Implementing Contamination Prevention, ed. 2 English (2008)
SECOND EDITION
Disclaimer
The information contained in this booklet is accurate to the best knowledge of the Manufacturing and
Supply Chain Steering Group (MSCSG) of the European Crop Protection Association (ECPA), but no
liability whatsoever can be accepted by this Group, ECPA, CropLife International or their member
companies in respect of the use of this information, nor in respect of any advice contained herein. The
contents of this booklet including the Guidelines are best practices, which are recommended by the
MSCSG. Implementing Contamination Prevention measures is the responsibility of individual
members of the ECPA and CropLife International together with their toll manufacturers. Each company
in its contracts is free to adopt its own standards, which may be different.
Implementing Contamination Prevention, ed. 2 English (2008)
Acknowledgements
The MSCSG would like to express their thanks to the authors:
Dr. Marten Snel, Dr. Urs Stutz, Mr. John K. Olsen, Dr. Wolfgang Schäfer, Dipl. -Ing. Heiko Wolf,
Dr. Börries Kübel
Implementing Contamination Prevention, ed. 2 English (2008)
Foreword
Spring 2008
Dear Reader,
Our entire Crop Protection-Branch is committed to Responsible Care™. This implies that we
produce and distribute our products safely and support our customers in applying them
correctly to avoid risks to humans, animals and the environment. Then why this booklet? It
should contribute to the promotion of Responsible Care in the entire supply chain.
The “Guidelines for Contamination Prevention Standards for Toll Manufacturing Operations” have
been developed by a taskforce of experts of the European Crop Protection Association (ECPA),
who are involved daily in finding answers to questions on Contamination Prevention. In first
instance, it is the aim of this booklet to inform toll manufacturers on how to implement these
guidelines effectively in their facilities. This will help to ensure a higher standard of Contamination
Prevention is achieved in our entire branch. These efforts have been strongly supported by CropLife
International (CLI), a co-sponsor of this booklet.
For any business involved in the synthesis of active ingredients, formulation or packaging of crop
protection products, a contamination incident can have far reaching consequences; not only for the
company itself, but also for its customers. It can not be excluded that the reputation of our entire
branch will be seriously damaged.
The first edition of this booklet, published in 2004, has shown that it is used intensively by toll
manufacturers to develop systems for effective management of Contamination Prevention, and
which compare favorably with the internal standards of ECPA member companies. Furthermore, it
became apparent that the booklet is used increasingly within the member companies as training tool
for Contamination Prevention.
I cannot stress the importance of good Contamination Prevention management strongly enough and
would like to conclude with the following messages:
“Some people may think that since the last weeks, the last month or the last two years no
Contamination incident happened it is not necessary to be reminded all the time of Contamination
Prevention. Wrong! Such an incident could happen anytime. The biggest enemy of Contamination
Prevention is – like with safety - complacency”.
I would like to encourage you to get the greatest possible benefit from this booklet by consulting it
intensively. Furthermore, I hope that the responsible people in the production, planning and
procurement departments of the member companies make use of this booklet to improve the
dialogue not only with our toll manufacturers, but also between the member companies.
Dr. Wolfgang Welter
Chairman Manufacturing and Supply Chain Steering Group (MSCSG) of
the European Crop Protection Association
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Implementing Contamination Prevention, ed. 2 English (2008)
Contents
Acknowledgements
Foreword
1
1. Introduction
4
2. Purpose and Scope
4
3. Case Histories and Learning Experiences
6
4. Contamination Risk Assessment
15
4.1
Key factors to be evaluated in the contamination risk assessment of a
production unit
15
4.2
Guidelines on separation of production units
16
4.3
Assessment of cleaning capability
17
5. Determination of Cleaning Levels
18
5.1
Principles
18
5.2
Calculation of cleaning levels
19
5.2.1 Formula
19
5.2.2 Example of a cleaning matrix developed for a herbicide packaging unit
20
5.2.3 Effect of the cleaning matrix on production scheduling / sequencing
22
5.2.4 Factors that require extra attention when scheduling the production
sequence
22
5.2.5 Responsibilities
22
6. Cleaning of the Production Unit
6.1
Page 2
23
Cleaning procedure
23
6.1.1 Generic cleaning procedure
23
6.1.2 Visual inspection
23
6.1.3 Wet cleaning
26
6.1.4 Dry cleaning
29
6.1.5 Cleaning with solid, inert material (“flush cleaning”)
29
6.1.6 Cleaning validation process
29
6.1.7 Application of the validated cleaning procedure
30
6.1.8 Recycling of used cleaning medium
30
Implementing Contamination Prevention, ed. 2 English (2008)
6.2
Equipment design for improved cleaning efficiency
31
6.3
Illustrations of the production units with practical tips for cleaning of critical
parts
32
6.3.1. Liquid formulations
33
6.3.2. Dry (solid) formulations
36
Documentation of changeover and release of cleaned equipment
42
6.4
7. Trace Analysis of Residual Impurities
43
7.1
Residual impurity analysis in the product vs. in the rinsate
43
7.2
Sampling
43
7.3
Development of trace analytical methods for residual impurities
44
8. Manufacturing Practice
45
8.1
Identification of incoming goods on site
45
8.2
Controls to ensure that the correct material gets delivered to the
manufacturing point and used in the manufacturing process
45
8.3
Traceability
45
8.4
Labeling
45
8.5
Rework
46
8.6
Shared portable / interchangeable equipment
46
8.7.
Retained Samples
46
8.8
Temporary storage tanks
46
8.9
Visual check of cleanliness
47
8.10
Modification of the production unit / equipment and plant design
47
8.11
Self Assessment
47
9. Contamination Prevention Checklist for Self-Assessment by Toll
Manufacturers
48
Glossary and Index
76
Appendix A
83
Guidelines for Contamination prevention standards for toll manufacturing
operations
Appendix B
EPA Pesticide Regulation Notice 96-8
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94
Implementing Contamination Prevention, ed. 2 English (2008)
1. Introduction
Contamination of products with residual impurities is a potential issue and area of concern for
any multi-purpose chemical synthesis, formulation and packaging unit. Contamination can
result in adverse effects on sensitive, treated crops or non-target species and may trigger
regulatory issues. Incidents may also tarnish the reputation and image of the entire industry.
2. Purpose and Scope
The purpose of this booklet is to help toll manufacturers (tollers) to successfully apply the
“Guidelines for Contamination Prevention standards for toll manufacturing operations” (the
“Guidelines”, Appendix A).
This booklet:
•
Is written for “practitioners” in toll manufacturing having to deal with Contamination Prevention in
their daily job.
•
Provides “best practices” on Contamination Prevention operating standards and tools.
•
Pertains to Contamination Prevention aspects in the synthesis, formulation and (re-)packaging of
Crop Protection chemicals.
The following Crop Protection chemicals fall under the scope of this booklet, either as active
ingredients or as formulated products:
•
Herbicides (for crop and non-crop uses, irrespective of the application method).
•
Safeners
•
Fungicides, Plant Growth Regulators (PGR’s), Plant Activators, Insecticides, Acaricides,
Molluscicides, Nematicides and Fumigants. These products can be applied as foliar spray,
granular formulation, seed treatments or as any form of soil treatment.
•
Rodenticides (applied as baits).
•
Adjuvants for agricultural application, spray tank cleaners, crop oils, and foliar fertilizers.
Excluded from the scope of this document are:
•
Contamination Prevention at farm level (e.g. tank cleaning).
•
Issues related to Contamination Prevention in biotechnology and seeds, e.g. GMO / non-GMO
contamination during seed production.
•
Bulk deliveries and storage of final product at distributors and dealers. Guidelines for
implementation of Contamination Prevention measures for handling final product in bulk are
considered the responsibility of the individual member companies and the regional Crop
Protection Organizations.
•
Contamination Prevention in:
o Public Health products for non-crop insect control (e.g. treatment of mosquito nets), where
humans might be exposed to a contaminant.
o Animal Health products specific for control of ectoparasites, which are manufactured under
pharmaceutical standards (GMP), where animals might be exposed to a contaminant.
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Fig.1. Dose response study of an auxin-type cereal herbicide as contaminant of a grape fungicide
illustrating the damage some active ingredients cause, even at low application rates, when applied on
non-target crops. The grape vines were treated with the registered amount of the fungicide with
increasing concentrations of the herbicide (numbers in white). The NOEL of the herbicide on grapes is
0.3 g a.i./ha, which corresponds with 1.7% of its registered application rate in cereals.
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Implementing Contamination Prevention, ed. 2 English (2008)
3. Case Histories and Learning Experiences
The basis for successful Contamination Prevention is effective risk management. The
“Guidelines”, which form the basis for this risk management, are primarily based on case
histories of actual incidents, rather than being developed only from theory. We would like to
invite you to study these case histories, for this will make it a lot easier to understand the
reasons for these “Guidelines”. Also, when you get involved in training staff on Contamination
Prevention, presenting the case histories described in this booklet will help you to get a lot
more attention from your staff, because we can all associate with real life experiences more
easily than with dry theoretical issues.
Case History 1:
Incident caused by improper cleaning process
•
Several growers complained that their pot roses showed severe chlorotic (= very striking, white)
spotting of the leaves after treatment with a soil herbicide for control of weeds. This greatly
reduced the market value of the container plants and required extra labor for pruning the plants to
improve their appearance.
•
The SC soil herbicide was made in a flowables plant after a cereal herbicide that had a highly
active broad leaf herbicide component that caused as first symptom chlorosis of the weeds.
•
Analysis of the soil herbicide for the active ingredient from the cereal herbicide showed that this
was present in a concentration of 87 ppm, which is considerably above the NOEL of the residual
impurity on roses.
•
Equipment was cleaned by two different shifts.
•
The first shift opted to clean the formulation vessels and the bead mills in the correct sequence. A
sample of the last rinsate was collected and the analysis showed that the concentration of the
residual impurity was below the required cleaning level.
•
So the second shift had to clean the hopper. After dry cleaning, the hopper was hosed down with
water and left to dry. The rinsate from the hopper was collected in the first vessel in which the
slurry of the next product is prepared. The slurry vessel was not drained as required in the
cleaning procedure, and the next shift was not told that the slurry vessel contained contaminated
water.
•
This incident resulted in seven expensive claims from rose growers plus a rework campaign that
took three years.
What can be learnt from this case history?
•
Have a written cleaning procedure with check list for equipment cleaning outlining every single
step of the cleaning procedure and the order in which these have to be carried out. The written
procedure must be tested, while its effectiveness must be confirmed.
•
Assure completion of each and every step and enter it on the batch card, with the time at which it
is finished, while it must be initialed by the operator. Missed steps must be investigated.
•
Take and analyze a sufficient number of samples of the rinsate(s) and/or of the next product to
confirm the cleaning has been effective.
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Case History 2:
Incident caused by inadequate cleaning methods
•
A toller had to formulate and pack an SC formulation of a Plant Growth Regulator (PGR)
registered for ornamental pot plants e.g. chrysanthemums, begonias, lilies, poinsettias etc.
•
The product, which preceded the PGR in the formulation and packaging equipment, was a highly
concentrated, low application rate EC formulation of a herbicide.
•
The PGR caused serious damage to foliage of ornamental pot plants. The damage was attributed
to a contamination of the PGR with the preceding herbicide.
•
Subsequent chemical analysis confirmed the presence of residual amounts of the herbicide both
in the PGR formulation as well as in the damaged plants.
•
The inventory of the contaminated PGR remaining in the distribution channels was recalled from
the market to prevent further applications and claims.
•
What did the Root Cause Investigation reveal?
o The herbicide formulation unit was not cleaned immediately after the production as usual, but
several days later. The cleaning method consisted of rinsing the equipment with warm water
(at 40°C).
o An alert operator observed and reported the unusual presence of crystals in the rinsate, but no
further investigation was undertaken by management.
o In this facility, the analysis of the residual impurities is generally carried out in the rinsate and
not in the succeeding product. The chemical analysis confirmed that the herbicide
concentration in the rinsate was below the cleaning level.
o It is believed that - as the equipment dried - crystals of the herbicide active ingredient formed
on the walls of the equipment, which were not easily removed by the warm water rinse.
What can be learned from this case history?
•
Always clean equipment immediately after use. This prevents that the film left behind in the
equipment by the preceding product dries out, which makes cleaning much more difficult. This is
especially critical for SC formulations, and even more so when dealing with flowables of highly
active molecules.
•
Verify in audits (assessments) whether effective cleaning methods are in place, e.g. type of
cleaning medium, number of rinses, volume of cleaning medium per rinse etc.
•
Investigate all unusual observations reported by operators working on the line.
•
The cleaning method must always include visual inspection of the equipment before the next
production run can be started.
•
The selected cleaning medium must sufficiently dissolve the potential contaminant, i.e. the active
ingredient of the preceding product. A typical practice is to clean with the solvent used in the
preceding formulation. In this case history, the herbicide active ingredient had very low water
solubility, so the crystals did not dissolve in the cleaning medium. If instead, the organic solvent of
the herbicide EC formulation would have been used, the crystals could have been removed,
provided the re-circulation would have been sufficiently long.
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Implementing Contamination Prevention, ed. 2 English (2008)
•
The analytical check of the rinsate alone is not always sufficient, as this does not necessarily
mean that traces of the previous product will also be below the acceptable cleaning level in the
succeeding product.
Case History 3:
Incident caused by an incorrect cleaning level
•
A fungicide formulation plant received rush orders for two soybean fungicides: a foliar fungicide
belonging to the azole family and a seed treatment fungicide.
•
The seed treatment fungicide contains a strong dye, making the cleaning process difficult and very
time consuming (the dye tends to stick to the walls of the equipment). Traces of the dye not fully
removed from the equipment, might color the almost white formulation of the foliar fungicide, thus
creating a quality issue. Therefore the formulation of the foliar fungicide was scheduled before the
formulation of the seed treatment product.
•
The assumption was made that - since a fungicide was following another fungicide on the line the EPA approved cleaning level of 1,000 ppm would be applicable.
•
After cleaning following the production run of the foliar fungicide, the concentration of the residual
impurity (i.e. the concentration of the active ingredient of the foliar fungicide) could not be
determined due to a breakdown of the analytical equipment. However, the production of the seed
treatment fungicide was started immediately without waiting for the analytical instruments to be
repaired.
•
Since these were rush orders, it had been decided without management approval to minimize the
number of cleaning cycles, because the products were both applied on soybeans.
•
The entire inventory of seed treatment fungicide was quarantined when analysis revealed that the
level of the azole contaminant (from the previous product) in the actual seed treatment fungicide
was more than 6,000 ppm.
•
A quick trial at a local field station showed that the alleged safe level of the azole as seed
treatment on soybean was 2,000 ppm.
•
Based on market pressure, the product was reworked (blended) to an azole level of 2,000 ppm.
•
On thousands of hectares, the treated soybeans failed to germinate and this resulted in a series of
expensive claims.
•
Subsequent research in a greenhouse showed that the actual safe level of the azole fungicide in
soybean seed treatment fungicides to be 200 ppm.
What can be learnt from this case history?
•
Never try to make shortcuts in the cleaning procedures, no matter how much business pressure.
You risk a contamination incident which can easily create more business disruption than before.
•
Even if a cleaning level of 2,000 ppm would have been safe, never use a cleaning level above
1,000 ppm, for this not only infringes the levels allowed by EPA (please see the EPA Pesticide
Regulation Notice 96-8, Appendix B), but also the regulatory limit for a non-listed extraneous
ingredient of max. 0.1 % w/w or 1,000 ppm.
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Implementing Contamination Prevention, ed. 2 English (2008)
•
The default EPA cleaning level of 1,000 ppm when switching from one fungicide to another
fungicide is not (always) applicable for changeovers from foliar fungicides to seed treatment
fungicides or insecticides. This can be especially dangerous when the preceding fungicide in the
equipment belongs to the azole family, which often can display, at certain concentrations, a growth
regulator effect (like inhibition of germination).
Case History 4:
Incident caused by inadequate separation of two formulation units
•
Two separate solids formulation units were operating simultaneously in different rooms separated
by a solid wall. One unit was formulating an insecticide, the other one a herbicide.
•
Customers complained of crop damage when using the insecticide. Subsequent analytical testing
showed low-level contamination of the product with the herbicide.
•
The wall between the two rooms in the plant was in fact not completely sealed as there were a few
small holes in it, primarily to accommodate piping.
•
An oversized exhaust blower was installed in the insecticide unit to improve personal protection
from the insecticide dust. This caused the insecticide room to be at a lower atmospheric pressure
than the herbicide room, thereby sucking herbicide dust through the holes into the insecticide dust
collector. Recycling dust from the collector transferred the herbicide into the insecticide.
What can be learnt from this case history?
•
Contamination can happen between two products that are running simultaneously even if
separated by a “solid” wall.
•
Do not make design changes, e.g. additional pipe work, increased blowers, additional doors or
windows, without understanding all the implications, including contamination risk.
•
Do not rely on a wall to be a fool-proof barrier; it is hard to seal all the holes.
•
Increased incompatibility of products requires more separation between production areas and may
even require separate buildings. Whilst an insecticide and a normal rate herbicide would require at
least separate rooms with a solid, air-tight wall and separate air handling systems, an insecticide
and a highly active herbicide would require at least separate buildings.
Case History 5:
Incident caused by improper use of interchangeable parts
•
A large grower got an unexpected contract to grow 10 ha of a special high value flower bulb. He
placed a rush order for a special “bulb treatment” fungicide, while the manufacturer was given less
than a week before the planting date.
•
The product was made in a dedicated fungicide formulation vessel.
•
A flexi hose was used to transfer material to the header tank of the fungicide filling line, using a
dedicated pump.
•
The operator could not find the flexi hose for fungicides at its usual place, so he used another flexi
hose found in the next room (the dedicated herbicide filling area).
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•
This flexi hose had last been used to transfer a phenoxy herbicide EC formulation and would be
used again for the same purpose the next morning. It had not been cleaned and contained a
residual amount of the herbicide, which now contaminated the fungicide.
•
The flower bulb crop failed completely, and the claim had to be settled in a long and expensive
court case.
What can be learnt from this case history?
•
Avoid the use of interchangeable parts, such as flexi hoses. Fixed, dedicated piping is always the
safest solution.
•
As best practice, interchangeable parts should be dedicated to a product and a production line
during the whole manufacturing campaign and their use (the product or the line) clearly labeled. At
the moment an interchangeable part is disconnected from the line, it must be cleaned immediately
irrespective whether it is used for another product or put into storage.
