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58054 Federal Register / Vol. 80, No. 186/Friday, September 25, 2015/Pro
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<br />is, the study investigated whether the
<br />concentration of warfarin in the
<br />residues of warfarin pill bottles was
<br />greater than 0.3% and therefore met the
<br />listing criteria for P001 or whether the
<br />residues were at or below 0.3% and
<br />therefore met the listing criteria for
<br />U248. Although nicotine is not a
<br />concentration -based P -listing, packaging
<br />from nicotine -containing products were
<br />also investigated to determine total
<br />remaining residues.
<br />The researchers collected a total of 59
<br />samples containers, including 44
<br />sample containers that had held
<br />warfarin pills but had been fully
<br />dispensed and another 15 sample
<br />containers from nicotine -containing
<br />products. The samples included
<br />warfarin and nicotine from several
<br />manufacturers, in a range of dose
<br />strengths and in various container, types.
<br />The residues were solvent -extracted and
<br />then dried by rotary evaporation to
<br />determine the total weight of residues.
<br />Subsequently, the residues were re-
<br />dissolved in methanol and analyzed
<br />using HPLC to determine the
<br />concentration of the active
<br />pharmaceutical within the residues.
<br />The majority of warfarin containers
<br />were plastic bottles, but some containers
<br />were blister packs and three samples
<br />were 30 -pill blister packs, sometimes
<br />referred to as a "bingo card." The results
<br />indicate that the concentration of the
<br />active pharmaceutical ingredient
<br />warfarin in the residues in plastic
<br />bottles was usually over the 0.3%
<br />concentration. However, the
<br />concentration of werfarin in the
<br />residues on blister packs, including the
<br />30 -pack blister pack, was consistently
<br />below 0.3%. Overall, in the majority of
<br />cases, the warfarin within the residues
<br />was present at a high enough
<br />concentration to be considered P001 (33
<br />of 44 samples, 75 percent of the
<br />samples).
<br />However, the results also confirm the
<br />results from the first two stakeholders.
<br />That is, the total weight of residues
<br />remaining in the containers after they
<br />were emptied of the warfarin pills is
<br />negligible. For the plastic bottles, the
<br />total weight of residue ranged from 4.3-
<br />82.3 mg. For the single-dose blister
<br />packs, the total weight of residue ranged
<br />from 3.5-7.6 mg. And for the 30 -pack
<br />blister pack, the total weight ranged
<br />from 134.8-273 mg. Taking the smallest
<br />amount of residue of 3.5 mg, it would
<br />take close to 300,000 containers per
<br />month to exceed the 1 kg threshold to
<br />be an LQG. Sven on the conservative
<br />side, taking the largest amount of
<br />residue of 273 mg, it would take close
<br />Rules
<br />to 4000 containers per month to exceed
<br />the 1 kg threshold to be an LQG.
<br />The results for nicotine residues were
<br />similar. For containers of gum and
<br />patches, the weight of total residues
<br />ranged from 9-111.2 mg, although the
<br />two containers of liquid nicotine
<br />solution contained more residues -1301
<br />and 1616 mg. Although nicotine is not
<br />a concentration -based listing, it is worth
<br />noting that the active pharmaceutical
<br />in of nicotine in the residues
<br />was below the quantifiable limit of 1.5
<br />µg/
<br />ml in 8 of the 15 samples and for the
<br />other 7 samples, the concentration of
<br />nicotine ranged from 0.01-0.09%.
<br />iv. EPA's Office of Research and
<br />Development. Finally, EPA's ORD
<br />conducted an analysis to evaluate
<br />whether simply removing a drug from
<br />the container is equivalent to triple
<br />rinsing the container. ORD's results are
<br />summarized in Table 11, but the Final
<br />Project Report containing the full results
<br />is in the docket for this proposed
<br />rulemaking (EPA—I3Q—RCRA-2007—
<br />Og32). ORD analyzed three different P -
<br />listed pharmaceuticals: Warfarin,
<br />nicotine and physostigmine salicylate.
<br />T 11 lists the 18 different
<br />combinations of active pharmaceutical
<br />ingredients, form, dosage strengths and
<br />P combinations that ORD
<br />analyzed.
<br />TABLE 11—PHARMACEUTICAL COMBINATIONS TESTED BY
<br />PA'S ORD
<br />Activo pharmaceutical Manufacturer/Brand name
<br />ingredient
<br />Warfarin ....................a Taro Pharmaceutical Industries, Ltd............
<br />Upsher-Smith/Jantoven..................................
<br />Nicotine ...................... � GlaxoSmithKiine/Nicorett
<br />Rugby Laboratories ........................................
<br />GlaxoSmithKiine/Nicorette .............................
<br />Rugby Laboratories ........................................
<br />Habitrol....................................................:......
<br />Rugby Laboratories ........................................
<br />Pfizer/Nicotrol.................................................
<br />Physostigmine Salicy- Akron Inc. .......................................................
<br />late.
