Chapter 22

Field Trials in Latin America: Se Habla GLP?

Steve West

Research Designed for Agriculture, 2246 West 19th Place, Yuma, AZ 85365

Agricultural research work that is conducted to support pesticide import tolerances in the United States and the European Community must be done with increasing regularity in Latin America. Performing such research in full compliance with the FIFRA and OECD Good Laboratory Practice requirements poses unique challenges in Latin America. Presented here are some of the obstacles and challenges one might face when conducting this type of field research.

As the pesticide and food safety regulatory systems of the United States and Europe have matured, the issue of residues in imported food has taken a higher priority. Non-Latin countries now regularly require field residue trials to be conducted in Latin America on commodities such as bananas and coffee. The United States EPA's policy of requiring 12 GLP field trials for bananas, or Europe's benchmark of 8 GLP field trials for "major crops", such as bananas, has added a new wrinkle to getting the work accomplished.

Without a doubt, a network of field researchers, both within the major chemical companies and the small contract research companies, does not exist in Latin America to the extent that it does in Europe or the United States. In Latin America, traditionally, the government agencies, such as the various universities or the federal or state run agricultural research services, have conducted virtually all of the field research except those projects conducted by sponsor staff. With the move of importing countries to require GLP field work in Latin America, there is a lack of infrastructure to accommodate the work required. Unfortunately, the reality is that the agencies, such as the universities and state run research services, are seldom in a situation to successfully conduct GLP studies. Sponsors, by and large, had quit using public agencies for GLP studies years ago, primarily, because the mission of these agencies and the expertise available were not consistent with the extensive requirements of GLP.

© 1999 Amer ican Chemica l Society 181

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This has led to the necessity of sponsors either to go to the arduous and time-consuming task of training their own people or hiring out their work. For companies that have large, on-going programs, setting up an in-house GLP unit is an option. But in Latin America, as in the United States and Europe, the major companies are discovering that maintaining a current, effective in-house GLP field staff is very expensive. The reality is that unless you do GLP work all the time, you fall out of practice. The extremely high levels of compliance required by the sponsor Quality Assurance Units and by the regulating agencies makes documentation mistakes unacceptable. The learning curve is now over, and the work must be either near perfect or it is rubbish.

Over the past 7 years, Research Designed for Agriculture has been conducting GLP field trials in various Latin countries. Our experience has led us away from sub­contracting fieldwork and now RDA conducts studies with its own, multi-national staff based in Yuma, Arizona. This paper attempts to convey some of the challenges and obstacles of accomplishing GLP fieldwork far from home.

Components of Conducting a GLP Field Trial in Latin America

What is GLP? For the purposes of field research, GLP is really very simple. The trial must be conducted according to a protocol, using SOPs, and with ample documentation to be able to reconstruct everything that happened. This is critical because unforeseen things will happen.

Reliable Information. The biggest single obstacle in getting started with field trials in a remote, or "off site" area is getting accurate information. This is the case whether you are doing a field trial across the county or across the ocean. The difference is that when you are across the ocean, poor information has the potential to be much more disastrous. The consequences of flying to another continent in anticipation of finding flowering grapes, for example, and then finding when you get there that they flowered 10 days ago, can be catastrophic. Obtaining reliable information on everything you can imagine is, without a doubt, the most important, the most critical, and yet the most difficult component to conducting a field research trial.

Why is this? It would seem that this should not be so difficult. The problem lies in the foundation of viewpoint. Most often the people we contact for information are not other small plot researchers. Often contacts are in company headquarters or tied to a desk. Even those who are out in the field are usually traveling to many areas and viewing many crops. Their information may be well founded from a field or area, but it is not accurate for the location where your plots need to be located.

Many times the growth stages or timings are somewhat ambiguous to those not accustomed to GLP residue trials. Frequently, the information we are asking for is not something people normally think about. For example, in most areas the broccoli goes from seed to harvest in about 120 days, but ask someone, even someone very familiar with broccoli, exactly what the growth stage will be six weeks before harvest, and you will get a range of answers. Since the harvest window on broccoli is only 10 days or less, being off two weeks is a significant problem.