•
Ensure that the history of the interchangeable parts can be traced even if they are dedicated to
one class of products, what was the last product, how was it cleaned and to which level?
Case History 6:
Incident caused by shared utilities or common lines for separate installations
•
A liquid corn herbicide was formulated, analyzed and released by the site quality control
laboratory.
•
The plant started to package the product. After packaging 20,000 liters, one of the operators
noticed the product had an unusual color. They stopped packaging and re-sampled the tank.
•
The subsequent analysis showed that an unexpected active ingredient was present at a
concentration above the residual impurity level.
•
Checks showed that the first 15,000 liters were within specification.
•
This formulation and packaging line shared a nitrogen purge line with another installation. During
the packaging, somebody had transferred a batch of a different product to the other installation.
The nitrogen purge line was open and siphoned some product into the corn herbicide tank.
What can be learnt from this case history?
•
Avoid interconnection of separate installations by purge lines, ventilation lines or utility piping
(steam, compressed air, etc).
•
Common lines and installations must have effective backflow prevention.
•
Operator training and constant awareness are major factors in preventing incidents.
•
Always report anything out of the usual (color, smell, consistency etc.).
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Case History 7:
Incident caused by using unlabeled bottles
•
A toll manufacturer had to formulate and package two incompatible products: A non-selective
herbicide EC for use on railways and a highly toxic nematicide EC used amongst others for band
application in sugar beets.
•
The formulation and packaging of the nematicide and herbicide products were carried out on
dedicated lines.
•
The herbicide was packaged in grey colored 1 liter plastic bottles.
•
The nematicide was packaged in black colored 1 liter plastic bottles.
•
To ensure the company could rapidly respond to demands in the market, the bottles were not
labeled. The country specific labels would be attached later after a firm order had been entered in
the system.
•
Due to a planning error, not enough grey bottles had been supplied and the toller decided to use
spare black bottles to finish the filling of the herbicide without obtaining approval from his client.
Also, this change was not communicated within the plant.
•
On the next shift, personnel responsible for transferring the packaged material to the warehouse
placed the unlabeled [now black herbicide] bottles on the shelves with the other black [nematicide]
bottles.
•
A rush order was received for the nematicide and a great number of the black bottles were labeled
with the nematicide label.
•
More than 250 ha of sugar beets were killed by the herbicide. Investigation revealed that the
residue of the herbicide could be demonstrated chemically in the treated crop, whilst bio assays
provided further proof that the wrong product was in the black bottles.
•
This resulted in a series of court cases, which all ended in favorable judgments for the farmers. An
acre of sugar beets is worth a lot of money and, since the herbicide was persistent, the courts also
insisted on compensation for yield losses in the two subsequent growing seasons!
What can be learnt from this case history?
•
Not only residual impurities can cause serious incidents, but the mix-up of unlabeled containers of
incompatible materials in manufacturing can be very harmful.
•
Never store any unlabeled containers, whether these contain intermediates, formulation
concentrates or final products.
•
Make sure that when temporary labels are used, the product can be fully identified. The suggested
minimum information is the product name (and code), batch number, and production date.
•
Store product labeled with temporary labels separately from final sales product, i.e. together with
raw materials and active ingredients for further processing (while fungicide/ insecticide raw
materials shall also be stored separated from herbicide raw materials in the warehouse).
•
Make sure any deviation – no matter how small – is approved by the client, documented, and also
well communicated within the organization of the toller.
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Case History 8:
Incident caused by old rework material with incomplete labeling and record keeping
•
A company formulated a herbicide in their own plant for a number of years, and then decided to
contract the formulation to a toll manufacturer to free up capacity in their own formulation unit for
other products.
•
When they started the contract formulation, they shipped the active ingredient plus the leftover
packaging material and a quantity of rework from their own plant to the toll manufacturer.
•
In the first season after the start of toll manufacture, the company received many complaints of
crop damage, ranging from mild to severe. The crop injury was traced back to herbicide damage.
•
When retained samples of the product were tested, a large number of batches were found to be
seriously contaminated with a different herbicide, one not made at the toll manufacturer’s site, but
made at the plant of the product’s owner.
•
What went wrong? Investigation revealed that much of the rework material was old and had labels
that were deteriorated or missing. In addition, inadequate records about the rework had been sent
from the manufacturer to the toller.
•
As a result, the toller used contaminated rework and created contaminated product. But, the fault
was with the manufacturer who allowed the inadequate labeling and record keeping.
What can be learnt from this case history?
•
Design and/or improve all processes to prevent rework from being created.
•
Use any rework as soon as possible so that labels and records are not lost.
•
It is critical to keep totally accurate records on all rework.
•
Never use improperly or incompletely labeled containers before the material is analyzed and
formally released.
Case History 9:
Incident caused by improper sample rework
•
More than 8,000 young citrus trees died following application of an insecticide.
•
One single sales package (a drum) of the insecticide was found to contain high levels of a low
application rate herbicide. All other drums were also tested analytically, but did not show any
traces of the herbicide.
•
Herbicide contamination was not detected in the retained sample of that particular insecticide
batch.
•
Herbicide production took place in a building separated completely from the insecticide / fungicide
production.
•
As standard practice, irrespective from the production line, 2 – 3 kg samples of all products were
collected in identical white buckets and brought to the Quality Control (QC) laboratory. After QC
analysis, all samples were returned to the production line to be reworked.
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•
The labeling of the white buckets was not consistent and showed a lot of variation, while after
analysis, the laboratory placed both herbicide and insecticide buckets in the same area for
collection and return to production lines.
•
A sample bucket of the low application rate herbicide was by mistake returned to the insecticide
drum filling and added to the contents of one drum.
What can be learnt from this case history?
•
Containers holding any product must always be clearly and consistently labeled.
•
Site labeling policy must be defined, understood and applied consistently by all.
•
Do not return samples collected for QC into the process without explicit (written) approval of this
procedure by the client.
•
Avoid recycling laboratory or retained samples if at all possible. Take small samples to reduce the
quantity to be disposed of.
•
Review (risk assess) existing rework processes to ensure they are appropriate and controlled
adequately.
•
Encourage plant operators to be vigilant and check labels before emptying contents into vessels,
containers, etc. Use different containers (size, color) for incompatible materials (herbicides,
fungicides/insecticides).
Case History 10:
Incident caused by failure to determine identity of one of the raw materials
•
A herbicide active ingredient was synthesized by esterification of its acid with n-hexanol to form
the n-hexyl ester.
•
The alcohol n-hexanol was supplied by an external manufacturer and delivered in a road tanker.
Quality Control (QC) for incoming goods released the alcohol shipment and it was pumped into a
40,000 L dedicated bulk tank still containing approximately 20,000 liters of n-hexanol.
•
The alcohol was pumped from the bulk tank through dedicated piping to the synthesis plant.
•
After completion of the esterification, the active ingredient batch was sampled and sent to the QC
laboratory. The gas liquid chromatogram revealed an unknown peak that was identified as the
corresponding n-propyl ester of the herbicide active ingredient.
•
The subsequent investigations showed that the dedicated alcohol bulk tank contained a blend of
n-hexanol and n-propanol.
•
In this facility, the standard quality check for bulk products in the raw materials acceptance
procedure is a check of the Certificate of Analysis (CoA) submitted by the alcohol producer with
each shipment. Since the CoA gave the expected information the material was released.
•
The active ingredient batch produced consisted of a mixture of the two esters. Since globally, only
the n-hexyl ester of this herbicide has been registered, the active ingredient was not in regulatory
compliance and had to be disposed of (incinerated).
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What can be learnt from this case history?
•
Although checking the CoA of incoming raw materials without additional analysis is cost-effective,
it creates a far bigger dependence on the reliability of the quality systems of the supplier, while an
error made during loading of the shipment at the supplier can not be detected before the raw
material has been processed. Therefore, an assessment of the facility of the supplier with a strong
emphasis on the correct Contamination Prevention and loading procedures is highly
recommended.
•
Consider simple lab checks such as refractive index, color, pH, viscosity, or other rapid identity
tests as QC check for incoming goods.
•
In synthesis where a mix-up of raw materials is not only a contamination, but also a safety hazard,
the identity check for incoming goods is a “must”.
Fig. 2: Dose response study of an experimental “low application rate” (“highly active”) cereal herbicide
on oilseed rape. The NOEL on oilseed rape is < 0.03 g a.i./ha. The cleaning levels necessary when
the succeeding product after this type of herbicide is used on oilseed rape are very low, often < 2 ppm
or even in the ppb range.
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4. Contamination Risk Assessment
A contamination risk assessment is conducted for the production unit and the products
manufactured in it. This includes all the products, the cleaning requirements and capabilities,
production unit lay-out, separation and manufacturing practices.
A change in any one of these must always lead to a reassessment of the contamination risk.
A „production unit” is a combination of equipment used for the manufacture of one product at any
given time. It may be used for multiple products in sequence. A manufacturing site may consist of
multiple production units. Separation of production units is a key element in Contamination
Prevention. „Separation” means that there is no common equipment (e.g. ventilation ducts) allowing
an unplanned transfer of product from one production unit to another. Separation can be achieved
through e.g. separate buildings, relocation of critical products into other production units,
compartmentalizing manufacturing lines in the same building. Design and lay-out of the production unit
greatly impact its cleanability and should be included in the risk assessment.
4.1 Key factors to be evaluated in the contamination risk assessment of
a production unit
•
What other active ingredients or their products are handled on the manufacturing site and in
particular in which production unit, so that the client can assess if there are products in the
toller’s portfolio that would present a risk when present as a residual impurity.
This should also include notification by the toller to manufacturers of non-agricultural products
sharing the same production unit that contamination of those non-agricultural products with
agricultural products may be a concern.
•
Agreements with existing clients allowing either the release of the name of the preceding
products, or permission to release the name of the Contamination Prevention focal point at the
preceding client.
•
Design and lay-out of the production unit (easy to clean and to dismantle, adequately
separated).
•
Demonstrated ability to clean down to low levels of residual impurities between existing
products in the portfolio of the toller.
•
Well understood and consistently implemented, written procedures for product changeover
processes, cleaning methods and product release.
•
Facilities and skilled personnel for chemical analyses of trace levels of residual impurities
in-house or at well recognized contract laboratories.
•
Assessment of contamination risk from airborne particles from products produced in
production units in adjacent buildings on the same manufacturing site or in the same vicinity,
especially when in these units highly active herbicides are manufactured. Aspects like
predominant wind direction, placement of windows and dust filters must be taken into
consideration.
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4.2 Guidelines on separation of production units
The ECPA / CropLife International member companies recommend – as key first step in
Contamination Prevention – the following separation rules in shared manufacturing facilities to
minimize the contamination risk (and also the cleaning costs):
•
Separate “Herbicides” from “Insecticides”
This separation is achieved by having production units, which are completely dedicated to either
“herbicides” or “insecticides”.
“Herbicides” include:
All herbicides (crop, and non-crop), plant growth regulators, defoliants, desiccants.
“Insecticides” include:
All insecticides, acaricides, molluscicides, nematicides, fungicides, plant activators, herbicide
safeners, rodenticides, crop oils and adjuvants, spray tank cleaners, fertilizers and fumigants.
•
Separate “low rate herbicides” (especially the highly active herbicides) from “normal rate
herbicides” if the herbicides are registered on different crops.
A possible way to achieve this separation is to combine herbicides registered on the same crops
in the same production unit, i.e. all rice herbicides or all cereal herbicides. In that case the
potential contamination risk is limited to product integrity / quality issues, whilst the cleaning
requirements between herbicides registered on the same crops will be minimal.
•
Consider manufacture of Plant Growth Regulators (PGRs) on “insecticide” lines.
EPA Pesticide Regulation (PR) Notice 96-8 (attachment B) classifies PGRs as “normal rate
herbicides”. Based on a Contamination risk assessment, a number of ECPA member companies
prefer to manufacture PGRs on “insecticide” lines instead of “herbicide” lines.1
•
Crop protection chemicals shall be synthesized, formulated, packaged and stored
completely separated from:
o Food and feed stuffs (including vitamins)
o Human pharmaceutical products which are applied orally, topically or as an injection
o Veterinary products which are applied orally, topically or as an injection
o Human cosmetic and other health care products
o Detergents and other household cleaning agents like washing powders, bleach
o Industrial chemicals, e.g. cleaning agents for the food industry
If any products belonging to any of the above product groups are manufactured on the same site,
the minimum separation level is different buildings.
1
PGRs are, like insecticides and fungicides, registered and applied on a wide range of crops and
ornamental plants belonging to many taxonomically unrelated plant families. This means that it is
virtually impossible to get a sufficiently wide data base of NOELs to calculate a reliable cleaning level.
None of the currently known PGRs show herbicidal activity at the registered rates and display a very
high level of selectivity across many botanical families.
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4.3 Assessment of cleaning capability
To assess the suitability of a production unit for handling a particular production sequence,
two components need to be evaluated:
• Design and lay-out of the production unit.
• Successful cleaning procedures. Their four key elements are:
o
Correct cleaning levels (see chapter 5)
o
Cleaning methodology (see chapter 6)
o
Analytical capability (see chapter 7)
o
Documentation (record keeping, retained samples; see chapter 8)
A helpful tool for determining whether a product changeover can be successfully achieved in a
production unit is to review historical data on cleaning ability. The toll manufacturer should have
routinely demonstrated results similar to the following cleaning levels:
• Synthesis of active ingredients: < 50 ppm typically achieved after the equipment has been rinsed
with solvent, partial dismantling of pipes and pumps (see table 1, page 24).
• Formulation and packaging of liquid products: < 100 ppm typically achieved after the equipment
has been rinsed with a cleaning medium at a maximum of three times (see table 1, page 24).
• Formulation and packaging of solid products: < 200 ppm typically achieved after dry cleaning
followed either by wet cleaning or “flush cleaning” (see table 2, page 25).
One of the highest contamination risks in production units for solids (active ingredients and
formulations) is caused by the “hold-up” of the previous product in dead spaces. This material can be
suddenly released and contaminate one or even more batches of the subsequent product.
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5. Determination of Cleaning Levels
The cleaning level required for a product-changeover is the primary indication of the risk
involved in the changeover, i.e. the lower the cleaning level, the higher is the risk of a
contamination incident if the cleaning process fails. In addition, more labor, time and cost
intensive cleaning will be needed to achieve the required lower cleaning levels.
To optimize production sequencing, a cleaning matrix based on reliable cleaning levels must
be developed. An example will be shown for a herbicide packaging unit in 5.2.2 and 5.2.3.
5.1 Principles
The No Observable Effect Levels (NOELs) of the preceding active ingredient on all crops, on which
the succeeding product is registered, must be a key consideration when calculating the cleaning level.
The lowest NOEL (for the crop most sensitive to the previous active ingredient) must be used.
Furthermore, the US Environmental Protection Agency (EPA) has issued Guidelines on the
Toxicologically Significant Levels of Contamination (TSLCs) of the previous product in the succeeding
one in the Pesticide Regulation Notice (PRN) 96-8, dated October 31st, 1996. The full text of this
document is available in Appendix B.
The Pesticide Regulation Notice 96-8 is applicable to products manufactured, imported, and / or used
in the US. This means that the cleaning levels for products with the US as final destination may never
exceed the values for the TSLCs listed in the various categories.
A word of caution is necessary: implementation of the EPA guidelines without proper consideration of
the biological effects could still lead to serious contamination incidents because the TSLC may be too
high to cover the “biological safety margin” necessary to prevent these incidents. If the cleaning level
based on biology is lower than the regulatory limits, the biology based level must be used.
In countries outside the US, the government agencies generally allow self-regulation of the cleaning
levels by the crop protection industry, provided that the limits do not infringe the crop protection
legislation. Some companies prefer to follow the EPA Pesticide Regulation Notice 96-8 (whenever it is
lower than the biology based cleaning level) in all countries where they are commercially active,
because this helps the flexibility of the supply chain. Others prefer to use a system where the EPA
guidelines are used only for products manufactured in, or being exported to the US. Outside the US,
those companies use biology driven cleaning levels, provided they do not exceed the regulatory limits
for non-listed extraneous ingredients of typically 0.1% w/w or 1,000 ppm.2
2
The “Manual on the development and use of FAO and WHO specifications for pesticides“, FAO
Plant Production and Protection Paper No. 173, ed.1 (2002) sets the regulatory limits for non-listed
extraneous ingredients to less than 1 g/kg (< 0.1 % w/w or < 1,000 ppm). For harmonization with the
EPA PR Notice 96-8 “Toxicologically Significant Levels of Contaminants”, in this booklet the limit for
non-listed extraneous ingredients, e.g. RIs, is set to max. 0.1 %w/w (max. 1,000 ppm).
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1.0
3.0
10
30
90
g a.i./ha:
Fig.3: Dose response study of clomazone on grape seedling (top) and sugar beet (bottom). For
cleaning level calculations, the NOEL of the residual impurity on the most sensitive crop that the
succeeding product is applied on must be used. Grape seedlings are clearly more sensitive than sugar
beet. NOEL of clomazone on sugar beet is 3.0 g a.i./ha, on grapes less than 1.0 g a.i./ha.
5.2 Calculation of cleaning levels
5.2.1 Formula
Biology based cleaning levels are calculated using the following formula:
Cleaning level in ppm = (106 x NOEL) / (SF x AR)
Definitions:
AR:
Maximum Application Rate of the succeeding product in gram or ml of formulated product / ha.
NOEL: No Observable Effect Level in gram a.i./ha of the preceding active ingredient on the most
sensitive crop on which the succeeding product is registered.
SF:
Safety Factor, ranging from 2 to 10. Each succeeding client defines the SF value
based on their company’s risk management policy (see 5.2.2 cleaning matrix example)
See also the “Guidelines” (Appendix A-VII) and Appendix B – V for information on EPA based
cleaning levels
To improve Contamination Prevention risk assessment, it was decided to add a third herbicide group,
the “highly active herbicides”, to the “low rate herbicides” and “normal rate herbicides” mentioned in
the EPA Pesticide Regulation Notice (PRN) 96-8. “Highly active herbicides” have maximum application
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rates of less than 50 g a.i./ha. These low application rates imply that these active ingredients are
active at very low concentrations on weeds and, for Contamination Prevention considerations even
more importantly, on non-target crops on which the succeeding product might be applied. NOELs of
less than 10 mg a.i./ha on sensitive crops are no exception. Therefore, extra attention is required
when calculating cleaning levels for “highly active herbicides”.
