Regulation of Biotechnology

Transcription

1 Section V Environment Books Inc. Page D1 Regulation of Biotechnology Summary of the Requirement: Any person who intends to manufacture or import for commercial purposes 1 a new 2 living microorganism 3, or who intends to manufacture, import or process for commercial purposes any microorganism for a significant new use, must file a Microbial Commercial Activity Notice (MCAN) with the US EPA at least 90 calendar days prior to such manufacture, import, or processing. Following the expiration of the MCAN review period including any extensions, and in the absence of regulatory action by EPA under Sections 5(e), 5(f), or 6(a) of TSCA, the submitter may commence manufacture or import. 4 The purpose of the 90-day review period is to allow EPA sufficient time to examine whether the planned activity presents an unreasonable risk of injury to health or the environment. The final rule, which is reprinted on the following pages, contains several exemptions from the requirement to submit an MCAN. Those exemptions apply to both R & D and post-r & D activities, and are discussed below. 5 Who is Subject to the Requirement? Any person conducting commercial R & D activities on, or any person manufacturing, importing, or processing for commercial purposes, intergeneric 6 microorganisms for a TSCA purpose 7 is subject to these requirements. The following table published by the US EPA, although not all-inclusive, is illustrative: 8 1. An activity is for a commercial purpose if it is conducted with the purpose of obtaining an immediate or eventual commercial advantage. Certain research and development activities are activities conducted for a commercial purpose. See 40 CFR which provides that an R & D activity is for a commercial purpose if it is directly funded in whole or in part by a commercial entity, or (regardless of funding source) if the researcher intends to pursue immediate or eventual commercial advantage. 2. New microorganisms are microorganisms not already listed on the TSCA Inventory which are formed by the deliberate combination of genetic material originally isolated from organisms of different taxonomic genera. See Special Notes below for a discussion of EPA s use of biological taxonomy in this rule. 3. Microorganism means an organism classified (using the 5-kingdom classification system of Whittacker) in the kingdoms Monera (or Procaryotae), Protista, Fungi, and the Chlorophyta and the Rhodophyta of the Plantae, and viruses or virus-like particles. Thus, microorganisms include but are not limited to bacteria, protozoa, fungi, mycoplasmas, mycoplasma-like organisms, spiroplasmas, microphytoplanktons, green algae, red algae, viroids, satellites and virusoids. EPA considers that if any new categories of organisms are identified within the 5 above kingdoms, those would also be considered microorganisms for purposes of this rule. 62 FR 17926, April 11, CFR (b). Required contents of an MCAN are specified at 40 CFR ff. A Notice of Commencement of Manufacture or Import must be submitted within 30 days following the first day of manufacture or import for commercial purposes. See 40 CFR EPA s rule addressing the regulation of biotechnology was published as Microbial Products of Biotechnology at 62 FR 17932, on April 11, For further information on the exemptions from the requirement to submit an MCAN, see the discussion below titled What are the Exemptions from MCAN Reporting? 6. An intergeneric microorganism is a microorganism that is formed by the deliberate combination of genetic material originally isolated from organisms of different taxonomic genera. 7. Many R & D and other activities involving intergeneric microorganisms are not subject to TSCA, for instance research being conducted with the intention of developing a product such as a drug, food, cosmetic, or medical device, the use of which is subject solely to the Federal Food, Drug, and Cosmetic Act. EPA s regulation of microbial products of biotechnology under 40 CFR Part 725 applies only if the R & D or commercial activity involving intergeneric microorganisms is subject to TSCA. See TSCA Section 3(2)(B) for exclusions of certain activities from TSCA coverage. See also of this regulation. 8. Source: 62 FR 17910, April 11, 1997.

