Simulated Leaching (Migration) Study for a Model Container … · RESEARCH Simulated Leaching...

10.5731/pdajpst.2016.007229Access the most recent version at doi: 68-8771, 2017 PDA J Pharm Sci and Tech

Dennis Jenke, Thomas Egert, Alan Hendricker, et al. Ophthalmic Drug ProductsContainer-Closure System Applicable to Parenteral and Simulated Leaching (Migration) Study for a Model

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RESEARCH

Simulated Leaching (Migration) Study for a ModelContainer-Closure System Applicable to Parenteral andOphthalmic Drug Products

Authors:

DENNIS JENKE1*THOMAS EGERT2

ALAN HENDRICKER3

JAMES CASTNER4

TOM FEINBERG5

CHRISTOPHER HOUSTON6

DESMOND G. HUNT7

MICHAEL LYNCH8

KUMUDINI NICHOLAS9

DANIEL L. NORWOOD5

DIANE PASKIET10

MICHAEL RUBERTO11

EDWARD J. SMITH12

FRANK HOLCOMB13

INGRID MARKOVIC13

Product Quality Research Institute (PQRI) Leachables and Extractables Working Group: Parenteral and OphthalmicDrug Products (PODPs), 2107 Wilson Blvd, Suite 700, Arlington, VA 22201-3042, USA; telephone: 703-248-4719,fax: 703-525-7136; e-mail: [email protected]

1Baxter Healthcare Corporation, Round Lake, IL, USA; 2Boehringer Ingelheim Pharmaceuticals, Inc., Ingelheim/Rhein,Germany; 3Becton Dickinson, Research Triangle Park, NC, USA; 4Pharma Interface Analysis, LLC; 5Scio AnalyticalConsulting, Chapel Hill, NC, USA; 6iuvo BioScience, Rush, NY, USA; 7United States Pharmacopeoia, Rockville, MD, USA;8Pfizer, Groton, CT, USA; 9Bureau of Pharmaceutical Sciences, Health Canada, Ottawa, ON, Canada; 10WestPharmaceutical Services, Lionsville, PA, USA; 11Materials Needs Consulting LLC, Montvale, NJ, USA;12Packaging Science Resources, King of Prussia, PA, USA; 13United States Food and Drug Administration,Washington, DC, USA ©PDA, Inc. 2017

ABSTRACT: A simulating leaching (migration) study was performed on a model container-closure system relevant toparenteral and ophthalmic drug products. This container-closure system consisted of a linear low-density polyethylenebottle (primary container), a polypropylene cap and an elastomeric cap liner (closure), an adhesive label (labeling),and a foil overpouch (secondary container). The bottles were filled with simulating solvents (aqueous salt/acidmixture at pH 2.5, aqueous buffer at pH 9.5, and 1/1 v/v isopropanol/water), a label was affixed to the filledand capped bottles, the filled bottles were placed into the foil overpouch, and the filled and pouched units werestored either upright or inverted for up to 6 months at 40 °C. After storage, the leaching solutions were testedfor leached substances using multiple complementary analytical techniques to address volatile, semi-volatile,and non-volatile organic and inorganic extractables as potential leachables.

The leaching data generated supported several conclusions, including that (1) the extractables (leachables) profilerevealed by a simulating leaching study can qualitatively be correlated with compositional information for materialsof construction, (2) the chemical nature of both the extracting medium and the individual extractables (leachables)can markedly affect the resulting profile, and (3) while direct contact between a drug product and a system’s materialof construction may exacerbate the leaching of substances from that material by the drug product, direct contact isnot a prerequisite for migration and leaching to occur.

KEYWORDS: Extractables, Leachables, Simulation studies, Parenteral and ophthalmic drug products, Leaching(migration) study.

* Corresponding Author: Dennis Jenke, Triad Scientific Solutions LLC, 181 Peregrine Lane, Hawthorn Woods, IL 60047.E-mail: [email protected]

doi: 10.5731/pdajpst.2016.007229

PQRI SPECIAL CONTRIBUTION DISCLAIMER: The following article is an invited contribution submitted by the Product QualityResearch Institute (PQRI) Leachables and Extractable Working Group. The article was internally reviewed by PQRI and by the author’s affiliatedorganizations and not peer-reviewed by the PDA Journal.Observations made, opinions expressed, and conclusions drawn in this article reflect the views of the authors acting in their role as members of the PQRIExtractables and Leachables Working Group and should not be construed to represent the views or policies of their affiliated organizations.

68 PDA Journal of Pharmaceutical Science and Technology

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LAY ABSTRACT: The migration of container-related extractables from a model pharmaceutical container-closure systemand into simulated drug product solutions was studied, focusing on circumstances relevant to parenteral and ophthalmicdrug products. The model system was constructed specifically to address the migration of extractables from labels appliedto the outside of the primary container. The study demonstrated that (1) the extractables that do migrate can be correlatedto the composition of the materials used to construct the container-closure systems, (2) the extent of migration is affectedby the chemical nature of the simulating solutions and the extractables themselves, and (3) even though labels may not bein direct contact with a contained solution, label-related extractables can accumulate as leachables in those solutions.

Introduction

Most pharmaceutical products are packaged in a con-tainer-closure system to preserve and protect the prod-uct during its manufacturing, distribution, storage, anduse. During this period of contact, the pharmaceuticalproduct and its packaging system can interact, poten-tially affecting product quality and safety. For exam-ple, substances in the container-closure system canleach from the system and become entrained in theproduct, thus becoming foreign impurities (leach-ables) in the product. The need to establish whateffect, if any, that such foreign impurities have onproduct quality and safety is well established in theregulatory literature (1–3), and the means of establish-ing the effect have been the focus of numerous au-thoritative texts on the subject (for example, 4 – 8).

A comprehensive strategy for assessing the potentialsafety and quality risk posed by such foreign impuri-ties generally involves three stages: (1) materials char-acterization, which is the procurement of knowledgeabout the composition and general properties of acontainer-closure system’s materials of construction,(2) extractables profiling of the container-closure sys-tem and/or its components (via a controlled extractionsimulation study), and (3) as necessary and appropri-ate, leachables profiling of the pharmaceutical product(leachables migration study). Material characteriza-tion establishes those chemical entities (including ad-ditives and ingredients) that are present in the materialand that may be extracted from the material, therebycreating a basis for the selection (and justification) ofappropriate materials of construction. The controlledextraction simulation study establishes which contain-er-closure system extractable profile is relevant to theclinical use of the pharmaceutical product (and thuswhich closely mimics the pharmaceutical product’sleachables profile). Thus, the controlled extractionsimulation study can assist in materials and packagingcomponent selection as well as contribute to the pack-aging system’s quality and safety impact assessment.Profiling the pharmaceutical product for leachablesduring the course of a long-term stability study (leach-

ables migration study) provides additional informationfor quality and/or safety assessment.

