Impact of 2016 Final Rule on FDA Review of Animal GRAS Notices

Several previous posts on the blog discussed the options for obtaining approval in the U.S. to market new animal food ingredients (such as spent microbial biomass from biofuel or bio-based chemical fermentation runs). One such option was to seek review by the U.S. Food and Drug Administration of a company’s determination that the product is Generally Recognized as Safe (GRAS) for the intended use in animal food. On August 17, 2016, FDA published a Final Rule to formalize the voluntary, interim GRAS notification procedures that had been in effect since 1997 for human food ingredients and since 2010 for animal food ingredients. This post will review the new 2016 policy and discuss how it is being implemented for new animal food substances. [Note that FDA has recently begun using the term “food” to apply both to humans and animals, in lieu of the older term “animal feed”.]

As discussed in more detail in my earlier blog posts in 2013 and 2015, under the Federal Food, Drug and Cosmetic Act, most new substances that are intended to be components of food or to affect components of food are considered to be “food additives” and would ordinarily need to be approved through the submission of a Food Additive Petition.  However, the law further provides that “substances that are generally recognized, among experts qualified by scientific training and experience to evaluate their safety as having been adequately shown …  to be safe under the conditions of their intended use,” are not considered as food additives. This is the category of substances known as GRAS: “generally recognized as safe”. Certain substances were “grandfathered” in as GRAS at the time of the legislation based on common prior safe use in foods, and other substances were later affirmed by FDA to be GRAS, often in response to manufacturer petitions. In addition, under the law, manufacturers are allowed to self-certify that a product or food additive is GRAS, and many companies have historically taken this route.

Back in April 1997, FDA published a proposed rule outlining a new, voluntary GRAS notification process for both human and animal foods to replace the old petition process, which was becoming unwieldy for FDA to administer. An interim program to review human GRAS notifications using the procedures of the proposed rule was instituted at that time, although a corresponding procedure for animal food ingredients was not instituted until 2010. These programs allowed applicants to submit notifications in which they informed the Agency that they had determined that a food substance qualified for GRAS status. FDA then had 180 days to evaluate whether the notice provided a sufficient basis to support a GRAS determination. The Agency’s determination would be conveyed in an opinion letter to the submitter, which would either state that FDA has “no questions” about the applicant’s determination of GRAS status (a “no action” determination that is the equivalent of approval), or would outline the reasons why the Agency has determined there is not sufficient data to support such a conclusion.

As of mid-2016, the Agency received over 600 Notifications under the interim human GRAS program, the great majority of which received “no questions” letters after FDA review. This program was widely believed to be operating efficiently and to meet industry needs. Unfortunately, the same was not the case for the animal GRAS Notice program, administered by FDA’s Center for Veterinary Medicine, that was instituted in a June 4, 2010 Federal Register notice. The program for animal food is described elsewhere on this blog and on the CVM website, and like the human program, it allowed applicants to submit notifications in which they inform the Agency that they believe an animal food substance qualifies for GRAS status. As I have previously discussed in blog posts in 2013 and 2015, in its first few years, the Animal GRAS Notification program was not particularly successful, and was not being administered by FDA CVM very efficiently.

On August 17, 2016, FDA published a Final Rule to formally institute a final, somewhat revised notification process under which any person may notify FDA of a conclusion that a substance for use in human or animal food is GRAS under the conditions of its intended use. The Federal Register notice announcing this final rule included a lengthy discussion of the comments FDA received in response to the 1997 proposed rule, and discussed the results of the interim notification programs. In adopting the final rule, FDA also issued revised, clarified guidance for the data and other information it expects to see in what are now called “GRAS Notices”. The rule became effective on October 17, 2016, and is now in full effect for both human and animal food ingredients. The text of the relevant portions of the regulation as they apply to the animal GRAS program, 21 CFR Part 570, can be found here.

The procedures for submitting GRAS Notices and FDA’s process for their review are substantially the same as under the interim policy. After making an initial determination of the suitability and completeness of a Notice for a food ingredient (“notified substance”), which in practice may take several months, FDA has 180 days to review the Notice and is obligated to inform the submitter of their findings within that time period. However, the Agency may also extend that period by up to 90 days, by notifying the submitter within the first 180 days.

Most importantly, the final rule standardized the format for GRAS Notices and specified what data and other information is to be included in each of seven required parts of the Notice. The seven parts of the notice are shown in summary form below – the more detailed outline as specified in the regulation can be found in the Federal Register notice. The complete outline goes into considerably more detail about the data and information required in the various sections, particularly Parts 2, 3, 6 and 7. The requirements for the human and animal GRAS programs are slightly different, and the version for the Animal GRAS program is the one shown below.