2 Section V Environment Books Inc. Page D2 Category Biotechnology research and development activities involving commercial funds Commercial biotechnology products Examples of Regulated Entities Persons conducting commercial research and development using intergeneric microorganisms for biofertilizers; biosensors; biotechnology reagents; commodity or specialty chemical production; energy applications; waste treatment or pollutant degradation; and other TSCA subject uses. Persons manufacturing, importing or processing products for commercial purposes using intergeneric microorganisms for biofertilizers; biosensors; biotechnology reagents; commodity or specialty chemical production; energy applications; waste treatment or pollutant degradation; and other TSCA subject uses. When Must the Report be Submitted? The MCAN must be submitted at least 90 calendar days prior to manufacturing or importing a new microorganism, and at least 90 calendar days prior to manufacturing, importing, or processing a new microorganism for a significant new use. 9 What are the Exemptions from MCAN Reporting? 1. During Research and Development: Rather than submitting an MCAN during research and development, manufacturers may qualify for one of several exemptions, or may choose to submit to EPA a TSCA Experimental Release Application (TERA) as follows: If a manufacturer is conducting research and development activities solely within a contained structure, the R & D may qualify for one of two exemptions. For contained research conducted by researchers who are required to comply with the NIH Guideline, EPA has established a complete exemption from EPA review and reporting and recordkeeping requirements. 10 For all other manufacturers conducting contained research and development activities EPA has established a more limited exemption. 11 The latter exemption specifies factors which the technically qualified individual must keep records to consider in selecting the appropriate containment. The manufacturer is required to 9. Just as the MCAN reporting requirements are analogous to the PMN requirements for new chemical substances (see Section II, Chapter A of this book), the significant new use requirements for microbial products of biotechnology are analogous to the SNUR requirements for chemicals (see Section II, Chapter E). At the time of promulgation of this final rule on April 11, 1997, the EPA had not designated any uses of specific microorganisms as significant new uses under TSCA. However, the EPA has reserved Subpart M of this rule (40 CFR ) for future listings and regulation of Significant New Uses of Specific Microorganisms. Subpart L of this rule (40 CFR ff) provides the procedures for reporting on significant new uses of microorganisms. Paralleling the processes used for SNURs as described in Section 2, Chapter E of this book, EPA has promulgated rules in Subpart L of this rule that allow it to expedite the issuance of SNURs for microorganisms that become subject to TSCA Section 5(e) Orders following MCAN submission and review. See 40 CFR CFR CFR and See also 62 FR , April 11, 1997.

3 Section V Environment Books Inc. Page D3 document compliance with the containment requirements, but is exempt from other TSCA Section 5 reporting requirements. For researchers conducting small-scale field tests with Bradyrhizobium japonicum and Rhizobium meliloti, the final rule creates an exemption from EPA review, provided that certain conditions are met. 12 The field testing must occur on no more than 10 terrestrial acres; the introduced genetic material must comply with certain restrictions; and appropriate containment measures must be selected to limit dissemination. If a manufacturer does not meet the requirements for one of the exemptions discussed above, he or she may submit a TERA. 13 The TERA is essentially an abbreviated MCAN submission for individual tests. EPA s review period is reduced to 60 days, although EPA may extend the period for good cause. EPA must approve the test before the researcher may proceed, even if the 60-day period expires. EPA s approval is limited to the conditions outlined in the TERA notice or approval After Research and Development: EPA has established two exemptions for new microorganisms, after the R & D development stage, which are being manufactured for introduction into commerce. In the Tier I exemption, 15 if three criteria are met manufacturers are only required to notify EPA that they are manufacturing a new microorganism that qualifies for this exemption 10 days before commencing manufacture, and to keep certain records. Under the Tier I exemption process a manufacturer is not required to wait for EPA approval before commencing manufacture. To qualify for the Tier I exemption, a manufacturer must use one of the recipient organisms listed by EPA in this rule, and must implement specific physical containment and control technologies. In addition, the DNA introduced into the recipient microorganism must be well-characterized, limited in size, poorly mobilizable, and free of certain sequences. A manufacturer who otherwise meets the conditions of the Tier I exemption may use modifications of the specified containment restrictions, but prior to doing to must submit a Tier II exemption notice. 16 The Tier II exemption requires manufacturers to submit an abbreviated notice describing the modified containment, and provides for a 45-day period during which EPA would review the proposed containment. The manufacturer may not commence manufacture or import under this exemption until EPA approves the exemption CFR See also 40 CFR 17925, April11, CFR See also 62 FR , April 11, In addition to the above exemptions a manufacturer may submit an MCAN for an R & D activity. However, the US EPA expects that most persons involved in R & D activity will choose to submit a TERA instead of an MCAN for two reasons: 1) the review period for an MCAN is longer than that for a TERA (90 days vs. 60 days) and 2) because of the more limited information that is usually available to EPA during the R & D stage, the Agency would likely issue a TSCA Section 5(e) Order to impose restrictions to address the uncertainties in risks to health and the environment. Those restrictions would need to be modified each time the manufacturer wants to vary the terms of the Order CFR See also 62 FR , April 11, CFR O. See also 62 FR , April 11, 1997.