In situations of challenging detection limits for leach-ables, and certain other circumstances, a simulationstudy can be used either to focus the leachables studyor even in place of the leachables study. A simulationstudy is a type of extraction or leaching study thatemploys simulating solvents, which are intended toclosely mimic the actual drug product vehicle and itsleaching potential, and accelerated leaching conditions.Extractables, leachables, and simulation studies are de-scribed in two recent USP informational general chapters(7, 8). In addition to leachables, which can accumulate ina drug product from direct contact with the packagingsystem, the USP recognizes the term “migrants”, whichcan accumulate in a drug product after crossing a barrier(e.g., from a label through a plastic bottle).

The Product Quality Research Institute (PQRI) hasbeen an active participant in the effort to developeffective, science-driven, and risk-based strategies forthe safety qualification of container-closure systemsfor pharmaceutical products. For example, in 2006,PQRI issued the report, “Safety Thresholds and BestPractices for Extractables and Leachables in OrallyInhaled and Nasal Drug Products”, which provides ascientific rationale and process to address packagingsystems use for orally inhaled and nasal drug products(OINDPs) (4). This report includes best demonstratedpractices for addressing extractables and leachables,specifically relevant to the OINDP dosage forms.More recently, the PQRI expanded its efforts to in-clude parenteral and ophthalmic drug products(PODPs). One aspect of the PQRI PODP activity wasto develop and examine the three-stage approach dis-cussed previously. To this end, the PQRI PODPLeachables and Extractables Working Group initiateda study that generated and interpreted data from con-trolled extraction studies performed on multiple poly-meric and elastomeric materials of construction com-monly encountered in PODP packaging systems(stages 1 and 2). In this study, the test materials weresubjected to different extraction conditions and the

69Vol. 71, No. 2, March–April 2017


resulting samples (i.e., extracts) were then character-ized for extracted substances to establish the materi-als’ general extractables characteristics (9).

Continuing its assessment, the PQRI PODP team per-formed a second study to address the third stage, theleaching (migration) study, via a controlled simulationstudy (10). In this study, a model container-closuresystem, more or less consistent with systems used withPODPs, was constructed from either materials that thePODP team had characterized in its previous study orthat were characterized as part of this study. Thismodel container-closure system was then filled withsimulating solvents relevant to liquid PODP dosageforms and the filled units were subjected to a leaching(migration) study.

The purpose of this report is to discuss the design andresults of the PODP leaching (migration) study, spe-cifically considering the role of such a study in thesafety assessment of a container-closure system usedfor PODP products.

Experimental

Test Article (see Figure 1)

The model container-closure system consisted of alow-density polyethylene (LDPE) bottle (4 oz NaturalLDPE, Boston Round Bottle; Container & PackagingSupply, part B347A), a polypropylene (PP) cap (20-410 Natural Smooth Disc Top; Container & PackagingSupply, part L764), an adhesive label (UPM Raflatac),a rubber gasket (brominated isobutylene isoprene co-polymer), and a foil overpouch (Figure 1). The com-ponents of the model container-closure system wereused as received.

Leaching (Migration) Simulation Study

General: The test units for the leaching (migration)study were prepared as follows. Individual bottleswere filled with extraction solvent (nominal 100 mL),a rubber gasket was inserted on the top of the neck ofthe bottle, and the cap was tightly screwed down on

Figure 1

The individual components of the model container-closure system. The bottle used is shown with the labelalready applied. The major ingredients or extractables from the individual components of the test system arelisted. The foil overpouch, used primarily as a barrier to reduce solvent loss from the test article, is not shown.



the gasket. Spiked labels were manually applied to theouter surface of the bottles and the labeled bottleswere placed in a foil pouch, which was subsequentlyclosed by heat-sealing.

The leaching (migration) study was performed twice.The first study, with relatively fewer and later timepoints, served the purpose of range finding. The resultsof this range finding study facilitated the optimizationof the experimental design. The second study, withrelatively more frequent and earlier time points, re-flected the optimized experimental design. Becausethe leaching (migration study) employed simulatingsolvents (as opposed to a drug product) and acceler-ated storage conditions, it is properly termed a simu-lation study.

Leaching Solvents: The leaching solvents were asfollows:

Water pH 2.5: A salt/acid solution was preparedcontaining 0.01 M KCl and 0.003 M HCl. The pHwas adjusted to 2.5 as needed.

Water pH 9.5: A buffer solution was prepared con-taining 0.066 M dibasic sodium phosphate andmonobasic 0.0045 M sodium phosphate. The pHwas adjusted to 9.5 with 1 N NaOH.

50:50 isopropanol (IPA) and water: Equal volumesof IPA and water were mixed. This solution isreferred to as IW in certain places in this manu-script.

These leaching solvents were chosen as PODPs areprimarily aqueous and formulated between these pHextremes. The 1:1 IPA/water mixture represents aPODP that contains an organic surfactant or solubilizingagent.

Leaching Conditions: Leaching was conducted at 40°C (humidity not controlled) for up to 6 months. Theseleaching conditions were chosen because they are gen-erally accepted to be the proper acceleration of a2-year ambient temperature product shelf-life. In therange-finding study, test units were stored in either anupright or inverted configuration, as the inverted con-figuration results in direct contact between the rubbergasket and the fill solution. The optimized study in-cluded only inverted test units.

The time points for the range-finding study included 1,2, and 6 months of storage. The time points used in theoptimized study included 0.75, 2, 5, 12, 25, 70, 98,105, and 180 days of storage.

Label Spiking: Four compounds were spiked onto thebottle-contacting surface of the label prior to placingthe label onto the bottle. These four compounds (seeTable I) were chosen because they possess a range ofphysiochemical properties and are known substancesassociated with labels. The labels were spiked withthese substances so that the pool of label-related ex-tractables was sufficiently high that they could beeffectively quantified in the fill solutions.

Spiking was accomplished as follows: For the range-finding study, a mixed standard of the spiking com-pounds was prepared at a nominal concentration of250 mg/mL, except for methyl ethyl ketone (MEK),which was used as the dilution solvent (at a level ofapproximately 615 mg/mL). Immediately before plac-ing the label on the bottle, two drops of 2.5 �L eachof the mixed standard spiking solution were placedonto the back of the label on the adhesive layer. Thelabel was then immediately pressed and sealed to thefilled bottle, followed by sealing the labeled bottle inthe foil pouch.

The spike level was chosen so that spiked substancescould be readily detected if migration occurred. A 5�L spike of a 250 mg/mL solution equates to a spikeamount of 1250 �g for the semi-volatile compoundsand 3080 �g for the MEK. If a 10% migration rate wasobtained in this study, then the resulting concentrationof the compounds in the extraction solvents would be1.25 �g/mL for each semi-volatile target [1250 �g �0.10 (10% migration)/100 mL (total solution vol-ume) � 1.25 �g/mL] and 3.08 �g/mL for MEK. Suchaccumulation levels were detectable and within theoperating range of the analytical techniques used inthis study.