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Protocol. Writing a proper protocol for the conduct of an "international" field residue study is somewhat more difficult than for a domestic study. Most commonly we work with studies that are being run by either a United States company or by the United States branch of a company. The protocols and SOPs referenced are all written for trials executed in the United States. They don't take into account the lack of infrastructure in many foreign countries or the scarcity of many items and services commonly found in the United States. These differences account for at least half of the GLP problems on international studies. Marcus Jensen discusses the topic of protocols and related GLP issues in greater detail in the next chapter of this publication.

Site Selection. With some studies we are allowed the option of choosing any location in one of several countries; however, in other studies we must stick to areas specifically required by a regulatory agency.

Site selection is broken down into two basic decisions. The first decision is the general area. For example, if we are doing tomato trials in Mexico, we need to decide if the trials should be in Sinaloa, Baja California, or Michoacan. With banana trials, the choices are broader. We decide if they are to be done in various countries, and then within the countries, we look at the various areas.

Personal Safety. Unfortunately, personal safety has become a significant issue for site selection in some areas. Whenever a new project is discussed, the question of personal safety moves to the forefront. At RDA, we have a policy of not taking projects in areas we perceive as dangerous. Columbia, parts of Mexico, and Bosnia, among others, make this list. The wisdom of this decision was reinforced in early 1997 when an American was kidnapped while conducting field trial GLP quality assurance inspections in Columbia. (After paying the ransom, he returned home.) Areas with high incidence of cholera, malaria, etc., are also avoided.

Field Considerations

After the general area is determined, a decision on the exact field location must be defined. Sometimes this is a field that is custom grown for the experiment, other times the work is conducted in a commercial field. In either case, finding someone you are confident will work with you today and tomorrow is critical. However, it is not just enough to feel good about the manager or owner. The worker making 5 dollars a day in the field has just as much (or more) influence on the outcome of your trial as the owner. It is important to talk to and get on good terms with the foreman and workers in the sections of the farm you are working.

Field Practices and History. Identifying a site with the proper field history can sometimes be challenging. In most Latin countries, the economies are such that price is the over riding factor in pesticide usage. Consequently, many of the older, off patent, organophosphate and carbamate insecticides are heavily used, as well as the lower priced fungicides such as EBDCs. If a protocol restricts either the history or

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current season use of one of these products, you may well be forced into the expensive choice of having a field custom grown. It is important that the protocol and appropriate SOPs, which reference the history, are referenced and appropriate GLP documentation is provided.

Current Season Practices. These are equally important to know. If you are planning a corn study that will be harvested for grain, be sure that the grower doesn't cut at normal silage time, and that alfalfa for that type of trial will be cut and allowed to dry for hay and not all cut and sold as fresh forage as in central Mexico.

Support Services. If you will be using support services such as aerial applicators, commercial freezers, trucking companies, etc., be sure you talk with them prior to starting. Having an aerial applicator that will work you into the schedule and treats you as a client is valuable. Working with an applicator who puts you off as a nuisance is often fatal.

Access. Access is an underestimated challenge in international work, and it means more than good roads to the field site. Do you have access to hotels that aren't always overbooked? Have you found access to places that supply C 0 2 for your sprayer or dry ice to freeze samples? How about rental car availability? This already assumes that you can fly into a reasonably close location, and that the one flight that day was on time, or even running. In a two-month period one fall, we had to delay starting trials by a week because of rained out roads and needed to scramble several times because the cars we reserved (and "guaranteed" with Hertz) were not available when we arrived.

Access problems of all sorts will cause delays and challenges that are seldom foreseen. In Costa Rica, on three different occasions the main road from San Jose to Limon was closed due to land slides on the nights I was trying to meet an early morning spray appointment. Is driving and extra 3 or 4 hours into the wee hours of the morning so you can sleep for 2 hours before meeting the pilot at 5:30 a.m. what you had in mind? Will the sponsor be receptive to the excuse that the application was not on schedule, for the third time?

Trial Layout

Trial layout brings on a set of unexpected challenges. Finding a suitable permanent marker can be frustrating and often takes some imagination. In many areas, the high amount of pedestrian traffic will thin out the plot flags. We have had some plots that have required reflagging every time we came to the field. On one occasion, we were marking off a 2000-meter long plot in a banana field by carrying a 100-meter tape. The person in front would stick in a flag at the end of the first 100 meters and the person following would move up and stop at the flag, then the person in front would move on and place another flag at the end of the second 100 meters. As soon as we were finished, we walked back down the farm road to collect the flags, which were already gone! !

