Introduction
Combination products are therapeutic and diagnostic products that combine drugs, devices, and/or biological products. These products may include “single-entity” items such as monoclonal antibodies mixed with a therapeutic chemotherapy drug, devices impregnated or coated with drugs such as drug eluting stents, pacing lead with steroid-coated tip, catheter with antimicrobial coating, transdermal patch and or prefilled drug delivery systems such as insulin injectors. “Co-packaged” combination products are two or more separate classes of product contained in a single package or as a unit and finally “cross-labeled” combination products encompass individual products that are provided separately but are specifically labeled for use together.1 However, products intended to be used together may not strictly meet the regulatory definition of a combination product if, for example, a syringe is marketed for general delivery of unspecified drugs. Additionally, two or more of the same class of medical product (drug-drug, biological- biological, device-device) or a medical product combined with a non- medical product such as a dietary supplement does not constitute a combination product.1
Shelf life, or the expiration date of a product relative to its manufacture date when kept in the indicated environmental conditions, is an essential aspect of the product lifecycle development for combination products but often lacks clarity. The shelf life of a drug-device combination product is determined by the shortest estimated shelf life of the following studies: drug stability, device aging, and packaging system/ sterile barrier aging. These stability studies provide regulatory agencies with critical information for approval, assure product quality throughout the storage period, provide health care providers with product label instructions for storage period and condition, and ensure patients that the product is safe and or has the potency expected at time of use. This article focuses on approaches for establishing shelf life for “single entity” drug-device combination products followed by some illustrative examples for drug-eluting stents which are a reasonably complex Class III medical combination product.
Shelf Life Estimated from Drug Stability Testing
Stability testing of combination products is performed to provide evidence on how the quality of the product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and to support the establishment of product shelf life or expiration dating period and recommended storage conditions. Evaluation of drug stability for combination products should be done in a formal or registration study to establish shelf life for market approval registration. All test samples should be representative of finished goods, manufactured with proposed commercial manufacturing processes, and subsequently packaged and sterilized per proposed commercial processes. At least three batches should be conditioned following ICH guidelines of “long-term” storage at 25 °C/60% RH, “intermediate” storage at 30 °C/65% RH and “accelerated” conditioning at 40 °C/75% RH. Typical time points in a study would include 0, 3, 6, 9, 12, 18, 24, and 36 months at long term storage; 0, 3, 6, 9, and 12 months at intermediate; and 0, 3, and 6 months at the accelerated condition.2 Stress testing including photostability (controlled exposure to UV/VIS light) and simulated thermal transportation conditions are likely to be carried out.2,3 By using accelerated aging conditions alongside long term storage conditions the rate of chemical degradation or physical change of a drug substance/ combination product can be used to assess and to evaluate the effect of short-term excursions outside the label storage conditions such as might occur during shipping or storage. Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating stability indicating analytical procedures. Comparative analysis or equivalency studies may also be considered for products that are iterative in nature to previously studied combination products on market with existing data sets; however, great precaution and good communication with agencies should be made regarding these types of studies. Finally, bracketing of the study design based on product configurations is recommended to reduce study size by testing at extremes of characteristics such as diameter, length, or strength.
The stability testing covers those attributes susceptible to change during storage and that are likely to influence quality, safety and/or efficacy of the combination product. Typical stability testing attributes should include Appearance, Total Drug Content (Assay), Drug Degradation Products/Impurities, Drug Release/Drug Elution/Dissolution (USP) Particulate Matter. In vitro drug release testing is a useful tool for obtaining data related to a product’s quality and, potentially, its clinical performance and sterility (packaging integrity). The in vitro drug release/elution kinetics should be evaluated under appropriate conditions based on the mechanism of drug release and to emulate hydrodynamics derived from clinical considerations. Drug release testing should expose the drug on the component within the finished product to an in vitro release media and be measured at multiple time points. The elution profile should be complete and cover at least 80 percent of drug release of the label amount or whenever a plateau is reached. For total content and drug degradation products/impurities testing it is acceptable to remove the drug component from the device to facilitate testing and ability to obtain a 100% extraction of drug. While not specific to chemical properties of the drug, other testing attributes often included with this testing are Packaging Integrity or Sterility, Bacterial Endotoxin USP, and Particulate Matter USP. Additionally, any characteristics specific to the combination product within the drug/excipient/device that has a high probability of changing chemical or physical form that may impact the product or patient should be evaluated and tested over the length of the study. The analytical procedures used for the stability testing should be stability-indicating and fully validated; i.e., they should be capable of detecting the changes that may happen in the chemical, physical or microbiocidal properties of the product over time, and that are specific so that the contents of active ingredient, degradation products and other components of interest can be accurately measured without interference.
