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The Product Quality Research Institute (PQRI) Leachables and

Extractables Working Group Initiatives for Parenteral and
Ophthalmic Drug Product (PODP)
Diane Paskiet, Dennis Jenke, Douglas Ball, et al.

PDA J Pharm Sci and Tech 2013, 67 430-447

Access the most recent version at doi:10.5731/pdajpst.2013.00936
 Downloaded from journal.pda.org on July 7, 2014
PQRI SPECIAL SECTION: The following article is an invited contribution submitted by the Product Quality Research
Institute (PQRI) Leachables and Extractable Working Group. The article was internally reviewed by PQRI and FDA members
and their affiliated companies and not peer-reviewed by the PDA Journal.

REVIEW

The Product Quality Research Institute (PQRI) Leachables

and Extractables Working Group Initiatives for Parenteral
and Ophthalmic Drug Product (PODP)
DIANE PASKIET1,*, DENNIS JENKE2, DOUGLAS BALL3, CHRISTOPHER HOUSTON4,
DANIEL L. NORWOOD5, and INGRID MARKOVIC6
Product Quality Research Institute (PQRI) Leachables and Extractables Working Group: Parenteral and Ophthalmic
Drug Products (PODP), 2107 Wilson Blvd, Suite 700, Arlington, Virginia 22201-3042, USA; 703-248-4719,
Fax: 703-525-7136; email: PennV@pqri.org
1
West Pharmaceutical Services, Exton PA, USA; 2Baxter Healthcare Corporation, Round Lake, IL, USA; 3Pfizer, Inc.,
Groton, CT, USA; 4Bausch & Lomb, Rochester, NY, USA; 5Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield,
CT, USA; and 6United States Food and Drug Administration, Washington, DC, USA ©PDA, Inc. 2013

ABSTRACT: The Product Quality Research Institute (PQRI) is a non-profit consortium of organizations working together
to generate and share timely, relevant, and impactful information that advances drug product quality and development. The
collaborative activities of PQRI participants have, in the case of orally inhaled and nasal drug products (OINDPs), resulted
in comprehensive and widely-accepted recommendations for leachables assessments to help ensure patient safety with
respect to this class of packaged drug products. These recommendations, which include scientifically justified safety
thresholds for leachables, represent a significant milestone towards establishing standardized approaches for safety
qualification of leachables in OINDP. To build on the success of the OINDP effort, PQRI’s Parenteral and Ophthalmic
Drug Products (PODP) Leachables and Extractables Working Group was formed to extrapolate the OINDP threshold
concepts and best practice recommendations to other dosage forms with high concern for interaction with packaging/
delivery systems. This article considers the general aspects of leachables and their safety assessment, introduces the PODP
Work Plan and initial study Protocol, discusses the laboratory studies being conducted by the PODP Chemistry Team,
outlines the strategy being developed by the PODP Toxicology Team for the safety qualification of PODP leachables, and
considers the issues associated with application of the safety thresholds, particularly with respect to large-volume
parenterals. Lastly, the unique leachables issues associated with biologics are described.

KEYWORDS: Extractables, Leachables, Safety assessment, Safety qualification thresholds, Parenteral and ophthalmic
drug products, Best practice recommendations, Biologic concerns, PQRI, Parenteral packaging, Ophthalmic containers.

LAY ABSTRACT: The Product Quality Research Institute (PQRI) is a non-profit consortium involving industry organiza-
tions, academia, and regulatory agencies that together provide recommendations in support of regulatory guidance to
advance drug product quality. The collaborative activities of the PQRI Orally Inhaled and Nasal Drug Products Leachables
and Extractables Working Group resulted in a systematic and science-based approach to identify and qualify leachables,
including the concept of safety thresholds. Concepts from this widely accepted approach, formally publicized in 2006, are
being extrapolated to parenteral and ophthalmic drug products. This article provides an overview of extractables and
leachables in drug products and biologics and discusses the PQRI Work Plan and Protocols developed by the PQRI
Parenteral and Ophthalmic Drug Products Leachables and Extractables Working Group.

*Corresponding Author: Diane Paskiet, West Pharmaceutical Services, 530 Herman O. West Drive, Exton PA
19341-1147. diane.paskiet@westpharma.com
doi: 10.5731/pdajpst.2013.00936
Observations made, opinions expressed and conclusions drawn in this article reflect the views of the authors
acting in their role as members of the PQRI Extractables and Leachables Working Group and should not be
construed to represent the views or policies of their affiliated organizations.