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When it comes time to put in area maps for general reference, you may find that none exist. I have been places where I think that everyone in the area was born with an innate road map. Everyone knows where even the most obscure place is, but no one has ever even seen a map of the area, let alone know where to buy one. I recently had to write in a trial notebook "No local map available, and this is one of those places you'll have to be taken too, as you can't really get there from here without a guide".

Without proper GLP documentation in the trial data, solving some of these challenges would be impossible. Actual maps of how to find the plots on the farm are critical. Care should also be taken to be sure that sponsor required items in the protocol and required SOPs are identified and addressed now to avoid mountains of problems later.

Test Substance

Bringing experimental compounds into a foreign country can be challenging. Bringing in small quantities of GLP characterized lots of a labeled compound into a foreign country can be just as big of a challenge.

The source of the shipment is significant. Shipments coming from the United States, if the product is not labeled, have to carry the warning that the product is not approved in the United States, which makes many countries nervous. In other cases, the sponsor company's import permit for a labeled product is for product coming from France, for example, but the GLP characterized product comes from the pilot plant in England. This creates more logistical hoops to jump through.

Another aspect of small lots it that they are labeled differently. Even if there are permits in place for either the commercial or experimental product to be imported, usually the people filling out the paperwork for the permit are not the ones in the lab labeling the containers. The containers of Test Substance arrive, labeled with the essential GLP information, but it is not the same information. The import permit says "methyl acidiazole", but the container is labeled "RD-4489".

In some countries, the delays in customs can be interminable. On one occasion in Costa Rica we had to wait 30 days for the sponsor to get the product cleared from customs. We had no idea what the storage conditions were in the customs house, and as is normally the case, the sponsor did not include a thermometer in the shipment. The sponsor was sure that this oil suspension product was stable, so we pulled a sample for analysis and started the trial. After the analysis came back, we did the trial again with a new lot.

It also is important to use the correct formulation. Too often we do trials with a substandard formulation. Starting an international trial with an experimental formulation is foolishness. On the airstrip in Guatemala is not where you want to find out that your new formulation settles into a concrete cake at the bottom of the 200-liter drum provided for the air trials we are doing.

Once you get the correct formulation there, you have to find a place to store it. It needs to be secure and accessible. Often the sponsor's people want to keep it in their warehouse or at one of their distributor's warehouses. However, they may not be

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around at 5 a.m. Sunday morning when you need it or be available Saturday night at 10 p.m. after you drove back in from the field and got delayed by an auto accident on the highway? What do you do with it now? Your flight is at 6 a.m. the next morning and everyone you know is out of touch!

The question of temperature during storage is fairly straightforward as recording thermometers or min/max thermometers can be used. Finding a temperature-controlled facility is not realistic. If you have a product that can't be stored over 90 degrees; you may be in trouble. Warehouses in the desert areas of Chile will regularly be 120° F in the afternoons. Unless the product containers are small enough to be kept in a refrigerator, keeping the Test Substance cool under such conditions is next to impossible. Even if you keep them in a refrigerator, power in many of these areas is subject to frequent outages. If the refrigerator is out on the porch in the sun and the power dies for two days, you will have a high peak temperature. If you are using a min/max, and are there only once every two weeks to make an application, you have a lot of explaining to do, and possible re-analysis of the compound.

Once the trial is completed what to do with the left over Test Substance? Better yet, if it is a United States EPA trial, what do you do with the containers?? Re­importing them into the United States is difficult unless they are really clean. If you have any significant amount of Test Substance left, disposal is challenging. There are no easy answers to this, and every situation is different, but the issues must be dealt with.

Application

The application equipment to be used is driven by the protocol, crop and plot size. Air trials in bananas require aircraft, and airblast applications to citrus require turbine blowers. Post harvest applications almost always require a unique set up, anything from a 5 gallon bucket dip tank to a commercial 300 PSI micro mist chamber. Field crops are usually treated with a conventional boom sprayer. If the plots are to be large, generally, commercial equipment will be used. If the plots are small, then small plot equipment is called for.

