concept of integrated pest management. It may also result in the increased use of environmentally-favourable herbicides and reduce the use of tilling.
Disease-resistant plants
Plant disease, including fungal and viral diseases, can devastate both the yield and quality of crop harvests. To minimize the economic loss resulting from plant disease, farmers often plant more than they expect to harvest. This increases the costs of planting and results in wastage of fuel, water and fertiliser. In addition, farmers use chemical insecticides to destroy pests such as aphids that carry viral disease. Researchers are working to develop crops protected from certain types of plant viruses. By introducing a small part of the DNA from a virus into the genetic makeup of a plant, scientists are developing crops that have in-built immunity to specific viral diseases. This allows reduced dependence on chemical inputs and improves both productivity and crop quality.
Improved food and crop quality
Since the beginning of time, farmers have sought to improve the quality and quantity of food crops through plant selection and hybridisation. By introducing a gene (or genes) through genetic modification, beneficial changes may be made to plant crops. Examples include:
• Consistently high-yielding oil palms
• Potatoes and tomatoes with a higher content of solids, making the plants more suitable for food processing.
• Tomatoes, squash and potatoes with higher levels of nutrients such as vitamins A, C and E.
• Corn and soya beans containing higher levels of essential amino acids.
• Potatoes with higher levels of essential amino acids.
• Oil seeds with lower levels of saturated fat.
• Garlic cloves with more allicin, an active ingredient that is being researched for a potential role in helping to lower cholesterol.
• Strawberries with increased levels of natural agents that are being studied for their role in helping to fight cancer.
• Slow-ripening tomatoes, peppers and tropical fruits with better keeping qualities and better flavour.
• Crops that can grow in very low temperatures.
• Animal feed crops with improved levels of proteins.
Crop improvements like these can help provide an abundant supply of food and protect our environment. The development of stronger crops would allow for increased food production in regions of the world where farming conditions are too severe for traditional crops. Increasing the nutritional content of staple foods could help certain populations get more nutrients without having to change their diets significantly.[2]
LABELING OF FOODS PRODUCED USING BIOTECHNOLOGY
Consumers increasingly demand accurate and helpful information about the food they buy. Making this information available helps ensure consumer confidence in the quality and safety of food. Food safety is of paramount importance to producers, consumers, governments and regulators. Once food safety and quality have been established, the task of providing useful and accurate information to consumers must be addressed.
In countries such as the United States and Canada, where labeling of foods is legally required to convey information related to health and safety, substantially equivalent crops and foods created with biotechnology do not require labeling because, by definition, these foods do not pose any new health or safety concerns. In other words, the U.S. and Canada require labeling based only on an assessment of the health, safety and nutrition of the final product. The U.S. and Canada agree with scientists from the WHO, FAO and OECD, that the use of biotechnology does not by itself pose a health, safety or nutritional concern There is general agreement that if the use of biotechnology results in a new plant or food which is no longer substantially equivalent to the original plant or food, labeling should be required to alert consumers to these changes. The change could be either positive, as in the case of increased vitamin content, or negative, as in the case of an allergen that has been introduced.
The most contentious debate around the world is whether plants and foods altered by biotechnology in ways which do not result in any changes in safety or nutritional value, should be labeled. That is, if a crop such as corn has been changed so that it now makes a single new protein which resists certain insects and the presence of that protein has no effect on the safety and nutrition of corn, is there a need for that corn or products derived from it, to be labeled?
Two underlying principles need to be recognised in all discussions of labeling. The first is that markets need to remain open to foods and feeds which have met national and international safety standards regardless of whether or not biotechnology was included in the process. The second is that for most commodity crops, segregation of supply streams will be expensive and costs will inevitably be borne by consumers.
In Europe, the European Union has enacted laws which require labeling of all crops and food products resulting from the use of biotechnology, regardless of whether they are substantially equivalent or not. This approach is justified not as a health and safety concern but rather as a way to meet the consumers' right to know whether or not they are buying a product of biotechnology.
Numerous technical issues have complicated the EU effort to create a labeling system based on whether or not biotechnology was used to create a crop plant or a food derived from that crop plant. For example, should labeling be based on the presence of the modified DNA, the protein it creates, or both? This question is further complicated by the state of analytical technologies available for DNA and protein. Detection techniques for proteins can be very accurate in identifying both the presence and level of a specific protein in a given sample. In many cases, protein analyses can be undertaken using simple test kits. Testing for DNA is more complicated and expensive. While analytical techniques can detect extremely small amounts of DNA, they can also generate false positive results and are usually not capable of determining how much DNA is in a given sample.