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Introduction aim of balancing the absolute safety risk with the level
of effort required to establish that risk, it is reasonable
Pharmaceutical products are manufactured, stored, to propose that there is a dose threshold for leachables
distributed, and/or administered in packaging systems, (or extractables as probable leachables) below which
including bottles, bags, vials, ampules, prefilled sy- the vast majority of leachables (or extractables as
ringes, inhalers, and others. Packaging systems are probable leachables) will have an acceptably negligi-
made up of components that are fabricated from ma- ble potential safety impact.
terials, such as rubber, plastic, glass and metal, which
contain both organic and inorganic chemical sub- This challenge of establishing such a threshold for
stances that are either added purposefully for func- the identification and qualification of leachables was
tional reasons, or which are present as surface residues addressed for orally inhaled and nasal drug products
due to the packaging components’ manufacturing. (OINDPs) by the Product Quality Research Institute
Packaging components can be in direct contact or (PQRI) Leachables and Extractable Working Group.
indirect contact with the drug product formulation. PQRI is a non-profit consortium of organizations
During the time that the drug product and its packag- working together to generate and share timely, rel-
ing system are in contact, the two may interact. One evant, and impactful information that advances drug
such interaction is the migration, or leaching, of chem- product quality and development (see pqri.org). By
ical substances out of the packaging system and into virtue of its diverse membership, PQRI provides a
the drug product formulation. These chemical sub- unique forum to focus critical thinking, conduct
stances have the ability, under certain circumstances, research, exchange information, and propose meth-
to migrate out of the packaging system (extractables) odology or guidance to pharmaceutical companies,
and/or potentially affect the quality of the drug prod- regulators, and standard-setting organizations. The
uct and have an adverse effect on the patient. PQRI OINDP Working Group considered a risk-
based approach to leachables safety assessment and
Regulatory guidance documents on packaging sys- developed and published recommendations related
tems, while missing sufficient guidance, have pro- to both safety thresholds for leachables and best
vided pharmaceutical manufacturers with a high level demonstrated practices for the chemical assessment
strategic process to assess and qualify the safety of of extractables and leachables (5). The PQRI
extractables and leachables in various dosage forms OINDP process and these recommendations are con-
using a risk-based approach and sound science. This sidered in greater detail in the Commentary publi-
strategic process includes identifying extractables, cation preceding this article.
performing migration studies, and evaluating toxicity
of extractables/leachables (1– 4). While the guidance Although the PQRI leachables qualification concepts
documents establish high-level strategies and pro- were developed specifically for OINDP, it is reason-
cesses, the practical implementation of this process is able to suggest that the general outline and concepts
problematic because it suggests that all extractables proposed for OINDP are also applicable to other rel-
and/or leachables, regardless of their accumulation atively high-risk drug products, such as parenteral and
levels, must be reported and undergo full toxicological ophthalmic drug products (PODP), considering that
safety assessments. Such an assessment would be nec- OINDP and PODP products are jointly classified by
essary even when the concentration of the leachables the Food and Drug Administration (FDA) in the quad-
in the drug product is so low that it is highly unlikely rant of highest/high concern with respect to the risk
that it will adversely affect patient safety. However, associated with undesirable packaging system– drug
some extractables may not be detected in the final drug product interactions (see Table I. Packaging Concerns
product (i.e., they are not leachables), and some leach- for Common Classes of Drug Products; 1). Neverthe-
ables may be present in the final drug product at levels less, specific differences between the OINDP and
so low as to be of negligible risk to human safety (5). PODP dosage forms and their associated packaging
Such a situation may be counterproductive, as regula- systems (e.g., type of packaging material, drug formu-
tory and industry resources are most effectively used lation, drug volume administered, etc.) must be ad-
and ensure the greatest level of product safety when dressed if the OINDP principles are to be modified for
they are focused on those substances to which patients application to PODP dosage forms. Thus, a PQRI
are actually exposed (i.e., leachables) and which are at Working Group comprised of toxicologists and chem-
levels that potentially affect patient safety. With the ists was tasked to extrapolate the OINDP threshold

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Table I
Examples of Packaging Concerns for Common Classes of Drug Productsb

Degree of Concern
Associated with
Likelihood of Packaging Component-Dosage Form Interaction
the Route of
Administration High Medium Low
Sterile Powders and
Inhalation Aerosols and Solutions; Powders for
Injections and Injectable Injection; Inhalation
Highest Suspensionsa Powders
Ophthalmic Solutions and Suspensions;
Transdermal Ointments and Patches;
High Nasal Aerosols and Sprays
Topical Solutions and Suspensions; Oral Tablets and Oral
Topical and Lingual Aerosols; Oral Topical Powders; Oral (Hard and Soft
Low Solutions and Suspensions powders Gelatin) Capsules
a
For the purpose of this table, the term suspension is used to mean a mixture of two immiscible phases (e.g., solid
in liquid or liquid in liquid). As such, it encompasses a wide variety of dosage forms such as creams, ointments, gels,
and emulsions, as well as suspensions in the pharmaceutical sense.
b
From Guidance for Industry. Container Closure Systems for Packaging Human Drugs and Biologics (1).

concepts and best practices recommendations to ● Expansion of OINDP extraction solvents to in-
PODP based on a three-point hypothesis (6): clude aqueous systems, and

1. Threshold concepts that have been developed for ● Extraction and/or analysis methods which have
safety qualification of leachables in OINDP and unique applicability to PODP.
the existing FDA/European Medicines Agency
(EMEA) guidance documents can be extrapolated The PODP Working Plan was driven by the predicate
to the evaluation and safety qualification of pack- knowledge gained by the OINDP Working Group,
aging systems (such as container closure systems) emphasizing concepts consistent with quality by de-
for PODP. sign (9), including the expectations that

2. The good science practices that were developed ● Requirements and acceptance criteria are defined
for the OINDP pharmaceutical development pro- early in the development process so that material
cess can be extrapolated to packaging systems for use decisions can be based on an understanding of
PODP. the chemistry of the material,

3. Threshold and best practices concepts can be in- ● Container closure materials and components are
tegrated into a comprehensive process for charac- evaluated to establish control points,
terizing packaging systems with respect to leach-
able substances and their associated impact on ● Multi-disciplinary team members communicate and
PODP safety. collaborate early in the product development stages
to establish sound methods for reducing risk,
Considering the specific characteristics of PODP, the
PQRI Leachables and Extractables Work Group de- ● Good science is used to develop and define effec-
veloped a Work Plan (7) and Testing Protocols (8), tive processes and products, and
taking into account
● Proper strategies are employed to ensure that qual-
● Materials components and/or packaging systems ity products are generated based on systems to
applicable to PODP, identify and control critical parameters.