<br />All combinations in '1"able 11 were
<br />analyzed in triplicate using the
<br />following three-step approach:
<br />(1) After removing the tablets, gum,
<br />lozenges, etc from the containers, the
<br />amount of total residuals remaining in
<br />the container was determined using a
<br />sensitive balance to weigh the container
<br />before and after triple rinsing,
<br />Form I Dosage
<br />Packaging type
<br />Tablet 4444... 1 mg ......... Plastic bottle.
<br />Tablet 4444... 5 mg ......... Plastic borile.
<br />Tablet ....... 10 mg 406.640 Plastic bottle.
<br />Tablet 4444... 2 mg ......... Single-dose blister pack.
<br />Tablet 4444... 1 mg .......,. Single-dose blister pack
<br />Tablet _4444.. 10 mg 4444... Single-dose blister pack.
<br />Gum ......... 2 mg ......... Single-dose blister pack.
<br />Gum ......... 4 mg ....,.... Single-dose blister pack.
<br />Gum ......... 2 mg ......... Single-dose blister pack.
<br />Gum ......... 4 mg ......... Single-dose blister pack.
<br />Lozenge ... 2 mg ......... Plastic vial
<br />Lozenge ... 4 mg ......... Plastic vial.
<br />Patch 4404.... 7 mg ......... Peel•off plastic.
<br />Patch 64440... 14 mg 4444... Peei•off plastic.
<br />Patch ........ 21 mg 4444... Peel -off plastic.
<br />Spray ....... 10 mg/mi .. Glass vial.
<br />In 4444.. 10 mg 1.6.440 Plastic container.
<br />Uquid 4444... 1 mg/ml .... Glass ampoule.
<br />(2) The "maximum possible weight of
<br />residual drug/total residual/container"
<br />was calculated for each compound and
<br />packaging combination. This calculated
<br />result was used to infer a theoretical
<br />upper limit for the amount of active
<br />pharmaceutical compound in the total
<br />residua remaining in the container, and
<br />(3) Thermal gravimetric analysis
<br />(TGA) was used to qualitatively evaluate
<br />the presence of active pharmaceutical
<br />ingredient in the residuals removed
<br />fr
<br />om the containers before and after
<br />triple -rinsing.
<br />With respect to the weight of the
<br />remaining residuals in the containers,
<br />ORD's results are similar to the results
<br />e.............................
<br />Rugby Laboratories ........................................
<br />GlaxoSmithKiine/Nicorette .............................
<br />Rugby Laboratories ........................................
<br />Habitrol....................................................:......
<br />Rugby Laboratories ........................................
<br />Pfizer/Nicotrol.................................................
<br />Physostigmine Salicy- Akron Inc. .......................................................
<br />late.
<br />All combinations in '1"able 11 were
<br />analyzed in triplicate using the
<br />following three-step approach:
<br />(1) After removing the tablets, gum,
<br />lozenges, etc from the containers, the
<br />amount of total residuals remaining in
<br />the container was determined using a
<br />sensitive balance to weigh the container
<br />before and after triple rinsing,
<br />Form I Dosage
<br />Packaging type
<br />Tablet 4444... 1 mg ......... Plastic bottle.
<br />Tablet 4444... 5 mg ......... Plastic borile.
<br />Tablet ....... 10 mg 406.640 Plastic bottle.
<br />Tablet 4444... 2 mg ......... Single-dose blister pack.
<br />Tablet 4444... 1 mg .......,. Single-dose blister pack
<br />Tablet _4444.. 10 mg 4444... Single-dose blister pack.
<br />Gum ......... 2 mg ......... Single-dose blister pack.
<br />Gum ......... 4 mg ....,.... Single-dose blister pack.
<br />Gum ......... 2 mg ......... Single-dose blister pack.
<br />Gum ......... 4 mg ......... Single-dose blister pack.
<br />Lozenge ... 2 mg ......... Plastic vial
<br />Lozenge ... 4 mg ......... Plastic vial.
<br />Patch 4404.... 7 mg ......... Peel•off plastic.
<br />Patch 64440... 14 mg 4444... Peei•off plastic.
<br />Patch ........ 21 mg 4444... Peel -off plastic.
<br />Spray ....... 10 mg/mi .. Glass vial.
<br />In 4444.. 10 mg 1.6.440 Plastic container.
<br />Uquid 4444... 1 mg/ml .... Glass ampoule.
<br />(2) The "maximum possible weight of
<br />residual drug/total residual/container"
<br />was calculated for each compound and
<br />packaging combination. This calculated
<br />result was used to infer a theoretical
<br />upper limit for the amount of active
<br />pharmaceutical compound in the total
<br />residua remaining in the container, and
<br />(3) Thermal gravimetric analysis
<br />(TGA) was used to qualitatively evaluate
<br />the presence of active pharmaceutical
<br />ingredient in the residuals removed
<br />fr
<br />om the containers before and after
<br />triple -rinsing.
<br />With respect to the weight of the
<br />remaining residuals in the containers,
<br />ORD's results are similar to the results
<br />
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