An alternate spiking process was used for the opti-mized study. In this case, the spiking standard wasprepared to contain approximately 50 mg/mL of eachspike compound, using polyethylene glycol (PEG) 200as the solvent. A 10 �L aliquot of the viscous spikingstandard was evenly distributed on the inner adhesivesurface of the label, which was immediately placed ona filled bottle, which in turn was immediately sealedinto a foil overpouch. Assuming a migration rate of100%, this spike would result in a fill solution con-



taining approximately 5 �g/mL of each spike com-pound.

Solvent Blanks: Solvent blanks were obtained bystoring portions of unused leaching solvent in inertcontainers (glass for pH 2.5 and IPA/water, Teflon forpH 9.5).

Leachate Analysis, Range Finding

Test Methods: The leachates (and solvent blanks)were analyzed for organic and inorganic extractables

(simulated leachables) using methods that are typicallyemployed for the purpose of extractables screening. Gen-erally speaking, this included gas chromatography withheadspace sampling and mass spectrometric detection(HS-GC-MS) for volatile substances, direct injectionGC-MS for semi-volatile substances, and high-perfor-mance liquid chromatography with both UV absorptionand mass spectrometric detection (HPLC-DAD-MS) fornon-volatile substances. Extractables (simulated leach-ables) were also measured based on their elemental con-stituents via inductively coupled plasma mass spectrom-etry (ICP-MS).

TABLE ILabel Spiking Compounds Employed in the Leaching (Migration) Study

Compound CAS # Supplier/Purity Structure/Info

Methyl ethyl ketone (MEK) 78-93-3 Fluka (St. Louis, MO),�99.5%

Aqueous solubility: �10000 mg/L1

Log Po/w: 0.471

Vapor pressure: 115 torr

Irgacure 1173 (Ic1173) 7473-98-5 Sigma-Aldrich (St. Louis,MO), �85%


Log Po/w: 1.491

Vapor pressure: 0.007 torr

Benzophenone (BzPh) 119-61-9 Sigma-Aldrich, 99%

Aqueous solubility: 150 mg/L1

Log Po/w: 3.211

Vapor pressure: 0.008 torr

Dipropylene glycol diacrylate(DPGDA)

57472-68-1 TCI America (Portland, OR),�85%


Log Po/w: 1.301

Vapor pressure: Not available1Value obtained from Advanced Chemistry Development, ACD/Labs Software V11.02.



Sample Processing Prior to Analysis: Solventswitching was performed on all leachates intended forGC-MS analysis. A portion of each leachate was liq-uid-liquid extracted with an equivalent volume ofmethylene chloride. The organic layer was analyzeddirectly. For HS-GC-MS and HPLC-DAD-MS analy-ses all extracts were analyzed directly. For ICP-MS,the leachates were analyzed directly, except the IPA/water extracts, in which case the IPA was evaporatedoff prior to analysis. The ICP-MS samples were acid-ified prior to analysis.

Test Systems and Operating Conditions: As thepurpose of this study was range finding, the specificanalytical instruments and test method operating con-ditions used in the chromatographic analyses per-formed in this study are not fully reported as theinstruments, methods and operating conditions used inthe optimized study are more relevant. As the ICP-MSanalyses were only performed during range finding,the analytical details for these analyses are shown inTable II.

Extract Analysis, Optimized Study

Test Methods: The leachates (and solvent blanks)were analyzed for targeted organic extractables usingappropriate gas chromatographic (GC) and liquidchromatographic (LC) methods developed for this pur-pose.

Sample Processing Prior to Analysis: Samples (lea-chates and blanks) were prepared for the GC analysis

by transferring 200 �L of the sample, 100 �L of aninternal standard solution (39 �g/mL 2-fluorobiphenylin methanol), and 800 �L isopropanol into a 2 mLsample vial. The vials were capped and vortexedbriefly. Samples were prepared for LC analysis bytransferring 100 �L of an internal standard solution(106 �g/mL Irganox 415 in methanol) and 1000 �L ofthe extract into a 2 mL sample vial. The vials werecapped and vortexed briefly.

Test Systems and Operating Conditions: The spe-cific analytical instruments and test method operatingconditions used in chromatographic analyses per-formed in the optimized study are delineated in TablesIII and IV.

Results and Discussion—Range Finding

Organic Extractables

Figure 2 illustrates the leaching trends of one of theintentionally added label-related extractables (MEK).The migration of MEK through the LDPE bottle andinto the leachate occurs quite rapidly and migration isessentially complete and asymptotic levels wereachieved at the first time point (1 month). BecauseMEK is label related, the accumulation levels of thisspiked extractable were not affected by whether thefilled bottles were stored upright (no direct contactbetween the extracting solution and the elastomericgasket or PP cap) or inverted (direct contact betweenthe extracting solution and the elastomeric gasket orPP cap). Similar leaching (migration) profiles were

TABLE IIInstrument Parameters; ICP-MS

ICP-MS Agilent (Santa Clara, CA) 7500A

Forward Power 1300 watts

Integration Time 0.1 s per point

Rinse Time 180 s

Rinse Rate 0.5 rps

Uptake Time 45 s

Uptake Rate 0.5 rps

Stabilization Time 20 s

Analysis Pump Rate 0.1 rps

All Other Settings Determined by Tune

Elements Scanned Li, Be, B, Na, Mg, Al, Si, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, As, Se,Br, Rb, Sr, Y, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, Sb, Te, I, Cs, Ba, La, Ce, Pr,Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl,Pb, Bi, Th, and U



obtained for the other spiked label-related extract-ables.

As the spiked extractables where intentionally addedto the labels, it is possible to determine their extent ofleaching. If 100% leaching of the spiked compounds—Irgacure 1173, dipropylene glycol diacrylate (DPGDA),and benzophenone—were to occur and the migrationwas strictly in the direction of the solution (and notoutward through the label), a solution concentration of

12.5 �g/mL would result. Under such an assumption, theextents of leaching for Irgacure 1173, DPGDA, andbenzophenone were calculated to be 26%, 27%, and48%, respectively, in the IPA/water extracts.