5.2.2 Example of a cleaning matrix developed for a herbicide packaging unit
This example shows how to develop a cleaning matrix for the packaging line for liquid herbicides in a
dedicated herbicide unit. The three herbicides are packaged interchangeably. The methodology for
developing cleaning matrices for synthesis, formulation and repackaging is identical.
Product A: Highly active cereal herbicide
•
Registered in all cereal species, maize (corn) and ornamental turf
•
Applied post-emergence for control of broad-leaved weeds
•
SC formulation containing 50 g a.i./L Formulated Product (= FP)
•
Highest application rate 0.25 L FP/ha = 12.5 g a.i./ha
•
NOEL on most sensitive broad-leaf crop tested, sugar beet, is 0.03 g a.i./ha
•
EPA classification: Low application rate herbicide
Product B: Traditional cereal herbicide
•
Registered in all cereal species, and maize (corn). Neither selective nor registered in ornamental
turf
•
Applied post-emergence for control of broad-leaved weeds
•
EC formulation containing 250 g a.i./L FP
•
Highest application rate 3.0 L FP/ha = 750 g a.i. ha
•
NOEL on most sensitive broad-leaf crop tested, cotton, is 16 g a.i./ha
•
EPA classification: Normal application rate herbicide
Product C: Broad-leaf crops grass herbicide
•
Registered and highly selective in following broad-leaved crops: cotton, soybean, sugar beet,
oilseed rape (Canola™), all vegetable brassicas, lettuce, cucumber and other cucurbits.
•
Applied post-emergence for control of annual- and perennial grasses in broad-leaved crops
•
EC formulation containing 150 g a.i./L FP
•
Highest application rate 2.0 L FP/ha = 300 g a.i./ha
•
NOEL on most sensitive [turf] grass species tested, Lolium multiflorum, is 1.6 g a.i./ha; on the
most sensitive cereals species tested, oats, is 9.0 g a.i./ha
•
EPA Classification: Low application rate herbicide
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For the formula for calculating the cleaning level see 5.2.1, while in this example, a ten-fold safety
factor is used for all product changeovers. Safety factors are the individual decision of the succeeding
company and typically range from 2 to 10. These safety factors should account for differences in
response of the plants tested, which can occur between the greenhouse test conditions and the actual
conditions on the farm, where soils, plant varieties, growth stage at the time of application, weather,
seasons etc. all vary. Additional safety factors may also be applied to account for sampling and
analytical variance.
Cleaning matrix (example)
Succeeding Product
Highly active
cereal
herbicide
Traditional cereal
herbicide
Broad-leaf
crops
grass herbicide
(Product A)
(Product B)
(Product C)
SC
EC
EC
g a.i./L FP
50
250
150
L FP/ha
0.25
3.0
2.0
g a.i./ha
12.5
750
300
Cleaning level*
in ppm
Cleaning level*
in ppm
Cleaning level*
in ppm
Biology based
N/A
1,000 2) 3) 4)
1.5 3)
EPA Regulation based
N/A
20 3)
100 1) 3)
(Category 8)
(Category 7)
N/A
800 2)
N/A
250
Formulation
Type:
Assay:
Application
Rate:
Preceding
Product
Product A
(EPA category) 5)
Product B
Biology based
1,000
EPA Regulation based
(EPA category)
Product C
5)
Biology based
(EPA category)
250 3)
(Category 4)
640
EPA Regulation based
5)
2) 3) 4)
(Category 4)
2) 3)
300
2)
100 3)
20
(Category 7)
(Category 8)
N/A
N/A
* Cleaning level when changing from preceding to succeeding product
1) Biology based cleaning level is applicable, since it is < “EPA“ value. Applies also in the USA.
2) For the USA, cleaning level needs to be based on EPA PRN 96-8; “EPA” value is < biology based
cleaning level.
3) Switch from aqueous formulation to organic solvent formulation or vice versa.
4) Value for non-listed extraneous active ingredients (i.e. from preceding products) may never exceed
1,000 ppm in order to meet regulatory requirements
5) For EPA category see Appendix A.
N/A: Not applicable - no cleaning level required, same active ingredient.
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5.2.3 Effect of the cleaning matrix on product scheduling / sequencing
Consequences of this cleaning matrix on the scheduling of the products A, B, C would be:
Possible Production Sequences
Product
Cleaning
level
(ppm)
Product
Cleaning
level
(ppm)
Product
Cleaning
level
(ppm)
Product
Sequence
1
A
1,000 1) 4)
B
800 1)
C
640 1)
A
Sequence
2
A
or 20 2)
1.5 3)
or 250 2)
C
300 1)
or 20 2)
or 100 2)
B
1,000 1) 4)
A
or 250 2)
1) Biology based cleaning level (CL)
2) EPA based cleaning level. Do not implement EPA based CLs when the biology based CL is lower.
3) Biology based CL for AÆC is lower than EPA based CL of 100 ppm; CL of 1.5 ppm must be applied
4) Value for non-listed extraneous active ingredients (i.e. from preceding products) may never exceed
1,000 ppm in order to meet regulatory requirements
For a full cycle of all 3 products, the sequence 1 (A Æ B Æ C Æ A) avoids the very low cleaning level
A Æ C. In the US, the lower EPA based CLs are required for all three changeovers in sequence 1.
The sequence 2 (A Æ C Æ B Æ A) requires a significantly lower cleaning level of 1.5 ppm for AÆ C
(also in the US, see footnote 3 above), and for C Æ B 300 ppm outside the US and 20 ppm in the US.
This shows that a careful selection of the production sequence can save time and waste (= money)
and reduce the contamination risk.
5.2.4 Factors that require extra attention when scheduling the production
sequence
•
Avoid scheduling a highly active herbicide against broad leaf weeds before a post-emergence
grass herbicide for broad-leaved crops, because the cleaning level is very low with increased risk
of cross contamination, cleaning efforts and cost of waste.
•
Highly colored active ingredients, e.g. dinitro compounds, or colored formulations like seed
treatments, often require cleaning to well below the biologically determined cleaning level in order
to meet the color standards specified for the succeeding product.
•
Switching from an aqueous formulation to an organic solvent formulation or vice versa requires
complete removal of the solvent used to formulate the preceding product. Additional rinsing of the
equipment with a solvent that is both miscible in water and organic solvents is one option to solve
this problem. To avoid this issue, scheduling EC formulations after EC formulations can reduce
cleaning time and consumption of solvents.
•
Some azole-fungicides (see case history 3) can cause phytotoxicity to seedlings when they
contaminate Seed Treatment fungicides and insecticides at cleaning levels considerably lower
than the default value of 1,000 ppm listed in the EPA Pesticide Regulation Notice 96-8.
5.2.5 Responsibilities
See the “Guidelines” (Appendix A-IV)
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6. Cleaning of the Production Unit
Cleaning of the production unit is an expensive and time consuming task in particular when
low cleaning levels are required. Therefore, finding an alternative production sequence
demanding less intensive cleaning may be economically more attractive without compromising
the principles underlying good Contamination Prevention management.
Alternative manufacturing solutions to be considered are:
•
Moving a “highly active” product to a production unit with a more favorable product mix (e.g. use of
a dedicated line or concentrate “high activity” products for uses in compatible crops in one
production unit). This reduces the contamination risk and avoids high costs for cleaning.
•
Sequencing of products, see 5.2.3. This avoids high risk product changeovers, but reduces
planning flexibility as a potential down side.
6.1 Cleaning procedure
A cleaning procedure must take into account the type of operation (synthesis, formulation or
packaging of liquids or solids), the configuration of the production unit as well as the specific
production sequence to ensure the concentration of the residual impurity is below the cleaning level
agreed with the succeeding client. In this chapter, a number of best practices recommended will be
discussed.
6.1.1 Generic cleaning procedures
Generic cleaning procedures for synthesis and formulation and packaging of liquid products are listed
in table 1 (page 24), and for formulation and packaging of solid products in table 2 (page 25)
respectively. The cleaning procedure must always be validated (see 6.1.6) and documented in writing
(see 6.4).
6.1.2 Visual inspection
Visual inspection is an essential, cheap, quick and effective way to assess the effectiveness of a
cleaning step. Any traces of material (dust, crusts and/or colored surfaces) visible in the equipment are
enough justification for repeating the cleaning step.
Mirrors and fiber-optic cameras are valuable tools for the inspection of dead spaces, e.g. interior of
flanges, pipes etc. in the equipment.
Fig. 4: Visual inspection of the interior of a reactor revealing unwanted material is still present, and
therefore, further cleaning is required.
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Recommended best practices for cleaning after changeovers in
Table 1:
synthesis and formulation and packaging of liquid products
Blue = "must have" cleaning steps / Green = optional cleaning steps
Preceding and succeeding product
contain the same a.i.(s)
Cleaning steps
Wet cleaning incl. dismantling of
equipment for manual cleaning of critical
parts (see 6.1.3)
Cleaning with detergent for chemical
destruction of the residual impurity (if
available)
Wet cleaning with the solvent of the
succeeding product or any other suitable
solvent (see 6.1.3)
Visual inspection (see 6.1.2)
Trace analysis (see 7.1)
Release of cleaned equipment (see 6.4)
Cleaning Costs
(downtime, man hours)
High
Medium
Small
Waste Generation
High
Medium
None to small
Synthesis
<-------- Cleaning Sequence --------->
Complete drainage of installation
Wet cleaning with the solvent of the
preceeding product or any other suitable
solvent.
Used cleaning medium to be disposed
of or recycled (see 6.1.8)
Remove solvent incompatible with the
subsequent product.
Used cleaning medium to be disposed
of or recycled (see 6.1.8)
Cleaning Level
≥ 100 ppm 1) 2)
Formulation and packaging of liquids
N/A
Used cleaning medium to be disposed
of or recycled
(see 6.1.8)
N/A
N/A
Remove solvent incompatiblewith the
succeeding product.
Used cleaning medium to be disposed
of or recycled (see 6.1.8)
Remove solvent incompatible with the
succeedingt product.
Used cleaning medium to be disposed
of or recycled (see 6.1.8)
Used cleaning medium
Used cleaning medium
Used cleaning medium
Remark: 1) Listed cleaning levels given for guidance only. Cleaning procedures have to be validated to assess achievable cleaning levels (see 6.1.6).
2) For cleaning level < 100 ppm apply multiple wet cleaning cycles.
N/A Not Applicable
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Recommended best practices for cleaning after changeovers in
Table 2:
formulation and packaging of solid products
Blue = "must have" cleaning steps
Preceding and
succeeding product
contain the same
a.i.(s)
Cleaning Level
> 200 ppm 1)
Cleaning Level
< 200 ppm 1) 2)
Cleaning Level
< 200 ppm 1) 2)
Cleaning Level
< 20 ppm 1)
Recovered material to
be recycled into
preceding product
Recovered material to
be recycled into
preceding product
Recovered material to
be recycled into
preceding product
Recovered material to
be recycled into
preceding product
Recovered material to
be recycled into
preceding product
N/A
N/A
Used cleaning medium
to be disposed of
N/A
Used cleaning medium
to be disposed of
N/A
N/A
N/A
N/A
N/A
N/A
Wet cleaning (see 6.1.3)
Flush cleaning (see 6.1.5)
Dry cleaning incl. dismantling of equipment
for manual cleaning of critical parts (see
6.1.4)
Visual inspection (see 6.1.2)
Trace analysis (see 7.1)
Release of cleaned equipment (see 6.4)
Cleaning Costs
(downtime, man hours)
High
Medium
Small
Waste Generation
<-------- Cleaning Sequence --------->
Cleaning Steps
Complete drainage of installation
Dry cleaning incl. dismantling of equipment
for manual cleaning of critical parts (see
6.1.4)
Flush partially disposed Flush partially disposed
of and partially recycled of and partially recycled
Recovered material to
be added to flush
N/A
N/A
Used cleaning medium
& flush
High
Medium
Recovered material to
be added to flush
Used cleaning medium
Used flush
None
Remark: 1) Listed cleaning levels given for guidance only. Cleaning procedures have to be validated to assess achievable cleaning levels (see 6.1.6).
2) Either cleaning sequence can be applied. Selection of sequence depending on design of equipment, drying possibility, waste disposal consideration.
N/A Not Applicable
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6.1.3 Wet Cleaning
Wet cleaning (also called “liquid cleaning”) is typically applied on manufacturing lines for liquid
products, but in many cases also forms one of the cleaning steps in manufacturing lines of solid
products.
Wet cleaning is not suitable for equipment where rinsate collection is difficult or even impossible
(e.g. tableting machine, fluid bed dryer).
The written wet cleaning procedure must detail (if applicable):
•
The cleaning medium used (e.g. organic solvent, water, detergent, bleach, caustic soda). It must
dissolve, emulsify or disperse the residual impurity at a rate > 1 % w/w. Pre-testing the
effectiveness of the cleaning medium can be done in the laboratory.
•
The sequence in which the individual parts of the manufacturing line are cleaned.
•
The charging of the cleaning medium into the equipment, e.g. by use of a rotating spray head. The
cleaning medium shall be agitated and / or circulated at a pre-defined temperature for a time
period sufficiently long to eliminate the contaminant. Where possible, distillation under reflux of the
cleaning medium is recommended.
•
The number of rinses applied and the minimum quantity of the cleaning medium per rinse.
•
The (partial) dismantling of the equipment and the manual cleaning of the individual parts with the
cleaning medium.
•
The rinsing of the interior surface of the equipment e.g. by use of a high pressure water jet.
•
The description of sampling locations for rinsate samples (see 7.2).
It must be stressed that the determination of the residual impurity in the rinsate (= used liquid
cleaning medium) does not always guarantee that the level of the residual impurity in the following
product is automatically below the agreed cleaning level, even if this level is found in the rinsate.
•
The process of drying inner surfaces (if necessary) by either heating or purging the equipment
with nitrogen or compressed air.
•
The disposal / recycling procedure of the used, contaminated cleaning medium (see 6.1.8).
•
Any potential health, safety & environment issues (handling, flammability) for non-aqueous
cleaning media (e.g. organic solvents) and recommendations on personal protection equipment
for the operator.
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Fig. 5: Interior of a mixer before and after wet cleaning using a rotating spray head, followed by drying.
Fig. 6: Mobile spray head for reactor and tank cleaning. To be installed on a free flange and connected
to a high pressure water supply. The spray head is rotating vertically and horizontally around the pipe
axis.
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Fig. 7: Workstation for the mechanical, manual cleaning (“brushing”) of small dismantled equipment
parts.
Fig. 8: Cleaning of a reactor with a hot water, high-pressure cleaner. Pipe cleaning nozzle spraying
forward (1 jet) and backward (3 jets), pulling a flexible hose through a pipe, even vertically upwards.
Note the personal protection equipment of the operator to protect him from splashes of the hot, high
pressure water.
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6.1.4 Dry cleaning
Deposits of solids (powder, granules) are removed from the manufacturing line by opening or (partially)
dismantling the equipment followed by brushing and/or vacuum cleaning the interior.
Fig. 9: Vacuum cleaning granules from partially dismantled packaging equipment using a special
industrial vacuum cleaner with HEPA filter to control dust.
6.1.5 Cleaning with solid, inert material (“flush cleaning”)
The solid flush material consists of solid, inert material without active ingredient, either the pure carrier
(e.g. bentonite, kaolin, sand, silica, sugar, talc etc.) or a combination of carrier and surfactants
(= formulation inerts) according to the composition of the preceding product.
Additional dry cleaning and (optional) wet cleaning must always follow the flush cleaning to remove
traces of the flush material left in the equipment.
It must be stressed that in a solids formulation line after dry cleaning and (optional) wet cleaning, the
rinsate and/or solid flush material analysis does never guarantee that the RI level in the succeeding
product is below the agreed cleaning level, even if this level is found in the rinsate / solid flush material.
Preceding product may remain in the equipment in the form of lumps “hidden” in dead spaces, which
may dislodge during the production of the succeeding product, thus contaminating the succeeding
product at a level above the cleaning level. This is the reason for the continued emphasis on
complete visual inspection of the formulation line to ensure there is no “hidden” material left.
6.1.6 Cleaning validation process
The cleaning validation process is designed to prove that, by applying the written cleaning procedure,
the required cleaning level is always achieved. The validation is even more important in those cases
where the residual impurity (RI) analyses are carried out in the used cleaning medium (rinsate / solid
flush material) and not directly in the subsequent product (see 7.1):
•
Select a product changeover requiring a cleaning limit below 100 ppm (liquids) or 200 ppm (solids).
Alternatively, choose a changeover with a preceding product that is difficult to clean (e.g. a sticky
active ingredient, a sticky formulation, a product containing a strongly colored a.i. or a dyestuff
etc.).
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•
Clean the manufacturing line according to the written cleaning procedure. Adhere strictly to the
cleaning procedure to ensure reproducibility of the process.
•
Analyze the used cleaning medium for the residual impurity. If several cleaning cycles are required
analyze each used cleaning medium individually. This allows determination of the “right” number
of cleaning cycles to achieve the requested cleaning level, with maximum efficiency.
•
Analyze the actual succeeding product for the RI of the previous product and compare the result
with the RI concentration found in the used cleaning medium. When the RI level in the used
cleaning medium is below the required cleaning level, the RI level in the succeeding product will
also meet the cleaning level requirements, provided the cleaning process is always performed
exactly the same way.3 For recommendations for the development of RI analytical methods
see 7.3.
•
The cleaning validation process should be based on data from at least three different changeovers
applying exactly the same cleaning procedure and shall be repeated periodically (e.g. annually).
6.1.7 Application of the validated cleaning procedure
It is necessary to follow exactly all the steps and conditions listed in the validated cleaning procedure
to ensure that the cleaning results are similar each time when the same changeover appears again in
the production schedule.
This also means that the configuration of the equipment must remain the same as described in the
validated cleaning procedure, e.g. if a larger formulation vessel is used in the process, either the
quantity of cleaning medium must be adjusted upwards or the recirculation time increased to meet the
requested cleaning level. In these cases, the cleaning procedure has to be re-validated to confirm that
the requested cleaning level can be achieved under these new, modified conditions.
Train the operators to adhere strictly to the cleaning process. For example changing the cleaning
medium, decreasing / increasing the cleaning medium quantity, shortening / increasing the time of the
rinsing cycle, or using a less concentrated detergent may distort the outcome of the residual impurity
analysis. Omitting a manual cleaning step may also cause material to be left in the equipment.
