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If the single entity combination product is not intended to mechanically infuse the drug into the patient but instead the drug is intended to passively diffuse into the patient, then the rate of drug release or elution needs to be determined. To perform this experiment, the single entirty combination product is placed in an appropriate media designed to model the target tissue. The analytical method is then used to measure the increase in drug concentration in the media over time. The instrument conditions used are usually similar to those used for the assay; however, more sensitive methods may need to be developed if the release of drug is expected to be slow. The method will need to be validated similar to an assay method with special consideration to sensitivity and additional ruggedness testing for the sample preparation factors that might impact the release rate.
Just like methods for traditional drug products, the assay and related substances/degradation products methods for single entity combination products need to be proven to be stability indicating. If the single entity combination product contains a new drug, a forced degradation study will be needed. If results of the stability of the drug product alone are available, these results should be used to evaluate if the methods are stability indicating. However, additional degradation experiment on the intact single entity combination product under appropriate conditions will likely be required. If the single entity combination product contains a generic drug, literature references on the stability of the drug product can similarly be used but degradation experiment on the intact single entity combination product under appropriate conditions will still likely be required.
In addition to evaluating the risk of leachables from a medical device used to deliver a drug, the compatibility of the drug product with the medical device also needs to be demonstrated. Analytical assay methods are needed to demonstrate the stability and compatibility of the drug product. If available, the USP method for the drug product should be used. If a USP method is not available for the drug product, an analytical assay method will need to be developed and validated.
Once the analytical methods are in place, the drug compatibility experiment can be described in the following steps:
If an analytical method for assay, related substances and degradation products of a combination product is intended to evaluate stability, the method will need to be proven to be stability indicating. If the combination product contains a new drug, a forced degradation study will be needed. If the combination product contains a generic drug, literature references to known degradation pathways and impurities can be used to evaluate if the method is stability indicating. However, if the combining process is significantly different from the literature references, additional degradation pathways may need to be explored experimentally.
The main difference between analytical methods for single entity combination products (SECPs) and traditional drug product formulations like oral or parenteral dosage forms is the sample preparation. For most methods the sample preparation will need to be developed to be unique and specific to the SECP but usually involves complicated multi-step procedures. Based upon the SECP, sample preparations of SECPs often involve extensive extraction for complete recovery of the drugs. In addition, depending upon the size of the SECP and the location of the drug, the SECP may need to be disassembled or reproducibly cut, which can be a significant challenge when the SECP is made from hard plastics or metals.
Single entity combination products (SECP) present unique analytical challenges compared to the other types of combination devices. Most notably, in a SECP the combining process and sterilization will most likely create impurities and degradants no observed in the individual component. This is especially common for SECP contains drugs.
In addition, an SECP may have specific design features that need to measure to ensure proper functioning of the product. For example, measuring the rate of the release of a drug could be a critical performance feature requiring a specific analytical method to evaluate.
Pine Lake Laboratories has a proven record of developing and validating analytical methods for single entity combination products. We also have the necessary equipment and expertise to identify degradation products and impurities that are unique to single entity combination products.
The FDA Guidance for Industry Titled “Current Good Manufacturing Practice Requirements for Combination Products (January 2017)” defines a combination product as “a product composed of two or more types of medical products (i.e. a combination of a drug, device, and/or biological product with another).” There are three types of combination products: single entity, co-packaged and cross labeled.
A single entity combination product has at least two components (i.e. drug/device, biologic/device, drug/biologic or all three) that are chemically or physically combined to form a single entity. Examples of single entity combination products would be a prefilled syringes or a drug coated surgical implant.
A co-packaged combination product has at least two components packaged together as a single unit. Examples of co-packaged combination products are surgical kits and drug products packaged with infusion sets.
With a cross labeled combination product, each component is packaged separately and is intended only for use with an approved second product. An example of a cross labeled combination product would be a light activated drug requiring a light emitting device.
Pine Lake Laboratories has experience with analytical methodologies to support all forms of combination products.
To help fulfill unmet medical needs, sophisticated drug delivery systems are being developed with many innovative combinations of pharmaceuticals, biologics and medical devices. While these combination products have enormous potential, they also present unique challenges in development and approval. One challenge for combination products is the development and validation of analytical methods to assess the quality, safety and stability of combination products. Please see our technical library for a free white paper titled “Analytical Methods for Single Entity Combination Products” This white paper will focus on the analytical methods needed for single entity combination products.
Pine Lake Laboratories has a proven track record in developing and validating methods used to insure the quality of combination devices, especially combination pharmaceutical medical devices. Our experience allows us to adapt validation strategies and assist in testing designs to meet the unique challenges of combination devices.
Our experience with methods for combination products includes:
We have the capacity to perform routine analyses once the methods are validated and can assist in investigations of unexpected results. We have also successfully transferred methods to clients manufacturing site laboratories.
All work performed in compliance with FDA GMP.