Required Components of a GRAS Notice for an Animal Food Substance
Part 1.  Signed statements and a certification.
Part 2. The identity, method of manufacture, specifications, and physical or technical effect of the notified substance.
Part 3. Dietary exposure (to the target animal and/or to humans) to the notified substance.
Part 4. Self-limiting levels of use in circumstances where the amount of the notified substance that can be added to human food or animal food is limited because the food containing levels of the notified substance above a particular level would become unpalatable or technologically impractical.
Part 5. The history of consumption of the substance for food use by a significant number of consumers (or animals in the case of animal food) prior to January 1, 1958, if a conclusion of GRAS status is based on common use of the substance in food prior to 1958.
Part 6. A narrative that provides the basis for the notifier’s conclusion of GRAS status, including why the scientific data, information, methods, and principles described in the notice provide a basis for the conclusion that the notified substance is generally recognized, among qualified experts, to be safe under the conditions of its intended use.
Part 7.  A list of the generally available data, information, and methods the notifier cites in the GRAS notice.

At this writing, the new policy has been in place for nearly 18 months, and so it is reasonable to see how FDA CVM is doing administering the Animal GRAS program. As shown on the Animal GRAS Notice Inventory page, there have been 25 notices submitted since the program began, five of which were submitted since the final regulations came into place (it’s not clear how up-to-date the web listing is, and it is possible that there are a number of other submissions that CVM is now reviewing but which are not yet posted on the website – I am aware of at least one). Of these 25 submissions, 4 are listed as “pending”, 9 received the “no questions” letter as the equivalent of approval, 6 were rejected by FDA as “not providing a basis for a GRAS determination”, and another 6 were withdrawn by the applicant (i.e., “at notifier’s request, FDA has ceased to evaluate the notice”). A few trends are evident from this listing:

  • Of the notices for which a decision was made, only a little less than half were favorably reviewed by FDA (9 out of 21).
  • Of the 5 notices submitted since the final rule came into effect, 3 are still pending, one was rejected as not providing a basis for the determination (AGRN 22, from Royal Canin US for a marigold extract); and one successfully received the “no questions” letter (AGRN 21, from Agrivida for ground grain from a genetically modified strain of corn expressing a phytase enzyme).
  • The five most recent “no questions” determinations all required between 9-12 months from the time FDA formally accepted the filing to the date of the opinion letter. The 6th most recent, a submission for a phytase enzyme from DSM, took only 6 months for FDA’s decision in 2012-13. Note that it commonly took a month or more from the actual submission date for FDA to complete its initial review and formally record the notice as being filed, so the actual review time at the agency was a little longer in all cases.
  • There has only been one Notice since 2011 that was rejected by FDA (AGRN 22, discussed above), and it took FDA about a year to make this determination. However, there were several Notices since 2011 that were withdrawn, which suggests that FDA’s preferred way of operating is to give the submitter the option to withdraw rather than to receive a negative decision letter.
  • Of the four Notices still pending, one has been pending since March 2016 (AGRN 19 for L-glutamine to be fed to post-weaning horses) while the others have been filed more recently.

It is too early to know if the final rule and the clarified guidance for the data to include in the submission are having any effect on making the process easier for companies to comply with, or whether the rule has made FDA’s review process more efficient. I can say from my own experience helping clients with FDA and AAFCO submissions (the latter of which are also reviewed by CVM’s technical team) that CVM staff review these submissions at a very high level of detail, and want to see a comprehensive and thorough data set that is free of incomplete or ambiguous descriptions, and which addresses all the issues which CVM believes are relevant to the analysis. CVM staff also requires that an exhaustive literature search be performed and documented, to ensure that there is no prior literature that might contradict the applicant’s determination of the safety of the substance. And having helped one client prepare a GRAS Notice under the new guidelines, I can say that it is an exacting process, and that it can be quite challenging to assemble all the information that FDA wants to see, in the specific format now required under the rule and to the level of detail expected in accordance with CVM practice. On the other hand, because CVM’s technical reviewers give a higher priority preference to GRAS Notices (and food additive petitions) than for AAFCO new ingredient definition requests, the pendulum has shifted and many are coming to feel that the GRAS Notice process is a quicker and more straightforward path for approval of new animal food ingredients, particularly those that are based on microorganisms.

