Daniel L. Norwood, MSPH, PhD
Containers critical to drug product safety and efficacy
The vast majority of patients take little or no notice of the
containers their medicines arrive in from the pharmacy, except perhaps
to complain about a tamper-resistant seal. Even patients required to
treat chronic disease conditions using medications with relatively
complex container closure/drug delivery systems like metered-dose
inhalers might only be interested when the drug appears not to work as
fast as they might like.
What the average patient does not know—what even many pharmaceutical
development professionals fail to fully appreciate—is the importance of
pharmaceutical packaging to the safety and efficacy of medicines, and
the level of science and engineering incorporated into many container
closure/delivery systems.
Governments and their regulatory authorities, however, have long
recognized the importance of pharmaceutical packaging. The Federal Food,
Drug, and Cosmetic Act addresses packaging directly, stating in section
501(a)(3) that a drug or device shall be deemed to be adulterated “if
its container is composed, in whole or in part, of any poisonous or
deleterious substance which may render the contents injurious to
health.”
1 Section 502 of the FD&C Act delineates
packaging situations for drugs and devices that can lead to charges of
“misbranding,” and section 505 mandates drug product approval by the
Federal government and lists the information required to obtain such
approval, including “a full description of the…packing of such drug.”
With this and other legislative mandates, governmental regulatory
authorities such as the FDA, the European Medicines Agency, and other
standard-setting bodies such as the U.S. Pharmacopeia-National Formulary
(USP-NF) have addressed packaging and packaging-related issues with
various guidance documents, characterization and quality control
methods, and standards.
In the past several decades of the 20th century, with the rapid
increase in new pharmaceutical dosage forms and new medical devices
(which are in many cases also container closure/drug delivery systems),
along with the replacement of many glass containers with various types
of plastic, interest and concern regarding pharmaceutical packaging has
significantly increased. As a result, in May 1999 the FDA released a
definitive guidance document titled Guidance for Industry – Container
Closure Systems for Packaging Human Drugs and Biologics – Chemistry,
Manufacturing, and Controls Documentation.
1 This guidance,
often called the “Packaging Guidance,” presents regulatory expectations
for packaging of new drug products based on the concept of “suitability
for intended use,” which includes the requirements of protection,
compatibility, safety, and performance. These terms are defined as
follows:
- Protection: The ability of a packaging system
to guard the dosage form from “factors that can cause degradation in
the quality of that dosage form over its shelf life” (e.g., temperature,
light, moisture, loss of solvent, reactive gases, microbial
contamination).
- Compatibility: The attribute(s) of a
packaging system and its various components that prevent interactions
that promote “unacceptable changes in the quality of either the dosage
form or the packaging component.” Such interactions can result in loss
of potency or reduction of an active ingredient or excipient through
absorption, adsorption, or degradation; precipitation and particle
formation; pH change; appearance changes in either the dosage form or
packaging system; or physical changes in the packaging system, resulting
in reduced protection and/or performance.
- Safety: The property of a packaging system
and its components not to leach potentially harmful substances into the
dosage form that could be delivered to the patient.
- Performance: The ability of a packaging
system and its components to “function in the manner for which it was
designed.” This includes the ability of the packaging system to deliver
the dosage form to the patient in an appropriate manner.
click for larger view
The requirements for packaging systems and their components are risk
based, taking into consideration factors such as route of administration
and the likelihood of packaging component–dosage form interaction (see
Table 1).
1 Additional details, such as the dose of the particular drug and the frequency and mode of administration are also considered.
2
Terminology, Nomenclature
Modern pharmaceutical packaging systems are enormously diverse, even
within specific dosage form types such as those listed in Table 1. To
begin to understand this diversity, it is useful to consider the
following terms as defined in the “Packaging Guidance” and in the
comprehensive books by Jenke and by Ball and colleagues.
1,3,4:
- Container closure system: The sum of packaging components that
together contain and protect the dosage form. The term “packaging
system” as used in this article is equivalent to container closure
system. Note that the term “container closure/delivery system” is used
because the packaging system can also serve to deliver the drug to
patients.