The accumulation level of both label- and container-related extractables is illustrated in Figure 3. Whilethe accumulation levels of the highly water-solublelabel targets (Irgacure 1173 and DPGDA) were gen-erally similar in the aqueous and organic solvents, the

TABLE IIITypical Operating Parameters, GC/MS Analyses

Operating Parameter Operating Value

Column Restek (Bellefonte, PA) Rtx®-VMS, 30 m � 0.25 mm, 1.4 �m filmthickness

Oven Program Start at 40 °C, hold for 4 min; ramp at 25 °C/min to 220 °C; rampat 5 °C/min to 250 °C; ramp at 25 °C/min to 260 °C, hold for 8min

Carrier Gas He at 1.8 mL/min

Injection Splitless; 0.25 �L

Injector Temperature 280 °C

MS Transfer Line Temperature 260 °C

MS Detection Details EI (70.3 ev), mass range 29–550 amu

Instrumentation Used Agilent (Santa Clara, CA) 7890 GC/7683B autosampler/7000BTriple Quadrapole MS (Agilent Mass Hunter B.07.01 data system)

TABLE IVTypical Operating Parameters, LC/UV/MS Analyses

Operating Parameter Operating value

Column Agilent Zorbax Eclipse Plus C18, 100 � 3.0 mm, 3.5 �m particles

Column Temperature 50 °C

Mobile Phase Components A � 10 mM ammonium acetate, B � acetonitrile

Mobile Phase Gradient Time % B

0.0 5

8.4 100

21.0 100

24.0 5

26.0 5

Mobile Phase Flow Rate 0.8 mL/min

Injection Volume 10 �L

Detection, UV 205–400 nm; step � 2 nm

Detection, MS API-ES or AP-CI, positive ion and negative ion (targeted m/z for each targetedanalyte)

Instrumentation Used Agilent 1200 LC (vacuum degasser, binary pump, heated column compartment)/Model G1315A diode array detector/6120 mass selective detector (MSD).Agilent Chemstation rev B.04.03-SP2 data system



poorly water-soluble, non-polar container-related or-ganic extractables, such as the nonyl phenol isomers,benzophenone, and Irganox 1076, only accumulated inthe IPA/water leachates in measurable quantities. Theaccumulation levels of the label- and bottle-relatedextractables were not affected by whether the filledbottles were stored upright (no direct contact betweenthe extracting solution and the elastomeric gasket orPP cap) or inverted (direct contact between the ex-tracting solution and the elastomeric gasket or PPcap).

These data established two areas for optimization inthe second study reported herein. First, it is clear thatfully establishing the leaching (migration) profilewould require test intervals much earlier and morefrequent than were used in the range-finding study.Second, the label spiking was found to be sub-optimal.

Specifically, the levels at which extractables werespiked onto the label were too high and the spiking ofthe label did not produce an even distribution of thespiked compounds across the surface area of the label.While the leaching of the spiked extractables wasreadily followed in the range-finding study, it was notpossible to follow the leaching of extractables thatwere not spiked into the label and were intrinsic to thelabel as the levels of the spiked extractables weresignificantly greater than the levels of the intrinsicextractables. Furthermore, the leaching of the spikedcompounds was mechanistically constrained by theiruneven distribution on the label. Thus, the spikinglevels were reduced and the spiking process was mod-ified in the optimized study.

Additionally, the leaching trends noted in the range-finding study established the approximate levels towhich the extractables accumulated in the fill solu-tions. Knowing the approximate accumulation levelsfacilitated the development of analytical methods thathad the necessary sensitivity, specificity, accuracy, andprecision to support the target extractables testing thatwas used in the optimized leaching (migration) study.

Elemental Extractables

While the ICP-MS testing was performed a using aperiodic table scan of 70 elements (see Table II for thelist of elements included in the scan), extractablescontaining most of these elements were not detected inany of the leachates. Those elements that were presentin the leachates at measurable levels included B, Mg,Al, Si, K, Ca, Ti, Zn, and Br. The likely source of mostof these elements is the elastomeric gasket: B and Brfrom the rubber itself, Ti from the titanium dioxideused as a colorant, Ca and Zn as counter-ions in thefatty acid salts used as lubricants, Al and Si from theelastomer’s calcined aluminum silicate, and Mg fromthe material’s calcined magnesium oxide.

The following observations were made concerning theleaching behavior of the elemental extractables (seeFigures 4 and 5):

1. The element-containing extractables were leachedin higher quantities at lower pH.

2. The levels of element-containing extractables werelarger, inverted (exaggerated) versus upright testunits. This is consistent with the elastomeric gasketbeing the source of these extractables, as the gasket

Figure 2

Leaching (migration) profile for methyl ethyl ke-tone during the range-finding Study. The leachingof this label-related extractable was relativelyrapid and was essentially completed by the firsttime point. The accumulation of this unchargedextractable is only marginally affected by the pH ofthe extracting medium.

Figure 3

Maximum accumulation levels for the organic ex-tractables measured during the range-finding study.



is in direct solution contact in the inverted config-uration.

3. Complete leaching of the element-containing ex-tractables was not achieved under the conditions ofthis study. While the leaching plots typically reflectan approach to asymptotic concentrations, the as-ymptotic behavior was not achieved for most ele-ment-containing extractables and thus the levels ofthese extractables would continue to increase forlonger storage durations. Nevertheless, the mostrapid leaching of the metallic extractables occurredin the early stages of the extraction study (less than1 month contact). Conversely, the leaching of thenon-metallic extractables (B and Br) at low pH didnot achieve asymptotic behavior over the course ofthe study, suggesting that either (1) the pool ofthese extractables is larger than the pool of themetallic extractables, (2) the mechanism of leach-ing is different than the metallic extractables, or (3)a combination of both.

Figure 6 documents the maximum levels of the ele-ment-containing extractables, aqueous versus IPA/

water leaching solutions. In general, the metallicextractables form two groups with respect to theirrelative leached levels, aqueous leachates versusIPA/water leachates. One group, reflecting Al, K,Ti, and Zn, accumulated at higher levels in theaqueous leachates (more specifically, the low-pHaqueous leachates). A second group, including Ca,Mg, and Si, accumulated at either similar or higherlevels in the IPA/water leachates. It is likely thatthis different behavior reflects a different leachingmechanism. For example, it is likely that the ele-ment-containing extractables that accumulated tohigher levels at the low-pH aqueous leachates wereleached from the test article via a process of eitherion exchange or dissolution of an inorganic oxide.On the other hand, the metallic extractables thataccumulated to higher levels in the IPA/water lea-chates were leached from the test article in the formof an organic compound that is more soluble inIPA/water than it is in water.

Unlike the metallic extractables, Br-containing ex-tractables accumulated at much higher levels, IPA/water versus aqueous. This behavior could reflect theleaching of Br-containing hydrocarbon oligomers bythe IPA/water extraction medium.

Results and Discussion—Optimized Study

Establishing Targeted Extractables

It is reasonable and appropriate to suggest that there bea relationship between (1) the ingredients intentionallyadded to a material of construction, (2) the extract-ables that are revealed when the material (or a com-ponent or system containing the material) is charac-

Figure 4

Leaching profiles for elemental extractables, range-finding study, pH 2.5.

Figure 5

Leaching profiles for bromine, range-finding study.