D. Glass Associates, Inc. is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated.

Advertisements

MCANs Reviewed by EPA Since 2016 TSCA Reform

Many were curious, as I speculated in an earlier blog post, whether EPA’s procedures for reviewing Microbial Commercial Activity Notices (MCANs) and chemical Premanufacture Notices (PMNs) under the Toxic Substances Control Act (TSCA) would be changed by the landmark TSCA reforms enacted in the June 2016 passage of the Frank R. Lautenberg Chemical Safety for the 21st Century Act. Although the Lautenberg Act had no provisions specifically affecting EPA’s biotechnology program under TSCA, some portions of the bill have caused EPA to change the way it reviews MCANs, the determinations it makes regarding each MCAN, and the way in which it publicizes the results of its review. But would this lead to any appreciable changes in EPA’s biotechnology program?

Specifically, the Lautenberg Act required EPA to affirmatively reach one of the following three determinations for each notice submitted:

  • A finding that the substance presents an unreasonable risk.
  • A finding that either the information is insufficient to permit a reasoned evaluation of the substance; or in the absence of sufficient information and evaluation, the substance may present an unreasonable risk; or the substance may be produced in substantial quantities or may enter the environment in substantial quantities, which may lead to substantial human exposure.
  • A finding that the substance is not likely to present an unreasonable risk.

Although largely conforming to prior practice regarding EPA’s risk assessment procedures, the key difference was that EPA now needs to affirm one of these determinations for each MCAN or PMN it reviews, whereas previously if the Agency took no action within the 90 day review period, the Notice was deemed to be accepted (“Dropped from Review”), and the chemical or the microorganism covered in the Notice could proceed to be commercialized.

EPA began following this procedure for all MCANs filed after the June 22, 2016 signing of the Lautenberg Act. For almost all of these MCANs, EPA was able to reach the finding that the microorganism “is not likely to present an unreasonable risk”, and to adopt the necessary paperwork as now required under the amended TSCA. At this time, the Agency also changed the way it had been reporting the filing and disposition of MCANs, and although the new procedures are in conformance with the requirements of the law, the new publication procedures have made it somewhat harder to track MCANs and to easily obtain information on the organism and its intended use covered in each reviewed MCAN.

EPA previously maintained a page entitled “TSCA Biotechnology Notifications Status” (now accessible here), where it chronologically listed all the MCANs (as well as TSCA Experimental Release Applications and Biotechnology Test Marketing Exemption Applications) reviewed by the Agency since 1998 (i.e. since the adoption of the current MCAN regulations). The tables on this page conveniently listed, for each MCAN, the name of the organism, the name of the submitter, and the intended use (except when any such information was claimed as confidential by the submitter), and more importantly each entry also had a link to a page with a 1-2 paragraph description of the organism and its intended use, and an explanation of the basis for EPA’s finding of no unreasonable risk. These tables can still be found at this site, although the links to the decision documents seem to be gone. But this page was convenient because it listed all biotech notices on a single page, separately from chemical PMNs, and it was easy to find and review the most recently-filed notices. In the past, I’ve posted periodic summaries of recently-filed MCANs, using information drawn from this page.

Since the passage of the Lautenberg Act, however, EPA has begun to use a new page where it publicizes all TSCA Section 5 Notices for which it has made the “no unreasonable risk” determination. This page, called “Chemicals Determined Not Likely to Present an Unreasonable Risk Following Pre-Manufacture Notification Review“, lists both MCANs and PMNs in the chronological order in which the determination has been made (additions to this page are announced from time to time in the Federal Register). From this page, you can follow links to a page entitled “Microbial Commercial Activity Notices (MCANs) Table” which indeed lists only reviewed MCANs, but the”No Unreasonable Risk” page is difficult to review and search because it intermingles PMNs and MCANs (note that PMNs and MCANs can be distinguished because PMNs are identified with a prefix of “P” followed by the fiscal year of submission, while MCANs are identified with a “J” and the fiscal year) The”No Unreasonable Risk” page does include links to EPA’s decision documents for each Notice (for example, this one here), but these documents are highly formulaic to meet the requirements of the law, and include little if any detail about the specific organism in question.

So, it is harder now to conveniently and quickly get an overview of recent MCAN activity, and so I’ve done the hard work for you. The table below shows all MCANs received by EPA since June 22, 2016 for which the Agency’s review has concluded. This table shows the MCAN number, the species of the microorganism, and the dates on which EPA review began, the date of EPA’s decision, and the effective date of the decision (i.e. the end of the review period, usually 90 days after submission). Each entry has a link to EPA’s decision document, although the link will first take you to an intermediate page, from which the actual decision document can be accessed.