6.1.8 Recycling of used cleaning medium
Recycling of used cleaning medium must be a balanced decision and agreed with the client, based on
a risk / benefit assessment considering the following items:
•
Contamination risks due to mix up or improper labeling of stored used cleaning medium.
•
Quality risks due to deterioration of the stored used cleaning medium (chemical or bacterial /
fungal).
•
Savings achievable by re-use of the used cleaning medium.
•
Ecological benefit from waste reduction.
3
Provided the cleaning process is reproducible and the solubility of the residual impurity (RI)
sufficiently high in the cleaning medium, there must be a proportional relationship between the RI
concentration measured in the rinsate and the RI concentration in the succeeding product. Periodic
repetition of the cleaning validation will establish confidence in the proportional relationship, thus
allowing the release of the final product based on the results of the routine rinsate analysis.
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6.2 Equipment design for improved cleaning efficiency
Contamination Prevention requirements must form an important consideration in the design of new or
in the modification of existing production units. The following design ideas for improving cleaning
efficiency should be considered:
•
Include state of the art technology to reduce contamination potential: Clean-in-place (CIP)
technology, e.g. rotating spray heads in tanks, in-line analyzers, etc.
•
Consider automation of the cleaning procedure on lines equipped with a Process Control System.
•
The type of cleaning has to be included in the design. In the case of wet cleaning (see 6.1.3) the
technical equipment must be liquid-tight, the internal surfaces of the equipment corrosion resistant
and smooth to avoid trapping of product.
Certain plastics (used for e.g. pipes) may absorb active ingredient and solvents and cannot be
cleaned properly. The use of non-absorbent material is recommended.
•
Design a sufficient number of cleaning access panels to allow good visual inspection of the interior
of the equipment and easy access with cleaning equipment.
•
Provide valves at the lowest point in the piping to allow easy drainage.
•
Design the production unit with adequate surrounding space and logical disassembly points to
facilitate cleaning. Consider quick fittings on equipment to allow rapid disassembly and inspection.
•
Slope piping to maximize drainage. Bends in piping (especially those with small radius that could
serve as a hold-up) shall be minimized whenever possible. Avoid U-shaped pipes.
•
Select technical equipment (reactors, valves etc.) with “zero dead spaces” (no rectangular corners
in containers, and no dead legs) to minimize the risk of trapping material and to allow easy
drainage.
•
Install sampling devices throughout the process to assist the analytical and troubleshooting needs
after cleaning. Design the sampling devices with easy cleaning in mind.
•
Consider closed unloading and packaging stations, for powders with dedicated pre-filter.
•
Provide the production unit with a “washing room / workstation” (see Fig. 7) for the cleaning of
dismantled smaller pieces of equipment.
•
Grating as floor in manufacturing areas is not recommended. Spills can be much better contained
with solid floors.
•
Construct walls that are washable and leak-proof or sealed at the edges with no crevices.
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6.3 Illustrations of the production units with practical tips for cleaning of
critical parts.
Cleaning of production units to levels below the agreed cleaning level is one of the key success factors
in effective Contamination Prevention management. In this chapter, special attention will be paid to
critical, hard-to-clean areas, in various types of formulation and packaging units. Although effective
cleaning of production units for intermediates or active ingredients is equally essential in
Contamination Prevention management, no illustrations will be provided because the various
synthesis processes require a much wider range of equipment configuration than formulation and
packaging units. Critical areas in synthesis units are centrifuges, filters, dryers and equipment by
which the final synthesis product (e.g. intermediates or final active ingredients) is transferred to bulk
containers, drums etc.
The drawings of the various formulation units are schematic and will vary from production unit to
production unit. However, in each production unit, similar critical areas will be present. These areas
are surrounded by red circles. The first time a particular critical area shows up in an illustration,
attention will be drawn to this area with a magnifying glass and relevant comments will be made. If this
critical area shows up again in a different production unit, the identical comments will not be repeated,
although the critical area is highlighted again in the drawing.
Legend:
Motor
Fan
Dust Collector/
Air Filter
Sifter Sieve
Screener
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Solid/liquid
Filter
Rotary Valve
Feeder
Pump
Implementing Contamination Prevention, ed. 2 English (2008)
6.3.1. Liquid formulations
6.3.1.1 SL and EC formulations
Comments:
1.
Lines coming from bulk tanks must have reliable backflow prevention that is checked periodically.
This is especially critical if the solvents and additives (e.g. surfactants) are drawn from bulk tanks
that also feed other production units. Where vessels or filling lines can be fed from multiple bulk
tanks containing different active ingredients, formulations or raw materials, the lines not in use
should be blanked off or disconnected to ensure the wrong material is not added by mistake or
mechanical failure.
2.
In the area of solids charging two points need to be managed very carefully:
a. Adding only the correct solids to the process.
b. Dust generation requires extra attention, not only during the process (Contamination
Prevention and industrial hygiene), but also when changing to the succeeding product. This is
an area where special attention must be paid to good housekeeping.
c. The dust collected in the filter shall preferentially be disposed of.
If a recycling of dust is envisaged, a procedure (agreed with the client) must be strictly
followed detailing the measures to avoid mix up of collected dust during storage and recycling
into the succeeding product. Never recycle dust collected from floors or walls into the process!
3.
Deposits may form at dip pipes and require longer cleaning time than the rest of the formulation
vessel. Especially when clean-in-place practices are followed, the cleanliness of the dip pipes
needs to be checked, ideally by a visual inspection.
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4.
Pumps are always difficult to clean and ideally the pump is cleaned separately.
5.
Replacing the filter bag before starting the formulation campaign of the succeeding product is a
“must”.
6.3.1.2. Wet (liquid) milling, SC formulations
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Comments:
Cleaning immediately after the campaign is completed is strongly recommended, even if it is not
decided which product will follow in the production sequence. In the case of a production unit for
flowable formulations, it is even more important due to the fact that a film of a flowable formulation,
which contains solid particles of the active ingredient(s), thickening agents etc. is very hard to remove
once dried. If this film has not been completely removed during cleaning, it may dissolve into the
succeeding product and cause contamination (see case history 2).
1.
The colloid mill needs extra attention in the cleaning process, because of the inherent design of
the unit and the high shear rates, a solid film is certain to build up in places which are difficult to
clean. Opening may be necessary for cleaning and inspection of the cleanliness.
2.
It is recommended to use dedicated beads for each active ingredient manufactured in the bead
mill. The beads should be cleaned and stored between campaigns - clearly labeled with the name
of the active ingredient for which they must be used.
6.3.1.3. Liquid product packaging / repackaging / refilling
Comments:
This illustration deals with packaging liquid products (this could be liquid active ingredients or
formulations) from bulk containers (drums, bulk tanks, isotainers, IBCs) into smaller end-user packs.
It is imperative to verify that the material in the bulk container corresponds with the labels on the
end-user containers. These comments apply equally to the packing of liquid active ingredients into
drums or similar packs.
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3.
The cleaning history and the attained cleaning levels of movable pumps as well as flexi hoses or
solid piping and the header tank of the filling unit from the bulk container must be known. Before
this equipment is used, a release procedure is required. It is important to have dedicated pumps
and flexi hoses for herbicides and insecticides / fungicides. Pumps are always difficult to clean
and ideally the pump is cleaned separately.
4.
Since certain plastics may absorb active ingredients and therefore cannot be cleaned properly,
equipment containing such plastics should be dedicated. Non-dedicated parts must be made from
non-absorbent material, e.g. stainless steel.
6.3.1.4. Packing line for liquid products
Comments:
A mistake at this final phase of the manufacturing process will have a similar impact on the customers’
opinion of the product as contamination with a residual impurity, i.e. negative publicity and loss of
customer confidence.
1.
Incorrect labeling of the containers can cause crop damage and/or safety risks to users. In
addition, it also infringes plant protection laws and can result in considerable fines.
2.
Incorrect labeling of the outer cartons and pallets results in similar issues. Incidents of this nature
often result in product recalls to allow relabeling of the cases and/ or containers.
These comments apply of course also in the case of repackaging solid formulations.
6.3.2. Dry (solid) formulations
6.3.2.1. Dry milling - WP formulations or premixes for granular formulations
(For illustration of this equipment see next page)
One of the general concerns in the manufacture of solid formulations is dust that can escape from the
equipment at a number of places. Good housekeeping is always of the greatest importance in any
type of manufacturing of Crop Protection products, but it is even more critical when manufacturing
solid products.
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Comments
1.
“Caking” of solid materials to the walls
and moving parts of screw conveyors,
rotary valves (feeders) and blenders is
hard to avoid, for it is often linked to the
physical properties of the solids used.
The most effective way of cleaning is by
(partially)
dismantling
the
screw
conveyor, rotary valves and blenders
followed by mechanical cleaning first to
remove any solid deposit. Only then,
cleaning with pressurized water should
be carried out.
2.
The air jet mill (or the mechanical mill)
should be opened and first cleaned
mechanically followed by wet cleaning.
Wipe tests (also referred to as swab
tests) are a very good method to
determine the potential residue of the
preceding active ingredient adhering to
the wall of the equipment. Sometimes
these residues may be invisible, but in
the case of highly active products, they
could still cause contamination of the
succeeding product.
3.
Since the “dust” collected in the filter
and in the cyclone could form “lumps”
which could be released into the
succeeding product, these parts require
extra thorough cleaning. Use of product
dedicated filter tubes / bags is
recommended instead of reuse of the
filter bags. Carefully manage the
packaging, labeling and storage of
dedicated
filter
bags
to
avoid
inadvertent reuse with the wrong
product in a future manufacturing
campaign.
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6.3.2.2. Extrusion Granulation
Comments:
1.
The screens in the extruder need to be removed and cleaned in a bath with an appropriate
detergent, and in addition it is recommended to keep them dedicated to the active ingredient.
Other parts of the extruder need special cleaning attention like the screw conveyor.
2.
Irrespective of the design of the dryer, product will typically adhere to some extent to the wall and
require extra attention during the cleaning operation. For fluidized bed dryers, the air inlet plate
needs a special cleaning process.
3.
The screens in the sifter require removal and manual cleaning followed by visual inspection.
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6.3.2.3. Fluidized bed granulation
Comments:
1.
The entire granulation unit is prone to build-up of solid material, especially in the filter. During
changeovers, dismantling of this unit and use / exchange of dedicated filter tubes is strongly
recommended. Again, as in fluidized bed dryers, the air inlet plate needs special care.
2.
Bucket elevators are not recommended at all, because they are so hard to clean. Elevators often
have dead spaces, which make them extra critical from an ease of cleaning point of view. Before
release for the manufacture of the succeeding product, a visual inspection is a must, and wipe
tests may help to confirm cleanliness.
3.
The roller mill needs to be dismantled and cleaned manually followed by visual inspection.
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6.3.2.4. Spray Drying - Granular Formulations
Comments:
1.
During the spray drying process, a film of solid material will form on the walls of the spray drying
unit. Cleaning should start with mechanical removal of this film.
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6.3.2.5 Solid products refilling / repackaging
Comments:
Although the same principles apply as ones for refilling and repackaging of liquid products, there are
some differences worth mentioning:
1.
As best practice each filling line should have its own individual filter and exhaust system.
2.
If the exhaust system is shared with other filling lines or formulation units then
a. any line / unit not in use shall be blanked off (fixed piping) or disconnected (flexible piping)
from the shared exhaust system,
b. pre-filters (also applies to mobile ones) shall be installed in the exhaust system at spots with
high dust loads, e.g. powder drum filling, to trap the dust at the source. Pre-filters are essential
in those cases where a low application rate herbicide is handled in the line / unit and the
potential translocation of the dust through the shared exhaust system into another line / unit is
a high contamination risk.
3.
If the dust is recycled, it is necessary
a. to have dedicated filter systems for each packaging line, and
b. to change filter bags at each product changeover. Labeling requirements are similar to those
for interchangeable parts, while proper storage rules for these filter bags apply if they are to be
re-used later.
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6.4 Documentation of changeover and “release” of cleaned equipment
A written record of each specific changeover of the production unit must be retained for a time period
defined by the client and / or local legislation and provide the following details:
•
The date of the last production as well as the date of the cleaning operation.
•
Each step of the cleaning procedure (for details see 6.1.1) with confirmation of its completion (date
and operator initials).
•
Analytical evidence that the concentration of the residual impurity is below the agreed cleaning
level (see chapter 7).
•
Completeness check of the cleaning record, including visual inspection and sign-off by an
independent person, e.g. the supervisor
•
The formal written “release” allowing the use of the cleaned equipment for the manufacture of the
next product.
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7. Trace Analysis of Residual Impurities
The succeeding client provides the cleaning level and analytical requirements to the toller. The
toll manufacturer and the succeeding client work together to design the trace analysis and
sampling regime.
7.1 Residual impurity analysis in the product vs. in the rinsate
Cleaning levels are the concentrations (in ppm) of the residual impurity (the active ingredient(s))
of the preceding product in the succeeding product, below which no undesirable effects will occur.
Since the cleaning level is the concentration of the residual impurity in the next product, not in the
rinsate, the RI should be analyzed in the product whenever technically feasible; as this gives the only
direct proof that the RI concentration of the succeeding product is below the required cleaning level.
Alternatively, where the analytical technology for product analysis is not available, a trace analytical
method shall be developed for the determination of the RI in the last rinsate.
If only the rinsate is routinely analyzed, a cleaning validation (see 6.1.6 & footnote 3) is an absolute
“must”.
A word of caution about the comparison of the RI concentration measured in the rinsate and in the
succeeding product: This is usually not a problem for solutions (e.g. EC, SL, EW type formulations
rinsed with the corresponding solvent). But WP, WG and SC formulations may have built crusts,
forming a “reservoir” for the contamination of many batches. If these are not well removed by the
cleaning medium, then no relationship can exist between the RI measured in the rinsate and in the
succeeding product.
7.2 Sampling
The toller will generate a written sampling plan and communicate it to its clients for agreement. The
sampling plan details:
•
How to sample e.g. appropriate sampling equipment, type of container:
o A contaminated sample presents a major contamination issue. It must be ensured that the
sampling method itself does not cause sample contamination (e.g. by using of dirty scoops,
dirty sample bottles).
o The operators have to be trained on the correct sampling procedures.
•
What to sample e.g.
o the last rinsate after having flushed cleaning medium through the equipment,
o the product from the actual formulation or synthesis vessel,
o the first bottle packaged on the line when analyzing the RI level in the succeeding product.
•
Where to sample e.g.
o at a critical spot in the technical equipment where product residues may accumulate,
o at a specifically labeled sample port such as a valve, or the final package filling spout.
•
Sample size
o Sample needs to be representative, but should be kept as small as possible because it must
not be returned to the process (unless approved by the client).
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7.3 Development of trace analytical methods for residual impurities
A trace analytical method may have to be developed for the determination of the RI in the last rinsate
and / or in the succeeding product. The preceding client should be consulted to find out whether they
can provide any information on analytical methods for the determination of trace levels of the
preceding active ingredients. However, it should be realized that methods are specific to analytical
equipment.
In practice, quality control or residue analytical methods are often adapted for RI trace analysis:
•
Thin layer chromatography (TLC) is a simple and cheap, semi-quantitative analytical method
suitable for the RI analysis in the succeeding product. However, its use is often limited to
changeovers with detection limits above 100 ppm and RIs that absorb UV light for detection.
•
Gas (GC) and Liquid Chromatography (LC) are applied for RI analysis in the succeeding product
or in the rinsate when low cleaning levels have to be confirmed.
•
LC-MS, GC-MS or other mass spec.-chromatographic methods are suitable for very low cleaning
levels (<< 50 ppm).
•
GC and LC trace analytical methods must be validated for linearity and recovery in the target
cleaning level range:
o A suitable, validated cleaning procedure should give a cleaning result X, which is equal or
below the target cleaning level. The target cleaning level is calculated by multiplying the
cleaning level (as listed in the RI matrix) with a safety factor to account for possible analytical
variability (Fig. 10 shows an example for a cleaning level of 100 ppm and a safety factor of
0.66).
o It is recommended that the limit of quantification relevant to this discussion should equal
40% of the cleaning level. This limit is not to be confused with the lower limit of detection of the
analytical method.
RI analytical level
[ppm]
Cleaning Level (CL)
100 ppm
X
Target Cleaning Level
= 0.66 x CL
66 ppm
X
Cleaning Result X
X
Limit of Quantification
= 0.4 x CL
40 ppm
X
Bx 1
1000
Bx 2
Bx 3
2000
3000
Bx 4
4000
X
Bx 5
5000
Limit of Detection
Batch no.
Quantity Succeeding Product or
Rinsate [kg or L]
Fig. 10: Example for a cleaning level (CL) of 100 ppm. In this example, the target cleaning level equals
0.66 x the CL listed in the cleaning matrix. The production batches (including Bx 1) can be released
safely, but the cleaning should be improved for next time, to be below the “target cleaning level”.
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8. Manufacturing Practice
„Good Housekeeping” is fundamental for successful Contamination Prevention management.
8.1 Identification of incoming goods on site
•
Check the bill of lading and Certificate of Analysis and ensure a Safety Data Sheet is available.
•
If the client requires identification or quality control (e.g. chemical and physical analysis, visual
inspection) of the incoming materials, these must be placed in quarantine. Only after review of the
quality control data may the material be released for production.
8.2 Controls to ensure that the correct material gets delivered to the
manufacturing point and used in the manufacturing process
•
Separation of storage areas, e.g. herbicide actives and raw materials stored separately from
fungicide active ingredients and raw materials.
•
Warehouse personnel to verify the name and batch number of the material when picking.
•
Production personnel to compare the product name of the material received from the warehouse
at the manufacturing point with the one on the batch card for the final product.
•
The client may require signatures of the personnel performing these tasks.
•
Apply bar coding (if implemented).
8.3 Traceability
Production records (batch cards) for each manufactured batch detailing:
•
Raw materials / active ingredients used including the batch numbers used by the supplier and the
quantities.
•
Operating conditions.
•
Batch number of the manufactured batch and its quantity.
•
Names and initials of the operators responsible for charging and verification of the materials.
The client may define the required retention time of the production records.
8.4 Labeling
•
Minimal requirements for all packed goods are :
o Product name
o Product code
o Batch number
o Quantity
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Implementing Contamination Prevention, ed. 2 English (2008)
•
In addition, packed goods for sale must be labeled according to all legal requirements.