Figure 6

Maximum accumulation levels the elemental extract-ables measured during the range-finding study.



terized by a controlled simulation study, and (3) theleachables that are present in a pharmaceutical productstored in the system constructed from the material.Going forward, one would expect that the ingredientswould be indicative of the extractables and that theextractables would be indicative of the leachables. Inthe reverse direction, one would expect that leachableswould be largely explainable on the basis of extract-ables and that extractables would be largely explain-able on the basis of ingredients. In fact, these obser-vations are the basis of extractables and leachablescorrelations. Furthermore, these observations establishwhy a three-stage assessment process including mate-rial selection (based on ingredients), system qualifica-tion (based on extractables), and product assessment(based on either leachables or simulating extractables)is an appropriate means of developing and qualifyingsafe and effective packaged pharmaceutical products.

Information that can guide the selection of targetextractables in the optimized leaching (migration)study is contained in Tables V through VII. Specifi-cally, Table V contains compositional information thatwas obtained from the vendors of the materials thatmade up this study’s test system while Table VI con-tains the extractables profiles that were obtained forthese materials via controlled extraction studies. TableVII qualitatively reconciles the compositional and ex-tractables information and uses this information toselect those extractables that were targeted in theoptimized leaching (migration) study. It should benoted that these targeted substances are termed tar-geted extractables because the optimized leaching(migration) study is a simulation of the actual clinicaluse of the test system. Had this leaching (migration)study been performed with a specific drug productunder the actual conditions of storage and use of thatdrug product, then the targeted substances would havebeen termed target leachables.

As seen in Table VII, the extractables profiles for thetest system’s individual materials of construction canbe well-correlated to the materials’ composition,known or speculated. For example, while the vendorof the polyethylene bottle did not provide its compo-sitional information, it is reasonable to suspect that thepolyethylene was formulated to contain one or moreantioxidants, and in fact commonly employed antiox-idants were present in the material’s extractables pro-file. Considering a material whose composition waswell known, the rubber material’s extractables cangenerally be linked to its intentional ingredients.

Several factors are relevant when selecting extract-ables to target in a leaching (migration) study. Gen-erally speaking, the overriding factor for the selectionof target substances (either extractables or leachables)is the potential for the substance to adversely affectsome quality attribute (including safety) of either thepharmaceutical product or the packaging system.Given that performing an impact assessment was notwithin the scope of this study, this means of selectingtargets was not used. Rather, the targets noted in TableVIII were chosen based on secondary considerations,including:

● measured level in the leachates (based on the gen-eralization that the extractables at the highest lev-els tend to have the greatest impact potential andare the most readily measurable),

● analytical expediency, and

● ability to represent a particular compound class ora particular source ingredient.

TABLE VVendor Information Provided about theComposition of the Materials Used in the TestedContainer-Closure System

Bottle Not provided

Cap Not provided

RubberLiner

Brominated isobutylene isoprene copolymer(57.3%);

Calcined aluminium silicate, 38.2%;Titanium dioxide, 1.2%;Paraffinic oil, 1.2%;Zinc oxide, 0.6%;Polyethylene, 0.6%;SRF carbon black mixture, 0.4%;Calcined magnesium oxide, 0.3%;4,4’-dithiodimorpholine/polyisobutylene, 0.3%

Label Adhesive:Surfynol PSA 336 Surfactant (wetting

agent);Dioctylsulfosuccinate, Sodium salt;Ethoxylated 2,4,7,9-tetramethyl 5 decyn-4,

7-diolBiocide:

Chloro-2-methyl-4-isothiazolin-3-one;2-Methyl-4-isothiazolin-3-one;Magnesium chloride;Magnesium nitrate;Copper nitrate

Ink:Modified polyester;Irgacure 369;Irgacure 1173;Trimethylolpropane triacrylate;Tripropyleneglycol diacrylate;3-Glyceryl triacrylate (propoxylated);Carbon black;Phato blue;Carbazole violet;Talc



Leaching Profiles for the Label-Related TargetedExtractables

Leaching profiles for the three spiked, label-relatedtarget extractables are shown in Figures 7 through 9.

The profiles of the individual extractables are bothsimilar and dissimilar, consistent with the chemicalnature of the extractable and the extracting matrix. Asall three extractables are highly soluble in the IPA/water extraction medium, it is to be expected that all

TABLE VIExtractables Profiles: Materials of Construction, Established via a Controlled Extraction Study

Material Extractable Level, �g/g

Name CAS RN

Bottle 4-Nonylphenol isomers 84852-15-3 4200

Irganox 1076 2082-79-3 10000

Trinonylphenylphosphate 26569-53-9 NE1

Cap Irganox 1010 6683-19-8 310

Irgafos 168 31570-04-4 5000

Irgafos 168 oxide 95906-11-9 2200

Monostearin 123-94-4 1200

Ethyl-4-ethoxybenzoate 23676-09-7 300

Label Dioctylsulfosuccinate, sodium salt 577-11-7 1900

2,4,7,9-Tetramethyl-5-decyn-diol 126-86-3 700

Octadecanoic (stearic) acid 57-11-4 50

Hexadecanoic (palmitic) acid 57-10-3 40

Hexanedioic acid, bis(2-methylpropyl) ester 141-04-8 10

Rubber liner2 Octadecanoic (stearic) acid6 57-11-4 �1000

Hexadecanoic (palmitic) acid6 57-10-3 �1000

C-21 Oligomers4 — 100–1000

Dimethylterephthalate 120-61-6 100–1000

Oleamide 301-02-0 100–1000

Octadecane 593-45-3 100–1000

Octacosane 630-02-4 10–100

1-(4-Morpholinyl)-octanoic acid 5299-54-7 10–100

Morpholine 110-91-8 10–100

Tetracosane 646-31-1 10–100

10-Oxo-octadecanoic acid 870-10-0 10–100

4,4’-Dioctyldiphenylamine 101-67-7 10–100

Hexadecanamide 629-54-9 10–100

Docosane 629-97-0 10–100

Nonadecanoic acid 646-30-0 10–100

Bromine3 — 215

Potassium3 — 75

Aluminum3 — 45

Magnesium3 — 45

Calcium3 — 45

1NE � level not established in this study.2Data from reference 9.3Only the rubber liner was tested for extractable elemental entities.4For example, 1-Isopropenyl-2,2,4,4-tetramethyl-6-(2,2,4-trimethyl-pentyl-1-)-cyclohexane. Certain of these oligo-mers were halogenated.5Measured in aqueous extracts only.6Various aliphatic esters of these compounds were also identified.