In Japan, labeling is required even for substantially equivalent products created with biotechnology. However, no testing of protein or DNA is required. Processed fractions which are not expected to contain DNA or protein are listed and foods which contain those listed fractions, such as seed oils and alcoholic beverages, do not require labeling. For foods which contain crops or fractions which would require labeling, the manufacturer can label them as, for example, "soybean (genetically modified not segregated)". The food processor is not required to test to make sure whether or not modified DNA or protein is actually in the ingredient but merely needs to state that no attempt was made to segregate and supply non-genetically modified ingredients. Under the Japanese system, only ingredients which are one of the top three ingredients in food or which are present at more than five percent by weight are considered for labeling purposes. Manufacturers are able to state on the label that the genetically modified ingredient has been approved by the government.
Another alternative which has been discussed in some countries is a proposal to allow labeling of "genetically modified organism free" foods on a voluntary basis provided the claim can be proven and provided that no misleading claims of health and safety benefits are made. [6]
Technical Challenges in Biotechnology Development Faced in the UK
The UK requires research across a spectrum of technically challenging fields, including work to improve capabilities of creating and working with nanofunctionalised materials and surfaces, and achieve novel surface patterning. Nanobiomimetics is seen as an important focus of development, where understanding and applying the structures and processes already evolved naturally at the nanolevel is a vector of creative effort and applications development. More generally, improved understanding of tissue structure and functioning is essential for progress, and proteomics is seen as a particularly important field for development. [6]
5. STABILITY-INDICATING PROFILE
On the whole, there is no single stability-indicating assay or parameter that profiles the stability characteristics of a biotechnological/biological product. Consequently, the manufacturer should propose a stability-indicating profile that provides assurance that changes in the identity, purity and potency of the product will be detected. At the time of submission, applicants should have validated the methods that comprise the stability-indicating profile and the data should be available for review. The determination of which tests should be included will be product-specific. The items tabilizer in the following subsections are not intended to be all-inclusive, but represent product characteristics that should typically be documented to adequately demonstrate product stability.
5.1 Protocol
The dossier accompanying the application for marketing tabilizers d should include a detailed protocol for the assessment of the stability of both active substance and medicinal product in support of the proposed storage conditions and expiration dating periods. The protocol should include all necessary information which demonstrates the stability of the biotechnological/biological product throughout the proposed expiration dating period including, for example, well-defined specifications and test intervals. The statistical methods that should be used are described in the Tripartite Guideline on Stability.
5.2 Potency
When the intended use of a product is linked to a definable and measurable biological activity, testing for potency should be part of the stability studies. For the purpose of stability testing of the products described in this guideline, potency is the specific ability or capacity of a product to achieve its intended effect. It is based on the measurement of some attribute of the product and is determined by a suitable quantitative method. In general, potencies of biotechnological/biological products tested by different laboratories can be compared in a meaningful way only if expressed in relation to that of an appropriate reference material. For that purpose, a reference material calibrated directly or indirectly against the corresponding national or international reference material should be included in the assay. Potency studies should be performed at appropriate intervals as defined in the stability protocol and the results should be reported in units of biological activity calibrated, whenever possible, against nationally or internationally tabilizer standard. Where no national or international standards exists, the assay results may be reported in in-house derived units using a tabilizers d reference material. In some biotechnological/biological products, potency is dependent upon the conjugation of the active substance(s) to a second moiety or binding to an adjuvant. Dissociation of the active substance(s) from the carrier used in conjugates or adjuvants should be examined i n real-time/real-temperature studies (including conditions encountered during shipment). The assessment of the stability of such products may be difficult since, in some cases, in vitro tests for biological activity and tabil-chemical tabilizers d on are impractical or provide inaccurate results. Appropriate strategies (e.g. testing the product prior to conjugation/binding, assessing the release of the active compound from the second moiety, in vivo assays) or the use of an appropriate surrogate test should be considered to overcome the inadequacies of in vitro testing.
