FDA “Loses” Court Case on Antibiotics in Livestock Feed

March 27th, 2012

FDA “Loses” Court Case on Antibiotics in Livestock Feed

On the evening of March 22, 2012 a federal court ordered the FDA to do more on antibiotic use in livestock to control its use in the hopes of slowing the spread of antibiotic resistance http://www.infozine.com/news/infozine/51254.html.  I wonder if there were not those at FDA celebrating this court loss.

Let’s go back a little while.  In the mid-1970’s FDA expressed concern about the use of low levels of antibiotics in livestock to increase the size of those animals.  This is consistent with my expectations of FDA.  Looking at the position consistently taken by FDA in the pharma industry we have to conclude that development of antibiotic resistance is a major issue to the Agency.    A brief history of the issue has been prepared by Maryn McKenna and can be found here.  The salient message from Ms. McKenna’s blog is that there is clear evidence that the use of antibiotics in livestock feed is a practice that directly leads to an increase in antibiotic resistance and FDA (staunchly opposed to practices leading to the development of antibiotic resistance – author’s note) does nothing of significance in this area for years.    Then, right before Christmas of 2011 the Agency issued an order prohibiting certain uses of the cephalosporin class of antimicrobial drugs in cattle, swine, chickens and turkeys.  An order which was to become effective April 5, 2012.  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm285704.htm

Curious.  Cephalosporin is not really widely used in livestock feed, especially compared to other antibiotics such as tetracycline.  Also, this order did not even halt all use, just some.  In addition, this order completely ignored the far more prevalent use of drugs which have led to drug resistance in the environment (see the McKenna blog entry above).   Finally, the notice was released just before the Christmas break (as if hoping it would be missed in the distractions of the holidays).  It is almost as if FDA was trying to spark a protest.

Now we come to last Friday where the FDA “lost” the court case.   The ruling was in conclusion of a lawsuit filed by the Natural Resources Defense Council, Center for Science in the Public Interest (CSPI), Food Animal Concerns Trust (FACT), Public Citizen, and Union of Concerned Scientists (UCS) last year.   Infozine reports  “The ruling compels FDA to take action on its own safety findings by withdrawing approval for most non-therapeutic uses of penicillin and tetracyclines in animal feed, unless the industry can prove in public hearings that those drug uses are safe.”   In other words, FDA is ordered to do what it has publically stated is a good idea but has not been able to actually accomplish since 1977.

I know several mid- and upper-level individuals at FDA and without exception these scientists are ethical, honest people sincerely concerned with the public health.  In fact, the only disagreement I may have with them is an occasional difference in opinion in how much control over some processes is necessary (they, predictably, are occasionally interested in far more control than I would consider warranted or economically feasible).  I can only infer that the organization supporting these individuals reflects their values.

So why the contradiction between public statements about antibiotic use in feed, and actual action?  There are perhaps two likely explanations.  The first is that FDA is a cynical, evil organization in the pay of big business who is making public statements to appease the masses while participating in a cabal to support profits.  The second is that FDA is trying to do its work, but is being restricted in some cases by external pressure.    Based on my experience, I think the second explanation is far more likely to be correct.

Please remember, I have no inside information on this – I am just reading blogs and news articles like everyone else.  However, I stand by my suspicion that there are people at FDA who are celebrating Friday’s “loss.”

Addendum added April 12, 2012:
FDA issued a press release yesterday on three steps it is taking “…to protect public health and promote the judicious use of medically important antibiotics in food-producing animals.”

“The FDA is publishing three documents today in the Federal Register.
  • A final guidance for industry, The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals, that recommends phasing out the agricultural production use of medically important drugs and phasing in veterinary oversight of therapeutic uses of these drugs.
  • A draft guidance, open for public comment, which will assist drug companies in voluntarily removing production uses of antibiotics from their FDA-approved product labels; adding, where appropriate, scientifically-supported disease prevention, control, and treatment uses; and changing the marketing status to include veterinary oversight.
  • A draft proposed Veterinary Feed Directive regulation, open for public comment, that outlines ways that veterinarians can authorize the use of certain animal drugs in feed, which is important to make the needed veterinary oversight feasible and efficient.”

Here’s the thing – I personally know of draft guidance documents that have taken close to a decade to release due to the intense interdepartmental discussions that are commonplace at FDA.   They got three out in three weeks?   I stand by my original suspicion that the “loss” of this court case was not entirely unwelcomed by FDA.