Our experience with commercial aircraft in Latin countries has been good. As an example, this past year we have been working off a runway in Costa Rica where I counted 8 turbine Thrushes one morning. Added to the three radial Ag Cats, I calculated there to be about 5 million dollars worth of aircraft there. These aircraft are state of the art, and the pilots operating them are first rate. The biggest hurdle to cross is getting an applicator that is available when you need them and willing to put up with the idiosyncrasies of GLP work. Finding an aerial applicator willing to do this every two weeks, even when they are busy and behind from five days of rain that has kept them grounded, is truly challenging.

When field trials require airblast or large plots, you're normally forced into borrowing equipment. Our experience with borrowing grower equipment has been less positive. Tractors without any tachometer make repeating speeds and spray pressure (on PTO driven sprayers) an art form. Functioning pressure gauges are on

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the endangered species list. You can count on pumps leaking, or being worn out, and the spray nozzles are seldom the same size, let alone in new condition. It is very important that you know the equipment intimately and are prepared to completely overhaul it if you want uniform spray patterns. We used a grower's sprayer in Chihuahua in 1996 where we brought down 300 feet of hose, 30 new pressure relief nozzle bodies and all new spray tips. This $500 investment was well worth it as the grower liked having his spray system completely redone, and the amount of time we saved in calibration and fixing leaky hoses and nozzles was immeasurable. Not all grower equipment is in poor repair. We have found some cooperators where the equipment was in top shape; however, that is the exception, not the rule.

In other cases, we are supposed to mimic local practice for application methods. Since labor is inexpensive in Latin America and equipment is not, the spray methods follow suit. Usage of the "Solo" type hand pump, single nozzle backpack sprayer is very common. In Central Mexico, the technique for spraying cabbage is to spray each head until runoff, with even more run-off on the plants damaged by worms. How do we do a uniform GLP application like that? Pole tomatoes are similarly handled, with crews with backpacks waving the wands up and down and pumping up the pressure every few meters as they walk the 1 meter tall rows. These methods may be effective controlling the pests, but when you are measuring parts per billion of residue on the fruit, you want to be more uniform in your methods.

Whenever possible, we try to use our own equipment for plot spraying. It is designed for the purpose, and we know the condition of it. While it is sometimes possible to borrow small plot sprayers (normally C02 backpack sprayers), we try to avoid that since there are seldom logs telling you what was in the sprayer last or what type of cleaning is needed to clean it up.

Mixing the chemical often presents problems. If the product is a dry powder, how will you weigh it? What if the balance you brought dies? What will you be using for standard weights? If the product is a liquid, things are easier, assuming you use plastic cylinders or syringes. If you like using glass cylinders, have in mind a good source where you can get replacements on Good Friday when yours is in pieces. Many protocols are now asking for potable mixing water. More than once I have stopped and bought a 5 gallon "water cooler" bottle to take to the field since only pond water was available there. When slurries need to be made, or water of a certain temperature is to be used, additional equipment is needed. Making small batches for big machines like aircraft also requires some forethought. We regularly use 200-liter drums with the lid cut off for small mix tanks and for agitation we have several electric trolling motors for boats in stock. The big mixers found at airstrips often won't even prime with our mixes.

When you do bring your own equipment, a safe place to leave it where you can get to it when you need it is required. The same comments about test substance availability apply here as well. Another issue to deal with is whether you need the sprayer elsewhere. Not many of us can afford to have several sets of $1,500 sprayers and related equipment scattered all over Central America at the same time. If you need to move it around, getting C02 is an issue, as is paying the fees and obtaining

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the permits to import it into the country. We spend hundreds dollars a year on import permits for Mexico alone, just for our equipment.

Invariably, when you move equipment around, and even if you don't, it will eventually break. Having the tools you need, and the parts required is critical. Finding a replacement part for a specialized sprayer in Honduras may be impossible, and if not, it will consume time at the least. Carrying pipe threaders, nozzle bodies, gaskets, gauges, etc., etc., is not a luxury, it is essential.

Making the application is about the same as anywhere, except that you are a long way from home and on a tight schedule. Windy days, hurricanes, rain storms, wet fields, labor crews in the way, etc., are all problems to deal with. The hitch is that when you get delayed you get to rebook your flights, hotels, rental cars, etc. It becomes expensive. If you have other trials you are moving to after the one your working on now is done, you may incur ill will for the people waiting for you there, and Sponsor A may not think that waiting out a storm for a trial with Sponsor Β is a good reason to deviate on their schedule.