Case Number Chemical Identify Final Disposition Review Start Date Decision Date Effective Date
J-16-0006 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 6/22/16 9/2/16 9/7/16
J-16-0010 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 6/22/16 9/14/16 9/15/16
J-16-0011 through 0016 Generic: Biofuel Producing Organism Not likely to present an unreasonable risk 6/22/16 9/14/16 9/15/16
J-16-0017 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 6/22/16 9/14/16 9/15/16
J-16-0018 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 6/22/16 9/14/16 9/15/16
J-16-0019 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 6/29/16 10/4/16 10/11/16
J-16-0020 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 6/29/16 10/4/16 10/11/16
J-16-0021 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/15/16 10/19/16 10/25/16
J-16-0022 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/15/16 10/19/16 10/25/16
J-16-0023 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/16/16 10/19/16 10/25/16
J-16-0024 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/28/16 11/14/16 11/21/16
J-16-0025 Generic: Trichoderma reesei modified Not likely to present an unreasonable risk 7/29/16 11/14/16 11/21/16
J-16-0026 Section 5(e) Consent Order – May present an unreasonable risk of injury to health and the environment 4/10/17
J-16-0033 Generic: Saccharomyces cerevisiae modified to express glucoamylase activity Not likely to present an unreasonable risk 8/22/16 12/1/16 12/7/16
J-16-0034 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 8/23/16 12/1/16 12/7/16
J-16-0035 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 8/23/16 12/1/16 12/7/16
J-16-0036 through 0041 Generic: Biofuel producing modified microorganism(s), with chromosomally-borne modifications Not likely to present an unreasonable risk 9/7/16 12/1/16 12/7/16
J-17-0001 through 0005 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 10/24/16 1/18/17 1/25/17
J-17-0006 Generic: Saccharomyces cerevisiae modified Not likely to present an unreasonable risk 11/23/16 2/13/17 2/13/16
J-17-0007 Generic: Biofuel producing Saccharomyces cerevisiae modified, genetically stable Not likely to present an unreasonable risk 2/1/17 4/27/17 4/27/17
J-17-0008 through 0013 Generic: Modified microorganism Not likely to present an unreasonable risk 5/8/17 7/27/17 7/27/17
J-17-0014 Generic: organic acid producing yeast, modified, genetically stable Not likely to present an unreasonable risk 

 

7/10/17 10/5/17 10/6/17

There is considerably less information now available about filed MCANs on these pages, and all the company names have either been claimed as confidential or simply omitted, but it is clear that the bulk of the activity is for familiar species of microorganisms. Specifically, there are 8 MCANs for modified strains of Trichoderma reesei, all of which are for enzyme production (some specified as “cellulose-degrading” enzymes) and thirteen MCANs for strains of Saccharomyces cerevisiae, all for production of ethanol. All but one of the T. reesei MCANs were filed in the span of a month in the summer of 2016 and thus may have come from the same company. There were a total of 12 MCANs for “generic biofuel producing organisms”, filed as two separate consolidated MCANs in June and September 2016, and one MCAN for an “organic acid producing yeast” of an unnamed species. There was also one MCAN that became the subject of a consent order, although details of this case do not seem to be available online.

There appear to have been as many as 41 MCANs submitted during Fiscal Year 2016 (October 2015 through September 2016), but only about 14 submitted through the first 10 months of Fiscal Year 2017 (i.e. through July 2017), although the full number received during FY17 has not yet been publicized. It would be interesting to see if the overall numbers for FY17 are indeed down from prior years, and whether this might represent a trend from the prior several years where MCAN numbers increased from year to year. This would not necessarily be surprising, in view of the financial difficulties that many in the biofuel sector have experienced in recent years.

It is somewhat surprising, and perhaps ironic, that the new procedures put in place under the Lautenberg Act have caused EPA’s MCAN listings to be less informative than the old practice. Many observers expected the Lautenberg Act to make EPA’s review of chemical substances more transparent than under existing practices, but these new websites are harder to use to extract useful information. Not only is it beneficial for the general public and environmental group watchdogs for EPA’s MCAN review process to accessible to the public, but these listings have also been useful to industry as a source of competitive information. On the other hand, EPA’s old listings page was notoriously slow to be updated, often no more than once a year, so at least the new listings pages seem to be reasonably up to date in listing decisions: at this writing in January 2018, the “No Unreasonable Risk” page lists PMN decisions made as recently as December 2017, although the most recent MCAN determination was from October of last year.

D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated.

 

 

Summary of EPA’s October 27, 2016 Engineered Algae Public Meeting

On October 27, 2016, the U.S. Environmental Protection Agency convened an open meeting to begin soliciting public comment on its recently-issued draft guidance for the preparation of TSCA biotechnology submissions involving genetically modified algae or cyanobacteria. The agenda for the meeting can be found here, and the Draft Algae Guidance can be downloaded here. The charge questions and other supporting material for the meeting are available here. The meeting also served as the kickoff for a public comment period that runs until November 30, 2016.