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The PODP Work Group divided the tasks established would have to be made. For example, translating the
in the Work Plan into two work streams. A Chemistry thresholds to large-volume parenterals (LVPs) is chal-
Team was charged with developing Best Practice Rec- lenging because thresholds for products with large
ommendations for conducting PODP extractables and daily dose volumes could be so low that they are
leachables studies and producing the data necessary to beyond the capabilities of modern analytical science
support and justify such recommendations. An impor- (also see the Commentary). The fundamental concept
tant aspect of this team’s task was extrapolating the of thresholds, introduced by the OINDP Leachables
OINDP analytical threshold concept to PODP dosage and Extractables Working Group, considered a safety
forms. Additionally, a Toxicology Team was formed concern threshold (SCT), that is, a value below which
to translate the OINDP safety qualification threshold leachables are not considered for identification and
concepts to PODP dosage forms. Both teams were toxicological qualification. The SCT would be used to
tasked with using a risk management scheme consis- derive an initial analytical evaluation threshold (AET)
tent with the appropriate references found in the FDA for extractables, which would lead to AETs for leach-
Container Closure Guidance (1), the PQRI OINDP ables. The AET is defined as the level at or above
Threshold and Best Practices Recommendations (5), which a leachable and/or extractable should be re-
and the FDA Guidance on Quality Systems Approach ported and considered for potential toxicological as-
to Pharmaceutical GMPs (9). sessment. The AET will vary depending on (i) the
particular drug product configuration and (ii) the
Chemical Aspects of Safety Assessment—The method(s) used to detect and quantify a leachable or
Chemistry Team extractable (5). For instance, Figure 1 contrasts the
AETs between LVPs and dosage forms with small
Background daily dose volumes based on the OINDP SCT of 0.15
␮g/day. As daily dose volume increases, the value of
The level of concern for potential patient safety issues the AET decreases. The effect of the decreasing AET
associated with packaging component– dosage form is illustrated in Figure 2, which shows an extractables
interactions is ranked highest for injections and inject- (or leachables) profile revealed in a chromatogram.
able suspensions and high for ophthalmic solutions The peaks in the chromatogram represent individual
and suspensions (1). Dosage forms delivered by these extractables and the size of the peak reflects the ex-
routes of administration have a history of reported tractables’ concentrations. The AET, shown as a line
leachables originating from various packaging system in this figure, divides the chromatographic peaks into
components and materials of construction. As (i) there two groups, those above the AET, which must be
is an abundance of polymer types and grades that are safety assessed, and those below the AET, which are
used to manufacture components for the manufacture, deemed to be safe by virtue of their low concentrations
packaging, storage, and delivery of pharmaceutical and thus do not have to be assessed further. It is clear
products, and (ii) the chemistry of a given material, that as the AET decreases, the number of peaks that
its polymerization process, formulation ingredients, must be safety assessed increases. Not only does this
physical properties, and manufacturing processes are circumstance increase the number of peaks that must
wide-ranging, a wide spectrum of chemical entities be assessed, but it increases the level of effort required
can migrate or leach into drug products. Additionally, to perform the assessment as it is typically the case
the diversity of leachables is exacerbated by the fact that the smaller the peak, the more difficult it is to do
that a material’s extractable (i.e., potential leachables) a proper chemical assessment.
profile can also vary between material lots and be
modified by exposure to various high-stress environ- To investigate and deal with the extenuating aspects of
ments in material processing, drug product manufac- PODP dosage forms, the PODP Chemistry Team con-
turing, in storage, and in distribution. Reviews of ceived a three-phase laboratory program consisting of
typical extractables, spanning a broad range of mate- three specific experiments:
rials used in pharmaceutical packaging, have been
published by Jenke (10 –12). 1) A controlled extraction study is the initial step,
designed to characterize the extractables profile of
During the translation of OINDP principles to PODP each material and, thus, inferring potential leach-
dosage forms, it was recognized that PODP dosage ables. In addition to facilitating raw material and
forms are sufficiently different that certain allowances packaging component selection and providing an

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Figure 1

The effect of daily dose volume on the analytical evaluation threshold (AET). The daily dose volume varies
greatly among various pharmaceutical dosage forms. Because the AET is related to the safety concern
threshold (SCT), which is a fixed quantity (taken as the 0.15 ␮g/day OINDP SCT for this example), the value
of the AET is inversely proportional to the daily dose volume. Thus an AET which is analytically achievable
in a small daily dose volume (SDV) dosage form (e.g., metered dose inhaler, MDI) may not be achievable in a
large daily dose volume (LDV) dosage form (e.g., large volume parenteral, LVP).

initial assessment of potential safety issues, such According to this scheme, extraction studies are sug-
a study facilitates the development of analytical gested as an excellent means to characterize packaging
methodologies for leachables. materials to develop a list of probable extractables and
potential leachables. Leachable studies seek targeted
2) A simulation study is an intermediate step to more leachables in actual drug product, but these studies may
effectively delineate extractables as probable be challenging for LVPs owing to extremely low AETs
leachables. In this study, a mock, laboratory-pre- in potentially complex media. The concept of a simula-
pared PODP packaging system was assembled, tion study is to match the leaching propensity of the drug
filled with extraction media relevant for PODP, product vehicle as closely as possible with a simple
and stored under accelerated use conditions. The solvent system. A simulation study might use accelerated
resulting fill solutions will be characterized for (not exaggerated) conditions to mimic worst-case condi-
tions. The output of such a study would be “extractables”
extractables. The outcome of this study should
with a high probably of becoming leachables.
provide the rationale for leachables assessment
(as further discussed by Jenke, 13) and would Simulation studies ameliorate the challenge posed by
allow the application of thresholds in cases such LVPs in several ways. First, unlike the metered dose
as LVPs. inhalers considered by the PQRI OINDP team (where
“all extractables are leachables”), an aqueous, LVP is
3) A leachables study is the final phase employing expected to present a subset of possible extractables as
targeted validated methods to confirm the actual potential leachables. By using a more relevant solvent
accumulation of target leachables in the drug system for the simulation study, extractables with low
product during shelf life. propensity to extract into product would be eliminated

