Michelle Pieh shares her experience leading the regulatory affairs and quality assurance teams at HCmed. As the Regulatory Affairs Manager of HCmed, Michelle has accumulated a great deal of experience working in the RA and QA fields, ensuring that the products that we provide to customers are compliant with internationally recognized standards and with regulations of different regions and countries.
1. What are the regulatory implications for marketing drug-device combination products in the EU and the U.S.?
The EU and the U.S. are the two major markets of drug-device combination products. As a contract development and manufacturing organization (CDMO), it is important for us to understand the latest updates on the guidance provided by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) in order to prepare our products accordingly for the aforementioned markets. Beginning with the U.S., as combination products consist of elements subjected to regulations under different frameworks, various U.S. agencies are involved in the assessment of the products. Depending on the part of the combination product that provides the primary mode of action (PMOA), the combination product is assigned to an agency that is considered the lead of the product’s assessment. Submissions related to the product are filed to this specific lead center. According to the U.S. guidance, Principles of Premarket Pathways for Combination Products, the application of the product review should be chosen depending on the part that provides the PMOA. This could be classified as a Premarket Approval Application (PMA), De Novo, or 510(k) for a device-led combination product. When it comes to a drug led combination product, a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) would be the way to proceed, while for biologic-led combination products a Biologics License Application (BLA) would be needed. In terms of definitions used in the EU, combination products can be divided into two main groups: integral Drug-Device Combinations (DDCs) and non-integral DDCs. As drug-nebulizers are not physically integrated during manufacturing, they are categorized as non-integral DDCs. The legal framework for combination products in the EU is based on Medicinal Products Directive for medicinal products and Medical Devices Regulation (MDR) for medical devices. Under the MDR, a Notified Body Opinion (NBOp) needs to be obtained and included to submit a marketing authorized application. Every country or region has its own regulations to follow, but no matter if it is to follow the regulatory pathways in the U.S. or the EU market, HCmed is able to provide technical documentation for submission of combination products and support pharmaceutical partners in the process of product review.
2. Following the previous question, as a drug-nebulizer CDMO, what can we provide to our pharmaceutical company partners as regulatory support?
As obtaining a combination product approval can be a lengthy and complex process, some of the support that we can provide as a CDMO includes providing documents required for review of the products and obtaining the NBOp to facilitate the assessment process. Moreover, when submitting a marketing authorization application to the EMA, a certificate on conformity of the device part with the MDR should also be included. Therefore, under the EU regulatory framework, a combination product will be assessed twice – one for the device and one for the whole product. Consequently, the time it will take to put a combination product out on the market will be prolonged. As HCmed’s vibrating mesh nebulizer, Deepro/Pulmogine, has already received CE marking, HCmed will be able to help relieve some of the burden off the growingly extensive review system of combination products in the EU. As MDR has entered into force and has replaced the existing directives, HCmed is currently undergoing regulatory transition from MDD to MDR to make sure that its CE Marked product complies with the latest regulations in the EU.
3. Is it necessary for us to obtain Good Manufacturing Practices (GMP) certification to provide combination products to the market? Please elaborate.
Complying with medical device regulations in different regions and countries is fundamental for HCmed. To fulfill the requirements of our customers, we need to comply with GMP regulations in different markets to ensure that our products are consistently manufactured according to proper quality standards. A quality management system is established to conform to the requirements of these regulations. By becoming a GMP-compliant manufacturer, we are able to ensure the safety and effectiveness of our mesh nebulizers utilized for combination products.
4. How is a Quality Management System (QMS) established for a drug-nebulizer combination product?
In order to ensure the safety and quality of our products, HCmed has established and maintained a documented QMS that conforms to the requirements of the GMP regulations. When a combination product is added to HCmed’s product portfolio, the QMS would have to be integrated with the requirements of our customers and the criteria of the product released would have to be updated in order to fulfill the efficacy of the combination products. With QMS covering a wide aspect of operations, including design, manufacturing, distribution, storage, complaint handling and so on, we make sure that we are following the GMP regulations from the development planning to the mass production of the devices.
