Daniel L. Norwood, MSPH, PhD
Containers critical to drug product safety and efficacyThe 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.
Terminology, NomenclatureModern 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.
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 ProductsAmong 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.)
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.
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
Biological Protein ProductsA 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 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
CASE STUDY: Leachables and the MDI CFC TransitionIn 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.
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
- 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 DrugsThe 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.
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.)
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.”
Current EnvironmentThe 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.
Dr. Norwood is a distinguished research fellow with Boehringer Ingelheim Pharmaceuticals.
- 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.
- 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.