As data becomes available from drug testing, it should be evaluated to determine if it meets specifications and then a shelf life estimate can be made by applying the decision tree in ICH Q1E Guidance for Industry: Evaluation of Stability Data Appendix A.4 The data from all three storage conditions will be evaluated for all stability attributes. Significant changes from accelerated and intermediate conditions will be considered and the data may be extrapolated to predict shelf life via the decision tree. If the stability data does not meet specifications at a specific time point or an adverse trend is discovered, then an out-of-specification or out-of- trend investigation should be conducted and later time points may be used to aid the data interpretation process. Statistical analysis can also be employed by performing extrapolation by linear regression analysis to propose a longer shelf life than the period from available long-term data. Analysis of covariance (ANCOVA) should be performed to decide if the stability data from multiple lots can be pooled. Then the shelf life can be predicted by using a 95% confidence interval using quantitative attributes, such as total drug content or impurities, where the shortest shelf life from any attribute will be the estimated shelf life for the product. The proposed shelf life cannot exceed the shelf life determined by decision tree and should always be verified by additional long-term stability data as soon as this data become available.
Shelf Lives Established from Device and Sterile Barrier System (SBS) Aging
Shelf lives for devices and sterile barrier systems are defined as the amount of real time that a fully packaged (and sterilized if applicable) product/sterile barrier system can be expected to remain in storage at specified conditions and retain its critical performance properties. The SBS is generally tested at regular intervals by testing seal strength, impact résistance, seal leaks, etc., following technical guidance, such as ASTM. Functional testing will be highly product specific as the functional requirements will differ amongst products. Device testing attributes need to be selected based on product design. For example, for drug eluting stents, attributes such as surface area, stent fatigue, and corrosion resistance are properties of the stent that are not expected to change much over time and might be excluded while conversely polymer molar mass and polydispersity of the excipient, fatigue on the balloon used to inflate the stent, the balloon burst pressure, and stent securement on the balloon are considered important as they are likely to change over the period of several months or present a serious risk upon failure. Other testing (e.g. particulates) should be performed after the stent has gone through a functional mock deployment through a reasonable simulation of a tortuous path.
For accelerated aging, the aging temperature should remain below any phase transitions of excipient (e.g. polymer coating TG) or below where the device or materials melt, become distorted or deteriorated.
If elevated temperatures are not possible then real-tie aging is the only option.
Accelerated aging (AA) techniques are widely used to estimate shelf life in a short period of time, bring the product to market at the earliest possible time, and to help identify potential future long-term design failures such as adhesive failures or mechanical malfunctions due to chemical breakdown of a component(s).5 However, before performing an accelerated aging study, it should be evaluated if the Arrhenius equation can be applied to the critical components in the combination product. A humidity factor to calculate the accelerated aging time is not applicable for an accelerated aging protocol and should be performed in a separate study if hydrolysis based degradation is deemed important.
The accelerated aging time required to establish equivalence to real time aging is determined by dividing the desired shelf life by the accelerated aging factor (AAF).6 The AAF is further calculated from a Q10 value which is a temperature coefficient factor (derived from Arrhenius equations) that is the ratio of chemical reaction rates as a consequence of increasing the temperature by 10 °C.5 The equations for AAF and Q10 are given below where TAA is the applied accelerated temperature, TRT is the room temperature/long term storage condition, R is the universal gas constant and Ea is the activation energy of the chemical process.
Aging Factor Q10 provides a practical way to predict product shelf life and is widely used in industry and recommended by technical guidelines,7 such as ASTM F 1980 – 07, and AAMI TIR 22, 2007.8 However, determination of Q10 involves testing several potential materials at various temperatures and then defining the differences in reaction rate for 10 °C change in temperature and is often impractical. Instead, the common practice is to simply assume a starting value of two as a conservative means of calculating aging factor. The impact of Q10 selection should be considered. If it is too aggressive (larger Q10), it may lead to failure of devices prior to their expiration date and if the choice is too conservative (smaller Q10), it may lead to unnecessary delays and costs in qualifying materials.
Summary
The shelf life for a combination product is determined from drug stability, device aging, and sterile barrier aging with the shortest estimate determining the overall shelf life. The shelf life of a product may vary between different countries/regions depending on regulatory requirements. Accelerated aging studies can be used for shelf life determination but must later be verified using data from the long-term storage conditions. Lastly, great attention should be paid in proper study design and early logistics as it is often unachievable to go back in time to fix a mistake or disagreement with agencies after several months or years have passed after a study has launched.
References
- FDA draft guidance for Industry, 2015 Current Good Manufacturing Practice for Combination Products
- ICH Guideline Q1A Q1A(R2) Stability Testing of New Drug Substances and Products
- ICH Guideline Q1B, Photostability Testing for New Drug Substances and Drug Products
- ICH Guideline Q1E Stability Data Evaluation
- ASTM F1980 – 07: Standard Guide for Accelerated Aging Sterile Barrier Systems for Medical Devices, Information for developing accelerated aging protocols to determine the aging effects on sterile barrier system (packaging)
- AAMI TIR 17 – 08: Compatibility of Materials Subject to Sterilization, Annex G Accelerated Aging Programs, Summary on accelerated aging principles and use of fixed and iterative aging methods
- Kenneth SE, Gordon LA and Kennon L, Chemical Stability of Pharmaceuticals, 3rd edition, 1979: 29.
- AAMI TIR 22, 2007. Guidance for ANSI/AAMI/ISO 11607, Packaging for terminally sterilized medical devices— Part 1 and Part 2: 2006