- Packaging component: Any single part of a container
closure/delivery system. Packaging components can be either primary, a
term that describes those that are or may be in direct contact with the
dosage form, or secondary, those that are not or will not be in direct
contact with the dosage form.
- Materials of construction: Substances used to manufacture a packaging component.
A container closure system can be relatively simple, such as a bottle
containing pills, or relatively complex, like a single-use syringe
containing an injectable solution or a dry powder inhaler. In the
former, the primary packaging components are the bottle (fabricated from
materials such as glass or a plastic such as polyethylene) and the cap
(likely also fabricated from a plastic material), while secondary
packaging components might include the paper label on the bottle (don’t
forget the ink and glue on the label), cardboard shipping containers,
and wooden shipping pallets. For the single-use syringe, primary
packaging components include the syringe barrel and plunger and the
syringe needle. The barrel and plunger are likely fabricated from
plastic materials, while the needle is metal, secured to the barrel with
a glue of some type. Secondary packaging components include the carton
containing the syringe.
The diversity of primary packaging components is significant,
including bottles, vials, ampoules, canisters, intravenous bags, septa,
overseals, gaskets, caps, liners, and mouthpieces.
1,4
Secondary packaging components are also diverse, including labels (inks
and glues), overwraps, and shipping containers. Materials of
construction include elastomers (i.e., rubber of various types), plastic
(many varieties), metal (aluminum and stainless steel), paper, and
wood. Note that any and all of these packaging components, both primary
and secondary, can affect protection, compatibility, safety, and
performance.
Inhalation Products
Among all dosage form types, none connects packaging systems more
intimately with safety and performance than inhalation drug
products—also referred to as orally inhaled and nasal drug products or
OINDP—including inhalation aerosols, inhalation solutions/sprays, nasal
sprays, and inhalation powders. Table 1 clearly shows that the
regulatory authorities consider these dosage form types to be of high
concern because of their route of administration and the likelihood of
packaging component-dosage form interaction. This is true because 1)
inhalation drug products are typically administered over many years
directly to the diseased organs of sensitive patient populations with
chronic conditions such as asthma and chronic obstructive pulmonary
diseases, and 2) the packaging system is typically a true container
closure/delivery system, with primary packaging components intimately
associated with proper administration of the drug formulation.
FIGURE 1. Schematic diagram of a metered dose inhaler drug product. (Image provided by Bespak, a division of Consort Medical;
www.bespak.com.)
Consider the metered dose inhaler drug product shown in Figure 1.
MDIs contain active ingredients either in solution or suspended in an
organic propellant, such as chlorofluorocarbons, hydrofluorocarbons,
along with cosolvents and excipients like ethanol, soy lecithin, or
oleic acid. Primary packaging components, also referred to as critical
components, include the dose metering valve with its rubber gaskets and
seals, plastic valve components, the metal canister, and a plastic
actuator/mouthpiece.
4
These components are designed and carefully controlled with respect
to dimensions and physical properties so that appropriate doses of drug
are delivered to the patient over the shelf life of the drug product
unit (a typical MDI might contain 200 actuations of drug formulation).
For example, the orifice shape and dimensions of the actuator/mouthpiece
affect the geometry of the aerosol “plume” of actuated drug formulation
dose, which in turn affects the delivery of active ingredient to the
patient’s lung.
Also, the physical properties of the rubber gaskets and seals—for
example, their elasticity—can affect the performance of the dose
metering valve during actuation of a dose, which can in turn affect the
delivered dose. Therefore, control of primary packaging components is
critical to the performance of an MDI. Other inhalation drug product
container closure/delivery systems, such as dry powder inhalers and
inhalation sprays, can be even more complex and also require rigorous
primary packaging component controls to ensure adequate dosage form
performance.
The term “likelihood of packaging component-dosage form interaction”
attempts to quantify the probability that a container closure/delivery
system will leach chemical entities with possible safety concerns for
patients into a drug formulation. This concept is easily conceptualized
with reference to the MDI schematic in Figure 1. As noted above, in an
MDI the formulation includes an organic solvent propellant and other
ingredients such as organic solvents.