The meeting took place at Arizona State University in Tempe, following the end of the Algae Biomass Summit which took place in Phoenix earlier that week. I attended the meeting via the live Web streaming that EPA and ASU arranged. The following is a brief summary of what I felt were the more important issues discussed.

The meeting began with brief presentations by EPA staff on the TSCA biotechnology regulatory program, the process by which EPA conducts risk assessments under the program, and finally an overview of the contents of the Draft Algae Guidance document. This was followed by three opportunities for public comment: the first focusing on the Charge Questions that addressed algae ecological effects; the second focusing on the more general Charge Questions; and the third featuring comments on the Draft Algae Guidance itself.

Overall, I felt that this meeting featured more substantive discussion than what I recall was the case at the Agency’s September 2015 Washington, DC public meeting that kicked off their efforts to provide guidance for algae submissions under TSCA. Several commenters at last week’s meeting offered substantive observations or critiques of the Draft Algae Guidance document, and there were also some (predictable) comments from industry critics regarding safety and risk assessment. Among the key issues discussed:

  • There was some discussion of the impact of the Lautenberg TSCA reform legislation on the biotech program. EPA staff summarized the major impacts as the requirement that the agency issue definitive statement on the results of TSCA risk assessments (as opposed to previous practice of simply “clearing” PMNs and MCANs without making a statement on the assessed risk); and the need for the agency to make more information on such decisions available to the public (i.e. the policy of “transparency” which came up often in discussions). EPA has already begun implementing both these directives in its ongoing practice under TSCA.
  • Comments from industry critics (Friends of the Earth, Biofuel Watch, Consumers Union and the International Center for Technology Assessment) focused on the their contention that the environmental effects of GE algae were unpredictable, the alleged inability to contain the organisms even when cultivated in contained photobioreactors, and the critics’ desire to see EPA regulate all applications of synthetic biology under TSCA, even those limited to single nucleotide changes. Some suggested that EPA needed to broaden their risk assessments to consider the entire life cycle of the product and commercial process, rather than just the microorganism, although EPA staff felt this was beyond their authority under TSCA.
  • The critics were also unanimous in criticizing the extent of confidential information that is allowed in TSCA filings, which is then redacted in public documents.
  • Several of the critics also commented on EPA’s definition of “new microorganism” which limits its TSCA oversight to intergeneric organisms and thus excludes modified microorganisms which do not contain coding DNA from outside the host organism genus. Several speakers contrasted this definition to Footnote No. 1 in the OSTP July 2015 memo that kicked off the Coordinated Framework Modernization effort in which “biotechnology products” was defined more broadly. EPA staff explained that TSCA applies only to “new chemicals” that are not naturally occurring, and so the biotech program under TSCA was limited to “new microorganisms” that were judged to have been unlikely to have emerged through natural recombination at any time in evolutionary history.
  • Although the industry critics generally offered comments at every opportunity on a variety of topics, some of their comments showed a surprisingly poor level of knowledge about the TSCA regulations and their background. Several critics were confused about how the tiered exemptions work and were afraid that EPA would act unilaterally and rashly to add algae species to the exempt list (something EPA could do only through rulemaking, and only after conducting an exhaustive risk assessment).
  • There were a handful of academic scientists who offered substantive remarks on specific risk assessment issues. A speaker from Oklahoma State University made an interesting point, that algal blooms are usually a function of the prevailing environmental conditions rather than being determined by the biology of the strain(s) causing the bloom, so that a GE algae that escaped containment would not necessarily form a bloom itself and in fact would need to compete with better-established algae species and strains that were already adapted to the environment and perhaps even selected for bloom-forming traits.
  • Several speakers touched on substantive scientific topics about the content of the newly-released draft guidance document for algae, but it was difficult to have much to say about that guidance in a short 3-minute public statement, particularly when it had only been available for public review and comment for a short time.
  • Several industry speakers (e.g. representing Algenol, TerraVia, Synthetic Genomics, BIO and ABO) had kind words to say about EPA staff and their diligence in administering the regulations, and several stressed that going through the MCAN process is not easy and that EPA gives MCANs a thorough review. Industry speakers defended the need for strong CBI protection, while arguing that confidentiality claims are not necessarily asserted for the most important environmental data.
  • Industry speakers generally thought that the draft guidance was comprehensive and covered the major topics, although some worried that its comprehensiveness may give some observers the erroneous impression that all the data would always be needed for all submission. Suggestions were made to possibly institute tiered requirements depending on the familiarity of the host strain, and one industry speaker even suggested adding common algae strains to the list of hosts potentially qualifying for the tiered exemptions, a comment unlikely to be adopted, as discussed above.

