Summary
The initial focus of container closure testing centred on the containers compatibility with the drug product, ability to accurately deliver the dose and maintain sterility. With the development of a multitude of formulation and container closure combinations, the risk posed by container closures is no longer considered “basic” evolving to focus on the role of packaging components and their interaction with the drug product. This has resulted in regulators focusing on leachables that may migrate from packaging components and assessing the risk leachables might pose. This article will briefly review the quality concerns and considerations for ophthalmic and injectable products relating to leachables in the context of the current regulatory environment.
Introduction
With the availability of a multitude of formulation and container closure combinations, the risk posed by container closures is no longer considered “basic,” evolving to focus on the role of packaging components. The original intent of container closure testing centered on compatibility with the drug product, impact on the drug product stability, accurate dose delivery and maintenance of sterility. The evolution of container closures has resulted in the use of new packaging and delivery devices made from plastics, elastomers, multi-laminate foils, and adhesives. This in turn has resulted in regulators focusing on leachables (also known as non-drug related impurities) that may migrate from packaging components and assessing the risk that they might pose.
The primary concern is the presence of impurities that may be harmful to the patient. Drug-related impurities (process related & degradation products) tend to be well controlled and understood. On the other hand, leachables chemicals that migrate from packaging materials into the drug product during normal storage are less well understood, and may be more difficult to control as they don’t have migration or generation pathways that are thoroughly understood.
Recently there has been significant media attention on leachables with the Kellogg’s Company recalling 28 million boxes of cereal [1,2] after consumers reported a strange taste and odor, and some complained of nausea and diarrhea. Kellogg’s attributed these symptoms on elevated levels of 2-methylnaphthalene in the packaging. In April 2010 McNeil Consumer Healthcare (Johnson & Johnson Family of Companies) announced a major recall of children’s medicines due in part to the presence of 2,4,6-tribromopheno [3], a pesticide and flame retardant in wood, which migrated from shipping pallets through all packaging and into the drug products. The media also played a strong role in highlighting the issue of bisphenol A [4], a suspected endocrine disruptor present in polycarbonate plastics used in packaging systems, which may migrate into aqueous products. Bisphenol A is widely used in baby’s bottles and was the subject of the news media after several governments issued reports questioning its safety, prompting some retailers to remove products containing it from their stores. Although the exact safety concern or risk to the patient/consumer was never defined in these cases, it does highlight the need to understand potential sources of leachables, and to proactively look for and control them.
Regulatory Background
Although the issue of leachables has been a concern for a long time, particularly in the food industry, it was only in the late 1990s that health authorities began to develop working policies for drug products. While the International Conference on Harmonization has issued guidance on impurities resulting from the manufacture of drug substances and drug products, the topic of leachables falls outside of their scope. Guidance on genotoxic impurities has been developed by the European Medicines Agency (EMA; guidelines final) and the Food and Drug Administration (FDA; guidelines currently in draft), but these also do not specifically cover the topic of leachables.
The FDA has gradually increased scrutiny on packaging materials and components used for drug products. Their initial focus was on inhalation devices, and draft FDA guidance [5] called for the identity and concentration profiles of the leachables in the drug product. This was followed in 1999 by the FDA container closure guidance [6] which broadened the scope of products included, and outlined the highest risk dosage forms (i.e., inhalation products and parenterals) as a function of the route of administration. This guidance was key in driving the toxicological evaluation of those substances which are extracted (not leached) to determine an acceptable level of exposure depending on the route of administration. More recently, the European Medicines Agency has issued guidance on the use of plastics in primary packaging. Recently there has also been added scrutiny from other countries (e.g., Israel) and in veterinary products.
Although the FDA sought more stringent oversight of leachables, other agencies have continued to monitor leachables in line with ICH guidance. Principally, leachables are being assessed as quality issues with ICH Q3A/B providing the foundation for control of impurities. However, as leachables are not specifically covered by ICH guidance, this has resulted in arbitrary specification setting and confusion, with contradictory approaches from within and across regulatory authorities.