These solvents can interact with primary packaging components, such
as the rubber gaskets and seals, as well as plastic valve components, to
leach organic and inorganic chemical entities into the formulation.
These chemical entities are then referred to as leachables and are
considered by regulatory authorities to be a separate class of drug
product impurity. (For a more detailed summary of leachables in MDIs,
see case study, “Leachables and the MDI CFC Transition.”)
click for larger view
FIGURE 2. Chemical
structures of some common chemical antioxidants used as additives in
rubber and plastic: A) Irganox 1010; B) Diphenylamine; C) Irganox 1076;
D) Irgafos 168.
Rubber and plastic are particularly good sources of potential
leachables because these materials require chemical additives to achieve
and maintain various physical properties of the finished components.
Functional categories of chemical additives include antioxidants, UV
light stabilizers, cross-linking agents, polymerization agents,
plasticizers, lubricants, anti-static agents, anti-slip agents, and mold
release agents.4 Each functional category also contains significant
chemical diversity; for example, note the various chemical types of
antioxidant in Figure 2. Along with chemical additives to rubber and
plastic components, potential leachables also include byproducts of
incomplete polymerization such as monomers and oligomers, organic and
inorganic residues on component surfaces, and chemical entities added to
component surfaces by processing equipment.
Obviously, liquid-based drug formulations are at highest risk for
potential leachables. These include the aforementioned inhalation drug
products, as well as injectables and parenterals, ophthalmic solutions,
and suspensions. Oral and topical solutions and suspensions, while still
considered to be at the highest risk for potential leachables, are
considered low risk with respect to route of administration. Aqueous
drug formulations also have a lower risk for potential leachables than
those that are organic solvent based like MDIs. Although direct contact
with primary packaging components is the main source of drug product
leachables, indirect contact with secondary packaging components is also
a potential source. Notable case studies include the following:
- Vanillin, a chemical entity associated with lignin (a primary
structural polymer in wood), detected at significant levels in aqueous
inhalation solution drug products contained in low-density polyethylene
containers. It was determined that the source of vanillin was the
cardboard shipping containers used as secondary packaging for the LDPE
containers, and that aluminum foil overwrap of the containers prevented
migration of vanillin through the LDPE into the aqueous drug product.5
- Photoinitiators, including 1-benzoylcyclohexanol and
2-hydroxy-2-methylpropiophenone, detected above regulatory thresholds in
a solid oral dosage form contained in a high-density polyethylene
bottle. These photoinitiators were found to derive from the paper label
(with ink and coating) used on the plastic bottle. The semi-volatile
organic compounds were able to migrate through the HPDE bottle material
and into the drug product.6
- Recalls of drugs such as Risperdal and Tylenol due to odor
problems linked to the migration of organic compounds such as
2,4,6-tribromoanisole from treated wooden shipping pallets.7,8
Although safety and performance are emphasized for the
container/closure systems of inhalation drug products, protection and
compatibility are also significant. For example, the rubber gaskets and
seals in an MDI also serve to protect the MDI formulation from moisture
ingress, which can reduce the shelf life of certain MDI drug products.
Also, as noted above, secondary packaging of inhalation solution plastic
containers with foil overwrap prevents migration of volatile organic
chemical entities from the environment into the drug formulation. Some
MDI metal canisters have an organic coating on their interior surfaces
to reduce to possibility of active ingredient particles sticking to the
surfaces and affecting the delivered dose, making the canisters more
compatible with the drug formulation.
Biological Protein Products
A packaging system or packaging component can be considered
incompatible with a drug product formulation if it interacts with that
formulation in ways that negatively affect the quality attributes of the
formulation, like potency or delivered dose, or the quality attributes
of the packaging system or component such as the ability to protect the
formulation from the external environment. All dosage form types have
potential compatibility issues with packaging systems; however,
biological active ingredients such as therapeutic biological proteins
may be particularly susceptible to compatibility issues associated with
leachables from packaging components, for reasons listed and described
by Markovic.
2 These include:
- The very large sizes and complex molecular structures of protein
molecules compared with other active ingredient molecules. In addition
to amino acid sequences (i.e., primary structure), protein molecules can
include secondary structures such as α-helices, tertiary structures
such as three-dimensional folding, and quaternary oligomeric structures.