5.3 Purity and Molecular Characterisation
For the purpose of stability testing of the products described in this guideline, purity is a relative term. Due to the effect of glycosylation, deamidation, or other heterogeneities, the absolute purity of a biotechnological/biological product is extremely difficult to determine. Thus, the purity of a biotechnological/biological product should be typically assessed by more than one method and the purity value derived is method-dependent. For the purpose of stability testing, tests for purity should focus on methods for determination of degradation products. The degree of purity, as well as individual and total amounts of degradation products of the biotechnological/biological product entered into the stability studies, should be reported and documented whenever possible. Limits of acceptable degradation should be derived from the analytical profiles of batches of the active substance and medicinal product used in the preclinical and clinical studies. The use of relevant tabil-chemical, biochemical and immunochemical analytical methodologies should permit a comprehensive tabilizers d on of the active substance and/or medicinal product (e.g. molecular size, charge, hydrophobicity) and the accurate detection of degradation changes that may result from deamidation, oxidation, sulphoxidation, aggregation or fragmentation during storage. As examples, methods that may contribute to this include electrophoresis (SDS-PAGE, immunoelectrophoresis, Western blot, isoelectrofocusing), high-resolution chromatography (e.g. reversed-phase chromatography, gel filtration, ion exchange, affinity chromatography), and peptide mapping. Wherever significant qualitative or quantitative changes indicative of degradation product formation are detected during long-term, accelerated and/or stress stability studies, consideration should be given to potential hazards and to the need for tabilizers d on and quantification of degradation products within the long-term stability program. Acceptable limits should be proposed and justified, taking into account the levels observed in material used in pre-clinical and clinical studies. For substances that can not be properly tabilizers d or products for which an exact analysis of the purity cannot be meaningfully determined through routine analytical methods, the applicant should propose and justify alternative testing procedures.
5.4 Other Product Characteristics
The following product characteristics, though not specifically relating to biotechnological/biological products, should be monitored and reported for the medicinal product in its final container:
• Visual appearance of the product (colour and opacity for solutions/suspensions; colour, texture and dissolution time for powders), visible particulates in solutions or after the reconstitution of powders or tabilizers cakes, pH, and moisture level of powders and tabilizers products.
• Sterility testing or alternatives (e.g. container/closure integrity testing) should be performed at a minimum initially and at the end of the proposed shelf life.
• Additives (e.g. tabilizers, preservatives) or excipients may degrade during the dating period of the medicinal product. If there is any indication during preliminary stability studies that reaction or degradation of such materials adversely affect the quality of the medicinal product, these items may need to be monitored during the stability program.
• The container/closure has the potential to adversely affect the product and should be carefully evaluated (see below) [6]
References:
1. https://www.google.co.in/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&source=hp q=EMERGING+PRODUCT+LIABILITY+ISSUES+IN+BIOTECHNOLOGY&meta=&btnG=Google+Search
2. https://www.google.co.in/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&source=hp q=FOOD+BIOTECHNOLOGY+-+A+Review+Paper&meta= btnG=Google+Search
3. https://www.google.co.in/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&source=hp&q=BIOTECH+SOLUTIONS+TO+HEALTHCARE+CHALLENGES+BIOTECH+MEDICINAL+PRODUCTS+Medicines+with+a+Community+marketing+authorisation&meta=&btnG=Google+Search
4. https://www.google.co.in/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&source=hp&q=biotechology+midicinal+product%3Aback+to+basics&meta=&btnG=Google+Search
5. https://www.google.co.in/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&source=hp&q=Enzyme+Biotechnology+in+Everyday+Life&meta=&btnG=Google+Search
6. https://www.google.co.in/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&source=hp&q=QUALITY+OF+BIOTECHNOLOGICAL+PRODUCTS%3A+STABILITY+TESTING+OF+BIOTECHNOLOGICAL%2F+BIOLOGICAL+PRODUCTS+*%29&meta=&btnG=Google+Search
7. https://www.google.co.in/search?client=firefox-a&rls=org.mozilla%3Aen-US%3Aofficial&channel=s&hl=en&source=hp&q=BIOTECH+SOLUTIONS+TO+HEALTHCARE+CHALLENGES+BIOTECH+MEDICINAL+PRODUCTS+Medicines+with+a+Community+marketing+authorisation&meta=&btnG=Google+Search
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