Overall, I felt it was a useful and substantive meeting, and I think EPA got some useful feedback. Public comments will be entertained until November 30, 2016, after which the agency hopes to finalize the algae guidance document. I am planning to submit comments before this deadline, and I’ll report on future developments in the blog.

D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.

 

EPA Public Meeting on Guidance for Algae Submissions

The Algae Biomass Organization recently announced that EPA will be hosting a public meeting entitled, “Opportunity for Public Comment on Algae Guidance for The Preparation of TSCA Biotechnology Submissions” in Tempe, AZ on October 27, 2016, immediately following the Algae Biomass Summit being held in Phoenix earlier that week. This meeting is to continue to seek public comment as EPA works on developing guidance for submitters of MCANs and other notices to EPA for the use of intergeneric algae for industrial purposes. EPA has not yet announced details of this meeting or its physical location, except that webcasting and teleconferencing will be available.

This meeting follows one that was held last year, also timed to coincide with the Algae Biomass Summit. I reported on that meeting from September 2015 in a previous blog entry, and I have also submitted comments to EPA during the public comment period that followed that meeting.

I’ll post updates as EPA provides more information about this meeting in the weeks to come.

D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.

Updating the Biotechnology Coordinated Framework: New Developments

As I’ve reported in previous blog posts, in July 2015 the White House Office of Science and Technology Policy issued a memorandum to the heads of the EPA, the U.S. Department of Agriculture, and the Food and Drug Administration, directing these agencies to begin a review of their biotechnology regulations under the 1986 “Coordinated Framework”, to determine whether revisions, updating, or other changes might be needed in view of new technologies and other developments since the adoption of the framework, as well as “to modernize the Federal regulatory system for the products of biotechnology and to establish mechanisms for periodic updates of that system”. As I’ve previously reported, and as covered elsewhere in the media, these agencies held a series of public meetings running from the fall of 2015 through March 2016, and solicited public comment on these questions.

Last Friday, September 16, the White House announced that EPA, FDA, and USDA have released two documents resulting from this process. The first is billed as “A Proposed Update to the Coordinated Framework for the Regulation of Biotechnology”, and the second is entitled “National Strategy for Modernizing the Regulatory System for Biotechnology Products”. The notice from OSTP said that
“Together, these documents present a comprehensive summary of the current roles and responsibilities of the three primary regulatory agencies with respect to the regulation of biotechnology products and a vision for ensuring that the Federal regulatory system is equipped to assess efficiently the risks, if any, associated with future products of biotechnology”.

I have not yet had the chance to review them in detail (the first document runs 60 pages), and I will plan to post a more detailed analysis on the blog in the days to come. But at first glance, these documents don’t contain a great deal of new information and certainly (in spite of the title of the first document) do not appear to contain any proposals for significant revisions or amendments to the regulations. The first document simply restates well-known agency jurisdiction, albeit in convenient tabular form, and perhaps better identifying potential areas of overlap for some product categories. It also reprints the various “case studies” that were presented at the public meetings in March 2016. And the second document primarily discusses ways in which these three agencies keep the public informed about their activities and the contents of their regulations, along with proposals for how such transparency could be improved in the future. To be sure, the documents characterize one goal of the effort as the mission to “update the Coordinated Framework … by clarifying current roles and responsibilities”, so by this token, the first of these documents can be seen as fulfilling this mission, while not offering very much new information.

I plan to follow up this post with a more complete analysis of these documents, and the status of the OSTP effort to update the Coordinated Framework, in the days to come.

D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.

President Obama Signs TSCA Reform Bill

On June 22, 2016, President Obama signed the Frank R. Lautenberg Chemical Safety for the 21st Century Act, which is the first major update of U.S. chemical regulation law in 40 years. The new law makes important revisions to the Toxic Substances Control Act (TSCA), which has been the U.S.’s primary law regulating the many chemicals produced for industrial purposes, consumer products, and other uses. Modified microorganisms developed for the production of fuels or chemicals may be covered under EPA regulations that are based on authority under TSCA, and my most recent blog post contains a summary of how this new law will affect EPA’s biotechnology regulations. More information about the law can be found on EPA’s website.