4 Section V Environment Books Inc. Page D4 Special Notes: Coverage of Microorganisms Under TSCA 1. Intergeneric Scope: EPA has defined new microorganisms as those microorganisms resulting from the deliberate combination of genetic material originally isolated from organisms classified in different genera because of the degree of human intervention involved, the significant likelihood of creating new combinations of traits, and the greater uncertainty regarding the effects of such microorganisms on human health and the environment. This approach, based on a taxonomic standard, both identifies a group of microorganisms whose behavior in the environment poses significant uncertainty, and which therefore warrant regulatory review under TSCA Section 5. TSCA Section 5 requires all manufacturers of new chemical substances to submit information to EPA 90 calendar days before commencing commercial manufacture, to permit EPA to examine whether those substances may present an unreasonable risk of injury in order to protect health and the environment. Congress rationale for creating this requirement was to have EPA attempt to resolve the uncertainties surrounding the new chemical substances--specifically, whether they are likely to cause unreasonable risks before they are introduced into the environment. When considering the various approaches that could be used to define a new microorganism for TSCA purposes, one important factor EPA took into account was the regulatory precedent established in compiling the Inventory of existing chemical substances under section 8(b) of TSCA (see Section I Chapter A and Section II Chapter A of this book). Any chemical substance not on the Inventory is new under section 5(a) of TSCA and is therefore subject to premanufacture notification (PMN) reporting. Naturally occurring substances and substances derived from nature with limited human intervention are considered to be automatically included on the Inventory, and thus are not new. EPA concluded that microorganisms found in nature could also be considered not new because they occur naturally without human intervention, and, therefore, naturally occurring microorganisms are automatically listed on the TSCA Inventory and are not subject to this EPA rule. In developing this rule EPA also considered that modern biotechnology techniques permit genetic material to be intentionally moved between and combined in disparate organisms. On occasion the genetic material combined would not be genetic material expressing traits possessed by both the donors of the genetic material and the recipients. In other words, the genetic material encoding these traits would not be commonly shared between the donor and recipient organisms without human intervention. Microorganisms formed from genetic material not commonly shared by donors and recipients would have a significantly higher probability of exhibiting new traits or new combinations of traits compared with naturally occurring microorganisms. Some of the microorganisms developed through modern biotechnology may exhibit new or altered traits affecting, for example, their survivability, host range, substrate utilization, competitiveness with other organisms, or protein or polysaccharide production. The