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Figure 2

The concept of a reporting threshold for extractables and leachables. Pictorially, the concept of the threshold
can be envisioned through the use of a chromatogram, which is the means by which information about organic
leachables or extractables is obtained. In the chromatogram, each peak corresponds to a substance that was
present in the test sample, and the size of the peak (either its height or its area) is proportional to the amount
of that substance that is present in the test sample. A threshold, representing that amount of any individual
substance that will not produce an undesirable safety outcome, can be superimposed on the chromatogram as
a straight line at its corresponding response level. Those substances whose responses are below the threshold
do not have to be considered further (e.g., identified), as their dose will be too low to produce an unacceptable
safety outcome. Those substances whose responses are above the threshold have the potential to produce an
unacceptable safety outcome. In order to more precisely specify the actual safety risk for such substances, they
must be identified so that their actual safety risk can be individually established. As the threshold decreases,
the number of substances (peaks) that have to be identified increases. Furthermore, the complexity of
establishing the identity increases as the peaks get smaller.

from consideration, thus reducing the number of com- prefilled syringe (PFS), small- and large-volume par-
pounds under scrutiny to those most pertinent to the enteral (SVP and LVP), and topical ophthalmic routes
drug product. Second, the observed extractables will of administration. These practices could also apply to
be present at more realistic concentrations, thus aiding materials if used for short-term or intermediate storage
safety assessment. Finally, use of a simulating me- such as disposable systems. To accomplish their ob-
dium less complex than the drug product formulation jective as it relates to extractables, the Chemistry
facilities the analytical testing and identification of Team acquired five materials typical of those used in
those compounds above the AET. packaging systems for PODP with the purpose of
producing extractables data to evaluate their hypoth-
Phase I: The Controlled Extraction Study esis. These materials, along with their typical uses, are
described in Table II. An understanding of the types of
The objective of the Chemistry Team was to establish materials used in packaging components and their
best demonstrated practices for the identification and potential leachables dictated the choice of the materi-
safety qualification of leachables in PODP, recogniz- als for the PODP evaluations. These five materials are
ing the means by which extractables information can among the most common and diverse classes of ma-
support and facilitate such qualifications. Relevant terials used in components of PODP packaging sys-
dosage forms within scope of the work plan included tems, and all five materials are known to have extract-

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Table II
Description of the Test Materials Used in the Chemistry Team Controlled Extraction Study

Test Materials Article Composition Application Category

Bromobutyl Rubber (BIIR) Compression Molded ● Brominated Isobutylene Closures SVP or LVP for
Sheet Isoprene Copolymer Plungers Multiple
(57.3%) Gaskets Doses per
● Calcined Aluminum Day
Silicate (38.2%)
● Titanium Dioxide (1.2%)
● Zinc Oxide, (0.6%)
● Polyethylene (0.6%)
● Carbon Black (0.4%)
● Calcined Magnesium Oxide
(0.3%)
● Morpholine/polyisobutylene
(0.3%)
Polyvinyl Chloride (PVC) Pellets ● PVC Resin Bags LVP
● DEHP (30%) Tubing
● Epoxidized Soybean Oil
(7%)
● Zn Stearate (0.5%)
● Ca Stearate (0.5%)
● Stearamide (1%)
Low-Density Polyethylene Blown Film ● Irganox B215 (Irgaphos Over-pouch BFS, SVP, LVP
(LDPE) 168 and Irganox 1010 BFS
Blend Containers
●(1000 ppm)
● BHT (200 ppm)
● Calcium Stearate (500
ppm)
● Erucamide (500 ppm)
● Chimassorb 944 (2000
ppm)
Cyclic Olefin Copolymer Plaques Irganox 1010 Syringes PVS, SVP or
(COC) Ultramarine Blue Vials LVP for
Multiple
Doses per
Day
Polycarbonate (PC) Injection Molded Irganox 1076 (0.05 PHR) Ports LVP
Plaques Irgaphos 168 (0.1 PHR) Tubes

ables that could become leachables in contained drug during molding and sterilization processes (14 –15).
products. Considering the rubber material, for exam- Furthermore, the conditions of contact between the
ple, butyl and halobutyl rubbers (isobutylene/isoprene elastomeric components of packaging systems and a
copolymer base) are commonly used with sterile par- therapeutic product can include elevated temperatures
enteral products and migration of chemical substances and long contact times. Lastly, pharmaceutical prod-
can occur, including the rubber’s formulation ingredi- ucts may contain solubilizing agents in their formula-
ents and substances or degradation products formed tion that may increase the potential for leaching.