TABLE VIIReconciliation of Ingredients, Extractables, and Targeted Extractables

Component Ingredient1 Extractable2 Targeted Extractable

Bottle (PE) Antioxidants3 Irganox 1076 Irganox 1076

4-Nonylphenol isomers 4-Nonylphenol isomers

Trinonylphenolphosphite Trinonylphenolphosphite

Trinonylphenolphosphate —

Cap (PP) Antioxidants3 Irganox 1010 Irganox 10105

Irgafos 168 Irgafos 1685

Irgafos 168 oxide Irgafos 168 oxide5

Catalyst3 Ethyl-4-ethoxybenzoate Ethyl-4-ethoxybenzoate

Antistat3 Monostearin Monostearin6

Liner (rubber) Brominated isobutylene isoprenecopolymer

Br, B —

Hydrocarbon Oligomers C21 Hydrocarbon Oligomer

Octadecane, Octacosane,Tetracosane, Docosane

—

Calcined aluminosilicate Al, Si —

Titanium dioxide Ti —

Zinc oxide Zn —

Calcined magnesium oxide Mg —

Processing aids3 Palmitic acid Palmitic acid8

Stearic acid Stearic acid8

10-Oxa-octadecanoic acid —

Oleamide —

Nonadecanoic acid —

Hexadecanamide —

Parafinnic oil — —

Polyethylene — —

SRF Carbon black mixture — —

Unknown source Dimethylterephthalate —

1-(4-Morpholinyl)-octanoic acid —

Morpholine —

Label adhesive Ethoxylated 2,4,7,9-Tetra-methyl-5-decyn-4,7-diol

2,4,7,9-Tetra-methyl-5-decyn-4,7-diol

2,4,7,9-Tetramethyl-5-decyn-4,7-diol

Dioctylsulfosuccinate,sodium salt

Dioctylsulfosuccinate, sodium salt Dioctylsulfosuccinate, sodiumsalt5

Surfynol PSA 336 surfactant — —

— — Benzophenone7

Label, ink Irgacure 369 — —

Irgacure 1173 — Irgacure 11734

Trimethylolpropane triacrylate — —

Tripropyleneglycol diacrylate — Dipropyleneglycol diacrylate4

3-Glyceryl triacrylate (propoxylated) — —

Modified polyester — —

Pigments — —

Label, biocide Chloro-2-methyl-4-isothiazolin-3-one

—

3-Methyl-4-isothiazolin-3-one 5-Ethyl-n-propylthiazole —

Magnesium chloride — —

Magnesium nitrate — —

Copper nitrate — —



three extractables would have similar leaching profiles inthis medium. This is the case, as shown in Figure 10,which indicates that the leaching of these three extract-ables is essentially complete after approximately 20 daysof storage, at which point an equilibrium level isachieved. This equilibrium level, approximately 4200ng/mL, is comparable to the total pool of these spikedsubstances, which was approximately 5000 ng/mL.

While the behavior of these three extractables is sim-ilar in the IPA/water medium, their behaviors are very

different in the aqueous extracts. As Irgacure 1173 isboth highly water soluble and non-ionic, its leaching isvery similar in all three leachate matrices (Figure 7).As benzophenone is less water soluble, its equilibriumlevel in the aqueous leachates is lower than its equi-librium level in the IPA/water leachate (Figure 8).

The leaching profiles obtained for DPGDA (Figure 9)are quite different than the profiles for the other spikedlabel-related extractables, as the profiles are quite dif-ferent in all three leachate media. Because this extract-

TABLE VII(continued)

Component Ingredient1 Extractable2 Targeted Extractable

Label Unknown 1,(1,4-Dimethyl)-3-cyclohexen-1-yl) Ethanone

—

N-acetyl-N-(hydroxyl phenyl)-butanamide

—

2-Propenoic acid, 2-ethylhexylester

—

1As specified by the component’s vendor; see Table V.2As revealed by a controlled extraction study; see Table VI.3Although this ingredient was not specified by the component’s vendor, this ingredient is commonly employed withthis type of material.4Targeted as a spiked compound.5Although these extractables were targeted, their leaching was limited and their levels in the fill solutions were at ornear the analytical method’s quantitation limit. Thus, leaching (migration) profiles were not generated for theseextractables.6Although this extractable was targeted, it undergoes transesterification in the presence of IPA. Thus leaching(migration) profiles for this extractable were not generated.7Although this extractable was not linked to the label by either its vendor or in the extraction study, it was added tothe label as a spiked target due to its known association with label adhesives and its well-documented migration andleaching behavior.8Although these extractables were targeted, the resulting data suggested that analytical issues were encounteredduring the testing of the fill solutions. Thus, leaching (migration) profiles were not generated for these extractables.

TABLE VIIIaExtractables Targeted in the Optimized Study, Label-Related

Compound CAS # Information Structure/Info

2,4,7,9-Tetramethyl-5-decyn-4,7-diol (TMDD)

126-86-3 Chemical formula: C14H26O2Molecular weight: 226.35Aqueous solubility: 10 mg/L1

Log Po/w: 4.371

Vapor pressure: 3.0 � 10-3 torr

Dioctylsulfosuccinate, sodiumsalt

577-11-7 Chemical formula: C20H38O7S.NaMolecular weight: 444.56Aqueous solubility: 18 g/L1

Log Po/w: 2.41

Vapor pressure: N/A

See Table I for additional information for other label-related extractables (benzophenone, Irgacure 1173).



able is both highly water soluble and non-ionic, it isreasonable to expect that it would exhibit similarbehavior to Irgacure 1173, where the profiles in allthree leachate media are essentially the same. The

lower and decreasing levels observed in the pH 2.5and especially the pH 9.5 leachates suggest that thisextractable is degraded by an acid- and base-catalyzedprocess.

TABLE VIIIbExtractables Targeted in the Optimized Study, Cap-Related


Irganox 1010 6683-19-8 Chemical formula: C73H108O12Molecular weight: 1177.63Aqueous solubility: 0.02 �g/L1

Log Po/w: 18.831

Vapor pressure: �10�14 torr

Irgafos 168 31570-04-4 Chemical formula: C42H63O3PMolecular weight: 646.45Aqueous solubility: 0.7 �g/L1

Log Po/w: 13.71

Vapor pressure: 1.8 � 10�13 torr

Irgafos 168 oxide 95906-11-9 Chemical formula: C42H63O4PMolecular weight: 662.45Aqueous solubility: 0.3 �g/L1

Log Po/w: 11.41


Ethyl-4-ethoxybenzoate(Et-4-EthBzate)

23676-09-7 Chemical formula: C11H14O3Molecular weight: 194.23Aqueous solubility: 370 mg/L1

Log Po/w: 3.431

Vapor pressure: 5.2 � 10-3 torr

Monostearin 123-94-4 Chemical formula: C21H42O4Molecular weight: 358.56Aqueous solubility: 3 mg/L1