•
Temporary labels (in case the final label cannot be applied) are allowed if they contain at least the
product name and / or product code, the batch number and the quantity per packaging unit.
•
Clients may decide whether they accept bar codes containing the above information combined
with automatic barcode checks to replace man-legible labels.
8.5 Rework
No rework (including blending) of off-spec. or over-aged batches from previous production runs is
allowed without a written procedure. In all cases, rework can only take place with full agreement from
the client.
For recycling of used cleaning medium see chapter 6.1.8.
8.6 Shared portable / interchangeable equipment
Define written procedures for the use of shared equipment (flexi hoses, pumps, tools, cleaning
equipment like vacuum cleaners, etc.). The following points ought to be considered:
•
Restricted movement: In a solids plant, it is strongly recommended to have dedicated vacuum
cleaners for each individual production unit.
•
Labeling of the equipment.
•
Traceability of the shared equipment (the preceding product and the cleaning level).
•
Flexi hoses and pumps dedicated to a product or a product family.
8.7. Retained samples
Define and agree with the client, a written procedure defining which samples need to be retained, the
retention time and the storage conditions. Retaining samples of used cleaning medium is not a
common practice; however, it is important to keep records of the analytical data of these materials,
e.g. the chromatograms during the agreed record retention period.
8.8 Temporary storage tanks
•
At least during the entire manufacturing campaign, temporary storage containers (IBCs, Isotainers
[= ISOs], silos, bulk storage tanks) must be dedicated to a specific product.
•
Never use IBCs or ISOs used previously for other crop protection products without adequate,
validated cleaning. A written cleaning procedure must be available for the cleaning of temporary
storage containers. If the cleaning is outsourced to another company (e.g. at an isotainer cleaning
station), checks to verify the cleanliness of the container must be described and confirmed by the
cleaning company by issuing a cleaning certificate.
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•
All temporary storage containers must always be labeled properly:
o Name of raw material, in-process intermediate or final product
o Product code
o Batch number
o Production date
o Quantity
Or when empty:
o Cleaning Status (cleaned / uncleaned)
o Date of last cleaning
8.9 Visual check of cleanliness
Ensure visual inspection of any part of the production unit is carried out and recorded prior to the start
of a new manufacturing campaign. This also applies to temporary storage containers before filling with
the following product. Use a checklist with operator signoffs.
8.10 Modification of the production unit / equipment and plant design
Whenever there is a need to modify / update the production unit, ensure that:
•
A Management of Change procedure is in place, which includes Contamination Prevention
aspects.
•
The design changes help to improve the cleanability of the production unit, e.g. no small radius
pipe bends, the right choice of material with smooth surfaces for piping, vessels and tanks, easy
dismantling, etc.
•
The cleaning procedures are validated after the changes have been completed.
8.11 Self Assessment
It is strongly recommended that the toll manufacturer carries out a “self assessment” using the
attached questionnaire: “Contamination Prevention Checklist for Self-Assessment by Toll
Manufacturers”.
•
The completed checklist should be used in discussions with all clients for it presents an up-to-date
picture of the level of Contamination Prevention management practices in place for any given
production unit at a toll manufacturer and helps the client to form an accurate picture and carry out
a risk assessment.
•
The checklist is also a tool to determine which improvements in the Contamination Prevention
management programs are desirable, to develop proposed actions and define their order of
priority in order to achieve the improvement goals.
•
The checklist should be updated by the toll manufacturer after implementing changes.
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9. Contamination Prevention Checklist for Self-Assessment by Toll Manufacturers
This Self-Assessment will help toll manufacturers to assess compliance of their manufacturing processes and technical equipment with
the key Contamination Prevention criteria and the competency of their staff. A negative reply to any of the questions in the checklist
should have a corresponding action plan to improve, or an explanation of why an improvement is not needed.
This checklist can also be used as the Contamination Prevention section of a client’s toller audit checklist.
The frequency of the Self-Assessment / toller audit is determined by each client and the toller individually based on their own
Contamination Prevention risk assessments and must be adjusted to cover events that impact the Contamination Preventions risk.
Frequent audits will be required whenever:
•
The product mix in a multi-purpose facility has been changed and a new active ingredient has been added to the toller’s portfolio.
•
After completion of the action plan to correct any non-conformity with the Contamination Prevention criteria.
When a proven, reliable Contamination Prevention performance has been demonstrated, and no equipment or portfolio changes have
taken place, the toller’s facilities may be audited less frequently.
Both in the case of Contamination Prevention Self-Assessment and toller audits, the lead auditor should preferably be an outside expert
(e.g. the QC manager from a different site of the same company, or an independent Contamination Prevention consultant).
Contents
1
Management Responsibility
6
Documentation
2
Information Exchange
7
Material Identification and Traceability
3
Type of Operation and Product Mix
8
Equipment Design for Improved Cleaning Efficiency
4
Separation of Product Groups
9
Further Contamination Prevention Aspects
5
Product Changeovers
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1.
Management Responsibility
1.1
Standards
Does your site have a company standard / guideline /
policy covering Contamination Prevention?
Or, are the ECPA “Guidelines for Contamination
Prevention Standards for Toll Manufacturing
Operations” being implemented?
•
1.2
If other, please describe.
Responsible person
Do you have an appointed person in your organization
for the implementation of the Contamination
Prevention program?
1.3
•
Name:
•
In the role since (date):
Training and awareness
Do you provide regular Contamination Prevention
training to:
Page 49
•
Existing personnel?
•
New personnel, including temporary seasonal
personnel?
•
How often?
Yes
No
Comments/ Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
1.
Management Responsibility
1.3
Training and awareness (cont.)
Are permanent training records maintained?
Do you have a formal Contamination Prevention
training module?
Describe any other awareness raising activities.
Page 50
Yes
No
Comments/ Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
2.
Information Exchange
2.1
Contact person
Who is the focal point in your company for your clients
for any discussions on information exchange?
•
2.2
Name:
Confidentiality of clients’ information
Do the contracts with your clients allow you to disclose
the name of the preceding products and their active
ingredients to the following client?
If not, due to existing secrecy agreements: Do your
previous clients allow disclosure of their company’s
name and the name of their Contamination Prevention
contact person to your succeeding client?
2.3
Active ingredients
Do you provide your clients with a list of all active
ingredients handled on your site, listed by production
units?
Do you provide your clients with updates of this list
when new active ingredients are added to your
portfolio?
•
Page 51
If yes, with which frequency?
Yes
No
Comments/ Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
2.
Information Exchange (continued)
2.4
Plant configuration
Do you discuss the configuration of the equipment
when you make a client’s product for the first time?
If the unit can be combined from different parts, do you
inform the client of all active ingredients which were
last in all these parts?
Example: the formulation vessel was used for the
previous product, but a charging hopper will be used
which contained a different active ingredient.
3.
Type of Operation and Product Mix
3.1
Type of operation
Does the manufacturing site:
•
Synthesize?
•
Formulate
o solids?
o liquids?
•
Package
o solids?
o liquids?
Page 52
Yes
No
Comments/ Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
3.
Type of Operation and Product Mix (cont.)
3.2
Product mix agricultural chemicals
Does the manufacturing site manufacture, formulate or
package:
Page 53
•
Low application rate herbicides (EPA definition;
≤ 560 g a.i./ha)?
•
Highly active herbicides (≤ 50 g a.i./ha)?
•
Normal rate herbicides?
•
Plant growth regulators?
•
Insecticides / fungicides for foliar or soil
application?
•
Insecticides / fungicides for seed treatment?
•
Rodenticides?
•
Non-crop pest control?
Yes
No
Comments/ Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
3.
Type of Operation and Product Mix (cont.)
3.3
Product mix non-agricultural chemicals
Does the manufacturing site manufacture, formulate or
package:
3.4
Page 54
•
Food and feed stuffs (inclusive vitamins)?
•
Human pharmaceutical products which are applied
orally, topically or as an injection?
•
Veterinary products which are applied orally,
topically or as an injection?
•
Human cosmetics and other health care products?
•
Household and industrial detergents (e.g. washing
powder, detergent for the food industry)?
Please provide a list of all active ingredients handled in
each of the production units on this site.
Yes
No
Comments/ Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
Separation of Product Groups
If the manufacturing site handles more than one of the
product groups mentioned in 3.2, please answer all
questions in chapter 4:
4.1
Herbicides and insecticides / fungicides:
Are the production units completely separated (except
steam, nitrogen, and compressed air lines) by:
•
Being in separate buildings?
•
Being in same building, but fully
compartmentalized, with
o no common ventilation system or other
potential cross flows,
o ancillary equipment (e. g. vacuum cleaners, air
filters, tools, used spare parts) dedicated
either to herbicides or to non-herbicides?
•
4.2
Are operating staff when moving from herbicides to
insecticides / fungicides required changing
footwear and work clothing?
Highly active herbicides:
Are the production units completely separated (except
steam, nitrogen, and compressed air lines) from other
product groups (including other herbicides) by:
•
Page 55
Being in separate buildings?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
4.2
(cont.)
Yes
Separation of Product Groups (cont.)
•
Being in same building, but fully
compartmentalized, with
o no common ventilation
potential cross flows,
system
or
other
o ancillary equipment (e. g. vacuum cleaners, air
filters, tools, used spare parts) dedicated either
to highly active herbicides or to other product
groups and marked accordingly?
4.3
•
Are the operating staff, maintenance workers and
visitors required to change (over)shoes, protective
equipment and overalls/ overcoats when moving
from highly active herbicide areas to other areas?
•
Are measures taken that no unfiltered air blows
outside, e.g. non opening windows, locked doors,
etc.?
•
Is the room under negative pressure and regularly
monitored?
Plant growth regulators (PGR):
Do you manufacture PGRs on shared lines together
with:
Page 56
•
Herbicides?
•
Insecticides / fungicides?
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
Separation of Product Groups (cont.)
4.4
Rodenticides and non-crop pest control products:
Are the production units completely separated (except
steam, nitrogen, and compressed air lines) from other
product groups by:
4.5
•
Being in separate buildings?
•
Being in same building but fully
compartmentalized?
Agricultural chemicals and non-agricultural chemicals
(see 3.3):
Are the production units completely separated (except
steam, nitrogen, and compressed air lines) by:
•
Page 57
Being in separate buildings?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
Separation of Product Groups (cont.)
4.6
Incomplete separation
4.6.1
Do herbicides and insecticides / fungicides, if not
completely separated, share equipment like:
Fixed equipment:
•
Bulk storage tanks in a tank farm:
o For raw materials / intermediates?
o Final product?
•
Container loading / unloading stations?
•
Transfer lines (“pipelines”) with manifolds?
•
Common ventilation system?
Mobile equipment:
Page 58
•
Containers for intermediates / products?
•
Pumps?
•
Flexible hoses?
•
Filters?
•
Charging devices, e.g. funnels, suction pipes?
•
Vacuum cleaners?
•
Tools, e.g. shovels, spoons, sampling devices?
•
Others? Please list.
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
Separation of Product Groups (cont.)
4.7
Fixed equipment
4.7.1
Common bulk
ingredients:
storage
tanks
(“tank
farm”)
Yes
for
Are there one-way valves or other backflow protection
installed?
Can these common bulk storage tanks feed ingredient
to the herbicide and insecticide / fungicide process at
the same time?
4.7.2
If you use a manifold to connect transfer lines:
How do you identify the correct connectors when you
set up the transfer line at product changeover?
Do you change the connections at the manifold during
a running manufacturing campaign?
How do you clean the transfer lines and the connectors
at the manifold? Please describe.
4.8
4.8.1
Mobile equipment
Is all the mobile equipment mentioned (e.g. pumps,
flexible hoses, vacuum cleaners, tool kits etc.):
•
Dedicated to herbicide or insecticide / fungicide
production units?
Or:
•
Page 59
Assigned to a specific product, never being
removed from the line at least during the whole
manufacturing campaign and cleaned as part of
the changeover process?
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
Separation of Product Groups (cont.)
4.8.2
Are there written procedures for the cleaning of mobile
equipment?
4.8.3
Is this mobile equipment properly labeled or color
coded, showing its dedicated use?
Is there a log book or tagging system for each
interchangeable piece of equipment?
Do these records include:
4.8.4
•
Last product this equipment was used for?
•
Date of last use?
•
Date when the equipment was cleaned?
•
Cleaning method applied?
Mobile bulk product containers
Are mobile bulk containers (e.g. IBCs, isotainers,
big-bags, road / rail tanks, waste containers) assigned
to the manufacture of a single product for the entire
manufacturing campaign?
Page 60
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
4.8.4
(cont.)
Separation of Product Groups (cont.)
Are they used for dedicated, temporary storage of:
•
Inert ingredients?
•
Active ingredient containing materials (premix, final
product, e.g. prior to packaging)?
•
Waste (e.g. used cleaning medium to be recycled)
Do such containers remain dedicated to the same
product after the end of its manufacturing campaign?
4.8.5
Are all these bulk containers properly labeled with
clear identification of the product?
Is the adhesion of the labels adequate?
Is the history of these containers traceable, i.e. the last
product?
Is the cleaning status shown?
Page 61
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
Separation of Product Groups (cont.)
4.8.6
Are all types of bulk containers decontaminated
in-house?
•
If not, please list exceptions
If yes, is there a written and validated cleaning
procedure available?
Is the decontamination of bulk containers
sub-contracted? If yes:
4.9
•
Which cleaning standard must the sub-contractor
adhere to?
•
How do you verify the cleanliness of the bulk
containers?
Melting products in drums:
If drums have to be placed in a hot water bath or hot
air oven, e.g. for melting an active ingredient or
lowering the viscosity of certain surfactants:
Page 62
•
Are measures taken to prevent labels being
destroyed and traceability being lost, e.g. by
marking the top of the drum with the name of the
product with permanent, waterproof paint?
•
Are the hot water baths or hot air ovens dedicated
to the campaign of one single product, i.e. no raw
materials or active ingredients for other products
will share the hot water bath or hot air oven at the
same time?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
4.
4.10
4.10.1
Separation of Product Groups (cont.)
Handling / warehousing of common raw materials to
herbicides and insecticides / fungicides manufacture
Handling:
Are there raw materials that are common to both
herbicides and insecticides / fungicides, e.g. solvents,
surfactants etc.?
Is it ensured that a partially consumed container of a
common material - after it has been opened in the
herbicide area - will never be taken into the insecticide
/ fungicide area?
Are such containers labeled “For Use in Herbicides
only” and stored with the herbicide ingredients?
4.10.2
Warehousing:
Are Herbicide and insecticide / fungicide ingredients or
materials for further processing stored separately in:
Page 63
•
Separate buildings?
•
Different compartments or in dedicated, clearly
marked areas in the same building, e.g. clear
markings on the floor, walls and /or signs and/or
color coding?
•
Same store room without visual markings?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
5.
Product Changeovers
5.1
Management of changeovers and cleaning levels
5.1.1
Management of changeovers
Has a person been assigned responsibility for the
approval of the release of the cleaned equipment for
the next manufacturing campaign, including sign-off?
5.1.2
Cleaning Levels
Are there up-to-date cleaning levels available for each
production sequence in each unit (a matrix as
presented in chapter 5.2.2 of this booklet is strongly
recommended)?
Is there a procedure to ensure that the cleaning levels
are updated whenever the product mix or production
sequences are changed in a shared production unit?
Do the cleaning levels include all active ingredients
handled in the production units?
Do the clients provide the required cleaning levels? If
not, how are the cleaning levels determined?
Page 64
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
5.
Product Changeovers (cont.)
5.2
Analysis of cleaning levels (residual impurity)
5.2.1
5.2.2
Are there analytical capabilities available to determine
residual impurities below the cleaning levels requested
by the client?
•
For “contaminant in the rinsate” analysis?
•
For “contaminant in the succeeding product”
analysis?
Where are the trace analyses of the residual impurities
performed?
•
In the analytical laboratory on site?
•
In an external contract laboratory?
o Which company? Please name:
•
5.2.3
Page 65
In the client’s analytical laboratory?
Is the residual impurity analytical method validated in
the target cleaning level range:
•
For linearity?
•
For recovery?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
5.
5.2.4
Product Changeovers (cont.)
Are the residual impurities determined:
•
In the succeeding product?
If yes:
o How many batches are typically analyzed?
o Is a sample taken from the vessel? Or
o Is a sample taken from the 1st pack?
•
In the last rinsate?
Is the cleaning level analyzed at every product
changeover?
•
5.2.5
Page 66
If not, please explain:
Are analytical samples, laboratory samples and / or
retained samples (at the end of their storage period):
•
Reworked back into the process?
•
Disposed off?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
5.
Product Changeovers (cont.)
5.3
Cleaning procedures
5.3.1
Are there written and validated cleaning procedures in
place?
How was the cleaning validation done? Please
describe.
5.3.2
Page 67
Does the cleaning procedure specify:
•
The cleaning medium used?
•
The sequence in which the individual parts of the
manufacturing line are to be cleaned?
•
How to charge the cleaning medium into the
equipment?
•
The number of cleaning cycles, the duration of
each cleaning cycle and the minimum quantity of
cleaning medium per rinse?
•
Dismantling and manual cleaning where required?
•
Sampling locations?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
5.
Product Changeovers (cont.)
5.4
Recycling of used cleaning medium
Yes
Is used cleaning medium recycled back into the
process? If yes, please provide more details.
Is the client in agreement that the used cleaning
medium is recycled into his product?
If the used cleaning medium is recycled, are the
containers in which the used cleaning medium is
collected immediately labeled after the cleaning has
been completed?
Are containers for used cleaning medium cleaned
before use?
5.5
5.5.1
Release procedure for the cleaned equipment of the
production unit
Is there a release procedure for the cleaned equipment
prior to starting the next campaign?
Does this procedure include the following:
Page 68
•
Visual confirmation for adequate cleanliness?
•
Verification
of
the
cleaning
record
completeness to ensure traceability?
•
Verification whether the installations and the
shared equipment (pumps, flexi hoses etc.) are
properly labeled including the name of the previous
active ingredient and the cleaning levels achieved?
•
Verification that results of the RI analysis meet the
specified cleaning limit (as the confirmation for
effective cleaning)?
for
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
5.
5.5.2
Product Changeovers (cont.)
Completeness check for cleaned equipment:
Do the operators involved in readying the equipment
for the next production run put their signature on the
cleaning record and enter the time at which the
individual cleaning steps have been completed?