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Given the nature of the rubber (e.g., complex chem- scientific information available. As recently as March
istry and transport properties) and the conditions of 30, 2012, the FDA issued an interim update finding
contact, consequential interactions between elasto- that BPA remains safe in food contact materials with
meric parts and parenteral solutions and pharmaceuti- the exception of those applications intended for pedi-
cal products have been reported (16 –23). atric use (42). The migration of BPA from food and
pharmaceutical packaging has been studied (43).
Considering the other test articles, thermoplastics are
another broad class of polymers commonly used in the Secondary components such as labels with varnishes
pharmaceutical industry. Unlike conventional rubbers, used on packages have also been reported as sources
they can be melted and then reformed. Polymerization of leachables in ophthalmic products during stability
mechanisms for thermoplastics typically involve an (44). In light of concerns for migration of extractables
addition or condensation reaction. For example, poly- through semipermeable containers, the PODP project
vinyl chloride (PVC) is manufactured by the addition also considered controlled extraction studies related to
reaction of substituted ethylene compounds (24). PVC secondary packaging labels (45).
was included in the PODP protocol because it is one of
the most common materials used in components Formulation information for the five PODP test arti-
(e.g., tubing) and packaging (e.g., blood bags and IV cles was provided by their various suppliers. However,
bags). The leaching of chemicals from PVC and into in addition to these anticipated extractables, unex-
parenteral products is well-documented (25–33). The pected extractables could be revealed by the testing
potential for plasticized, PVC-related substances to performed in this study due to the materials’ multifac-
leach into drug product formulations and produce ad- eted supply chains. While the test articles were repre-
verse events in patients has been considered in studies sentative of materials used in pharmaceutical applica-
evaluating risk for various patient populations (34). tions, the specific test articles themselves are not used
in commercial packaging systems.
Polyolefin is the generic term for a family of plastics
derived by addition of ethylene and/or propylene and A semi-quantitative extractables protocol was devel-
it is used for various types of drug product contact oped by the Chemistry Team with the objective of
surfaces (35). Given their wide use in the food and acquiring “first pass” data to characterize representa-
pharmaceutical industries, a plethora of information is tive materials used in components for packaging par-
available on polyolefins. Polyethylene components enteral and ophthalmic drug products for extractables.
have been extensively characterized for extractables This protocol, consistent with the predicate OINDP
and leachables in numerous applications (36 –39). The study, incorporated multiple solvents, extraction tech-
PODP Chemistry Team evaluated two types of mate- niques, and analytical methods (5, 8). The extractions
rials from the olefins family, a low-density polyethyl- utilized organic and additional aqueous-based solvent
ene (LDPE) formulation and a cyclic polyolefin copo- systems associated with PODP formulations and in-
lymer (COC). Cyclic olefin polymers and copolymers volved extraction techniques relevant to the PODP
have been gaining interest in the pharmaceutical in- dosage forms. The resultant extracts were character-
dustry as they are recognized as having very low ized for extractables by multiple orthogonal analytical
levels of potential leachables (40, 41). techniques, including gas chromatography/mass spec-
trometry (GC/MS), gas chromatography flame ioniza-
Polycarbonate (PC) is another material that was con- tion detection/ (GC/FID), liquid chromatography/mass
sidered as it is frequently used in connectors and ports spectrometry (LC/MS), inductively doupled plasma/
for large volume parenteral systems. The polymeriza- mass spectrometry (ICP /MS), and headspace GC/MS.
tion mechanism for PC involves condensation in Specific details associated with the extraction and
which two reactive molecules join to form a new analysis processes are contained in a companion man-
compound; common PC materials are formed from uscript appearing in this issue of the PDA Journal. The
bisphenol A (BPA) and phosgene (24). PC has been analytical testing was performed so that extractables
extensively researched in terms of its leaching poten- with estimated concentrations of 10 ␮g/g or greater
tial because concerns have been raised about the safety were targeted for identification.
of BPA. In 2008, a subcommittee of the FDA’s sci-
ence board raised questions about whether FDA’s The “first pass” PODP data were acquired by industry
review had adequately considered the most recent volunteer laboratories and were presented, in a pre-

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liminary manner, at the 2011 PODP Workshop on proposed toxicological thresholds were developed for
Thresholds and Best Practices for Parenteral and Oph- PODP, based on a classification strategy and an addi-
thalmic Drug Products (46). A more extensive presen- tional uncertainty factor to account for dose adminis-
tation of these study results and their implications to tration differences. The developed qualification clas-
best demonstrated practice recommendations is con- sification included a risk assessment model and
tained in the companion manuscript in this current decision trees, as appropriate, to account for the PODP
issue of the PDA Journal. routes of administration, dose, duration, local vs sys-
temic exposure, and patient population. The Toxicol-
Phase 2: The Simulation Study ogy Team evaluated the use of existing standards and
best practices— environmental pollutants, indirect
Adopting the three-step approach described above led food additive regulations, International Conference on
to the generation and implementation of a Phase II Harmonisation (ICH), USP monographs, ISO stan-
Protocol which involves a migration, or simulation, dards, EMEA guidance on genotoxic impurities—for
study. This study is being conducted on a laboratory- application to PODP.
produced “packaging system” modeled after the flex-
ible bottle typically employed with ophthalmic prod- This classification process proceeded as follows. The
ucts, including secondary labels. This study, whose Toxicology Team, together with the Chemistry Team,
design is indicated in the relevant PQRI Work Plan compiled a list of ⬃600 potential chemicals associated
(45), is currently ongoing; results from this study and
with leachables and/or extractables to explore a classifi-
their implications with respect to best demonstrated
cation scheme for leachables in PODP. The list of leach-
practices and thresholds will be the subject of future
able and extractable chemicals was initially sorted via
communications.
ToxTree (49) into Cramer classes as follows (50):

Toxicological Aspects of Safety Assessment—The ● Class 1: substances of simple chemical structure

Toxicology Team
with known metabolic pathways and innocuous end
products which suggest a low order of oral toxicity.
The PQRI OINDP Leachables and Extractables Work-
ing Group developed the concept of the analytical
● Class 2: substances that are intermediate; possess
evaluation threshold (AET), which is to be applied to
structures that are less innocuous than those in
data from controlled extraction or leachable studies;
Class 1 but they do not contain structural features
this threshold is a benchmark to allow for a prelimi-
that are suggestive of toxicity like those in Class 3.
nary determination of which extractables should be
identified and quantified (5). This benchmark is de-
rived from the SCT relative to doses per day and doses
● Class 3: substances with chemical structures that
per container where the SCT is defined as the thresh- permit no initial presumption of safety and may
old in which a leachable would have a dose so low as even suggest significant toxicity.
to present negligible safety concern from carcinogenic
and noncarcinogenic effects. This SCT differs from In addition to the traditional three Cramer classes that
the threshold of toxicological concern (TTC) (47, 48), sort chemicals into categories from least toxic to most
as it is used as a benchmark for identification pur- toxic (1800 to 90 ␮g/day), a fourth class was added to
poses, not as a safety control limit. A similar concept capture chemicals of known or suspect genotoxic po-
is reflected in the qualification threshold (QT), where tential using Deductive Estimation of Risk using Ex-
the QT is a threshold below which a given non- isting Knowledge (DEREK) software (51). Additional
carcinogenic leachable is not considered for safety safety factors to account for body weight (BW) and
qualification (toxicological assessments) unless the route of administration differences (oral vs parenteral)
leachable presents a structural–activity relationship. were considered to add orders of magnitude to the
already conservative estimates established by Cramer
Building on the threshold concepts developed for and refined by Munro (51). The sorting produced a
OINDP, specifically the SCT and QT, the Toxicology recognizable and actionable distribution of com-
Team considered the unique circumstances of PODP pounds among the four classes. As was anticipated,
dosage forms and packaging systems to establish com- the sorting indicated that approximately 10% of the
parable thresholds for PODP products. Specifically, Class 3 chemicals sorted by ToxTree are known hu-