Log Po/w: 7.091




The behavior of a fourth label-related extractable,2,4,7,9-tetramethyl-5-decyn-4,7-diol, is shown in Fig-ure 11. This targeted extractable differs from thespiked targets in that (1) this extractable is native to

the label, and not artificially spiked as were the pre-viously discussed targets and (2) it is a degradationproduct of, or impurity in, one of the constituents ofthe label’s adhesive (Surfynol PSA 336). As a degra-

TABLE VIIIcExtractables Targeted in the Optimized Study, Gasket-Related


C21 rubber oligomer N/A Chemical formula: C21H40Molecular weight: 376.24Aqueous solubility: N/ALog Po/w: N/AVapor pressure: N/A

Structure not available

Palmitic acid 57-10-3 Chemical formula: C16H32O2Molecular weight: 256.42Aqueous solubility: 5.4 mg/L1

Log Po/w: 6.811

Vapor pressure: 3.5 � 10�5

torr

Stearic acid 57-11-4 Chemical formula: C18H36O2Molecular weight: 284.48Aqueous solubility: 1.2 mg/L1

Log Po/w: 7.831

Vapor pressure: 8.6 � 10�6

torr

TABLE VIIIdExtractables Targeted in the Optimized Study, Bottle-Related


Irganox 1076 (Ix 1076) 2082-79-3 Chemical formula: C35H62O3Molecular weight: 530.87Aqueous solubility: 0.4 �g/L1

Log Po/w: 13.51


4-Nonylphenol 104-40-5 Chemical formula: C15H24OMolecular weight: 220.35Aqueous solubility: 2 to 20 mg/L1

Log Po/w: 6.11


Trinonylphenolphosphite(TNPPite)

26523-78-4 Chemical formula: C45H69O3PMolecular weight: 689.00Aqueous solubility: �0.05 mg/L1

Log Po/w: 8.01

Vapor pressure: N/A

1Value obtained from Advanced Chemistry Development, ACD/Labs Software V11.02.2N/A � Information not available.



dation product, its leaching would be slower than thespiked extractables because its leaching rate reflectsthe combination of its production rate and its diffusionrate whereas the leaching rate of the spiked extract-ables reflects solely the diffusion rate. Nevertheless,this extractable achieves its equilibrium level in solu-tion after approximately 105 days of storage. Becausethis non-ionic extractable has a low water solubility,its equilibrium level in the aqueous leachates is similar

in both the low- and high-pH media but lower than itsequilibrium level in the IPA/water medium.

Leaching Profiles for the Cap-Related TargetedExtractables

Due to the nature of the test system, the cap is anindirect solution contact component of the system.This observation is significant as it is the explanationfor the behavior of the cap-related target extractables.Although Irganox 1010, Irgafos 168, and Irgafos 168oxide were targeted, these substances did not accumu-late in the extraction media at any point in the migra-tion study. As these substances are large moleculeswith low volatility, their migration from the cap andthrough the barriers (either the bottle or the liner) wasanticipated to be very slow. Additionally, their solu-bility in aqueous solutions is very low, and even ifthey did migrate to the point where they achievedsolution contact, they would not dissolve in the aque-ous media to any measurable extent.

On the other hand, ethyl-4-ethoxybenzoate was readilymeasurable in the IPA/water leachate throughout thecourse of the leaching (migration) study (Figure 12).As this compound is smaller, more soluble, and morevolatile than the other cap-related targets, it is reason-able to expect that it would migrate faster than theother targets. In fact, the chemical properties of thistarget are similar to those of benzophenone, a spiked

Figure 7

Leaching profile of a spiked label extractable, Ir-gacure 1173, optimized study. The leaching of thisnon-ionic, highly water soluble and stable extract-able is similar in all three leachate media.

Figure 8

Leaching profile of a spiked label extractable, benzo-phenone, optimized study. The different leaching be-havior of this extractable in the aqueous leachatematrices likely reflects its limited aqueous solubility.

Figure 9

Leaching profile of a spiked label extractable,dipropylene glycol diacrylate (DPGDA), optimizedstudy. The different leaching behavior of thishighly water-soluble, non-ionic extractable in theaqueous leachate matrices likely reflects its acid-and base-catalyzed degradation.



label-related target, and thus it is reasonable to expectthat the ethyl-4-ethoxybenzoate would have the abilityto migrate out of the cap, through the bottle, and intothe fill solution. Of course, such a process for ethyl-4-ethoxybenzoate would be slower than for benzophe-

Figure 10

Leaching profile of three spiked label extractables in isopropanol/water, optimized study. All three spikedextractables behave similarly in this leachate matrix, achieving an equilibrium state after roughly 20 days ofstorage.

Figure 11

Leaching profile of a native label extractable,2,4,7,9-tetramethyl-5-decyn-4,7-diol (TMDD), opti-mized study. The different leaching behavior of thisextractable in the aqueous extraction matriceslikely reflects its limited aqueous solubility.

Figure 12

Leaching profile of a cap-related extractable, eth-yl-4-ethoxybenzoate, optimized study. The signif-icantly lower levels of this extractable in theaqueous versus the IPA/water leachates are amanifestation of this compound’s propensity topartition into the various components of the con-tainer-closure system. Thus, it leaches from the capand then preferentially partitions into the othersystem components (e.g., bottle) as opposed to thefill solution.



none, given ethyl-4-ethoxybenzoate’s longer, andlikely more complex, migration pathway.

As shown in Figure 12, ethyl-4-ethoxybenzoate doesnot accumulate in the aqueous leachates to appreciablelevels. Although this behavior does not reflect therelatively high aqueous solubility of this compound(which is greater than 300 mg/L), it could be explainedby either acid- and base-catalyzed decomposition ofthe benzoate, the small surface area of contact betweenthe fill solution and the cap, and/or the partitioningof this compound into the other components of thecontainer-closure system, such as the bottle.

Leaching Profiles for the Gasket-Related TargetedExtractables

The leaching profiles of the single measured gasket-related extractable, the C21 oligomer, are shown inFigure 13. This oligomer accumulates in the fill solu-tions at very low levels, even in the case of theIPA/water fill solution. This behavior suggests that thevarious container-closure system components have astrong affinity for this oligomer and thus that theoligomer partitions primarily into these components,thereby limiting its accumulation in the fill solutions.

Leaching Profiles for the Bottle-Related TargetedExtractables

Due to the large contact surface area between thebottle and the leaching solution, relative to the other

components of the test system, and their relativelylarge total pools in the bottle, it is reasonable to expectthat bottle-related extractables would quickly accumu-late in the fill solutions in readily measurable quanti-ties. This expectation is realized for the three targetedbottle-related extractables in the IPA/water leachate,as shown in Figures 14 through 16. Given the verylimited aqueous solubility of Irganox 1076, it is ex-

Figure 13

Leaching profile of a gasket-related extractable,C21 rubber oligomer, optimized study. Theleaching behavior of this extractable reflects itslimited aqueous solubility and strong partition-ing into the various components of the container-closure system.

