Jennifer Riter, senior director, analytical services for West Pharmaceutical Services, explores the impact of extractables and leachables on combination product development.
Extractables and leachables analysis is an essential and integral part of qualifying combination product packaging and delivery systems during drug development. With combination products, there are typically multiple elements that comprise the device and/or packaging - and all must be meticulously studied to ensure compliance with regulations requiring sufficient data and information to prove that the packaging system chosen maintains the quality, sterility and efficacy of the product.
Plastic materials are commonly utilized in combination products - from different parts that come into contact with the drug product, such as tubing or other fluid paths, to incorporating a primary packaging containment system into a device.
Jennifer Riter, senior director, analytical services, West Pharmaceutical Services
Definitions, differences and correlations
It is important to discern the definitions of extractables and leachables, as well as the relationship between the two. Extractables are defined as organic and inorganic chemical entities that are released from a pharmaceutical packaging/delivery system and into an extraction solvent under laboratory conditions. Extractables themselves, or substances derived from extractables, have the potential to leach into the drug product and thus become leachables.
Leachables are defined as organic and inorganic chemical entities that are present in a packaged drug product because they have migrated into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under standard conditions of storage and use or during drug product stability studies. This means that the leachables ultimately can then reach the patient.
Leachables can be of little or great consequence, so it is critically important to have a thorough understanding of what may be present in a drug prior to it being administered.
Key sources
There are different sources of extractables and leachables that need to be considered and evaluated. In general, sources of extractables can include plastics as well as glass, paper, adhesives, and inks. In addition to the primary packaging materials, the secondary packaging materials, interim storage containers and processing equipment may also need to be evaluated for compounds that may leach into the drug product.
For example, an advanced polymer vial container or pre-filled syringe system that utilizes a Cyclic Olefin Polymer (COP) or Cyclic Olefin Copolymer (COC), which is a semi-permeable material, may need to be evaluated when a label is applied. Adhesives and inks on the label contain compounds that can migrate through the polymer and leach into the drug product over time. As for interim storage containers of Active Pharmaceutical Ingredients (API), drug substance, or drug product, these may need to be considered for extractables and leachables analysis due to contact with products over a prolonged period, prior to final packaging.
Impact of assessing and testing
Proper evaluation, studies, and analysis of extractables and leachables serve an essential function during drug and device development. This includes:
- Characterizing packaging and delivery system components and materials of construction
- Facilitating the selection of components and materials
- Enhancing an understanding of the effects of manufacturing processes like sterilization
- Establishing the worst-case potential leachables profile in a manner which facilitates leachables studies
- Confirming qualitative and quantitative leachables–extractables correlations
- Facilitating investigations to the origin of an identified leachable
- Assessing patient exposure to chemical entities
A combination product example may be cartridges, which would be considered the primary containment system for the drug product which may then go into an on-body injection device. The process of determining an appropriate approach for extractables and leachables testing for a complex combination product like a cartridge begins with an extractable assessment to understand and ensure all materials are characterized appropriately, which in turn reveals what can extract or come out of any given material in general.
This means characterizing every material that comes into contact with the drug e.g. glass cartridge, rubber plunger, plastic cartridge, and plastic tubing, as it carries the drug product from the primary packaging container and device into the patient. For on-body combination products, not only would the primary containment system need to be evaluated, but also plastic tubing needs to be carefully considered when conducting such studies. A good example of this is our SmartDose injector - a wearable, subcutaneous injector with an integrated drug delivery system that delivers a truly patient-centric approach to self-administration.
In addition, a pharmaceutical manufacturer may label the plastic cartridge holding a primary drug with an expiration date and shelf life information. If so, the label, its adhesive, and the ink used, need to be studied because elements of these may migrate into the drug over time - it is just a matter of how much and how long it will take. Such migrational tendencies will change depending on exactly what is packaged, and how much it will extract from that containment system over time, so it’s important to evaluate each containment system and each material appropriately, and characterize it upfront in order to fully understand what may potentially leach into the product over time.
Leachables, as a subset of extractables, should then be evaluated to further determine what, under normal shelf-life conditions, will potentially come out of a material such as plastic and get into the drug product over time. While not every extractable will leach into a drug product, manufacturers must carefully evaluate the compatibility of the drug and packaging/device materials in order to calculate risk and optimize both safety and efficacy.
Conclusion
It is well-established that combination product materials contain extractables that can leach into drug products and may significantly impact development processes. Nothing is without extractables - every material has the propensity to extract and contains compounds that will leach into the drug over time.
As plastic is semi-permeable, it has the potential to be more susceptible to the migration of adhesives and inks from labels into a drug during long-term storage. To ensure proper evaluation and understanding of this, a collaborative process can be helpful. For instance, when conducting a migration study on a semi-permeable packaging product and its labels, it can be beneficial to work closely with the label manufacturer in order to fully understand what the material profile may be of the label material and adhesive.
Extractables and leachables can be most effectively managed through timely and meticulous evaluation and testing, as well as knowing what to look for and examine. The list of factors to consider and evaluate can be complex in order to be truly comprehensive and create a complete and holistic approach. It begins in the concept and planning stages and continues through production, shipping, storage, and delivery/administration - and must factor in primary packaging and the device, as well as secondary and tertiary packaging every step of the way.
Extractables and leachables cannot be fully mitigated, but the risks and challenges can be minimized when a complete understanding and analysis of the material(s) being used is ascertained.