If a step in the cleaning of the equipment is not carried
out, will this be marked on the cleaning record with a
brief explanation?
Is it ensured that the next campaign can not be started
before the person responsible for the equipment
release has inspected the cleaned installation and has
signed the appropriate documentation?
5.6
5.6.1
Page 69
Release procedure for the product manufactured
after changeover
Does the product release procedure include the
following:
•
Who is authorized to release the product?
•
Steps to be agreed with the client for the release of
non-conforming product?
•
Quarantine of product manufactured after
changeover until the first batch(es) is (are) formally
released?
•
Release decision based on the residual impurity
analysis (see 5.2.3) to confirm that the agreed
cleaning level has been achieved?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
6.
Documentation
6.1
Records retention
Yes
How long do you retain the following documents?
6.2
•
Cleaning records:
years.
•
Batch cards:
years.
•
Analytical results of residual impurity levels,
including chromatograms:
years.
Final product sample retention
Do you keep retained samples?
•
If yes, how long are they retained?
What are the storage conditions for retained samples?
Are these samples kept under lock and key?
Do you have a sample log book?
At the end of the storage period are the retained
samples:
Page 70
•
Reworked back into the process?
•
Disposed of?
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
7.
Material Identification and Traceability
7.1
Raw material identification
7.1.1
Are incoming goods identified by:
•
The material code (“identity number”) and the
batch number(s) mentioned on the bill of lading?
•
Chemical / physical analysis to confirm identity?
Do you record the arrival time of the delivery?
If yes, please specify what system you use, e.g. SAP,
other computer system, paper system etc.
7.1.2
Which controls are in place to ensure that the correct
material is delivered from the warehouse to the
production unit and added to the process?
Please specify:
Page 71
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
7.
Material Identification and Traceability
(cont.)
7.2
Material traceability
Yes
Are production records / batch cards completed and
retained for each individual batch manufactured?
Do the records itemize the following details:
7.3
•
Batch numbers and the exact quantities of raw
materials added into the process?
•
Batch number
produced?
•
The names of the operators and their initials for
each step completed?
and
quantity
of
each
batch
Labels
Is there a procedure to ensure that only the correct
labels will be applied to the products (This includes
temporary labels.)? Please explain methodology.
In case temporary labeling is required before the final
labels can be attached, do these labels include (as a
minimum) the following information:
Page 72
•
Product name and / or product code?
•
Batch number and production date?
•
Quantity (for bulk containers only)?
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
8.
8.1
Equipment Design for Improved Cleaning
Efficiency
Pipe work:
Is the technical equipment aligned from top floor down
to bottom floor, with no U-shaped pipe work in the
manufacturing line where material could get trapped?
Is the pipe work sloped to allow easy drainage?
Does the pipe work provide valves at the lowest point
to allow easy drainage?
Does the pipe work avoid bends with small radius
(especially in solids and flowables production units) to
minimize the risk of trapping material?
Does the pipe work offer enough cleaning access
panels for easy access with cleaning equipment and
easy visual inspection?
8.2
Technical Equipment
Are formulation and packaging lines equipped with
“Clean in Place” (CIP) installations?
Do you apply an automated cleaning
controlled by a Process Control System?
process
Are unloading and packaging stations closed in (i.e. in
their own compartment), and in the case of powders
equipped with dedicated pre-filters?
Page 73
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
8.
8.2
Equipment Design for Improved Cleaning
Efficiency (cont.)
Technical Equipment (cont.)
Does the technical equipment (reactors, mills, driers
etc.) have:
8.3
•
Enough cleaning access panels to allow easy
access with cleaning equipment and thorough
visual inspection for cleanliness?
•
Internal surfaces that are corrosion proof and
smooth to avoid trapping of product?
•
Adequate surrounding space and logical
disassembly points equipped with quick fittings to
allow rapid dismantling and inspection?
Change of equipment configuration
In case the configuration of the production unit is
changed (e.g. new apparatus, different [e.g. larger or
smaller] vessels, filling line, changed geometry of pipe
work) are the following steps undertaken:
Page 74
•
Are the clients informed in writing about the
change of the configuration?
•
Are the cleaning procedures revalidated and
adjusted if required?
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
9.
Further Contamination Prevention
Aspects
9.1
Are spills returned back into the process?
9.2
Is the client informed when material does not meet
final product specification and rework or blending of
this material could be an option?
9.3
Is rework of off-spec material done following a
procedure approved by the client and with his/her
written authorization for each occurrence?
Page 75
Yes
No
Comments / Proposed Action Plans
Implementing Contamination Prevention, ed. 2 English (2008)
Glossary and Index
Term
Explanation
Page(s)
a.i.
Active Ingredient
5, 14, 19-21, 53,
92, 93
ACL
Acceptable Concentration Level, synonym of cleaning level
App. A-III
Analysis
of residual impurity, see chapter 7 and checklist chapter 5.2
29, 43, 44, 65
Analytical
capability
A combination of available analytical equipment,
methodology and know-how, demonstrated by successful
analysis of residual impurities
17, App. A-VII
ARIL
Acceptable Residual Impurity Level, synonym of cleaning
level
App. A-III
Batch card
Production record with the specific data of a single batch
produced, see chapter 8.3
6, 45, 70, 72
Beads
Glass or zirconium oxide balls used in bead mills (ball mills);
cleaning of -
35
Bulk
Containers
Examples of -
35, 60
Changeover
Documentation, see chapter 6.4
15, 42
App. A-VII
Certificate of
Analysis
Report of analytical results of a batch and confirmation that
they meet the specification
13, 45
Clean-in-place
(CIP)
Technology for cleaning production units without dismantling
by e.g. built-in spray nozzles
31, 33
Cleaning
capability
A combination of facilities, procedures and know-how to
achieve reliably a given cleaning level
17
Cleaning level
The concentration (in ppm) of the previous active
ingredient(s), or any other extraneous substance(s), below
which it will not cause any adverse biological, toxicological, or
ecological effects or regulatory issues in the succeeding
product. Various abbreviations with the same meaning are
used (see “Guidelines”)
18-22, 29, 43, 44,
64
App. A-III, VI, X,
XI
Cleaning
matrix
A table showing the required cleaning levels (in ppm) for
changeovers; the headers of its rows and columns show all
potential products of a production unit as preceding (e.g. in
rows) and succeeding (e.g. in columns) product and the cells
give the cleaning levels
18-22, 44
Page 76
Implementing Contamination Prevention, ed. 2 English (2008)
Term
Explanation
Page(s)
Cleaning
methodology
A combination of methods to clean a production unit including
the sequence of the single cleaning steps, e.g. rinsing top
down all parts with water + detergent, dismantling and
manual cleaning, exchange of dedicated parts like pumps
and milling beads, and visual inspection
17,
App. A-VI
Cleaning
procedure
Cleaning methodology adjusted to the required cleaning level
plus analytical control of success, organization of the release
of the unit and documentation of all steps, see chapter 6.1
and checklist chapter 5.3.
23-31, 42, 46, 62,
67
Client
Company contracting the production of a product with a toll
manufacturer
App. A-III
Responsibilities of -
15, 42, 43, App.
A-IV, V, VI, VIII
Colloid mill
Cleaning of -
35
Configuration
Of a production unit: the configuration specifies which parts
of a production unit are used for a defined production process
23, 31, 52
App. A-V
Change of - : see checklist chapter 2.4 and 8.3
30, 74,
App. A-V, VIII
Contamination
in a product
A component, not defined in the product specification, at
levels which will prejudice safety and efficacy or does not
meet regulatory requirements (see “Guidelines”)
4, 15, 18,
App. A-III
Contamination
Prevention
Any measure, be it organizational or technical, to prevent the
occurrence of a contamination incident – checklist
6, 15, 16, 23, 31,
45, 48 ff, App. A
Contamination
risk
assessment
See chapter 4
15 ff
Cross
Contamination
See contamination in a product
Dead space
Space inside a production unit, which may hold up product
that is not subject to the normal flow of material (product
and/or cleaning medium) through the unit; should be avoided
through design / construction
17, 23, 29, 31, 39
Design
Of a production unit: how its various parts and equipments
are arranged and linked together, see also checklist
chapter 8
15, 17, 31, 73
Change of -
47, 74
Storage of written information (e.g. procedures, cleaning
records, batch cards, analytical results) and of retained
samples, see chapter 6.4 and checklist chapter 6
17, 42, 70
Documentation
Page 77
Implementing Contamination Prevention, ed. 2 English (2008)
Term
Explanation
Page(s)
Dry
formulation
Synonym for solid formulation
36
Dry milling
Schematic production unit
36
Dryer
Cleaning of -
38, 39
EC
Emulsifiable Concentrate (a solvent based formulation type)
7, 10, 11, 20-22,
33, 43
ECPA
European Crop Protection Association
Foreword, 16, 49,
App. A-VIII
EPA
Environmental Protection Agency (USA)
8, 16, 18-22, 53,
App. A-VI, VII, X,
IX, App. B
Extruder
Cleaning of -
38
Filter
Cleaning of -
32-34, 37, 39, 41
Flexi hose
Flexible hose, used for transfer of materials when no fixed
piping is installed; requires special care in Contamination
Prevention
9, 10, 36, 46, 68,
App. A-VIII
Flowable
Formulation type, synonym of SC
6, 7, 35, 73
Fluidized bed
A method for the formulation and/or drying of granules
38, 39
Formulation
a) a preparation of active ingredient(s) and “inert” chemicals
(additives) which are necessary for the application of the
active ingredient(s);
Foreword, 4,
20-22, 33, 36, 43
b) the production of a formulation
17, 23, 73,
App. A-II, III
Formulation
unit
Production unit for formulations
7, 9, 32, 41
Granulation
Schematic production units
38, 39
HEPA
High Efficiency Particulate Air filter.
Generic term for highly efficient filters for airborne particles
≥ 3 micrometers.
29
Highly active
herbicide
Application rate typically below 50 g a.i./ha, e.g.
sulfonylureas, triazolopyrimidine sulphonanilides,
imidazolinones. This is by no means an exhaustive list and
there are other herbicides that could fall in this category.
16, 19, 22, 53, 55
App. A-IV, V
IBC
Intermediate Bulk Container: movable container for liquids or
solids between 200 L and 5,000 L
35, 46, 56
App. A-VIII
Page 78
Implementing Contamination Prevention, ed. 2 English (2008)
Term
Explanation
Page(s)
Information
exchange
Exchange of contamination-relevant information (e.g.
phytotoxicity, NOELs, analytical methods, ...) between
different clients and/or a toll manufacturer
51, App. A-V
Isotainer,
ISO tank
ISO standardized container for liquids between 5 and 25 m3
Volume, which can be transported by road, rail or ship
35, 46, 56
Labeling
of products, see chapter 8.4 and checklist chapter 7.3
12, 13, 36, 45, 72
Limit of
detection
Lowest residual impurity concentration that can be
analytically detected with the assurance, that the signal
being detected is due to the residual impurity and not from
other causes such as instrument noise (Signal-to noise
ratio: 3)
44
Limit of
quantification
Lowest residual impurity concentration that can be
determined repeatable with acceptable precision
(Signal-to-noise ratio: 10)
44
Liquid
formulation
Schematic production unit
33-35
Liquid
products
Refilling and packaging
35, 36
Low
application
rate herbicide
EPA classification: a.i. application rate ≤ 0,5 lb/acre
equivalent to ≤ 560 g/ha
12, 13, 20, 41,
53,
App. A-VI, X, XI,
App. B-V, VI
Manufacturing
All steps in the operation of manufacturing, including
synthesis, and/or formulation, and/or packaging (filling,
labeling etc.) and/or repackaging
Foreword, 45,
App. A-III
Manufacturing
site
May consist of multiple production units in the same or in
separate buildings
15, 52 - 55
MSCSG
Manufacturing & Supply Chain Steering Group, group in
ECPA involved with manufacturing and supply chain policy
issues affecting our industry
Foreword
Mill
Cleaning of dry and wet mills
6, 34, 35, 37, 39
NOEL
No Observable Effect Level, the highest rate in g active
ingredient / ha at which the active ingredient has no
observable effects on a given, tested species
5, 6, 14, 18, 19,
App. A-III, VII, X,
XI
Non-crop pest
control
Non-agricultural control of insects, weeds and fungi in
industrial areas, railways, public areas, household, sport and
recreation areas, in construction materials (e.g. wood), etc.
53, 57
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Term
Explanation
Page(s)
Normal
application
rate herbicide
EPA classification: a.i. application rate > 0,5 lb/acre
equivalent to > 560 g/ha
20,
App. A-VI,
App. B-VI
Packaging /
repackaging
In this booklet, the terms “packaging” and “repackaging” can
be used interchangeably for the process of enclosing and
protecting products for storage, distribution, sale and use.
Generic cleaning procedure
23-25
Schematic drawing (re-)packaging unit
35, 36, 41
Packaging unit
Production unit for packaging
20, 35, 36, 41
Pesticide
Regulation
Notice 96-8
(PRN 96-8)
US EPA document issued on October 31st, 1996, specifying
statutory cleaning levels for products sold or manufactured in
the US when changing from different families of products, e.g.
from insecticides to plant growth regulators
8, 16, 18, 19, 22
App. A-VI, VII, XI
App. B
Preceding/
succeeding
client
Indicates the sequence in which the products of these clients
are manufactured in the same production unit (applies equally
to synthesis, formulation, packaging and repackaging)
App. A-III, IV, V,
VI
Product
Intermediates, active ingredients, technical concentrates,
premixes of active ingredients, formulated products (either in
bulk or in temporary or final sales pack)
App. A-IV
Product mix
See checklist 3.
23, 48, 52
Product
scheduling
Planning the production sequence of different products;
different sequences may result in significantly different
cleaning levels
22
Production
record
Production data (e.g. batch card) of individual batches, cf.
Chapter 7.3
45, 72
Production
unit
Definition see chapter 4.1
15
Separation see chapter 4.2
16
Cleaning see chapter 6, especially 6.3
23-41, 47
Modification of -
31, 47
Used as shared equipment
36, 46, 58, 59, 68,
App. A-VIII
Cleaning of -
33-35
Pump
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Term
Explanation
Page(s)
Recycling
Dust, see chapter 6.3
9, 33
Rework
46, App. A-VIII
Used cleaning medium, see chapter 6.1.8 and checklist
sect. 5.4
26, 29, 30, 68
Samples, see checklist chapter 10
13, App. A-VIII
Release limit
Synonym for cleaning level
App. A-III
Release
procedure
For a plant/ production unit: organizational procedure to be
followed before a production unit can formally be allowed to
produce the next product after a product or
configuration change, see also checklist chapter 5.1.1., 5.5
24, 25, 36, 42
For a product after changeover: see checklist chapter 5.6
69
Residual
impurity (RI)
Traces [especially of active ingredient(s)] of the preceding
product present in the succeeding product manufactured in
the same production unit
4, 15, 19, 23, 26,
29, 42, 43, 65
App. A-IV
Residual
impurity
analysis
See chapter 7 and checklist chapter 5.2
43, 65
Retained
sample
Sample of a produced batch stored to allow later verification
of its quality, see chapter 8.7
12, 13, 17, 46, 66,
70, App. A-VIII
RI
Abbreviation for residual impurity – typically residues of the
active ingredient of the preceding product
29, 30, 43, 44, 68
RIL
Residual impurity level, synonym for Cleaning Level
App. A-III
Rinsate
Used liquid cleaning medium (water + detergent) or solvent
having been used to wash the residual product out of a
production unit
5, 10, 20, 26, 29,
41, 42, 59, 61
Rodenticide
Product for control of rodents e.g. rats and mice
4, 16, 53, 57,
App. A-III,
App. B-I, VI
Safener
A chemical added to a pesticide formulation to eliminate or
reduce the phytotoxic effects of that pesticide to certain
crops. Typical examples are safeners used in formulations of
grass "killers" that are applied in cereals and maize to make
them safer to the crop.
4, 16
Safety data
sheet
Material Safety Data Sheet (MSDS): Data required by the
Government(s) to assure worker protection and treatment for
exposure.
45
Safety factor
This factor is used to enhance the safety margin in the
calculation of the cleaning level. Each company is
responsible for setting its own safety factors. Safety factors
usually range from 2 to 10.
19, 21
App. A-VII
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Implementing Contamination Prevention, ed. 2 English (2008)
Term
Explanation
Page(s)
Sampling
Sampling should follow an agreed plan describing: how to
sample, what to sample, when to sample, from which sample
point to take samples, which quantity [sample size)], how and
where to store them, as well as the period during which the
samples have to be retained.
43
SC
Suspension Concentrate (a water based formulation type),
also designated as “flowable”
6, 7, 20, 21, 34,
43
Seed
Treatment
Treatment of seeds to protect them against insects or
diseases. Germinating seeds may be significantly more
sensitive to agrichemicals than more developed plants
4, 6, 8, 9, 22, 53
App. A-V, VI
Separation of
production
units
See chapter 4 and checklist chapter 4
16, 55-63
Separation of
materials
Separate storage of raw materials and products,
e.g. herbicide / non-herbicide usage
45, 63
Solid
formulation
Production units used for formulation of solid products
36-41
Solid Flush
Material
Solid inert material used to remove residual product from a
production unit; e.g. bentonite, kaolin, sand, silica, sugar,
talc.
17, 29
Solid products
Refilling and repackaging of -
41
Sulfonylureas
Class of highly active herbicides
App. B-VI
Temporary
label
A label to identify a packed product before the final product
label can be applied
11, 46, 72
Toller, toll
manufacturer
A company making a product for its client on a contractual
basis. The term “toller” is synonymous with contract
manufacturer (cf. “Guidelines”) or contractor
4
App. A-IV, V, VIII
Used cleaning
medium
Generic term for “rinsate” and used “solid flush material”, see
Glossary
29, 30, 46, 68
Vacuum
cleaner
Used as portable equipment
29, 46, 55, 56, 58,
59, App. A-V
Validation
of a cleaning procedure, see chapter 6.1.6
29, 43, 67
of a trace analytical method
44
Wipe test
(= Swab test)
A test method for the cleanliness of surfaces by wiping them
with a clean (optionally solvent wetted) filter paper or cloth
and then analyzing it for active ingredient
37, 39
WP
Wettable Powder (formulation type)
36, 43
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Appendix A - I
Appendix A – Guidelines for Contamination Prevention
standards for toll manufacturing operations
Table of Contents
Page
1. Introduction
App. A - II
84
2. Purpose
App. A - II
84
3. Scope
App. A - II
84
4. Policy Statement
App. A - III
85
5. Definitions/ Abbreviations/Terminology
App. A - III
85
6. Responsibilities
App. A - IV
86
7. Information Exchange
App. A - V
87
8. Establishing NOELs and calculating Cleaning Levels
App. A - VII
89
9. Minimum Requirements for Toll Manufacturers
App. A - VII
89
10. Minimum Requirements for Clients (ECPA Member Companies)
App. A - VIII
90
11. Recommendations for Tolling Operations
App. A - IX
91
Example 1 of Cleaning Level Calculation
App. A - X
92
Example 2 of Cleaning Level Calculation
App. A - XI
93
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Appendix A - II
1. Introduction
Contamination of products with residual impurities is a potential issue and area of concern for any
multi-purpose chemical synthesis, formulation and/or packaging facility. Contamination can result in
adverse effects on sensitive, treated crops or non-target species and may trigger regulatory issues.