FDA Public Meeting on Cosmetic Microbiology Safety – Nov. 30, 2011

December 6th, 2011

FDA Public Meeting on Cosmetic Microbiology Safety – Nov. 30, 2011

Scott Sutton, Ph.D.


On Wednesday, November 30th of 2011 I had the pleasure of attending the USFDA CSFAN meeting on “Cosmetic Microbiology Safety Issues”.

This meeting had been announced in the November 1, 2011 Federal Register (vol. 76, no. 211 pp. 67461-3) with a stated purpose to:

“provide stakeholders an opportunity to present information regarding cosmetic safety and to suggest areas for the possible development of FDA guidance documents.   FDA is seeking information regarding microbiological testing of cosmetics; types of preservative systems and how to test their efficacy; the identity and prevalence of microorganisms, including antibiotic-resistant strains, that pose specific health risks in finished products; routes of exposure to microorganisms and the corresponding infective doses; product and packaging characteristics that affect microbial growth and risk of infection; particular subpopulations that may be at greater risk of infection when using different cosmetic products; the occurrence of adverse events associated with microbial contamination of cosmetics; and any other issues relevant to the microbiological safety of cosmetics.”

It was with great anticipation then that I went, hoping to learn what was behind some confusing recent actions in the cosmetic realm of microbiology.  One of the most disruptive of these is the de facto (albeit unwritten) requirement for absence of Bacillus cereus from cosmetics, especially cosmetics for the eye.

The meeting opened with a welcome from Dr. Linda Katz who reviewed the responsibility of FDA in the cosmetics arena, and how FDA interacts with industry.  There was also a brief discussion in this presentation of how FDA gathers information.  Dr. Katz concluded by reminding the audience that this was primarily a “listening session” for FDA.

The following speaker, Dr. Patricia Hansen, presented on FDA’s perspective in cosmetics, focusing on the need for safety.    She pointed out that ISO had developed a GMP (ISO 22716), an antimicrobial efficacy test (ISO/DIS 11930) was discussing the possibility of an international standard for identifying objectionable organisms and setting microbial limits standards for cosmetics.   Dr. Hansen went on to discuss the need to update FDA guidance, eliminating inconsistencies and harmonizing with international standards.   She stated specific needs for input on preservation and microbial quality, on Microbiological Risk Assessment, and on adverse events.  An interesting point was made during this presentation was that the agency feels antibiotic resistant strains of bacteria are objectionable.  This is a debatable point.  As antibiotic resistance is frequently conferred by promiscuous plasmids, the mere trait of “antibiotic resistance” may be a transient state and one that many commensal organisms can share (Mathur, S and R Singh. 2005.  Intl J Food Microbiol 105(3):281-295, Macovei, L and L Zurek.  Appl. Environ. Microbiol. 2006, 72(6):4028-4035, Smith, D L et al.  2002. PNAS 99:6434–6439).

The first public comments were from the Environmental Working Group (http://www.ewg.org/).  Their website states that their “team of scientists, engineers, policy experts, lawyers and computer programmers pores over government data, legal documents, scientific studies and our own laboratory tests to expose threats to your health and the environment, and to find solutions. Our research brings to light unsettling facts that you have a right to know.”   The speaker, Etan Yeshua, urged FDA to protect the microbiological safety of cosmetics, prevent the use of toxic preservatives and require accurate labeling of preservatives (including expiry dating).    He asserted that their organization’s database listed 948 aqueous-based cosmetic products that had no recognizable preservatives (an obvious problem), and that their data show approximately 3500 products were preserved with one or more of 22 toxic preservatives.  Among these preservatives was parabens, problematic, in the opinion of EWG, for its links to cancer and reproductive issues.    He concluded with several specific recommendations:

  • Conduct a comparative analysis of foreign and domestic formulations.  Mr. Yeshua stated that Europe has more stringent limits on hazardous chemicals than does the US, and that many companies will market one formulation in the US and a different one in Europe as a result.  If the product can be made to meet European standards, why should theUS be provided a more toxic formulation, he asked.
  • Improve product labeling to include all ingredients and expiry dating
  • Evaluate the disparity in preservative concentrations among products.  This disparity can be very wide, and FDA should develop guidelines for the safe formulation of preservative products.