D. Glass Associates, Inc.is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.

Impact of TSCA Reform (H.R. 2576) on EPA’s Biotechnology Program

As I’ve previously reported in several blog posts over the years, many modified microorganisms that are being developed for use in the manufacture of fuels or chemicals are potentially subject to regulation under the U.S. EPA’s biotechnology regulations (40 CFR Part 725) under the Toxic Substances Control Act (TSCA). TSCA has been in the news in recent weeks because, after many years of hearings and negotiations, the U.S. Congress has passed new legislation that would revise TSCA to substantially overhaul the way chemicals are regulated in the U.S.. This bill, H.R. 2576, formally entitled “The Frank R. Lautenberg Chemical Safety for the 21st Century Act”, was passed by the Senate on June 7, 2016, and at this writing is awaiting signature by President Obama, who is expected to sign it within days.

Passage of this bill is quite significant, not only because it passed with strong bipartisan majorities in Congress and was supported by the chemical industry, but also because TSCA has been the subject of criticism from environmental groups for years. These groups have maintained that the law gave EPA very limited ability to review the safety of chemicals already on the market, and this aspect of the law has been significantly strengthened in “new TSCA”. In fact, this was the driving force behind TSCA reform, and is its major impact.

There are already a number of excellent, detailed summaries of H.R. 2576 posted online by several Washington law firms (e.g. from Bergeson & Campbell; Keller & Heckman; and Beveridge & Diamond). So I won’t provide a general summary of the law, except to note that some of the key provisions of the bill are requirements for EPA to conduct reviews of existing chemicals on the market, provisions governing when state chemical safety laws can or cannot be pre-empted by federal law, and some revisions to the way confidential information must be claimed in submissions under TSCA and to what information may not be claimed as confidential. I’ll summarize the few provisions of H.R. 2576 that might affect EPA review of modified microorganisms that are the subject of Microbial Commercial Activity Notices (MCANs) or other TSCA notices.

It is important to note that there is nothing in H.R. 2576 that explicitly mentions microorganisms or biotechnology. The provisions of H.R. 2576 most likely to affect EPA’s biotechnology program are those which amend Section 5 of TSCA, “Manufacturing and Processing Notices”. This is the section on which the regulations requiring premanufacture notification (PMN) of new chemicals and MCAN notifications of new microorganisms are based. H.R. 2576 made only minor changes to TSCA Section 5, and none of these changes would affect the authority for EPA’s 1997 decision to create MCANs, TERAs, and the other parts of the biotech regulatory program. But some of these changes may affect the way EPA reviews MCANs and PMNs, as follows.

Consideration of affected populations. First, the bill says that, when evaluating the risk of a substance covered in a notification, EPA cannot consider costs or other nonrisk factors, but is required to consider the potential impact of the substance on populations that may potentially be exposed to the substance. EPA arguably had this authority under existing law, but H.R. 2576 would make it a requirement. For biotechnology notices, this would likely require the agency to explicitly review whether the proposed uses of the microorganism might affect specific populations found near the anticipated locations where the organism would be used, and it might therefore be desirable for applicants to consider whether any such populations exist near their production sites and whether any additional measures would be needed to inform local communities about the intended activities. (As an aside, it would be interesting to consider how this requirement would affect EPA’s review of a microorganism that might someday be intended for use in a consumer product or non-centralized manufacturing).

Provision for fee refunds. Second, the bill provides that, if EPA does not make a definitive decision and/or take action within 180 days of the submission of the notice (i.e. the statutory 90 days for review plus the additional 90 days EPA can unilaterally impose), EPA must refund all applicable fees to the submitter, but the agency would still be required to complete its review and render a determination. This is of course favorable to industry, but may have little practical impact, particularly on the biotech program, since EPA’s usual procedure when it needs more time for the review is to ask the submitter to voluntarily agree to suspend the review period (thus stopping the 180-day clock), making it less likely that decisions would not be reached within the stated deadline (unless a submitter refused to agree to a voluntary suspension, for whatever reason).

EPA determinations of risk. Of more importance, the bill requires EPA to reach one of the following three determinations for each notice submitted:

  • A finding that the substance presents an unreasonable risk.
  • A finding that either the information is insufficient to permit a reasoned evaluation of the substance; or in the absence of sufficient information and evaluation, the substance may present an unreasonable risk; or the substance may be produced in substantial quantities or may enter the environment in substantial quantities, which may lead to substantial human exposure.
  • A finding that the substance is not likely to present an unreasonable risk.

In the case of the first two determinations, EPA must then restrict the use of the substance through a consent order or a Significant New Use Rule.

Although this formulation is quite similar to what has previously been found in TSCA, the statement is potentially broader through the use of the word “or” to delineate all three options under the second determination. At least one law firm has cautioned that this might provide EPA broader authority to reject a notice based on insufficient data or information, and this firm is advising applicants to be sure that their PMNs and other notices contain enough information to avoid this possibility. The firm has also speculated on whether any notifications pending at the time H.R. 2576 takes effect would be assessed under the new standards or those originally found in TSCA.

