Definition of Combination Products in Taiwan
Combination products are classified based on the “Key Points for Combination Product Determination.” These products fall into two main categories. The first category includes a single product that integrates pharmaceuticals and medical devices, where the components are combined physically, chemically, or through other means, and are manufactured by a single entity. The second category consists of a set or package containing two or more pharmaceutical and medical device items that are intended to be used together. These products are designed to work synergistically to achieve a combined therapeutic effect, ensuring better treatment outcomes for patients. Given the complexity of combination products, regulatory frameworks must clearly define their classification and approval processes.
Regulatory Classification
The regulatory classification of combination products is determined by their Primary Mode of Action (PMOA). This refers to the principal mechanism through which the product achieves its intended therapeutic effect. If the primary effect is achieved through the pharmaceutical component, then the product is classified and regulated as a drug. Conversely, if the main effect is achieved through the medical device component, the product is categorized and regulated as a medical device. In cases where the PMOA is unclear, the Taiwan Food and Drug Administration (TFDA) may seek advice from an external committee to make a final determination on the classification.
To ensure that applicants have a clear understanding of how their product will be regulated, the TFDA encourages them to first submit an application for combination product determination. Once the PMOA is identified, the TFDA will determine the product attributes and designate the relevant division that will serve as the main regulatory body. If the product’s primary mode of action is attributed to a drug, the TFDA Drug Division will be the primary reviewer, while the Medical Device and Cosmetic Division will provide additional support. If the product’s primary mode of action is attributed to a medical device, the Medical Device and Cosmetic Division will be the main reviewer, with the Drug Division offering supplementary support. The regulatory clarity provided by this classification process helps streamline the approval pathway, reducing unnecessary delays in market entry.
Registration Process
When the PMOA is a Pharmaceutical
For combination products where the primary mode of action is pharmaceutical, the Marketing Authorization Application (MAA) process begins with site registration. The manufacturing site must first obtain a Plant Master File (PMF) registration. If the manufacturer is located in a non-PIC/S (Pharmaceutical Inspection Co-operation Scheme) member country, Taiwan will require a foreign on-site factory inspection. However, for manufacturers located in a PIC/S member country, it is possible to coordinate the review process using the PMF documentation.
To qualify for a simplified PMF review, applicants must submit documentation that includes a list of GMP inspections conducted within the past five years. This list should provide details such as the date of inspection, the topics covered, and the scope of the inspection. Additionally, an inspection report from the most recent GMP evaluation conducted by the local competent health authority must be provided. This report should also include a GMP certificate or any other equivalent GMP approval documents.
Once the site registration process is completed, the next step is product registration. The application must be submitted in the Common Technical Document (CTD) format. However, for generic pharmaceutical products, the contents of Module 5, which pertains to clinical data, are not required. New drug applications must be submitted electronically via the TFDA ExPress platform using the Electronic Common Technical Document (eCTD) format. This format is based on ICH eCTD Specification V3.2.2. While Modules 2 to 5 of the application can be submitted with supporting documents in English, Module 1, which contains administrative documents, must be submitted in Chinese. The key documents required for registration include manufacturing site registration documents, a quality system documentation report, risk evaluation and mitigation strategy (REMS) documentation if applicable, clinical study status reports, and bridging study evaluations when necessary.
When the PMOA is a Medical Device
For combination products where the primary mode of action is attributed to a medical device, the first step in the registration process is Quality System Documentation (QSD) registration. This requirement applies to some Class I medical devices and all Class II and Class III medical devices. Manufacturers must establish a quality management system that ensures compliance with regulations governing facility operations, equipment maintenance, personnel management, production processes, quality control, storage and logistics, and handling of customer complaints. Before a medical device can be marketed, the physical manufacturing site must apply for QSD document review and obtain a QSD approval letter issued by the TFDA.
Manufacturers that do not hold an ISO 13485 certificate or any equivalent conformity verification document must undergo an on-site audit by the TFDA or its designated organization before the final QSD approval is granted. However, manufacturers located in the United States, the European Union, and Japan may qualify for an abbreviated QSD application process. To qualify for this pathway, manufacturers must submit recognized audit reports such as the MDSAP (Medical Device Single Audit Program) report, an audit report issued by the U.S. FDA, or a PMDA audit report from Japan.
After QSD registration, the applicant can proceed with product registration. While it is possible to submit the Marketing Authorization Application (MAA) before obtaining QSD approval, the final product license will only be issued once the QSD approval letter has been submitted to the TFDA. Products that do not have locally approved predicate devices (essentially equivalent devices) are classified as new devices and will undergo a more stringent review process. In addition to standard documentation requirements, Class II and Class III devices may require additional preclinical testing and safety documentation. For example, devices that generate ionizing radiation must provide documentation supporting radiation safety. Additionally, clinical evidence may be required on a case-by-case basis at the discretion of TFDA reviewers.
Registration Timelines
The timeline for registering a combination product varies depending on whether the PMOA is a pharmaceutical or a medical device.
For pharmaceutical products, the Plant Master File (PMF) review typically takes 200 calendar days, excluding any clock stop periods during deficiency responses. The on-site GMP inspection also takes approximately 200 calendar days. For new drug applications, the total approval time ranges from 200 to 360 days, depending on whether clinical data is required.
For medical devices, the QSD on-site inspection process takes approximately 240 days, while the QSD document review takes about 120 days. The total registration timeline for new medical devices varies depending on their classification. For Class II medical devices, the process takes 140 days, whereas for Class III medical devices, it takes 200 days. If the device is considered new with no locally approved predicate, the timeline extends to 220 days due to additional review requirements.
Regulatory Fees
The cost of registering a combination product depends on its classification. The below fees are all Taiwanese government fees. The administrative fee for PMOA determination is NT$10,000. For pharmaceutical combination products, the Plant Master File (PMF) review fee is NT$120,000, while the GMP on-site inspection fee ranges from NT$600,000 to NT$700,000. The registration fee for new chemical entities (NCEs) is NT$1,500,000, while the cost of generic drug registration varies from NT$80,000 to NT$140,000.
For medical device combination products, the QSD registration fee is NT$60,000. The registration fee for Class I medical devices is NT$15,000, for Class II medical devices it is NT$58,000, and for Class III medical devices it is NT$100,000. The cost for priority review is NT$180,000, and for new medical devices with no local predicate, the fee is NT$130,000.
Conclusion
The regulatory framework for drug-device combination products in Taiwan is determined primarily by the Primary Mode of Action (PMOA). Pharmaceutical-led products must comply with GMP regulations and eCTD submissions, while medical device-led products must complete QSD registration and additional device-specific reviews. Manufacturers should carefully assess their product’s classification and ensure compliance with all TFDA requirements to facilitate the approval process and achieve timely market entry.
Written by: Ames Gross – President and Founder, Pacific Bridge Medical (PBM)
Mr. Gross founded PBM in 1988 and has helped hundreds of medical companies with regulatory and business development issues in Asia. He is recognized nationally and internationally as a leader in the Asian medical markets. Mr. Gross has a BA degree, Phi Beta Kappa, from the University of Pennsylvania and an MBA from Columbia University.