Each of these structural elements can be critical to the potency and
efficacy of the therapeutic protein;
- The large surface areas of protein molecules, resulting from their
large molecular sizes and complex molecular structures, which include
many sites of potential interaction and chemical reactivity with
leachables; and
- The relative complexity of manufacturing processes for therapeutic
biological proteins, which allows for contact between active
ingredients and numerous materials and components, with the accompanying
increased possibilities for leaching.
In addition, therapeutic biological proteins are typically
administered with relatively high frequency as sterile injectables of
relatively high volume.
In other reports, Markovic has presented various case studies related
to compatibility issues with therapeutic biological proteins and
leachables, including the following:
- Chemical degradation (N-terminal) of a therapeutic protein due
to the presence of a leached divalent metal cation from a rubber
stopper included in a new liquid formulation of the drug product;
- Foreign particle formation due to barium leaching from glass
vials into a drug formulation and reacting with sodium sulfate
excipient, forming insoluble barium sulfate crystals; and
- Protein oxidation followed by aggregation resulting from
reaction with leached tungsten oxide salts in a pre-filled syringe
container closure/delivery system. 9,10
continues below...
CASE STUDY: Leachables and the MDI CFC Transition
In the 1970s, scientific investigations and theories came together to
confirm that when chlorofluorocarbons get into the upper regions of the
earth's atmosphere, they deplete the amount of ozone in the ozone layer
that surrounds the Earth, thus increasing the risk of potentially
serious health problems such as skin cancer and cataracts, as well as
other health and environmental problems.
1,2
The chemistry of ozone depletion involves CFCs drifting from the
lower atmosphere, where they are relatively stable, into the upper
atmosphere, where they are degraded when solar radiation releases
chlorine radicals, which in turn reacts with ozone. At that time, CFCs
were used in many ways, two of the more common uses being as
refrigerants and as propellants in many types of aerosol products.
In order to lower the risk of health and environmental problems
caused by ozone depletion and to help restore the earth’s ozone layer,
the Montreal Protocol was adopted in 1987. This agreement restricted the
production of CFCs by nations that were party to the agreement. In
1992, the Protocol signatories further agreed that CFC production would
be phased out except for so-called “essential uses,” which included
their use as propellants in metered dose inhaler drug products. The
International Pharmaceutical Aerosol Consortium was formed in 1989 to
help address the regulatory consequences of the Montreal Protocol for
MDIs and to help manage the CFC transition to alternative propellants
such as hydrofluorocarbons, HFAs, and other innovative inhalation dosage
forms such as dry powder inhalers.
The timing of the Montreal Protocol and the formation of IPAC
coincided with a period of heightened concern by regulatory authorities
regarding leachables in MDIs.
3 Rubber gaskets and seals that
contacted the MDI drug formulation were identified as sources of
potential leachables. In 2001, the International Pharmaceutical Aerosol
Consortium on Regulation and Science was officially formed as a
pharmaceutical industry consortium separate from IPAC. The mission of
IPAC-RS was, and continues to be, to advance consensus-based and
scientifically driven standards and regulations for inhaled and nasal
drug products.
4
Responses to the leachables concern and the CFC transition, led by
IPAC-RS and individual innovator pharmaceutical manufacturers, in
collaboration with packaging component suppliers, included:
- Initiation of research programs to characterize, and determine the sources of, leachables related to MDIs under development;
- Consideration of strategies to create “cleaner” MDI container
closure system components (e.g., use of peroxide cured rubber,
pre-washing rubber components, customized and optimized rubber curing
processes, and chemical additive packages); and
- Development of innovative dosage forms, such as DPIs and
aqueous based inhalation sprays, to minimize leachables and replace
MDIs.
In addition, beginning in 2001, IPAC-RS led an initiative within the
Product Quality Research Institute in which representatives of academia,
the pharmaceutical industry, and the FDA worked cooperatively on the
leachables issue. This collaboration resulted in a recommendation
document titled “Safety Thresholds and Best Practices for Leachables and
Extractables Testing in Orally Inhaled and Nasal Drug Products,” which
was submitted to the FDA in 2006.