Sampling

Unquestionably the toughest part of sampling is having the right crop stage to sample. With one of our first trials with Cauliflower in Arizona, we were working in a commercial field of Tanamura and Antle, the second largest vegetable company in the United States behind Dole. We wanted to set up our spray schedule based on their predicted harvest maturity, after all, they are the experts. We asked, "When will the crop harvest be so we can start our sprays 6 weeks before then?" The answer? "Your guess is as good as ours, we missed the harvest dates by 30 days last year!! The weather turned cold, and we were off!". Last year in Arizona, the early head lettuce took only 65 days rather than the usual 80 because it was hot. This unpredictability plays havoc on long distance trials especially, because you are normally not there all the time to see the delays or speeding up of the development of the crop.

Assuming you are lucky enough to be close on your timings and the crop is ready when the trial is, getting dry ice to freeze or ship samples, freezers to store retain samples in (essential), finding the labor to assist you when needed, arranging for the combine or other commercial harvest equipment you need, and so on requires patience, forethought and often, luck.

After the samples are in the ice chests and ready to go, you either need to have a good freight forwarder that can assist you in shipping the samples to the destination country, or you need to carry the samples as baggage. We normally prefer to follow the baggage procedure, as we have the permits needed to import frozen Ag products, and it is much quicker to hand carry them through Customs and Plant Quarantine inspections. The catch is that you are limited on the amount of dry ice you can carry on a plane, so you'll need to have the samples super frozen so they can remain frozen with the approved quantities.

Having a good supply of dry ice available is really helpful. Over the years we have located virtually all of the dry ice suppliers in Latin America. Even with good

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plans, samples get lost, so it is quite important that you have a reserve set of samples reliably stored frozen where you can come get them in the event of a problem later.

The cost of sample shipping is very expensive. It is not unusual to spend five thousand dollars on shipping samples over seas. We recently spent over one thousand dollars on excess baggage for hand carrying some samples. It would have been twice that, but the Mexicana people gave us a break since we flew out of that airport so much and they knew us.

Data Documentation

In order for any of this work to be acceptable, it needs to be GLP. This is much easier if your SOPs are written flexibly enough that you don't have countless deviations in the normal course of work. Normally, this means not using the sponsor SOPs. You will need to make up training logs on the spot for pilots, harvesters and anyone else who helps you in the field. Developing equipment logs and documentation in the data of all the various equipment such as freezers and sprayers that you borrowed is a given.

As in the United States, plan on all field data except that which you generate to be nonGLP. Sometimes the field history data we can obtain in Latin America is better than the same data obtained in the United States. Commonly though, fields are rented, so you often have a situation where the last farmer for that field is unknown. If the sponsor has a problem with this, the time to know it is prior to the work being conducted. Unless there is a potential chemical conflict found from the use history, it is a noncritical requirement; however, it is amazing how some QA people, in particular, believe the world is ending if we don't know how many times an insecticide was sprayed on an onion crop three years ago.

Availability of weather data, GLP or otherwise, can be challenging. Mexico has an excellent weather data collection system, on a par with NOAA in the United States. It took us a couple of years to find the right people to call, but now that we have that connection many problems are solved. You may have to settle for weather that is a long way away, however, especially in countries other than Mexico and Chile. The concept of on site data is great, especially if you have a big budget for replacing expensive automated equipment. When you cannot keep plot flags in the field, there is little chance of keeping a $1,200 automated rain collector. Now that EPA is just asking for a general statement regarding the weather compared to "Normal" there is less need for on-site data.

Conclusion

Conducting a good quality GLP study in Latin America is possible if you are willing to make the commitment to make it happen. To do so successfully takes a more flexible mind set from the study director, extensive planning, qualified people who can make something out of nothing, imagination to make do with what is available, and, of course, luck. No amount of planning and money can buy a sunny day. The realities of culture, distance, and nature validate the agriculture version of Murphy's Law "Some things will go wrong, we are just never sure which things." and then the International Anecdote "Murphy was a damned optimist".

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