Incidents may also tarnish the reputation and image of the industry as a whole.
2. Purpose
The purpose of these Guidelines is to ensure the quality of agricultural chemical products by
preventing contamination during toll manufacturing. This will be achieved by:
•
Setting minimum standards for Contamination Prevention between clients and toll manufacturers.
•
Information exchange between toll manufacturers (= toller) and its clients and direct
communication between clients to allow adequate risk assessments.
These Guidelines are available to all member companies and their current and potential toll
manufacturers. Implementation of these Guidelines is mutually beneficial for the toller and its clients.
Responsibility for the implementation of Contamination Prevention programs remains with the
individual companies and the toll manufacturers.
3. Scope
•
Provide minimum standards regarding Contamination Prevention to be written into toll
manufacturing agreements/contracts.
•
Exchange of relevant information on Contamination Prevention between member companies and
between member companies and their tollers.
•
Pertains to Contamination Prevention aspects in the synthesis, formulation, packaging and
repackaging of agricultural chemicals.
•
Sets minimum standards regarding Contamination Prevention for toll manufacturers.
•
Excluded from the scope of this document are:
o Contamination Prevention at farm level (e.g. tank cleaning).
o Issues related to biotechnology and seeds, e.g. GMO / non-GMO contamination during seed
production.
o Bulk deliveries and storage of finished product at distributors and dealers. Guidelines for
implementation of Contamination Prevention measures for handling finished product in bulk
are considered the responsibility of the individual member companies and the regional Crop
Protection Organizations.
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Appendix A – III
4. Policy Statement
The member companies will commit to the following:
•
They will ensure that their products on the market do not contain residual impurities in the form of
active ingredients not defined in the product specification, at levels which will prejudice safety and
efficacy, or which do not meet regulatory requirements. Limits will be set by the individual
companies for their products following an appropriate risk assessment.
•
They will provide a named Focal Point able to speak authoritatively on behalf of the company on
all aspects of Contamination Prevention.
•
A company which has its products toll-manufactured will provide available information to their best
knowledge to enable the succeeding client of the toller to carry out appropriate risk assessments
and to set limits for residual impurities.
5. Definitions/ Abbreviations/ Terminology
•
A / F / H / I / N / PGR / R:
Acaricide / Fungicide/ Herbicide/ Insecticide/ Nematicide / Plant Growth Regulator / Rodenticide
•
ARIL, ACL, RIL and Release Limit:
These terms are used by the different member companies and form the basis for the
communication of the required cleaning level.
o ACL: Acceptable Concentration Level
o ARIL: Acceptable Residual Impurity Level
o RIL: Residual Impurity Level
•
Cleaning Level:
The concentration of the previous active ingredient(s), or any other extraneous substance(s),
below which it will not cause any adverse biological, toxicological, or ecological effects or
regulatory issues in the succeeding product.
•
Client:
A company contracting the production of a product with a toll manufacturer.
•
Contamination in a product:
A component, not defined in the product specification, at levels which will prejudice safety and
efficacy or does not meet regulatory requirements.
•
Manufacturing:
Synthesis, and/or formulation, and/or packaging (filling, labeling etc.) and/ or repackaging.
•
NOEL:
No-Observable Effect Level: The highest rate in g active ingredient / ha at which the active
ingredient has no observable effects on a given, tested species.
•
Preceding / succeeding Client:
Indicates the sequence in which the products of these clients are manufactured in the same
equipment (applies equally to synthesis, formulation, packaging and repackaging).
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Appendix A – IV
•
Product:
Intermediates, active ingredients, technical (manufacturing) concentrates, premixes of active
ingredients, finished formulated products (either in bulk or in final sales pack).
•
Residual Impurity:
Traces [especially of active ingredient(s)] of the preceding product present in the succeeding
product manufactured in the same production unit.
•
Toller / Toll Manufacturer:
A company making a product for its client on a contractual basis. The term “toller” is synonymous
with contract manufacturer.
6. Responsibilities
The succeeding client is responsible:
•
To define the cleaning level(s) of the active ingredients of preceding clients’ products in its own
product to be manufactured at the toller.
•
To specify whether the cleaning level must be achieved in the succeeding product or in the
wash/flush material. In all cases, the finished product must meet the agreed cleaning level.
•
To establish and agree on any other requirements, e.g. segregation, labeling and warehousing.
•
To undertake detailed site audits and other due diligence activities (including the cleaning process
and results) and support the toller where appropriate.
•
To include these in an agreement with the toller.
•
To use the information obtained from the preceding client exclusively for the purposes of
Contamination Prevention.
•
To inform the toller of any special risks (e.g. highly active herbicide) associated with the product
being brought onto the toller’s site.
•
To review and if necessary update existing contracts and/or agreements with tollers to include the
best practices as outlined in this document.
The toller is responsible:
•
To meet its client’s minimum standards with regards to Contamination Prevention as defined in
Chapter 9.
•
To tell the succeeding client who to contact at the preceding client.
•
To clean the equipment to agreed cleaning levels and to document and retain records of cleaning
levels achieved.
•
To meet any other requirements of the succeeding client, e.g. segregation, labeling, simultaneous
operations, information on other products handled on the site, and warehousing.
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Appendix A – V
The preceding client is responsible:
•
To provide the succeeding client whose product will be manufactured in the same equipment with
any available information as requested in accordance with Chapter 7.
•
To provide the toller with any available information as requested in accordance with Chapter 7.
Disclaimer
Regardless of the information provided, it is the sole responsibility of the succeeding client to
determine the cleaning levels for the product(s) in question.
The resulting cleaning process and the demonstration of the cleaning result achieved, is the
responsibility of the toller.
The preceding clients supplying the information to allow the risk assessment will in no case be
responsible for any problem caused by their active ingredients in the products of the succeeding client;
such responsibility solely belongs to the succeeding client. In cases where local legislation is stricter
than these Guidelines, the legislation will take precedence.
7. Information Exchange
The toller must supply the following information to the succeeding client:
•
The names of the active ingredients of the preceding product in any part of the line. If restricted by
secrecy agreements, who to contact at the clients for those products. In case the toller has highly
active herbicides in its portfolio, the succeeding client may require information when this product
was in the equipment and which products were produced between the highly active herbicide and
the client’s product.
•
Configuration of the production unit in which the succeeding product will be synthesized,
formulated and/or packaged. Establish whether this configuration is identical to the one used to
manufacture the two preceding products.
•
Information on the physical lay-out of the facility that could impact Contamination Prevention.
•
Information about parallel operations with emphasis on the degree of segregation, common
equipment (including ancillary equipment like tools, vacuum cleaners, fork lift trucks) and
personnel.
•
Any information related to changes in the production sequence relevant to Contamination
Prevention.
The preceding client must supply to the succeeding client the following information if requested
and available for the previous products:
•
Confirm the active ingredients present in its product(s).
•
Registered crops and pest spectrum of the preceding product.
•
Method of application, e.g. post-emergence, pre-plant incorporated, seed treatment.
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Appendix A – VI
•
NOELs: method of calculation and determination of the NOEL (e.g. growth stage of crop at time of
treatment, application method, spray volume) on the registered crops of the succeeding product.
•
In the case of lack of NOEL information on the relevant crop(s), similar information on related
crops.
•
The minimum and maximum label rates.
•
Classification of the product according to the EPA Pesticide Regulation Notice 96-8, based on the
worst case scenario, i.e. if the product (irrespective of the formulation) is applied both as low and
normal application rate herbicide, then it should be indicated that this is a low application rate
herbicide.
•
Samples of the product for tests to develop missing NOELs.
•
In case of pre-commercial products, agreement on information exchange will have to be
determined on a case by case basis.
The succeeding client must supply to the preceding clients the following information if
requested:
•
Registered crops.
•
Method of application, e.g. post-emergence, pre-plant incorporated, seed treatment.
The preceding client must supply to the toller the following information if requested and available
for the previous products:
•
Analytical standards.
•
Analytical methods to allow determination of the cleaning levels required by the succeeding client.
In case it is possible to provide these methods, the toller is required to verify that these methods
work in his laboratory.
•
Cleaning methods. In case it is possible to provide these methods, the toller is required to verify
that these cleaning methods are effective in his plant, equipment and configuration.
Disclaimer pertaining to information provided by preceding client:
All information provided by a preceding client on the biological characteristics, analytical methods for
determining trace amounts, and cleaning methodology of its active ingredients should be reasonably
accurate, but the preceding client will not be held liable or otherwise responsible for the sufficiency of
such information or results of any assessment using this information. Such information is provided
without any warranty or other representation, expressed or implied. Analytical methods are equipment
and laboratory specific, whilst cleaning methods are site, configuration and equipment specific.
Therefore, these methods are to be considered as guideline only.
It is understood that whenever information is exchanged between the preceding client, its toll
manufacturer, and the succeeding client, this is done under confidential conditions. Individual partners
will decide on the need for a separate secrecy agreement on a case by case basis.
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Appendix A – VII
8. Establishing NOELs and calculating Cleaning Levels
•
Consult the US EPA Pesticide regulation Notice 96-8 (See Appendix B). Products sold in the USA
must conform to the values listed within this notice. These values may serve as guidance in other
geographies at the company’s discretion. If biological data dictate that the cleaning level should be
lower than the value indicated in the EPA Notice, the biological values should take precedence.
(See example 1 / Appendix A-X). In the USA, in cases where the biological values clearly exceeds
the values in EPA notice, the EPA notice takes precedence as shown in example 2, App. A – X.
•
Calculation of cleaning levels:
Cleaning level in ppm = (106 x NOEL) / (SF x AR)
Definitions:
AR = Maximum application rate of the succeeding product in gram or ml of formulated product / ha
NOEL = No observable effect level in gram active ingredient / ha
SF = Safety Factor
•
The NOEL used in the cleaning level calculation is based on the biological effects of the active
ingredient(s) of the preceding product on the most sensitive crop on which the succeeding
product is registered.
In determining NOELs, all relevant information should be assessed and where possible, existing
data from field trials or glass house tests should be used. When companies exchange the relevant
information on their active ingredients, they need to provide details on how the NOEL was
determined.
•
The Safety Factors are the individual decision of the [succeeding] company. Safety factors
typically range from 2 to 10.
9. Minimum Requirements for Toll Manufacturers
These items are to be incorporated in the agreement / contract between the client and the toller.
Details and additional requirements may be added by individual clients.
•
Tollers must co-operate in a full technical audit for Contamination Prevention.
•
Tollers must follow the requirements defined in Chapter 7: “Information Exchange”.
•
Tollers must be able to trace materials and must retain all relevant records as defined by the client
to enable traceability.
•
Adequate analytical capability must be available to meet the client’s requirements regarding the
cleaning levels. The analytical facilities are either in-house or at an agreed and approved location
(contract laboratory or at the client’s analytical laboratory). In the case of involving a contract
laboratory, the analytical data should be retained at the facilities of the toller.
•
Written changeover procedures, including the clean-out procedures and a check-list to be followed
as agreed with the client.
•
Contamination Prevention training of existing personnel and newly recruited personnel (before
being allowed to participate in the manufacturing process), and permanent records of the training.
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Appendix A – VIII
•
Segregation of simultaneous operations based on the outcome of the client’s risk assessment.
•
Complete, permanent labeling of the facilities, all equipment (including ancillary equipment), raw
material, ‘in-process’ and ‘finished’ product containers and waste containers in accordance with
the client’s requirements.
•
Well defined procedures based on the outcome of the risk assessment for the use of shared
equipment (flexi hoses, pumps, tools, pallets etc.), e.g. restricted movement, labeling, traceability
of the history of this equipment (previous products and cleaning level).
•
No change in configuration of the manufacturing equipment without written notification to the
succeeding client.
•
No change in the manufacturing sequence without written notification to the succeeding client.
•
No recycling of samples, i.e. samples cannot be returned in the process, without the approval of
the client.
•
No rework (blending, recycling) without the approval of the client. Client may insist on a written
procedure for rework.
•
Clear identification of finished product by minimum labeling (Batch/Lot number, product name) in
case of packed product without its final label (e.g. country/ product label, transport label).
•
Good housekeeping practices maintained consistently.
•
During operations, re-use of containers (IBCs, ISOs, Big Bags) previously used for other products
is prohibited, unless the client specifies differently.
•
The retention time and storage conditions of retained samples specified by the client must be
followed.
•
The toller must appoint a person responsible for implementation of the Contamination Prevention
Guidelines at the toller’s site.
10. Minimum Requirements for Clients (the Member Companies)
•
The ECPA member companies, the clients, will provide a named Focal Point able to speak
authoritatively on behalf of the company on all aspects of Contamination Prevention.
•
The ECPA member companies will incorporate these Guidelines into their toll manufacturing
contracts.
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Appendix A – IX
11. Recommendations for Tolling Operations
•
The ECPA member companies recommend that herbicides, especially highly-active herbicides, be
separated from non-herbicides (A/ F/ I/ N/R) in simultaneous operations. The amount of
segregation required is to be determined by each individual company based on the products
involved and its own risk assessment.
•
The ECPA member companies advise against campaigning herbicides, especially highly-active
herbicides, in sequence in the same equipment with non-herbicides (A/ F/ I/ N/ R).
•
The ECPA member companies recommend adequate risk assessments whenever highly-active
herbicides are campaigned in sequence or produced simultaneously with normal rate herbicides.
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Appendix A - X
Examples of Cleaning Level Calculations:
Example 1:
The changeover from metosulam to haloxyfop-P-methyl shows that the cleaning level resulting
from the EPA guidelines does not automatically guarantee a sufficiently high safety margin to
avoid a contamination incident.
Metosulam
•
Highly active triazolopyrimidine sulphonanilide.
•
Registered in cereals and maize (corn) for control of broad-leaved weeds.
•
Highest registered application rate is 25 g a.i./ha.
Haloxyfop-P-methyl
•
Formulation contains 108 g a.i./liter formulated product.
•
Registered for post-emergence control of grass weeds in a wide range of broad-leaved crops
including many vegetables.
•
Maximum dose is 2.0 liter formulated product/ha.
Cleaning level derived from EPA guidelines:
•
Category 7 applies: a low application rate herbicide in a low application rate herbicide.
•
A cleaning level of 100 ppm is allowed.
•
At the highest application rate of the following herbicide haloxyfop-P-methyl, this cleaning level
could result in an application of 200 mg/ha metosulam.
Cleaning level based on foliar NOEL data:
•
The crop most sensitive to metosulam that haloxyfop-P-methyl is registered on is oilseed rape
(Canola™).
•
Foliar NOEL of metosulam on oilseed rape is 0.002 g a.i./ha (2.0 mg a.i./ha)
•
The cleaning level is (106 x 0.002) / (10 x 2,000) = 0.1 mg/liter (0.1 ppm or 100 ppb)
Conclusion:
8 The cleaning level based on the EPA guideline would allow an application rate of metosulam to be
100-fold above the NOEL of metosulam on the most sensitive crop – clearly an insufficient
biological safety margin.
9 The cleaning level based on the foliar NOEL of metosulam does not give this problem.
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Appendix A – XI
Example 2:
The changeover from cyhalofop-butyl to haloxyfop-P-methyl illustrates that the biologically
defendable cleaning level could in some cases be considerably higher than the level permitted by EPA.
This will be irrelevant in the USA, where the EPA Pesticide Regulation Notice 96-8 must be
implemented. In other areas, however, this is of importance and manufacturers may for this reason
prefer to use biology based cleaning levels as it could result in a reduction of cleaning time and the
amount of contaminated waste produced without significantly affecting the safety margin.
Cyhalofop-butyl
•
200 g a.i./liter
•
Highly selective in broad-leafed crops.
•
Registered in rice for post-emergence control of grass weeds.
•
Highest registered application rate is 200 g a.i./ha.
Haloxyfop-P-methyl
•
Formulation contains 108 g a.i./liter formulated product.
•
Registered for post-emergence control of grass weeds in a wide range of broad-leaved crops
including many vegetables.
•
Maximum dose is 2.0 liter formulated product/ha.
Cleaning level derived from EPA guidelines:
•
Category 7 applies: a low application rate herbicide in a low application rate herbicide.
•
A cleaning level of 100 ppm is allowed
•
At the highest application rate of the following herbicide haloxyfop-P-methyl, this cleaning level
could result in an application of 200 mg/ha cyhalofop-butyl (0.2 g a.i./ha).
Cleaning level based on foliar NOEL data:
•
The crop most sensitive to cyhalofop-butyl that haloxyfop-P-methyl is registered on is soybean
•
Foliar NOEL of cyhalofop-butyl on soybean and oilseed rape is greater (>) 400 g a.i./ha
•
The cleaning level is (106 x 400) / (10 x 2,000) = 20,000 mg/litre (20,000 ppm).
•
For regulatory reasons, a cleaning level must never be allowed to exceed 1,000 ppm.
Conclusion:
8 The cleaning level for this product changeover based on the EPA guideline could necessitate the
level of cyhalofop-butyl in haloxyfop-P-methyl to be 200-fold below the NOEL on the most sensitive
crop.
9 Taking regulatory criteria into account, the cleaning level based on the foliar NOEL is still 10-fold
higher than the cleaning level based on the EPA guidelines.