5 The document included
science and data-based recommendations and best practices for leachables
characterization and control in MDIs, as well as other inhalation
dosage forms. A new book, titled “Leachables and Extractables Handbook –
Safety Evaluation, Qualification, and Best Practices Applied to
Inhalation Drug Products,” written and edited by pharmaceutical
development scientists involved in IPAC-RS and PQRI, has also recently
become available.
6
This case study demonstrates that, in many instances, regulation
fosters and promotes innovation in both dosage form and packaging system
development, to the ultimate benefit of patients and all humanity.
—DN
References
- International Pharmaceutical Aerosol Consortium. A message about IPAC. Available at: www.ipacmdi.com. Accessed March 25, 2012.
- International Pharmaceutical Aerosol Consortium. Ensuring patient care: the role of the HFC MDI. 2nd edition. Available at: www.ipacmdi.com/Ensuring.html. Accessed March 25, 2012.
- Schroeder AC. Leachables and extractables in OINDP: An FDA
perspective. Paper presented at: The PQRI Leachables and Extractables
Workshop; Dec. 5-6, 2005; Bethesda, Md.
- International Pharmaceutical Aerosol Consortium on Regulation and Science. IPAC-RS website home page. Available at: www.ipacrs.com. Accessed March 25, 2012.
- PQRI Leachables and Extractables Working Group. Safety thresholds
and best practices for extractables and leachables in orally inhaled and
nasal drug products. Product Quality Research Institute. Sept. 8, 2006.
Available at: www.pqri.org/pdfs/LE_Recommendations_to_FDA_09-29-06.pdf. Accessed March 25, 2012.
- Ball DJ, Norwood DL, Stults CLM, Nagao LM, eds. Leachables and Extractables Handbook. Hoboken, N.J.: John Wiley and Sons; 2012.
Counterfeit Drugs
The meaning of protection can be taken in a broader context than
simple protection of the drug product formulation from environmental or
other factors that could potentially reduce shelf life and potency. This
broader context might include, for example, protecting patients from
safety and efficacy risks associated with counterfeit drug products.
The term “counterfeit” refers to “the theft of a product or brand by reproducing and substituting a similar product.”
11
Unlike the legitimate product, however, counterfeit products can
contain a reduced amount, or even none, of the active ingredient, as
well as potentially higher levels of impurities or a very different
impurity profile than the approved product. These issues pose
significant potential safety risks for patients who unknowingly take
counterfeit drug products. The World Health Organization has reported
that the worldwide pharmaceutical market includes approximately 10%
counterfeits and up to 50% of branded products in certain countries. It
has also been reported that the annual cost to consumers in the United
States is around $200 billion. Counterfeit drug products have become a
source of funding for both international organized crime and terrorist
groups.
Packaging systems and their components can be employed in
anti-counterfeiting strategies for drug products. Tamper-evident designs
for packaging systems and authentication technologies—both overt and
covert—are well established and relatively simple anti-counterfeiting
strategies.
11,12 Overt authentication technologies are
apparent to human senses and are therefore easily detected by patients
and pharmacists. These include holograms, microtext, and line-screen
printing. Covert technologies, which require instrumentation for
detection, include elements that are sensitive to invisible light such
as ultraviolet or infrared, nanotext, and hidden images.
A novel covert authentication strategy is potentially available from
the leachables profile of the drug product, assuming that the drug
product contains a significant and unique leachables profile throughout
its shelf life. In principle, the leachables profile is unique to the
branded drug product’s primary packaging components.
The future holds the promise of being able to establish a drug
product’s “e-pedigree” through use of two-dimensional bar coding or the
inclusion of radio frequency identification tags within the packaging
system. The reader should be aware that at the time of this writing, the
USP-NF has proposed a new General Chapter <1083> entitled “Good
Distribution Practices¬ – Supply Chain Integrity,” which addresses
counterfeit drug products and the important relationship of packaging
systems.
Quality Control
click for larger view
FIGURE 3. Schematic
representation of a pharmaceutical packaging system supply chain.