This situation has led to the need for general agreement on approaches for addressing leachables. Industry, in collaboration with regulatory agencies, is pursuing a risk-based approach to assessing container closure systems and addressing leachables as a safety risk rather than a quality one. Recently, PQRI (which includes FDA, Health Canada, USP and industry membership) has developed best practices encompassing this approach for leachables with orally inhaled and nasal drug products (OINDP) [7]. The aim is to gain greater regulatory acceptance of scientific risk-based approaches and control only those leachables which pose threats to human health. PQRI is continuing its efforts based on the OINDP experience and is currently working on developing best practices for parenteral and ophthalmic drug products (PODP). This team hopes to release its recommendations in 2011.
Product Experience
Ophthalmics
The most common packaging used in multi-dose ophthalmics is a semi-permeable polyethylene bottle. Although this packaging system allows for ease of use in dose administration, it does not provide a barrier to migrating chemical moieties and thus poses a challenge in the control of leachables. The majority of these leachables often are from the label which is in direct contact with the bottle (e.g., adhesive, inks and varnish) and from the carton where leachables can migrate through air.
Historically, ophthalmic leachables were treated as a quality issue particularly by FDA with specification setting based on batch data and not accounting for ICH guidance. The agency’s justification for this was that the eye is especially sensitive and the ICH guidelines weren’t written with ophthalmic products in mind. The challenge for the drug manufacturer is that leachables do not have a profile like process or drug related impurities. The leachable profile can vary widely with supplier, ink types and age of plastics used. Having a low and arbitrary limit not accounting for the safety profile of the leachable in the registered drug product specification could lead to batch failures.
There has also been inconsistent feedback from FDA and other Health Authorities. An example of this was the control of benzophenone, a leachable commonly found in UV-based inks/labels which can cause eye irritation. Here the agency proposed limits for benzophenone of 1 ppm, while externally advocating a tiered approach [8] e.g.,
- For DPs > 0.01% strength: NMT 0.1%
- For DPs < 0.01% strength: Incremental increase
- For DPs 0.001% strength: NMT 1%
The concern here is that this approach does not account for the toxicological risk, whereby a benzophenone impurity at 1% (~4 ppm) is at a concentration over 150,000 times lower than the minimally irritating dose for benzophenone of 20 mg/eye. The goal of the pharmaceutical industry is to address these leachables as a safety rather than quality issue and set limits in line with the risk to the patient. More recent guidance from the FDA is moving in this way with proposed limits of
- 1 ppm for reporting
- 10 ppm for identification
- 20 ppm for toxicological qualification
However, in the absence of formal guidance and resistance to accepting scientific and toxicological approaches, the issue of leachables in ophthalmics will continue to be a challenge, particularly as new novel container closures are developed in the move to preservative-free products (e.g., unit dose or sterility maintaining multi-use bottles). Unit dosing containers will dramatically increase the drug product/container contact due to the large number of containers required to provide for chronic daily administration. Many preservative free multi-use topical dropper bottles maintain sterility by using either a silver coil in the dropper or a 22 mm filter in the tip. In both cases eliminating the preservative may result in additional challenges, as one may see a change in the leachable profile (e.g., metals, filter or device components). The associated risks need to be appropriately addressed through toxicological assessment and qualification.
Injectables-Novel Delivery Systems
Standard syringes made of either glass or high-density polyethylene provide relatively good barriers to migrating leachables. However, with the advent of both new injectables systems and greater utilization of delivery devices, leachables may again be of concern. An example of a novel injectable system is a single-use, pre-filled syringe delivery system with a collapsible reservoir to prevent re-use. The delivery system is composed of several plastic components including polyethylene, polypropylene, and polystyrene. One of the benefits of this system is that there are no attached labels vis-à-vis ophthalmic presentations to the delivery system primarily due to their small size. This provides the added benefit of reducing the concern for ink and labeling leachables but puts greater emphasis on evaluation of the plastic components and environmental leachables such as sanitizers.