Figure 14

Leaching profile of a bottle-related extractable,Irganox 1076, optimized study. The differentleaching behavior of this extractable in the aque-ous leachate matrices likely reflects its very lim-ited aqueous solubility.

Figure 15

Leaching profile of a bottle-related extractable, tri-nonylphenylphosphite, optimized study. The lowaccumulation levels of this extractable in the aque-ous leachate matrices reflect both its limited aque-ous solubility and its hydrolytic degradation inaqueous solutions.



pected that its accumulation in the aqueous leachateswould be low, and this was the outcome that wasobserved. The low accumulation levels of trinonylphe-nylphosphate in the aqueous leachates reflect both thelimited aqueous solubility of this compound and itshydrolytic degradation in aqueous solutions. Given itshigher aqueous solubility, 4-nonylphenol accumulatedat measurable concentrations in the aqueous leachates,and as it is non-ionic there was no difference in itsleaching behavior as a function of extraction solutionpH. However, its relatively low accumulation levels inthe aqueous leachates and the rapidity with which theplateau in the leaching (migration) profile is achievedindicate that 4-nonylphenol partitions preferentiallyinto the bottle material, as opposed to partitioning intothe fill solution.

Conclusions

The results of the simulated leaching (migration) studyperformed on a model container-closure system that ismore or less relevant for parenteral drug productssupports the following generalizations:

1. The extractables profile revealed by performingsuch a simulation study on a packaging system canqualitatively be correlated with compositional in-formation obtained for the system’s materials ofconstruction.

2. The chemical nature of the extracting/leaching me-dium can markedly affect the extractables and theleachables profiles.

3. The chemical nature of the extractable itself canmarkedly affect its leaching (migration) profile.

4. An extractable’s leaching (migration) profile re-flects the interplay between the chemical propertiesof the leaching medium and the extractable (as per2 and 3 above).

5. Element-containing extractables are leached frommaterials in different forms and by different mech-anisms, depending on the chemical nature of theleaching medium and the chemical form of theextractable’s source material.

6. While direct contact between a drug product and asystem’s material of construction may exacerbatethe leaching of substances from that material by thedrug product, direct contact is not a prerequisite forextraction to occur. Thus label-related and certaincap-related extractables were able to breach thebarrier provided by the LDPE bottle and accumu-late in the leaching solutions. Furthermore, whilegasket-related extractables accumulated to higherlevels when the model packaging system wasstored inverted versus upright, some leaching wasnoted even in the upright (non-direct solution con-tact) configuration.

7. LDPE is a poor barrier to volatile and semi-volatileextractables, given that this study established thatthe migration and leaching of label-related extract-ables was quite rapid.

Furthermore, this study established that a simulatedleaching (migration) study can produce an extractablesprofile that could reasonably be expected to mimicthe leachables profile of a packaged pharmaceuticalproduct.

Conflict of Interest Declaration

The authors(s) declare that they have no competinginterests, either as representatives of their individualorganizations or as volunteer members of the PQRILeachables and Extractables Working Group.

Figure 16

Leaching profile of a bottle-related extractable,4-nonylphenol, optimized study. The significantlylower levels of this extractable in the aqueousversus the IPA/water leachates is a manifestation ofthis compound’s propensity to partition into thevarious components of the container-closuresystem.



References

1. U.S. FDA Guidance for Industry: Container Clo-sure Systems for Packaging Human Drugs andBiologics-Chemistry, Manufacturing, and Con-trols Documentation, May 1999; http://www.fda.gov/downloads/Drugs/Guidances/ucm070551.pdf

2. U.S. FDA Guidance for Industry Nasal and Inhala-tion Solution Drug Products-Chemistry, Manufac-turing, and Controls Documentation, July 2002;http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070575.pdf

3. Draft U.S. FDA Guidance for Industry. MeteredDose Inhalers (MDI) and Dry Powder Inhalers(DPI) Drug Products-Chemistry, Manufacturingand Controls Documentation, October 1998;http://www.fda.gov/downloads/Drugs/Guidances/ucm070573.pdf

4. Product Quality Research Institute Safety Thresh-olds and Best Practices for Extractables andLeachables in Orally Inhaled and Nasal DrugProducts, September 2006; http://www.pqri.org/pdfs/LE_Recommendations_to_FDA_09-29-06.pdf

5. Leachables and Extractables Handbook; SafetyEvaluation, Qualification, and Best Practices Ap-plied to Inhalation Drug Products, Ball, D. J., Nor-wood, D. L., Stults, C. L. M, Nago, L. M., Eds.;John Willey & Sons, Inc.: Hoboken, NJ, 2012.

6. Jenke, D. Compatibility of Pharmaceutical Prod-ucts and Contact Materials; Safety Consider-

ations Associated with Extractables and Leach-ables; John Willey & Sons, Inc.: Hoboken, NJ,2009.

7. �1663� Assessment of Extractables Associatedwith Pharmaceutical Packaging/Delivery Sys-tems. First Supplement to USP 38 –NF 33; UnitedStates Pharmacopeial Convention, Inc.: Rock-ville, MD, August 1, 2015; pp 7166 –7180.

8. �1664� Assessment of Drug Product Leach-ables Associated with Pharmaceutical Packag-ing/Delivery Systems. First Supplement to USP38 –NF 33; United States Pharmacopeial Con-vention, Inc.: Rockville, MD, August 1, 2015;pp 7181–7190.

9. Jenke, D.; Castner, J.; Egert, T.; Feinberg, T.;Hendricker, A.; Houston, C.; Hunt, D. G.; Lynch,M.; Shaw, A.; Nicholas, K.; Norwood, D. L.;Paskiet, D.; Ruberto, M.; Smith, E. J.; Holcomb,F. Extractables Characterization for Five Materi-als of Construction Representative of PackagingSystems Used for Parenteral and OphthalmicDrug Products. PDA J. Pharm. Sci. Technol.2013, 67 (5), 448 –511; http://journal.pda.org/content/67/5/448.full.pdf�html

10. Study Protocol—Stage 2 “Experimental Protocolfor Simulation Study of Blow-Fill-Seal (BFS)PODP Container Closure Systems.” PQRI Paren-teral and Ophthalmic Drug Products (DODP)Leachables and Extractables Working Group,September, 2011. Available at http://www.pqri.org/commworking/minutes/pdfs/dptc/podpwg/Addl/StudyProtocolStage



http://www.fda.gov/downloads/Drugs/Guidances/ucm070551.pdf


http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070575.pdf





http://www.pqri.org/pdfs/LE_Recommendations_to_FDA_09-29-06.pdf



http://journal.pda.org/content/67/5/448.full.pdf+html

http://journal.pda.org/content/67/5/448.full.pdf+html

http://www.pqri.org/commworking/minutes/pdfs/dptc/podpwg/Addl/StudyProtocolStage



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