(Images provided by Bespak, a division of Consort Medical;
www.bespak.com.)
Maintaining quality in the packaging component supply chain first
involves understanding the supply chain. Figure 3 shows a schematic of
the supply chain for an MDI dose metering valve critical component—for
example, a valve stem constructed from polybutyleneterephthalate, or PBT
plastic. Packaging component supply chains are typically viewed in
reverse, with the drug product manufacturer designated as N.4 Working
backward in the chain, the valve assembler would be N-1, the component
fabricator or molder N-2, and the synthesizer of the base polymer resin
N-3.
In some supply chains for this type of packaging component, the
component fabricator and valve assembler are the same, making the resin
synthesizer N-2. The pharmaceutical manufacturer has the approved drug
product and is responsible for supply chain quality and integrity.
Formal quality systems are always in place at the N level and also
typically at the N-1 and N-2 levels, with supply and quality agreements
established between the N level and the N-1/N-2 levels. Supply
agreements cover issues such as security of supply, change management,
availability of compliance statements and other supplier information,
and material/component testing.
13
Security of supply, and the problems associated with both anticipated
and unanticipated changes at all levels less than N, are an
ever-present challenge in the pharmaceutical industry. A typical
scenario might involve an N-3 supplier being required to close an
environmentally unfriendly chemical plant and change to a new
polymerization process. Even though the new process might produce a
superior material of construction for the valve stem, the N-1 supplier
would be required to perform various studies on the resulting finished
components as well as on assembled valves to ensure physical performance
of components molded from the new material of construction.
Further, the drug product manufacturer would be required to ensure
that drug product made with valves, including the new stems, performed
according to approved specifications and acceptance criteria throughout
the approved shelf life of the product. Formal approval of appropriate
regulatory authorities after review of submitted documentation is
required. Such a “change-control” process often requires years to
complete. In order to avoid potential problems with drug product supply,
the International Pharmaceutical Aerosol Consortium on Regulation and
Science recommends that supply agreements include a 36-month rolling
availability of unchanged material.
13
FIGURE 4. The quality-by-design “universe.”
The potential supply problems inherent in any change-control
situation, along with release testing requirements for individual
batches of certain high-risk dosage form components, can be partly
ameliorated with a quality-by-design process. In QbD (see Figure 4), a
“design space” is created within the sum total of knowledge, or the
so-called “knowledge space,” of a process. Design space is the
multi-dimensional combination and interaction of design input
variables—for example material critical quality attributes, such as
elasticity for rubber—and process parameters, like molding temperature
for a plastic, that have been demonstrated to provide assurance of
quality in a finished product.
14 In principle, as long as the
process is controlled within an approved design space, then changes
could be made within the design space without prior regulatory approval.
In addition, release testing of finished products manufactured within
the approved design space might not be required. QbD remains a goal
rather than a reality in the pharmaceutical packaging industry.
Current Environment
The landscape of pharmaceutical packaging is both broad and diverse.
At the center are the drug product manufacturers, whose business it is
to produce innovative, safe, and effective medicines to treat disease.
Critical to this business are drug product packaging systems, and
critical to these packaging systems are the supply chains with all their
various levels of individual suppliers. Effective partnerships between
drug product manufacturers and packaging component/material suppliers
are required to maintain the quality and integrity of the supply chain,
particularly related to high-risk dosage forms. Additional partnerships
with regulatory authorities, who should provide the most guidance both
possible and practical, are also required.
The landscape also includes:
- Industry consortia, such as the previously mentioned IPAC-RS and the Extractables and Leachables Safety Information Exchange;
- Scientific organizations such as the Parenteral Drug Association; and
- Non-governmental standard-setting bodies, such as the U.S. Pharmacopeia/National Formulary.
These groups provide best practice guidances, set standards, create
and validate test methods, and provide training in all areas related to
pharmaceutical packaging systems. The future suggests even greater width
and diversity for the landscape of pharmaceutical packaging, and it is
hoped that this brief overview has provided the reader with some
appreciation for the current reality and future possibilities.