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Table III noted in Table III. When compared to Cramer, the

Proposed Safety Classification of Extractables/ PQRI Class 1 level of 150 ␮g/day is similar to a
Leachables Cramer class 3 (90 ␮g/day) chemical (52). In other
words, the overall approach in sorting known chemi-
Threshold
cals that have extracted or leached from packaging
␮g/kg/day, components puts them into a single class that estab-
Class ␮g/day Adult lishes a conservative estimate of risk. Note that the
Initial PQRI Classification for PODP lowest threshold of concern for genotoxicants was
1 (low toxicity) 150 3 raised to 1.5 ␮g/day versus the OINDP SCT of 0.15
2 (moderate toxicity) 50 1 ␮g/day. The OINDP SCT was derived assuming a 10-6
3 (marked toxicity) 5 0.1 lifetime risk of carcinogenicity. This conservative
4 (genotoxicant) 0.15 0.003 value was chosen because of the chemical nature of
Current PQRI Classification of PODP likely extractables and leachables from metered dose
inhaler (MDI) packaging systems, the strong solvents
1 (general toxicity, QT) 150 3
present in MDI formulations that significantly enhance
2 (sensitizers) 5 0.1
the likelihood of leaching, and the fact that the dose is
3 (genotoxicant, SCT) 1.5 0.003
delivered directly to the diseased organs of a sensitive
patient population. The higher working value for
PODP (1.5 ␮g/day) is less conservative than the
man carcinogens and/or known mutagens (e.g., poly- OINDP SCT and is strongly influenced by the nature
nuclear aromatic hydrocarbons (PNAs), nitrosamines). of PODP vehicles (primarily aqueous) and packaging
systems such that the team determined that a less
With the four categories fully populated, the Toxicol- conservative threshold was logical for PODP.
ogy Team considered appropriate thresholds for each
class. Consistent with the sorted data and with current An additional safety endpoint that the Toxicology
thinking on genotoxic impurities with regard to com- Team considered was irritation and sensitization. The
pounds of concern, the daily limit for exposure to a PQRI OINDP best practices recommendation provided
Class 4 chemical was initially set at 0.15 ␮g/day as the a rationale that the qualification threshold for chemi-
starting point for PODP safety assessment. This train cals with known or suspect sensitization or irritation
of thought led to an initial classification proposal, as potential is 5 ␮g/day (46). No additional data were
indicated in Table III. In considering thresholds for the found to suggest that the qualification threshold should
other classes, the Toxicology Team recognized that be any different for PODP and thus this value was
the degree of risk associated with a Class 3 chemical preserved for PODP. Ultimately, this thought process
may not significantly differ from that for a Class 1 led to the current proposed PQRI classification shown
chemical, suggesting that only three classes instead of in Table III.
five classes were relevant. The Team validated the
need for three distinct classes by evaluating twenty- A challenge recognized by the Toxicology Team is
five Class 3 chemicals for acute and repeat dose tox- whether or not all PODP dosage forms have the same
icology, developmental and reproductive toxicology, safety concerns. For example, parenteral dosage forms
genetic toxicology, carcinogenicity, and any other per- can reasonably be assessed for their systemic safety
tinent information related to risk. With three excep- impact. As with OINDP, cancer risk serves as a con-
tions, the evaluation demonstrated that, where data servative endpoint in those cases. On the other hand,
were available, there was at least a 100 fold margin ophthalmic solutions and suspensions are applied lo-
from the No Observed Adverse Effect Level in an cally as topicals and ocular irritation is commonly
animal study when compared to the dose of the chem- regarded as a key endpoint. These differences between
ical in a 50 kg human. None of the 25 chemicals had parenteral and ophthalmic dosage forms may drive
published study results suggesting genotoxicity or car- separate strategies. By way of example, the FDA as-
cinogenicity. Based on the risk assessments of the 25 sesses drug product leachables against a set of con-
Class 3 chemicals and discussions with regulators centration-based thresholds: Reported at above 1 ppm;
around the acceptable level for genotoxicants (1.5 Identified at 10 ppm, and Qualified at 20 ppm (53).
␮g/day) in PODP, the classification was modified to This is a different paradigm than the exposure-based
produce 3 classes with the proposed thresholds as thresholds typically applied in the evaluation of sys-