The second public speaker was Jay Ansell, Ph.D. Vice President, Cosmetics Programs, Personal Care Products Council (PCPC) (http://www.ctfa.org/).    Their website states that “the Council’s more than 600 member companies manufacture, distribute, and supply the vast majority of finished personal care products marketed in the U.S.  As the makers of a diverse range of products millions of consumers rely on everyday, from sunscreens, toothpaste and shampoo to moisturizer, lipstick and fragrance, personal care products companies are global leaders committed to product safety, quality and innovation.”  He presented an overview of the safety, Quality Assurance program and controls that PCPC member companies have in place through a system of voluntary standards.  In addition to the “built-in quality” of the cosmetic manufacturers, there is currently post-market surveillance for the industry.  As a result, Dr. Ansell noted that the FDA discontinued its Product Experience Report program in 1996.   There is an adverse events reporting system in place, which shows (at least from 2004-2011) that these events are rare, with infections from cosmetics extremely rare.   The ISO, he notes, has an “objectionable organism” standard under development with which they are participating.   He concluded with a pledge to continue PCPC use of quality techniques, risk assessment, regulatory compliance based on science and to assist and participate in FDA initiatives.

The next presentation was from Phil Geis, Ph.D. of Geis Microbiological Quality (an independent consulting company affiliated with Advanced testing Lab).  Dr. Geis, having worked at P&G for 30 years, is a long-standing member of the PCPC Microbiology committee and reviewed several of the projects that the PCPC Microbiology Committee has completed or are developing in terms of product quality and patient safety.   He discussed Quality product design from R&D, and the need for controls on raw materials, preservation, packaging, reasonable consumer use and risk assessment.   Quality is preserved on  the manufacturing side by controls on the facility, raw materials, environmental monitoring and finished product testing ensure safe products.   This testing was assisted by the use of modern microbiological techniques that gave rapid answers to the level of one CFU/g.    The last aspect of safe products, as described by Dr. Geis, was the need for safe use by the consumer. Dr. Geis apparently addressed industry concerns that B. cereus would be identified as an objectionable by emphasizing that cosmetic, though typically including no detectable microorganisms, are not and need not be sterile and that innovation and consumer choice would suffer if sterility was required.   He concluded with the assertion that the US Consumer Industry is the leader in safety, and that industry’s development of appropriate risk assessment tools will continue to ensure that state. “The cosmetic industry has an excellent record of microbiological quality and safety as accomplished with appropriate use of a small number of safe and effective preservatives.  These products are not sterile nor should they be.”

It was after this presentation that the first questions from the floor were raised (although the opportunity had been provided after every presentation).  This author asked the first, noting that the day was more than half over and little had been said about the situation with B. cereus, and none of that definitive.  Dr. Katz replied that FDA needs industry input on what should be considered “objectionable” in a cosmetic formulation.  In addition, there needed to be further definition of products marketed to specific locations (hospitals, assisted care living, etc).    Another question dealt with the use of rapid methods in the cosmetic industry, and how this could be done to the level of 1 CFU (enhancement of numbers by preliminary incubation in recovery broth was the answer).     Dr. Geis, in reply to further questions, repeated an earlier statement that preservatives (parabens and the so-called formaldehyde releasing agents) were safe for use in cosmetics and if forbidden would make cosmetics very difficult to preserve.

The next public comment was presented by Mr. David Steinberg (Principal of Steinberg & Associates, an independent consulting firm – http://www.steinbergconsult.com).  Mr.  Steinberg is Executive Director of the Cosmetic Preservative Council (an organization he founded in 2006).  He presented a review of current cosmetic regulation and the concern over “pathogens”.   Mr. Steinberg then discussed the actual use of preservatives in cosmetics as determined by a voluntary registration program administered by FDA.  According to these data (see Cosmet Toilet Oct. 2008 for article http://www.cosmeticsandtoiletries.com/magazine/pastissues/2008/31010244.html) there are only about 20 preservatives in significant use.  Of these, perhaps a total of eight are responsible for the majority of cosmetic systems on the market.   These preservatives are reviewed for safety by the independent Cosmetic Ingredient Review (CIR).    The problems seen with preservatives in cosmetics, Mr. Steinberg asserted, were due to excessive preservative concentrations in the formulation and this has led to the marketing claim of “preservative-free” being seen as desirable.   This has, in turn, led to a number of dubious “-free” claims.  Mr. Steinberg pointed out the Canadian response to this was to regulate the claim with specific requirements to safeguard the consumer.  He also noted that it is very unlikely that new preservatives will be developed soon.   Mr. Steinberg presented some of the basic economics of the problem, based on increases in expectations for safety and efficacy testing.  In the 1960’s the cost to develop a preservative was about $2,000 (USD). In the 1980’s this had increased to about $100,000 and the last preservative approved for general use in the US took 5 years of development at a cost in the 7-figure range.  He concluded with a pledge to support the FDA in ensuring the continued safety of cosmetics.