Dr. Norwood is a distinguished research fellow with Boehringer Ingelheim Pharmaceuticals.
References
- U.S. Food and Drug Administration. Center for Drug Evaluation and
Research. Center for Biologics Evaluation and Research. Guidance for
Industry: Container closure systems for packaging human drugs and
biologics: chemistry, manufacturing, and controls documentation. May
1999. Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070551.pdf. Accessed March 25, 2012.
- Markovic I. Evaluation of safety and quality impact of extractable
and leachable substances in therapeutic biologic protein products: a
risk-based perspective. Expert Opin Drug Saf. 2007;6(5):487-491.
- Jenke D. Compatibility of Pharmaceutical Products and Contact
Materials: Safety Considerations Associated with Extractables and
Leachables. Hoboken, N.J.: John Wiley and Sons; 2009.
- Ball DJ, Norwood DL, Stults CLM, Nagao LM, eds. Leachables and Extractables Handbook. Hoboken, N.J.: John Wiley and Sons; 2012.
- Conkins D, Economou JE, Boersma JA, Dedhiya MG, Hansen G. Reversed
phase-high performance liquid chromatographic (RP-HPLC) method to
measure migration of semi-volatile compound, vanillin, in ipratropium
bromide inhalation solution. AAPS PharmSci. 1999;1(3):E15.
- Fang X, Cherico N, Barbacci D, Harmon AM, Piserchio M, Perpall H. Leachable study on solid dosage form. Am Pharm Rev. 2006;9(7):58, 60-63.
- Cerra A. J&J subsidiary recalls one lot of Risperdal,
risperidone tablets. DSN Drugstore News online. June 20, 2011. Available
at: http://drugstorenews.com/article/jj-subsidiary-recalls-one-lot-risperdal-risperidone-tablets. Accessed March 25, 2012.
- PR Newswire. TYLENOL recall confirms Congress, FDA must regulate
wood pallets to prevent threats to U.S. food, drug supply. PR Newswire
online. Dec. 31, 2009. Available at: www.prnewswire.com/news-releases/tylenol-recall-confirms-congress-fda-must-regulate-wood-pallets-to-prevent-threats-to-us-food-drug-supply-80407777.html. Accessed March 25, 2012.
- Markovic I. Challenges associated with extractables and/or leachable substances in therapeutic biological protein products. Am Pharm Rev. 2006;9(6):20-27.
- Markovic I. Risk management strategies for safety qualification of
extractable and leachable substances in therapeutic biological protein
products. Am Pharm Rev. 2009;12(4):96-101.
- Forcinio H. Technology advances anticounterfeiting options. PharmTech. 2002:26-34.
- U.S. Pharmacopeia/National Formulary. Proposed General Chapter
1083: Good distribution practices¬ – supply chain integrity. Available
at: www.usp.org/USPNF/notices/generalChapter1083.html. Accessed March 25, 2012.
- International Pharmaceutical Aerosol Consortium on Regulation and
Science. Baseline requirements for materials used in orally inhaled and
nasal drug products (OINDP). June 22, 2011. Available at: www.ipacrs.com/PDFs/Baseline.pdf. Accessed March 25, 2012.
- International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use. ICH
harmonised tripartite guideline. Pharmaceutical Development Q8(R2).
Current Step 4 version. August 2009. Available at: www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf. Accessed March 25, 2012.
Editor’s Choice
- Jenke D, Odufu A. Utilization of internal standard response
factors to estimate the concentration of organic compounds leached from
pharmaceutical packaging systems and application of such estimated
concentrations to safety assessment. J Chromatogr Sci. 2012;50(3):206-212.
- Chan EK, Hubbard A, Hsu CC, Vedrine L, Maa YF. Root cause
investigation of rubber seal cracking in pre-filled cartridges: ozone
and packaging effects. PDA J Pharm Sci Technol. 2011;65(5):445-456.
- Butschli J. Pharmaceutical packaging growth forecast in emerging
economies. Healthcare Packaging online. Feb. 22, 2010. Available at: www.healthcarepackaging.com/archives/2010/02/pharmaceutical_packaging_growt.php. Accessed March 25, 2012.