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temic toxicology. As a result, ophthalmics may be best ● Large size (e.g., recombinant human erythropoie-
served by the development of a threshold for ocular tin is ⬃30 kD and an average antibody molecule is
irritation. Moreover, on-eye concentration may be ⬃150 kD);
more relevant for ocular irritation than daily exposure
(the FDA approach serves as a precedent for this idea). ● Complex structure (e.g., secondary, tertiary, and
The strategy for ophthalmic solutions and suspensions quaternary) whereby changes in protein configu-
is still evolving. rations via random unfolding or other possible
conformational changes may lead to a loss of pro-
Lastly, the PQRI Toxicology Team recognizes that the tein structure and/or function, which may lead to
subject of thresholds for potentially genotoxic substances adverse safety outcomes due to exposure of immu-
in marketed drug products continues to be a matter for nogenic epitopes that were originally buried in the
international discussion (ICH M7, Step 2, 2012) (54) and protein interior;
the acceptable limit for a genotoxic impurity may be
higher based on multiple factors. As noted in the original ● Extensive surface area providing numerous reactive
PODP hypothesis, although the individual threshold val- sites, which may serve as nucleation zones for struc-
ues may differ from OINDP, the threshold concepts tural and chemical modifications including those that
remain the same. Thus, the PODP thresholds serve as have been previously discussed in this paper (e.g.,
reporting or identification thresholds and not as TTC-like aggregation, degradation, oxidation, etc); and
control thresholds or limits.
● Amphiphilic nature whereby proteins possess both
Safety and Compatability Considerations for hydrophilic and hydrophobic sites possibly making
Leachables and Extractables in Biologics them more effective solubilizers of leachables
compared to small-molecule compounds.
The PODP Working Group recognizes that, in addition
to primary safety issues (i.e., safety issues due to the Additional risks for leachables may not be limited to
intrinsic toxicity of the leachable), leachables can also biologics, but contribute to the overall risk assessment
exert an undesired effect to product quality thereby including
altering physico-chemical, biological (i.e., potency),
and/or stability properties of the active pharmaceutical ● Systemic administration allowing 100% bioavail-
ingredient. Some of the plausible mechanisms by ability and access to critical tissues;
which leachables interact with therapeutic proteins
include a direct effect on the recombinant therapeutic ● Administration at relatively high volumes,
protein catalyzing oxidation, aggregation, truncation,
formation of protein adducts; or indirect effects, via ● Administration with high frequency (in many
interaction with formulation excipients inducing for- cases).
mation of particulates; or by affecting the upstream
steps of production causing altered protein translation For these and other possible reasons, special consid-
or post-translational events during fermentation (55– eration may need to be given to therapeutic biologic
57). Potential leachables (e.g., silicon oil, monoethyl- molecules when designing production, quality, and
hexylphthalate, (di-2-ethylhexyl phthalate polycyclic packaging components in order to minimize undesir-
aromatic hydrocarbons, alkyl phenols, metals, etc.) able product quality and safety outcomes. For the
from various sources have similarly been implicated to purpose of the PODP Work Plan, thresholds are being
act as adjuvants (e.g., inducing antibody response) considered for identification of chemical constituents
and/or as general immune-modulators (e.g., causing based on the safety aspect with the understanding that
up- or down-regulation of specific cytokines) in ani- other thresholds may be applicable to address quality
mal studies thus providing further support for immu- and efficacy concerns.
nogenicity as a plausible mechanism of leachable ac-
tion (58 – 68). Conclusions

The nature of biologic therapeutics may render them The PQRI PODP Leachables and Extractables Work-
especially susceptible to the impact of leachables due to ing Group started with the hypothesis that safety
their thresholds for leachables and best demonstrated prac-

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tices for performing controlled extraction studies, de- unteer laboratories and suppliers led to a well-defined
veloped for OINDP dosage forms, could be extrapo- process for understanding the science of packaging
lated to the PODP dosages forms; taking into account component materials of construction in relation to
the clear differences between OINDP and PODP drug extractables, and correlation to leachables in support
products and their associated packaging systems. To of drug product quality. Sound science is demon-
facilitate the extrapolation, the PODP Chemistry Team strated based on the PQRI PODP Work Plan and
devised a three-phase laboratory investigation, de- Protocols that will lead to recommendations to aug-
signed to address SVP, LVP, PFS, and ophthalmic ment guidance to pharmaceutical manufacturers and
solution and suspension dosage forms. Phase 1 of the enable appropriate selection and qualification of pack-
investigation involved characterizing five materials aging systems early in the drug development process.
typically used in PODP packaging systems for extract-
ables; the design of this study and the results obtained The ongoing efforts to develop best practices for sec-
are considered in greater detail in a companion man- ondary components, specifically the ongoing simula-
uscript in this issue of the PDA Journal. Phase 2 of the tion studies, will be completed in 2013, at which time
investigation, the migration or simulation study, in- the teams will finalize their recommendations and
volves the accelerated aging of a mock packaging build consensus with input from U.S. FDA and Health
system filled with simulating solvents, and is currently Canada regulators. In addition, reviews from Medi-
ongoing. Data obtained from this second-phase study cines and Healthcare products Regulatory Agency
will guide the design of the third phase of the inves- (MHRA) and other industry organization will be con-
tigation, which will involve leachables testing of one ducted prior to submitting the PODP recommenda-
or more laboratory-generated drug products (or simu- tions to the PQRI steering committee and subsequent
lants) stored in the mock packaging system. Ulti- submission to the FDA. All research work is supported
mately such experimental data will be instrumental in under the direction of the PQRI organization; the
establishing and justifying best demonstrated practice leachable and extractable activities, work plan and
recommendations for performing extractables and protocols are publically available for both OINDP and
leachables studies for PODP. PODP on the PQRI website (www.PQRI.org). The
PQRI Working Group gratefully acknowledges partic-
Additionally, the PODP Toxicology Team has pro- ipation by the following industry experts, regulators,
posed a three-tier classification scheme for leachables, laboratories, and suppliers.
proposing safety thresholds for the three categories of
leachables. The classification scheme, based on struc- PQRI PODP Leachables and Extractables Working
ture activity relationships analysis of a database of Group
approximately 600 known extractables/leachables and
rigorous safety assessment of a smaller subset of these Diane Paskiet, Director of Scientific Affairs, West
chemicals and designed to be consistent with relevant Pharmaceutical Services, Chair
related regulatory guidance, assigns a SCT of 1.5
␮g/day for genotoxicants, a threshold of 5 ␮g/day for Douglas J. Ball, Research Fellow, Pfizer, Inc., Toxi-
sensitizers/irritants, and a QT of 150 ␮g/day for com- cology Team Chair
pounds that exhibit general toxicity. It is important to
note that these thresholds apply to parenteral products Dennis Jenke, Ph.D. Baxter Distinguished Scientist,
with systemic dosing; a strategy for topical ophthal- Baxter Healthcare, Chemistry Team Chair
mics is still developing.
Frank Holcombe, Jr., Ph.D. U.S. FDA, PQRI Devel-
Lastly, the Chemistry and Toxicology Teams continue opment Technical Committee Liaison
to collaborate to establish means by which the best
demonstrated practices and safety thresholds can be Chemistry Team Members:
applied to dosage forms with large daily dose volumes
so as to provide for effective and efficient safety ● Jim Castner, Ph.D., Pharma Interface Analysis,
assessments for such dosage forms. LLC.