As the range of drug products expands, so too does the use of delivery devices. An example of this is the increased use of dual chamber syringes/cartridges. In some cases due to the physical properties of the drug substance, the use of novel excipients/surfactants are required which may in turn enable the migration of leachables; polysorbate 80 is known to extract the plasticizer di(2-ethylhexyl) phthalate (DEHP) from PVC tubing. Silicone, widely used as lubricant that allows the plungers to slide, can itself migrate into the solution post-reconstitution. Therefore the effect of silicone oil on the quality and safety of the product may need to be addressed. Regulators have been paying closer attention to the role of lubricants in dual chamber cartridges in recent times, with a greater number of queries relating to pharmacopeial compliance of components and compliance with USP/ISO Tests reported. In both cases, EU Regulatory Authorities have assessed leachables with reference to the guidance on genotoxic impurities which outlines a limit of 1.5 μg/day, based on the Threshold of Toxicological Concern (TTC) . However, this limit assumes that the leachable itself is genotoxic, negating any toxicological assessment of the compound where the toxicological risk could be much lower allowing for a higher or absence of a limit.
Conclusions
In the absence of formal guidance from regulatory agencies or broad acceptance of risk-based approaches, the control of leachables in drug products will continue to be a challenge for industry for the foreseeable future. As leachables present in drug products receive greater regulatory scrutiny, pharmaceutical development will require greater alignment with suppliers in the selection of components and materials to reduce the impact of leachables on the finished product. However, there is also a need for improved regulatory understanding and interaction with the provision of clear guidance on the expectations for submissions.
In addressing this issue, it is important that safety and quality limits should be governed by reasonable scientific expectations relative to typical environmental exposure. The limits should not be arbitrary standards that significantly exceed typical environmental exposure. The development of best practices for extractables and leachables in POPD by the PQRI working group should provide improved understanding and engagement by both Regulators and Industry in addressing leachables present in drug products. This will enable the assessment of leachables as a safety concern, and eliminate the need for the control of low levels of chemical impurities which pose negligible threats to human health while maintaining the focus on the control of leachables that do.
References
- Kellogg Company Voluntarily Recalls Select Packages of Kellogg’s® Corn Pops®, Kellogg’s® Honey Smacks®, Kellogg’s® Froot Loops® and Kellogg’s® Apple Jacks®http://www.fda.gov/Safety/Recalls/ucm217338.htm
- U.S. regulators lack data on health risks of most chemicals. Washington Post, Monday, August 2, 2010.
- McNeil Consumer Healthcare Announces Voluntary Recall of Certain Over-The-Counter (OTC) Products in the United States, Fiji, Guatemala, Dominican Republic, Puerto Rico, Trinidad & Tobago, and Jamaica. http://www.fda.gov/Safety/Recalls/ucm218437.htm
- Update on Bisphenol A for Use in Food Contact Applications: January 2010. http://www.fda.gov/NewsEvents/PublicHealthFocus/ucm197739.htm
- Guidance for Industry. Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products. Draft Guidance. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070573.pdf
- Guidance for Industry. Container Closure Systems for Packaging Human Drugs and Biologics. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070551.pdf
- Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products: An Overview of the PQRI Recommendations. Daniel L. Norwood, Diane Paskiet, Michael Ruberto, Thomas Feinberg, Alan Schroeder, Guirag Poochikian, Qingxi Wang, Tian Jing Deng, Fran DeGrazio, Melinda K. Munos, Lee M. Nagao. Pharmaceutical Research, Vol. 25, No. 4, April 2008.
- Ravi S. Harapanhalli, PDA 2007 Extractables and Leachables Forum.
- Guideline on the Limits of Genotoxic Impurities EMEA CPMP/SWP/5199/02 EMEA/CHMP/QWP/251344/2006. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002903.pdf
Author Biography
Dr. Michael Lynch has over ten years experience in the Pharmaceutical Industry primarily in the area of Regulatory Affairs and Chemistry, Manufacturing and Controls in multiple Therapeutic Areas including sterile injectables and ophthalmics. He is a member of The Organisation for Professionals in Regulatory Affairs and The Product Quality Research Institute’s Parenteral and Ophthalmic Drug Products Leachables and Extractables Working Group.