Richard Whiting, Ph.D. next presented on a project to develop a risk assessment model undertaken at the behest of PCPC.  Dr. Whiting is Senior Managing Scientist of Exponent (an engineering and scientific consultancy – http://www.exponent.com).    He presented on the mechanisms of risk analysis, focusing on the development of a risk assessment tool to quantify the risk to the consumer of pathogenic organisms in cosmetics.   This presentation emphasized the need for data in determination of risk to the consumer.

There were several questions posed after Dr. Whiting’s presentation.  The first was about risk assessment proper – that this was not really a new topic.  Dr. Whiting agreed, but stated that the quantitative aspect of this effort was new to the industry.   This author then posed a question, noting that investigations into OOS or excursions were expected to follow a particular logic, that a problem was identified, the root cause of that problem determined, a solution to the root cause was proposed and then the efficacy of the solution to correcting the problem was established through data collection.  The first act in this is always to identify the problem.  What was the problem in Cosmetic Microbiological Safety that FDA was attempting to correct with changes in regulatory positions?  An FDA representative answered that this effort was preventative in nature.

After this question and answer period Dr. Linda Katz presented a summary of the conference.   She thanked everyone and reminded the audience that the deadline for submission of written comments to FDA (Docket No. FDA-2011-N-0770) was January 30, 2012.  At this point the meeting concluded.

As I left the meeting I have to admit to experiencing some disappointment.  It is not that FDA was unclear about the purpose of the meeting (to listen to stakeholder comments) or that industry is to be criticized for failing to press points of interest (this probably was not the forum for a “frank and candid” discussion).  However, I did feel the sense of an opportunity missed.  The US faces some significant challenges in terms of product safety – not only in the personal care side but also in pharma, biotech, OTC and medical devices.  However, most of the microbiological safety issues I see evidence of as a consultant and as a fairly well-read observer of the regulated industries (at least that portion related to microbiology and biological contamination control) is the result of either willful or ignorant violations of basic GMP.   In other words, it really does not seem to me that at this time we need new regulation to ensure product Quality and consumer/patient safety.  Instead, at least in my opinion, we need to encourage continued vigorous enforcement activity to remove those manufacturers willing to conduct manufacturing under slovenly conditions and those willing to decrease overhead costs by sacrificing the “Quality” function.   FDA is to be commended for the Agency’s clear increase in enforcement activity, not only against the primary companies but also, as appropriate, the contract manufacturing and contract testing facilities.

However, this meeting did not seem focused on addressing specific problems but rather on a general desire to revise guidance which has, admittedly, been on the books a number of years.  However, spending significant effort on trying to prevent undefined problems does not seem productive and may be distracting.  I wish that the reasons for the Agency’s concern in Cosmetic Microbiological Safety could have been communicated clearly so that everyone could focus on finding solutions to well-defined problems not addressed by current guidance, if these problems exist.

Dr. Robert Mello Reports on Draft of FDA Endotoxin Q&A at PMF Conference

November 7th, 2011

Dr. Robert Mello (FDA/CDER) presented the current draft of FDA’s effort to replace the 1987 Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-product Endotoxin Test for Human Parenteral Drugs, Biological Products, and Medical Devices withdrawn July 12, 2011.   This presentation was made at the PMF 2011 Bacterial Endotoxin Summit being held in New Brunswick, NJ.

This Q&A document will be published in this Q&A format to speed its release over that required for a full-fledged guidance document (as described by Dr. Mello a Level I document takes longer to be released through the regulatory system).  Participants in this effort at FDA include CDER (OPS/NDMS, OPS/OGD andOC/DMPQ), CBER/OVRR/DPQ, CVM, CDRH and ORA (NE Regional Lab and PHIL-DO).  This is, therefore, a document with wide consensus throughout the agency.    The Q&A is a level II document – clarification rather than any new policy, and although this is a “final form” which in due time (when finalized) will be published in the Federal Register, the agency will maintain an open docket for comments.