5 Section V Environment Books Inc. Page D5 behavior of organisms expressing a new trait or new combinations of traits is thus less predictable and their probable behavior less certain. EPA chose to focus particular regulatory attention on microorganisms that have a higher potential for exhibiting a new trait or combinations of traits. EPA concluded that a standard based on the taxonomic taxon of genus defined a class of sufficiently high probability of exhibiting a new trait or new combinations of traits to warrant review. Taxonomy is a system of orderly classification of organisms according to their natural relationships. Because the organisms contributing genetic material to intergeneric microorganisms are, in general, more distantly related than the microorganisms contributing genetic material to intrageneric microorganisms (and are thus less likely to have traits in common), intergeneric microorganisms have a higher probability of exhibiting a new trait or new combinations of traits and their behavior is therefore significantly less predictable than intrageneric microorganisms. A regulatory scope based on a taxonomic standard such as intergeneric has certain advantages. A taxonomically-based regulatory scope relates directly to the potential of the resulting new microorganism to display a new trait or new combinations of traits, since organisms that share a close evolutionary ancestry are more likely to have traits in common than organisms that are more distantly related. In addition, the taxonomy standard is independent of the technology used to create the microorganism. A number of techniques may be used to produce intergeneric microorganisms. Any intergeneric microorganisms created by techniques developed in the future would also be subject to this final EPA rule. EPA includes the phrase originally isolated in the definition of intergeneric to clarify that, for the purpose of this regulation, genetic material belongs to the genus from which it was originally isolated or originally observed. For example, if a sequence of genetic material was originally introduced from microorganism A into microorganism B, subsequently reisolated from microorganism B to be combined in microorganism C, the manufacturer or developer must consider the genera of microorganisms A and C in determining the status of the microorganism resulting from the second combining event described above. 2. Mobile Genetic Elements (MGEs): MGEs, which are elements of genetic material such as plasmids and transposons, may in nature move within or among organisms and may carry with them and transfer genetic material in addition to their own. MGEs, which are used as vectors for moving genetic material among organisms, may move across taxonomic boundaries and therefore are not a constant part of the genome of one particular taxonomic group or another. Consistent with its intergeneric definition of new microorganism which focuses on the origin of the introduced genetic material, EPA has concluded that microorganisms should be considered intergeneric if they contain an MGE first identified in a microorganism in a genus different from the recipient microorganism genus. Microorganisms are

6 Section V Environment Books Inc. Page D6 considered intrageneric, and not new, if the literature indicates that the MGE was first identified in a microorganism in the same genus as the recipient. The issue of whether the MGE may be indigenous to the recipient genus is not considered in EPA s approach to determining whether the final microorganism is inter-or intrageneric. The major consideration is the source of the organism in which the MGE was first identified. The source of the organism in which the MGE was first identified may be determined by a search of relevant published scientific literature or by reviewing available data bases such as GENBANK. Such a literature or data base reference is often the first to name, and possible describe, the MGE. Subsequent references postdating this first reference are frequently not relevant for determining the intergeneric status of the MGE, because after isolation an MGE is often transferred to a different taxon where it can be more easily maintained and studied. EPA will continue to use this approach until it can reevaluate the status of MGEs within an intergeneric standard in a future rulemaking. EPA has included a statement about MGEs in its definition of intergeneric microorganisms in this final rule Well-characterized, Non-Coding Regulatory Regions. EPA has historically excluded from the definition of intergeneric microorganisms, those microorganisms that result from the addition of intergeneric material that is well-characterized and contains only non-coding regulatory regions such as operators, promoters, origins of replication, terminators, and ribosome-binding regions. Where only regulatory material is transferred, no distinctly new combinations of traits are introduced. Instead, quantitative changes in existing traits in the recipient microorganisms may occur. EPA recognizes that insertion of well-characterized, non-coding regulatory regions may result in expression of previously cryptic regions; however, the genetic material in cryptic regions is present in the population and could be expressed in some members of the microbial population at any time naturally. A microorganism expressing such material as a consequence of insertion of non-coding regulatory regions would thus not be new under TSCA. Therefore, EPA believes that microorganisms formed through intergeneric transfer of well-characterized, non-coding regulatory regions should not be considered new microorganisms under TSCA Section 5. The above exclusion applies only to intergeneric microorganisms that have resulted solely from the addition of well-characterized, non-coding, regulatory regions. If the final microorganism contains any regions from organisms of other genera that do not meet this restriction, such as coding regulatory regions or any poorly characterized regions, the microorganism is considered new and is not eligible for the exclusion See the definition of Intergeneric microorganism at 40 CFR FR , April, 11, See the definition of Non-coding regulatory region at 40 CFR