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Appendix B-1
Appendix B – Pesticide Regulation Notice (PR) 96-8
Pesticide Regulation (PR) Notice 96-8
October 31, 1996
PESTICIDE REGULATION (PR) NOTICE 96-8
NOTICE TO MANUFACTURERS, FORMULATORS, PRODUCERS
AND REGISTRANTS OF PESTICIDE PRODUCTS
ATTENTION:
Persons Responsible for Registration of Pesticide Products
SUBJECT:
Toxicologically Significant Levels of Pesticide Active Ingredients
This notice sets out the Environmental Protection Agency’s (EPA’s) interpretation of the term
“toxicologically significant” as it applies to contaminants in pesticide products that are also pesticide
active ingredients. This notice provides risk-based concentration levels of such contaminants that will
generally be considered toxicologically significant. These concentrations are defined according to the
type of pesticide that is contaminated and the pesticide category of the contaminant. As provided by
regulation, registrants must report to EPA contamination exceeding toxicologically significant levels.
This Notice sets out procedures for reporting such contamination.
The following contamination scenarios are excluded from this notice:
(1) rodenticides as a contaminant and/or as the contaminated product;
(2) microbial and biochemical pesticides that are manufactured in fermentors and that are
contaminated by active microbial pesticide ingredients; and
(3) plant-pesticides that are contaminated with other active plant-pesticide ingredients.
EPA would like to clarify that the Agency’s previous position on toxicologically significant levels of
impurities that are also AIs would apply to pesticides that are exempt from this notice. In other words,
any level of a contaminant in these three exempted categories would be considered potentially
toxicologically significant and must be reported to EPA.
I. BACKGROUND
EPA requires all impurities of toxicological significance to be reported and accepted as part of product
registration (40 CFR 158.167). EPA also requires that registrants propose upper certified limits for
toxicologically significant impurities in technical grade active ingredients or products produced by an
integrated system (40 CFR 158.175), and may require upper certified limits for other impurities.
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Appendix B – II
At the time EPA promulgated these regulations it did not set quantitative criteria for determining
whether an impurity is toxicologically significant. Rather, EPA has taken the position that any level of
an active ingredient that is an impurity or contaminant in another product is potentially toxicologically
significant and must be reported to the Agency. Failure to report such an impurity is a violation of
FIFRA section 12(a)(1)(C) (composition of the product differs from that registered with the Agency).
The Agency did make clear at the time it promulgated its current reporting regulations that its
interpretation of the term toxicologically significant could be subject to further refinement to the extent
new information on impurities was available to the Agency. Based on the analysis conducted during
the development of this notice, the Agency has now determined that for certain pesticides (see section
IV below) it can establish generally applicable quantitative criteria for determining the toxicological
significance of contaminants that are also active ingredients. For this reason, EPA is today further
refining its interpretation of the term “toxicologically significant.”
In Section IV of this notice, EPA is setting risk-based levels at which active ingredients that are
contaminants will generally be considered “toxicologically significant.” For the purposes of this notice,
a contaminant is defined as an active ingredient that is not accurately listed on the product’s
confidential statement of formula or listed in the discussion of impurities. This notice addresses only
impurities that are also active ingredients; EPA’s position on other impurities has not changed.
Additionally, nothing in this notice changes the conditions outlined in the Bulk Pesticides Enforcement
Policy (Bulk Policy) dated July 11, 1977 and amended on March 4, 1991. The Bulk Policy is an
important part of applying the 40 CFR Part 158 standards to bulk pesticides at repackaging/refilling
establishments (often retail dealers). Specifically, EPA’s position that both parties (the registrant and
the repackager) are accountable for the integrity of the product as set out in the Bulk Policy remains
the same.
II. OBJECTIVES
EPA determined that this interpretation on cross contamination should:
•
Recognize that cross contamination is a reality, and that not all cross contamination is
problematical;
•
Set a clear standard that can be readily applied by EPA/States and the regulated industry alike;
•
Ensure that allowable cross contamination does not pose unreasonable adverse effects;
•
Minimize the paperwork burden for EPA and registrants;
•
Maintain accountability for the product from the registrant to the end user; and
•
Not preclude marketplace/private solutions to correct problems that do arise.
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Appendix B – III
III. APPROACH
EPA decided that a risk-based approach would most likely meet these objectives. EPA considered the
risks for several endpoints, including human health, adulterated food, contamination of ground water,
and ecological effects to determine which endpoints would be most sensitive to cross contamination
and what levels of cross contamination could be tolerated and remain generally protective of human
health and the environment. For each endpoint, an analysis was done to evaluate a reasonable worst
case scenario or a range of potential scenarios to see if an overall, generally protective contaminant
concentration could be determined. EPA grouped contaminants and pesticides into different
categories (see the table in section IV) to yield a scheme of toxicologically significant concentrations.
The following end points were considered. In most cases phytotoxicity to the target plants is the most
sensitive endpoint and, therefore, the limiting factor in determining toxicological significance.
Human health effects: Because cross contamination caused by a specific AI is most likely an
intermittent event, short-term exposure is most likely. Therefore, EPA focused on the potential risks to
individuals who would be handling contaminated products. The analyses of these human health risks
show that acute risks to humans at the cross contamination levels allowed by this interpretation are
negligible. Although intermittent contamination is the most likely scenario for cross contamination, it is
possible that the same AI contaminant would be present in a particular pesticide product over a long
period of time. EPA analyses indicate that chronic exposure to cross contamination is unlikely to
present an unreasonable risk to human health.
EPA also considered contamination in pesticides applied to the human body (e.g. insect repellents)
and concluded that the risks from cross contamination at the level set in this notice for these pesticides
are negligible.
Adulterated food: Theoretically, a contaminant could cause residues in food or feed for which no
tolerance has been established or that are in excess of an established tolerance. In this case, that
food or feed would be adulterated under the Federal Food, Drug, and Cosmetic Act. EPA’s analysis
indicates that this is a highly unlikely occurrence. Moreover, because cross contamination with a
specific AI occurs intermittently and at low levels, EPA believes that potential exposure to and dietary
risk from residues of unreported contaminants under this notice would be negligible.
Ground water: The possibility of the contamination of ground water was raised as a potential concern
in locations with sandy soils and shallow aquifers. The Florida Department of Agriculture and
Consumer Services (DACS) conducted a preliminary ground water modeling exercise using a number
of conservative assumptions regarding leachability, pesticide half-life, and product application rate.
EPA accepts the Florida DACS conclusion that, while contamination of ground water is possible, it is
of minimal concern because pesticide AIs as contaminants at the levels allowed by this notice are
unlikely to move to ground water in concentrations that would pose significant risk to human health.
Ecological effects/ phytotoxicity: Based on a preliminary review of potential ecological effects from
cross contamination (e.g. risks to birds, aquatic organisms, and plants), EPA believes that plant
toxicity, or phytotoxicity, is the most sensitive endpoint given the relatively low concentrations of
contaminants being considered. EPA believes that phytotoxicity damage poses the greatest potential
for ecological harm. EPA’s phytotoxicity analyses focus on the direct application of the contaminated
product to terrestrial plants because this scenario represents a higher level of exposure than other
exposure pathways, such as runoff and off-target drift.
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Appendix B – IV
EPA conducted several risk analyses based upon phytotoxicity as the end point of concern to
determine the appropriate toxicologically significant levels. These analyses are presented in a
technical support document (See section VII on how to obtain more information).
Rationale for not including certain microbial and biochemical pesticides and plant-pesticides: Many
microbial and certain biochemical pesticides are manufactured in fermentors. A likely source of
contamination of these pesticide products arises when a fermentor is used also for the production of a
different microbial pesticide active ingredient. Quantitative criteria are not appropriate for determining
whether active microbial pesticide ingredients are contaminants of ‘toxicological significance’. This is
because microorganisms can multiply in the environment, and especially in association with target
pest hosts. The criteria of from 20 ppm to 1000 ppm as “toxicologically significant levels” (Section IV)
when applied to a microbial pesticide active ingredient could allow for the presence of thousands to
millions of contaminating micro organisms per gram or milliliter of pesticide product. It cannot be
assumed that such levels of contamination are of insignificant toxicity, especially to non-target
organisms.
EPA is in the process of developing policy for regulatory oversight of plant-pesticides, including
defining the scope of oversight. Therefore, any determination of whether the quantitative criteria for
toxicological significance apply to plant pesticides should be made once the plant-pesticide rule is
finalized. Where applicants/registrants voluntarily submit plant-pesticides for EPA regulation, the
reporting as discussed in Section V of this Notice will remain applicable unless otherwise changed by
regulation.
IV. TOXICOLOGICALLY SIGNIFICANT LEVELS OF CONTAMINATION
The following table defines the levels of contaminants that EPA generally considers to be
toxicologically significant. Specifically, the presence of a contaminant at a concentration greater than
the concentration specified in the table will generally be considered toxicologically significant. Each
contaminant should be considered individually.
The toxicologically significant levels apply to all registered products that are sold or distributed,
regardless of whether the container is non-refillable (i.e., “packaged product”) or refillable (i.e., “bulk
product.”) The toxicologically significant levels do not apply to products that are not sold or distributed,
such as tank mixtures in an end user’s application equipment.
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Appendix B – V
Toxicologically Significant Levels of Contaminants (1, 2)
Category
Type of Contaminant
Type of Pesticide that is
contaminated
1
Insecticide (5), fungicide,
molluscicide, or
nematicide in …
Any insecticide, fungicide,
molluscicide, nematicide, herbicide,
plant growth regulator, defoliant, or
desiccant
1,000
2
Herbicide, plant growth
regulator, defoliant, or
desiccant in …
Any pesticide (6) where the
contaminant is accepted for use on
all sites for which the product is
labeled
1,000
3
Any pesticide (6) other
than a low application rate
herbicide (7) in …
An antimicrobial pesticide
1,000
4
Normal rate herbicide (8),
plant growth regulator,
defoliant, or desiccant
in …
Any herbicide, plant growth regulator,
defoliant, of desiccant
250
5
Any pesticide (6) in …
A pesticide (6) applied to the human
body
100
6
Normal rate herbicide,
plant growth regulator,
defoliant, or desiccant
in …
Any insecticide, fungicide,
molluscicide, or nematicide
100
7
Low application rate
herbicide in
A low application rate herbicide
Level of
quantification (9)
or 100 ppm,
whichever is
higher
8
Low application rate
herbicide in
A normal rate herbicide, plant growth
regulator, defoliant, or desiccant
Level of
quantification (9)
or 20 ppm,
whichever is
higher
9
Low application rate
herbicide in …
A pesticide (6) other than a herbicide,
plant growth regulator, defoliant, or
desiccant
Level of
quantification (9)
or 1 ppm,
whichever is
higher
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Toxicologically.
Significant Level
(3) (ppm) (4)
Implementing Contamination Prevention, ed. 2 English (2008)
Appendix B – VI
Notes:
(1) For the purposes of this notice, a contaminant is defined as an AI that is not on the product’s
confidential statement of formula or listed in the discussion of impurities.
(2) The following contamination scenarios are excluded from this notice:
a) rodenticides as a contaminant and/or as the contaminated product;
b) microbial and biochemical pesticides that are manufactured in fermentors and that are
contaminated by active microbial pesticide ingredients; and
c) plant-pesticides that are contaminated with other active plant-pesticide ingredients. EPA would
like to clarify that the Agency’s previous position on toxicologically significant levels of impurities
that are also AIs would apply pesticides that are exempt from this notice. In other words, any level
of a contaminant in these three exempted scenarios would be considered potentially toxicologically
significant and would have to be reported to EPA.
(3) This column presents the toxicologically significant level, i.e., the concentration at or above which
EPA would consider the contaminant to be toxicologically significant.
(4) The concentration is determined in ppm based on the ratio of the weight of the contaminant to the
weight of the formulated product.
(5) The FIFRA definition of insect includes mites and other arthropods that are not classified by
scientific nomenclature as “insects.” See FIFRA section 2(o).
(6) The phrases “any pesticide” and “a pesticide” do not include the pesticides that are specifically
exempt from this notice as described in note #2 above.
(7) For the purposes of this notice, a low application rate herbicide is defined as a herbicide with a
maximum labeled application rate of AI less than or equal to 0.5 pounds AI/acre. This definition is
intended to include products with AIs that are amino acid inhibitors or ALS inhibitors, including but
not limited to the sulfonylureas, imidazolinones, and triazolopyrimidines.
(8) For the purposes of this notice, a normal rate herbicide is defined as a herbicide with a maximum
labeled application rate of AI greater than 0.5 pounds AI/acre.
(9) For purposes of this notice, the level of quantification is the level of quantification achievable by
EPA or its designated representative (State Lead Agency) using an analytical method suitable for
enforcement purposes at the time the analysis is performed.
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Appendix B – VII
For categories 7, 8 and 9, the level of quantification is included in the table because EPA does not
currently have analytical methods to detect and quantify these AIs in other products at concentrations
as low as 100 ppm for category 7 (or lower for categories 8 and 9). EPA does not want to set a
standard it cannot enforce. Conversely, EPA does not want to set a standard that constantly changes
over time as analytical methods are continuously refined. Therefore, the standard of category 7 is the
level of quantification until the point in time when the quantification limit drops below 100 ppm. The
standard would then be 100 ppm, which is the limit based on toxicological significance. For purposes
of this notice, the level of quantification is the level of quantification achievable by EPA or its
designated representative (State Lead Agency) using an analytical method suitable for enforcement
purposes at the time the analysis is performed.
In selecting the levels in the table, EPA attempted to strike a reasonable balance between greater
protectiveness and cost/burden considerations. If future experience indicates that these values are not
sufficiently protective, the Agency may find it appropriate to modify these levels of toxicological
significance.
EPA believes the values in the table are generally protective in most contaminant/ product
combinations. Because it is impracticable to consider every potential contaminant/ product
permutation, however, adverse effects could occur when contamination is present below the
concentrations in the table.
The Agency recognizes that these standards will not prevent all possible adverse effects from
occurring; this is not a zero risk standard. For example, EPA is aware of a situation where a normal
rate herbicide contaminated an insecticide at levels below 100 ppm (as set out in Category 6) and
plant damage occurred. The Agency will continue to deal with such situations using other regulatory
tools including section 6(a)(2) of FIFRA.
Accordingly, this notice does not excuse applicants or registrants from the requirement to submit to
EPA factual information regarding unreasonable adverse effects of a pesticide under section 6(a)(2) of
FIFRA and EPA regulations at 40 CFR 152.50(f)(3). If an applicant or registrant possesses factual
information not previously reported to EPA indicating that a contaminant in a product may pose risk to
human health or the environment in concentrations lower than those specified in the above table, that
information must be submitted to EPA. Failure to submit such information on a timely basis is a
violation of sections 12(a)(2)(B)(ii) and 12(a)(2)(N) of FIFRA. In addition, the distribution or sale of any
product containing an unreported contaminant that exceeds the levels identified in this notice is a
violation of section 12(a)(1)(C) (composition differs) of FIFRA.
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Appendix B – VIII
V. WHAT REGISTRANTS MUST DO
A.
CONTAMINANT LEVEL EQUAL TO OR GREATER THAN THETOXICOLOGICALLY
SIGNIFICANT LEVEL
If an applicant or registrant knows or has reason to believe that a contaminant that EPA would
consider toxicologically significant (i.e. an AI at a concentration equal to or greater than the
appropriate level in the table) may be present, s/he must then include an expanded discussion of the
possible formation of the impurity and the amounts at which it might be present in accordance with 40
CFR 158.167(c). EPA would then make a regulatory decision on whether to approve the registration or
amendment to allow the sale and distribution of the product under FIFRA. Sale or distribution of a
pesticide, which equals or exceeds the toxicologically significant level prior to EPA approval of the
registration amendment, would be a violation. Reporting would be required regardless of where the
contamination would be expected to occur in the production and distribution processes. As noted in
the preamble to the regulations at 40 CFR 158.167, formulators utilizing registered materials are not
required to seek information on the identity or level of impurities in the registered technical products
they purchase. The Agency realizes that such information may not be made known to the formulator.
To submit an expanded discussion in accordance with 40 CFR 158.167(c), an applicant or
registrant must provide EPA with
(1) the identity of the contaminant and
(2) the concentration at which it might be present.
The information should be sent to EPA as follows.
For US Postal Service submissions:
Document Processing Desk (PM Team #)
Office of Pesticide Programs (7504C)
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460-0001
For courier deliveries:
Document Processing Desk (PM Team #)
Office of Pesticide Programs (7504C)
U.S. Environmental Protection Agency
Room 266A, Crystal Mall 2
1921 Jefferson Davis Highway
Arlington, VA 22202-4501
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Appendix B – IX
B.
CONTAMINANT LEVEL LESS THAN THE TOXICOLOGICALLY SIGNIFICANT LEVEL
If an applicant or registrant knows or has reason to believe that a contaminant may be present at a
concentration that is less than the toxicologically significant level, s/he is not required to report this
information to EPA. Please note that if a product is distributed or sold with levels of contamination that
are equal to or exceed the toxicologically significant level, the product is in violation of FIFRA,
irrespective of the registrant’s knowledge.
However, adverse effects could still occur below the “toxicologically significant” concentrations set out
in this notice. Registrants are reminded that they are responsible for reporting any adverse effects
under FIFRA section 6(a)(2). Specifically, if an applicant or registrant possesses factual information
not previously reported to EPA indicating that a contaminant in a product may pose risk to human
health or the environment in concentrations lower than those specified in the above table, that
information must be submitted to EPA. Failure to submit such information on a timely basis is a
violation of sections 12(a)(2)(B)(ii) and 12(a)(2)(N) of FIFRA.
This notice is not intended to relieve registrants from liability that may exist under State law resulting
from damage caused by contaminants.
As noted above, this notice is intended to inform registrants of the interpretation of the term
“toxicologically significant” that the Agency intends to apply in implementing the provisions of 40 CFR
Part 158. It is not intended, nor can it be relied upon, to create any rights enforceable by any party on
litigation with the United States. EPA officials may act at variance with the guidance when
circumstances indicate that a contaminant is of toxicological significance at levels different from those
set forth in this notice.
EPA will take any regulatory action necessary to ensure that the levels of contamination in a product
do not cause unreasonable adverse effects to human health or the environment.
VI. EFFECTIVE DATE
This notice is effective immediately.
VII. FURTHER INFORMATION
The public comments received on the proposed interpretation, the comment summary and response
document, and the technical support document for this notice are available in the public docket under
document number “OPP-00424.” The public docket is located at: Public Docket and Freedom of
Information Section, Field Operations Division, Office of Pesticide Programs, U.S. Environmental
Protection Agency (7506C), Room 1132, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington,
Virginia, 22202.
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