From the draft introduction:

“This guidance provides recommendations for biologic, drug, and device firms on FDA’s current thinking concerning the testing recommendations and acceptance criteria in…”
  • USP<85>  Bacterial Endotoxins Test
  • USP<161> Transfusion and Infusion Assemblies and Similar Medical Devices
  • AAMI ST72:2002 Bacterial Endotoxins—Test Methodologies, Routine Monitoring, and Alternatives to Batch Testing
“These three documents describe the fundamental principles of the gel clot, photometric, and kinetic test methods and recommend that appropriate components and finished products be tested for the presence of pyrogens and endotoxins.”
Organized in a series of questions, the topics addressed in this document include (with a brief -and highly unoffical- summary of answer as presented):
  1. How do I establish a sampling plan for in-process testing and finished product release?
    Start with maximal coverage in this dynamic plan, adjust downward with experience (notify FDA of changes)
  2. When is retesting appropriate?
    It depends – all testing records must be retained and reported but review USP <85> for some guidance.  Further:     “All testing procedures, including those for retesting within the above limits should be specified in advance in written standard operating procedures approved by the firm’s quality control unit.”
  3. Is sample storage and handling important?
    Yes – firms should have data to support written practice
  4. Can finished product samples be pooled into a composite sample prior to analysis?
    Yes, but there are some important restrictions based on manufacturing and product characteristics.    If done for small volume parenterals it is important to adjust MVD to reflect pooling dilution.
  5. What is the best process for transitioning from one bacterial endotoxins test (BET) method to another?
    This is a bit involved in the guidance, but generally follows USP <1225> and needs FDA involvment either through a Prior Approval Supplement (existing product) or Prior Approval Supplement-Comparability Protocol (CP) (approval of a general method for transitioning).  The changes in individual products are presented to FDA then as a CBE (change being effected).
  6. May a firm use alternative assays to those in the USP for a compendial article?
    Yes, but it must be validated (USP <1225>) and in the event of a conflict the USP method serves as the referee test.
  7. What happened to the endotoxins limit table in Appendix E of the 1987 LAL Guidance?
    It is out-of-date.   “The appropriate way to establish the endotoxins limit is to use the calculation methods provided in the USP or AAMI standards.”
  8. How can endotoxins limits support Quality by Design concepts?
    This section provides some very useful information on the establishment of raw material and in-process specifications.  Trending is encouraged.
  9. When is the USP Chapter <151> Pyrogenicity Test (the rabbit pyrogen test) appropriate?
    Generally, when required by monograph, although some consideration should be given to the potential for contamination of the product by non-endotoxin pyrogenic material.
  10. How would an appropriate endotoxins limit be determined for a product that targets multiple species?
    “For a veterinary product labeled for use in multiple species, the limit should be based on the maximum product dose used on the smallest species…”
  11. What are the endotoxins limits for medical devices?
    These are basically described in USP Chapter <161> Transfusion and Infusion Assemblies and Similar Medical Devices and ISO 11979-8, Ophthalmic Implants, Intraocular Lenses, Supplemental Information Sheet, although devices associated with the eyes are a special case and need to be considered as such.  It is advised to consult the medical division for additional information on established these limits.
  12. What is the FDA’s expectation for regular screening of therapeutic drug products?
    It should be done at the most concentrated form that does not have interference in the test from the product formulation.
  13. Are control standard endotoxins (CSEs) still acceptable for use in running BETs?
    Yes – so long as they “are suitably calibrated to the international reference endotoxins standard.”

In summary then, Dr. Mello provided a preview of the soon-to-be-released Q&A on bacterial endotoxin testing by FDA.  This presentation was given to the 2011 PMF Bacterial Summit, moderated by Karen McCullough and presented by PMF, a not-for-profit scientific and educational associate.   Other speakers at this conference include such notables in the bacterial endotoxin field as

  • Ron Berzofsky, Ph.D. Wako Chemicals USA
  • Alan Baines, Lonza
  • Mick Dawson, Ph.D., Associates of Cape Cod
  • John Dubczak, Charles River Laboratories
  • Dennis Guilfoyle, Ph.D., FDA ORA
  • Amy Karren, W.L. Gore and Associates
  • Karen McCullough, MMI Consulting
The PMF presents directed conferences and workshops to the microbiology community on topics of interest.  These conferences present the most recent information from a regulatory and scientific perspective from international experts in the industry.
This summary is provided for information only and should not be used as regulatory guidance.  The PMF, Microbiology Network, or any affiliated institution or individual is not responsible for decisions and actions taken by others after reading this posting.  This summary is prepared by the author and should not be assumed to be the work of any employee or associate of FDA.
Scott Sutton, Ph.D.