In my opinion, this change will have a very limited impact on the biotechnology program. In its “Points to Consider” document, EPA provides ample guidance on the data it wants to see in MCANs and other biotech submissions like TERAs, and the agency encourages presubmission consultation, so it is rare for a biotech submission to be rejected solely on account of missing important data. Most MCANs are reviewed and cleared by EPA with very few concerns over the safety of the microorganism, and receive the “no unreasonable risk” finding, but even where the agency had substantive questions, the process to request and obtain additional data from the submitter is straightforward. In the rare case where a submitter is unable to provide any requested information, it would be more common for the submitter to withdraw the MCAN or place it on indefinite hold, rather than to force the agency to issue a finding of insufficient information.

There have been a handful of situations under the biotech program where EPA felt it had sufficient information only to allow certain limited industrial uses of an MCAN microorganism, and in those cases, the agency has used its existing authority to determine that it lacked sufficient information to allow unrestricted commercial use of a microorganism, and instead asked the submitter to enter into a consent order limiting the allowed uses of the microorganism. For example, because the MCANs from Joule and Algenol both proposed the use of photobioreactors to culture modified cyanobacteria, which had never been the subject of any prior MCANs, EPA used the “insufficient information” finding to ask each company to voluntarily enter into consent orders, initially limiting the use of the MCAN strain to the specific facility and photobioreactor described in the MCAN. So, the new language under H.R. 2576 may come into play for a small number of MCAN submissions, but would not substantially change current practice.

Biotechnology exemptions. Unlike some of the earlier versions of TSCA reform bills that Congress has considered, H.R. 2576 makes no significant changes to Section 5(h)(4) of TSCA. This is the section under which EPA created the tiered exemptions and other exemptions from MCAN reporting, and in reviewing one of the earlier Congressional drafts  a few years ago, I had some concerns that an unintended consequence of modifications to this section would have been to place the basis for the biotech exemptions in doubt. As far as I can tell, the one change that H.R. 2576 makes to Section 5(h)(4) is minor and does not affect the portion of this section allowing EPA to grant exemptions, so this is not a concern.

Confidential business information. As mentioned above, H.R. 2576 makes changes to the process of claiming confidential protection for certain information in chemical substance notifications. It establishes by statute the requirement that confidential business information (CBI) claims be substantiated at the time the notification is submitted (with certain exceptions such as marketing and sales data); but this has been required under the biotech regulations for MCANs and TERAs (and I believe also for chemical PMNs), so this will have little practical impact on the biotech program. However, the bill carries forward the provision, as under original TSCA, that health and safety information cannot be claimed as CBI, but it clarifies that process information, explicitly including molecular formulas and structures, contained in health and safety information (e.g. test results) can be claimed as CBI. Such CBI claims have been common in MCANs, and this is likely to continue unless EPA makes a shift in its policies. There are other provisions relating to CBI that have been changed – see some of the law firm general summaries referenced above for more information.

EPA biotech website updated. Finally, I’d note that EPA’s biotech program has recently updated its website listing of MCANs it has received and reviewed. The website had previously listed only those MCANs received through the end of the federal government’s fiscal year 2014 (i.e. September 30, 3014). The site now lists the MCANs received in fiscal year 2015 (there were at least 36 MCANs received that year, not all of which were reviewed favorably and cleared) and six additional MCANs received in the first six months of fiscal year 2016 (trough March 31, 2016). Many of the new MCANs covered modified strains of S. cerevisiae, and as always there were a number of MCANs where the identity of the company and the microorganism were claimed as confidential. There were also listings of three new TERAs received and approved by EPA during FY15. I hope to review and comment on these new MCANs and TERAs in a future blog post.

In summary, although H.R. 2576 represents a significant event that may substantially change many aspects of chemical regulation in the U.S., its impact on the biotechnology program will be minimal. After all, the biotech program is a minor component of EPA’s regulatory programs under TSCA — the agency receives about 1,000 chemical notices a year, but received only 36 MCANs in its busiest year (FY15). I don’t expect any major procedural changes or policy shifts in the biotech program as a result of TSCA reform, although I do see the chance for an unintended consequence: because the biotech staff in EPA’s Office of Pollution Prevention and Toxics also have responsibilities in the New Chemicals Review program, it is possible that new regulatory requirements in the chemical review program might result in less staff time for review of biotech submissions. Otherwise, I expect it will be “business as usual” for the biotech program under TSCA.

D. Glass Associates, Inc. is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.