24 January 2019
Whether they are part of the pharmaceutical industry or not, many people are familiar with individuals who use combinations of drugs and delivery systems to deal with a chronic condition or ease an acute condition. An examples would be a person with diabetes who uses a human GLP-1 receptor antagonist (a Type 2 diabetes medicine enhancing the secretion of insulin) in a pen injector system to provide a subcutaneous injection, or a person who has asthma or COPD (chronic obstructive pulmonary disease), who uses a breath-activated powder inhaler to deliver the bronchodilator albuterol sulfate, to treat or prevent bronchospasm with medication to relax muscles in airways to prevent wheezing and shortness of breath. As there is growing demand for more patient-centric drug delivery, and improved healthcare cost management via self-administration, there is a growing demand for these types of products, designated as Combination Products by the U.S. FDA.
Combination Products bring together drug or biologic products and medical devices to more effectively deliver treatments to patients. Over recent years, the FDA has provided greater guidance and focus in this space to encourage and enable the pharmaceutical industry to successfully bring these products to market—in a manner which delivers safe and effective treatments. Combination Products are defined in the Code of Federal Regulations - 21 CFR 3.2(e).
Nine types of combination products are given on the FDA web site—with descriptions and examples of each. Examples of some of the most common are:
Although many of these types of products have been available for years, recent FDA and ICH guidances have clarified expectations from both a developmental and commercialization standpoint. This has led to increased industry challenges in meeting regulatory expectations. To stay ahead of these challenges, it is essential to stay familiar with the changing regulations and also receive additional insights from various sources.
There are several examples in the public domain of FDA warning letters that provide visibility to the areas of focus and expectation from regulatory agencies. Some of the areas of weakness identified are:
These examples highlight several key areas on which any company producing drug/device combination products should focus. Putting these examples into everyday language—there are three major themes.
The first is the ability to define adequate user requirements, and then prove that the design and user requirements are documented and met through appropriate design verification and design validation testing processes. The key message here is the ability to understand each unique combination product application and build towards that end generating the data that supports the decisions being made throughout the development cycle. Ultimately, this means documentation of the packaged drug product requirements and the requirements of the delivery system in combination. This must be done keeping in mind that some of the highest risks to be mitigated occur at the intersection of the drug and its primary package with the delivery system itself.
The second concerns change control and the ability to document and manage this successfully during the development process. This is covered in the recent ICH Q12 draft guidance entitled Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, which provides clarity on the management of change once a Combination Product is approved and commercialized. Change management is critical during the entire lifecycle. The aspect of market surveillance is key in providing feedback and establishing a continuous improvement mindset.
The third is prioritizing the choice and engagement of suppliers who are qualified and understand the unique challenges of building the components and constituent parts of a Combination Product. Quality agreements clarifying requirements and responsibilities should be in place. The dynamics of the relationship must be different from that of many historic supplier relationships because it is critical to have improved transparency and collaboration. The critical nature of component and constituent part suppliers to the overall success of a final combination product changes the nature of the relationship and should be a major consideration in evaluating partners to successfully manage risks.
Combination products bring a great benefit to patients and the overall pharmaceutical industry in an assortment of ways. A common theme in managing risks and meeting the regulatory requirements is the building of evidence that conveys why choices are made throughout the development process. This evidence throughout the supply chain is critical to achieving a successful end goal.Print
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