Combination product

COMBINATION PRODUCT THAT CONSIST COMBINATION OF MEDICAL DEVICE WITH DRUG, DRUG WITH BOILOGICAL PRODUCT, DRUG WITH DRUG ETC.

1. COMBINATION PRODUCT NAME: RICHA PATEL M.PHARM SEM II REGULATORY AFFAIRS ROLL NO: 27 KBIPER

2. DEFINITION A combination product is a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product. Under  21 CFR 3.2 (e) , a combination product is defined to include: 1. A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity [often referred to as a “single-entity” combination product]; 2. Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products [often referred to as a “co-packaged” combination product];

3. 3. A drug, device, or biological product packaged separately that according to its investigational plan or proposed labelling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where, upon approval of the proposed product, the labelling of the approved product would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose) [often referred to as a “cross- labeled ” combination product]; or 4. Any investigational drug, device, or biological product packaged separately that according to its proposed labelling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect [another type of “cross- labeled ” combination product].

4. EXAMPLES OF COMBINATION PRODUCTS Examples of single-entity combination products (where the components are physically, chemically or otherwise combined) ( 21 CFR 3.2(e)(1) ): Monoclonal antibody combined with a therapeutic drug Device coated or impregnated with a drug or biologic Drug-eluting stent, pacing lead with steroid-coated tip, catheter with antimicrobial coating, condom with spermicide , transdermal patch Prefilled drug delivery systems (syringes, insulin injector pen, metered dose inhaler)

5. Examples of co-packaged combination products (the components are packaged together) ( 21 CFR 3.2(e)(2) ): Drug or vaccine vial packaged with a delivery device Surgical tray with surgical instruments, drapes, and anesthetic or antimicrobial swabs First-aid kits containing devices (bandages, gauze), and drugs (antibiotic ointments, pain relievers) Example a of product that may be cross- labeled combination products (components are separately provided but specifically labeled for use together) ( 21 CFR 3.2(e)(3) or (e)(4) ): Photosensitizing drug and activating laser/light source

6. WHO REGULATE? In US the lead center is defined by the primary mode of action (PMOA) The lead center assignment can be from one of the following: Center for drug evaluation and research (CDER) Center for devices and radiological health (CDRH) Center for biologics evaluation and research (CBER)

7. EXAMPLE: Drug eluting stent or wound dressing with antimicrobial- typically a device (CDRH) Asthma inhaler or medicinal patch- typical a drug (CDER)

8. CURRENTLY MARKETED PRODUCT CONSIDERATION For example, developer should consider: Are the constituent parts already approved for an indication? Is the indication for a given constituent part similar to that proposed for the combination product? Does the combination product broaden the indication or intended target population beyond that of the approved constituent part? Does the combination product expose the patient to a new route of administration or a new local or systemic exposure profile for an existing indication? Is the drug formulation different than that used in the already approved drug? Does the device design need to be modified for the new use? Is the device constituent used in an area of the body that is different than its existing approval?

9. Are the device and drug constituents chemically, physically, or otherwise combined into a single entity? Does the device function as a delivery system, a method to prepare a final dosage form, and/or does it provide active therapeutic benefit? Is there any other change in design or formulation that may affect the safety/effectiveness of any existing constituent part or the combination product as a whole? Is a marketed device being proposed for use with a drug constituent that is a new molecular entity? Is a marketed drug being proposed for use with a complex new device?

10. DEVICE CONSTITUTE CONSIDERATION For example, it may be appropriate to conduct studies to evaluate the potential for the following: Leachable/ extractable of the device materials into the drug/biologic substance or final combination product; Changes in stability of the drug constituent when delivered by the device or when used as a coating on the device ; Drug adhesion/absorption to the device materials that could change the delivered dose ; Presence of inactive breakdown products or manufacturing residues from device manufacture that may affect safety, or device actions that could change the drug performance characteristics at the time of use; or Changes in stability or activity of a drug constitute when used together with an energy emitting device

11. COMBINATION PRODUCT GUIDANCE DOCUMENT

12. ROLE OF THE OFFICE OF COMBINATION PRODUCT To serve as a focal point for combination product issues and for medical product classification and assignment issues for agency staff and industry . To develop guidance and regulations to clarify the regulation of combination products . To classify medical products as drugs, devices, biological products or combination products and assign them to an FDA center for premarket review and regulation, where their classification or assignment is unclear or in dispute . To ensure timely and effective premarket review of combination products by overseeing the timeliness, alignment of coordination of reviews involving more than one agency center , including through monitoring and management of the intercenter consult process. To ensure consistent and appropriate postmarket regulation of combination products . To resolve disputes regarding the timeliness of premarket review of combination products.

13. WHAT TYPE OF MARKETING APPLICATION REQUIRED FOR COMBINATION PRODUCT? Combination products are typically marketed under a marketing authorization type associated with the constituent part that provides the primary mode of action (PMOA) for the combination product (i.e., a new drug application (NDA) or abbreviated new drug application (ANDA) if it has a drug PMOA, a biologic license application (BLA) if it has a biologic PMOA, or a premarket approval application (PMA) de novo certification, or premarket notification (“510(k)”) if it has a device PMOA). A single marketing application is generally sufficient for a combination product. In some cases, however, a sponsor may wish to submit separate marketing applications for different constituent parts of a combination product, and FDA may consider this permissible.

14. EXAMPLE OF COMBINATION PRODUCTS Drug Eluting Stents Peripheral Vascular Stents Coronary Stents Infusion Pumps Implantable Infusion Pumps Ambulatory Infusion Pumps Orthopaedic Combination Products Wound Care Combination Products Inhalers & Nebulizers Dry Powder Inhalers Metered Dose Inhalers Nebulizers Ultrasonic Nebulizers Compressor Nebulizers Mesh Nebulizers  Transdermal Patches Other Products

15. INHALER (data required to be submitted) Physical characterisation Minimum Fill Justification Extractables / Leachables Delivered dose uniformity and fine particle mass through container life Delivered dose uniformity and fine particle mass over patient flow rate range Fine particle mass with spacer/holding chamber use Single dose fine particle mass Particle / droplet size distribution Actuator / Mouthpiece deposition Drug delivery rate and total drug delivered Shaking requirements Initial priming of the container Re-priming of the container Cleaning requirements Low temperature performance Performance after temperature cycling Effect of environmental moisture Robustness Delivery device development Preservative effectiveness / efficacy Compatibility

16. DRUG PRODUCT SPECIFICATION Assay Moisture content Mean delivered dose Delivered dose uniformity Content uniformity/ uniformity of dosage units Fine particle mass Leak rate Microbial/ microbial limits Sterility Leachable Preservative content Number of actuations per container

17. references www.fda.gov.in www.ema.europe.eu