Panel Discussion - Common Pitfalls in Submissions

Brian Belliveau, Ph.D., Health Evaluation Division, PMRA

Thanks, Mike; and Thanks, Jerry.

        Lisa Lange has already given a walk-through of some of the common administrative pitfalls that are encountered with submissions to the Pest Management Regulatory Agency. I'll be touching a little bit on those as well. And I'll be echoing some of the same kind of comments that Mike just made about common administrative and scientific deficiencies.

        I come from the science evaluation side of the PMRA. The particular group that I'm currently working with is the Microbial Unit which is part of the Health Evaluation Division, one of the three science review decisions in the Agency. The one distinction that the Microbial Unit has to other evaluation sections in the PMRA is that it has reviewing responsibilities for three main areas: product characterization and analysis, human health and safety, and environmental fate and effects. The one reviewing responsibility we don't have for microbials is the value and efficacy component.

        Right now, I'm just going to try to walk through some of the issues that Mike and Lisa just raised, but from an evaluation perspective. So, yes, while some of these are administrative problem areas, they also impact on how we as evaluators are going to review your product submission.

        Labeling issues. The PMRA requires standard statements that are described in our Registration Handbook which can be found on the PMRA web site. It is a fairly large document, but it contains specific guidance on labeling for TGAIs, manufacturing products, and end-use products. It's primarily geared for chemicals, but there are common labeling issues for microbials as well as for pheromones.

        For microbials, the PMRA has a regulatory directive that Lisa already pointed out, Directive 2001-02. In one of the appendices in the back of that document, there is specific labeling guidance for microbial products.

        In Canada we recognize that all microbial agents, by definition, will have foreign antigens which can elicit a hypersensitivity response in humans. What we have done to address this concern is require on the principal (front) panel of Canadian labels the signal words "potential sensitizer." And we also require the signal words "caution eye irritant" on the principal display panel. Now, let me qualify that labeling requirement by saying that we don't require as part of a basic data package an eye irritation study for microbials. We've basically drawn the conclusion that all microbial products have the potential to be mild reversible ocular irritants, and we will label them as such. If you do not want to have that statement on your label, then you will have to provide us with an eye irritation study that shows that it's not an irritant.

        Continuing with the labeling issues, one of the things that we do require on microbial labels because they are biological products and their field performance is often dependent on their viability is a date of manufacture stamp and an expiry date. The determination of an expiry date is based on results of storage stability data. And I'll be going into a little more detail on that tomorrow in the product characterization presentation.

        The next issue is product name and guarantee. Guarantee refers to the minimum or nominal concentration of the active ingredient that's found in end-use product. Often the product name and the guarantee on the label do not correspond with the name and guarantee on the Product Specification Form. The reason for this anomaly may be because there were changes made to the product sometime during product development. I think it might be obvious to you, because you're more familiar with your package and your product than we are, but you cannot assume that we will be able to make assumptions that they are equivalent. You have to make it clear to us.

        Strain designation. This is often not included on the guarantee line of either the end-use product or technical grade of the active ingredient label. Again, this is a specific requirement for microbial product labels because we don't grant registration for a specific microbial species, but for specific strains of that species. And that's very important to remember. The main reason for strain-specific registrations is because there could be a competitor's product that has the same genus and same species name of the active ingredient as in your product, and we must have a means of distinguishing between them.

        These are some of the issues from an evaluation perspective that are often missing on a Product Specification Form. On this form, all the ingredients in the product must be listed on a percent weight-by-weight basis. The nominal concentration (or the average concentration) of each ingredient, with designated upper and lower limits, must also be specified for the active ingredient, and in the case of end-use products, for all the formulants, or what is most commonly referred to in the U.S. as inerts. All the ingredients in the nominal concentration column of the PSF must total 100 percent. That was mentioned earlier today. You'd be surprised at how many times we find the ingredients don't you take out the calculator and add it all up, and it doesn't total 100 percent. So the PSF goes back to the applicant for correction. It's another example where we as a regulatory body can't make assumptions about what is in your product and how much is present. We can't assume you've just made an arithmetic mistake. You could be leaving something out of the list of ingredients.

        Not reporting CAS (Chemical Abstract Service) numbers for formulants isn't always a problem, but it can be for obscure ingredients. You'd be surprised how often CAS numbers are not included on the Product Specification Form. They should always be reported, where one exists.

        We recently added a number of standard forms on the PMRA web site, including the PSF, that can be filled in electronically, but there is still an option to submit forms filled in by hand. We prefer the electronically filled in forms because oftentimes the writing on the written forms is illegible. So my advice is to print legibly if you're not submitting an electronic version of the PSF.

        Now on to some of the data issues. This first item has already been touched on a couple of times today, but I'd like to repeat it because it's so important and it's often overlooked or underappreciated by applicants. Rationales for data omission (or the more common term "waiver requests") are either missing or not based on sound scientific reasoning.