Invaluable contributions from industry subject matter ● Thomas Egert, Boehringer Ingelheim Pharma
experts, national and international regulators, and vol- GmbH & Co. KG

Vol. 67, No. 5, September-October 2013 441

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● Thomas Feinberg, Ph.D., Director, Structural ● Jacqueline A. Kunzler, Ph.D., Director of Life
Chemistry, Catalent Pharma Solutions Sciences Technology Resource Division, Baxter
Healthcare
● Alan Hendricker, Ph.D., Principal Scientist, Catal-
ent Pharma Solutions ● Mary Richardson, Ph.D., Executive Director, Pre-
clinical Development, Bausch & Lomb
● Christopher Houston, Ph.D., Senior Principal Sci-
entist, Bausch & Lomb ● Timothy Robison, Division of Pulmonary, Allergy,
and Rheumatology Products, CDER, FDA
● Desmond G. Hunt, Ph.D., Scientist, Dept. of Stan-
dards Development, USP ● Alisa Vespa, Ph.D., Assessment Officer, Metabo-
lism and Musculoskeletal Drugs Division, Bureau
● Michael Lynch, Ph.D., Associate Research Fellow, of Metabolism, Oncology and Reproductive Sci-
Reg CMC, Pfizer ences, Therapeutic Products Directorate, Health
Canada
● Ingrid Markovic, Ph.D., Special Advisor to the
Volunteer Laboratories
Associate Director for Review Management, Of-
fice of the Center Director, CBER, FDA Baxter

● Kumudini Nicholas, Team Leader, Pharmaceutical ● Roopang Shaw, Research Associate II

Quality Review, Bureau of Pharmaceutical Sci-
ences, Health Canada ● Marek Ciosla, Research Associate II

● Frank (Yousheng) Hua, Research Scientist

● Daniel L. Norwood, M.S.P.H., Ph.D., Distin-
guished Research Fellow, Boehringer Ingelheim Bausch & Lomb
Pharmaceuticals, Inc.
● Christopher Houston, Senior Principal Scientist
● Michael Ruberto, Ph.D., Material Needs Consult-
● John Rider, Research Scientist
ing, LLC
Boehringer Ingelheim Pharmaceuticals, Inc.
● Art Shaw, Ph.D., Associate Research Fellow,
Pfizer ● Daniel L. Norwood

● Scott Pennino
● Edward J. Smith, Ph.D., Packaging Science Re-
sources, LLC ● Jamie O. Mullis

Boehringer Ingelheim Pharma GmbH & Co. KG

Toxicology Team Members:
● Thomas Egert
● Stephen A. Barat, Ph.D., Senior Director, Toxicol-
ogy and Operations, Forest Laboratories ● Jürgen Mattes

● Steve Beck, CEMDD Liaison, GlaxoSmithKline ● David Strassburger

● William P. Beierschmitt, Ph.D., Associate Re- Catalent Pharma Solutions

search Fellow, Pfizer, Inc.
● Paul Cvetich
● Abigail Jacobs, Ph.D., Associate Director for
Pharmacology/Toxicology, CDER, FDA ● Kimberly Davis

442 PDA Journal of Pharmaceutical Science and Technology

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● Michelle Cree Evaluation and Research (CDER). Draft Guidance

for Industry—Metered Dose Inhaler (MDI) and Dry
● Tom Feinberg Powder Inhaler (DPI) Drug Products, 1998.

● Alan Heindricker 3. U.S. Department of Health and Human Services,

Food and Drug Administration, Center for Drug
Pfizer Inc. Evaluation and Research (CDER). Guidance for In-
dustry—Nasal Spray and Inhalation Solution, Sus-
● Cindy Magee pension, and Spray Drug Products—Chemistry,
Manufacturing, and Controls Documentation, 2002.
● Miguol Sandoval
4. European Medicines Agency, Committee for Me-
● Arthur Shaw dicinal Products for Human and Use (CHMP) and
Committee for Medicinal Products for Veterinary
Toxicology Support Use (CVMP). Guideline on Plastic Immediate
Packaging Materials, 2005.
● Breda Seidman, PhD, TOX-RSA, LLC
5. Product Quality Research Institute (PQRI),
● Angela Howard, PhD Cosmetic Ingredient Review Leachables and Extractables Working Group.
Safety Thresholds and Best Practices for Extract-
● Russel Naven QSAR, DEREK, ToxTree, Pfizer, ables and Leachables in Orally Inhaled and Nasal
Inc. Drug Products; Product Quality Research Insti-
tute: Arlington, VA, 2006.
● Patricia Ellis, QSAR, DEREK, ToxTree, Pfizer,
Inc. 6. Ball, D.; Paskiet, D.; Norwood, D. L.; Jenke, D.
PQRI Research Project Proposal: Reporting and
● David Jones, Principal Scientific Officer, New Qualification Thresholds in Parenteral and Oph-
Chemical Entities Unit, MHRA thalmic Drug Products; Product Quality Research
Institute: Arlington, VA March 2007; available at
Supplier Support http://www.pqri.org/commworking/minutes/
pdfs/dptc/podpwg/Addl/PQRI_PODP_proposal_
● Stephanie Hubers, Cameo Craft 04072.pdf.

● Micheal Ruberto, Ciba Specialty Chemicals 7. PQRI. Parenteral and Ophthalmic Drug Products
(PODP) Work Plan; Product Quality Research
● Horst Koller, Schott Institute: Arlington, VA, 2008; available at http://
www.pqri.org/commworking/minutes/pdfs/dptc/
● Peter Galland, Teknor Apex podpwg/Addl/podp_work_plan_schedule.pdf.

● Jeff Smythe, West Pharmaceticals Services Inc. 8. Study Protocol—Stage 1 Experimental Protocol
for Qualitative Controlled Extraction Studies for
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