        Now, Mike already mentioned that you can't make the assumption that we will know as much about the microorganism in your product as you know. You have to approach writing up your waiver requests as though we know nothing about the organism and spoon feed us the necessary information to gain the familiarity that you have. It may be obvious to you why you shouldn't have to fulfill a certain data requirement, but it may not be obvious to us. Use of published literature on either the specific strain to be registered or closely related strains or even species can be used to support a waiver request.

        Now if you submit published papers to address a particular data requirement as justification for why you should not have to do an actual study on your microbial active ingredient or end-use product, that's fine. Submit the papers, and they should be legible and complete photocopies. You'd be surprised at how many times we'll get double sided photocopies with every other page missing or the margins cut off. You've got to take the time to check over the quality of the papers and make sure that we're going to be able to read and review them.

        Now if there isn't a whole lot published on a particular group of organisms and you still feel that you shouldn't have to demonstrate safety of your active ingredient through actual test data, then at the very least, provide us with a list of key search words and the data bases that you've searched when you've done your literature search and provide us with the printouts.

        One of the other things that we'd like to see because it facilitates our scientific review (and if it facilitates our scientific review, we might finish our review a little earlier than time lines specify) is to critically assess the scientific quality of the papers in the form of a mini-literature review so that you have a very firm understanding of what you're proposing and why you think the particular papers that you're using to support your argument address the underlying concern behind the data requirement. So I think it's quite important to accompany the papers with a literature review.

        Another pitfall that Mike brought concerning microbial products is the lack of quality control data. Both agencies essentially require five-batch analysis testing for microbial contaminants. And you have to provide us with the results of those analyses and demonstrate an absence of primary animal pathogens.

        For other contaminating microorganisms, you must quantify or enumerate them, preferably using microbe-specific growth media, and then the Agencies will determine whether or not the contamination levels are acceptably safe. It's difficult to say what levels are going to be acceptable because we need to factor in the use rates, use patterns, frequency of application, and the potential exposure to nontarget organisms, including applicators and bystanders. One of the key considerations in the human health and environmental safety assessments is not what just the impact can be of the active ingredient but of any contaminating microorganisms that may be presents in the end-use product.

        The next item I already alluded to is either no or inadequate storage stability studies that address the shelf life of the product. One of the key things that we have to factor into our assessments covers off performance and Suzanne Chalifour will go into this in more detail tomorrow when she discusses efficacy requirements for microbial products. But part of the reason for requiring storage stability data has to do with efficacy. We have to ensure that the product is stable for a specific period of time so that it will perform at rates claimed on the label. In storage tests, it may also be important to address contaminant microorganisms and whether they stay at or below acceptable levels or increase to levels which could pose a health or environmental risk. These are just two reasons why we need to have good storage stability data.

        Also, from an evaluation perspective, you must submit either Material Safety Data Sheets (or MSDSs) or manufacturer specifications for each formulant in the end-use product or TGAI if it's a stand-alone product. For many microbial products, there may not be a separate technical grade of the active ingredient especially if the product is produced via a continuous manufacturing process. However, the PMRA still requires registration of the technical product, but this may be considered more of a paper exercise. Another of the other data issues which Mike already touched on is proper reporting of the test substance in study reports. You'd be surprised how often we encounter this problem. Oftentimes it's caused by a miscommunication or a lack of communication between the applicant and the testing facility (the contract house, that's doing the test for you). Alternatively, the name of the product (technical and/or end-use) may have changed since the study was conducted and you may not have provided us with a list of previous names. So it's very important that you indicate what it is that you've tested.

        Sometimes it can be a simple mistake of not testing the right product. For example, a requirement for dermal toxicity testing on animals is with the end-use product. And you'd be surprised at how often we get that study done with the technical product instead. This is problematic because the main purpose of the dermal toxicity study is to test the toxicity of the active in combination with the formulants. If this happens, we will ask that you write a waiver or a justification why you shouldn't have to redo that study with the end-use product to account for the potential effects or impact of the formulants.

        One of the problems that we often encounter when reviewing study reports is not having enough of the raw data or worked-up data that will allow independent analysis of the test results. We need to be able to verify interpretation of the results by looking at the data and redoing calculations to ensure that there aren't any mistakes made. It is critical that you supply us with all the necessary data to conduct statistical analyses where necessary to interpret the results.

        And lastly, another key issue that's already been touched on several times is the importance of presubmission consultations to identify specific data requirements for your product. We're going to be discussing this in greater detail tomorrow, but I'd like to point out that for microbials it isn't possible to have a preset list of data requirements that will be relevant for all microorganisms. Every microorganism is unique and therefore the data requirements needed to assess the safety of a particular microbial pesticide must reflect its uniqueness.

        So I'll leave you with that for today.