Background 

A drug manufacturer planned to sell a drug, which already had a marketing approval, in a prefilled syringe presentation, and wanted to apply for marketing authorization for the prefilled syringe presentation. Since the company was primarily into the drug field, they were looking for assistance in demonstrating compliance with the device regulations and all the requirements that are applicable to a combination product.

Challenges 

The primary challenge for the Company was understanding how to implement the various medical device regulatory and compliance requirements. The following were the ones that were more difficult to decipher:   

1. Combination device and types
   The company wanted to know how they fall within the combination device category and under what type of combination device they would be categorized. 
2. Quality Systems Requirements
   Since the prefilled syringe is a single-entity combination product, the manufacturer was not sure how to demonstrate compliance with both the drug cGMPs and device QS regulation at the same time.
3. Subcontracting set up
   While the manufacturer sold the syringe as a part of the combination product, the manufacturer bought the syringe components from an Original Equipment Manufacturer (OEM), and wanted to know how to manage the subcontracting set up from a documentation and compliance standpoint. 
4. Design Verification and Validation (V&V)
   The company was not adept at design control requirements and wanted some hands on help in this area.  

Solutions

As Elexes specializes in combination products, Elexes knew exactly how to tackle the challenges that the Client faced. Some of the solutions that was provided to the Client are as follows: 

1. Combination device and its types – choosing the right subcategory
   The Client was provided details about a combination device where under 21 CFR 3.2 (e) a combination product is a product composed of any combination of drug/device; biological product/device; drug/biological product; or drug/device/biological product.
2. Types
   The Client was provided information on different types of combination devices, so the most apt one can be selected for document structuring and creation purposes.
   • Single entity combination products: A product composed of two or more regulated components that are chemically, physically, or otherwise mixed or combined and produced as a single entity. E.g., pen injector, prefilled syringe, etc. 
   • Co-packaged combination products: A single packaging of two or more separate products, or two or more products packaged together as a unit and comprised of –
     1. device & biological products
     2. biological & drug products
     3. drug & device products
     4. E.g., drug & syringe & needle 
   • Cross-labeled combination products: A separately packaged device, biological, or drug product that as per its labeling is intended for use only with a specific or multiple (that meet predefined specifications) approved device, drug or biological product. E.g., photosensitizing drug activating laser light source.
3. Quality Systems Requirements – Integration of the device QS requirements
   As the first step Elexes reviewed and analysed the existing cGMP quality set up, and identified opportunities of integrating the syringe related 21 CFR Part 820 requirements into the quality systems by adding new drafted procedures like design control, risk management (as per ISO 14971), management responsibility, and purchasing control. 
4. Subcontracting set up – Legal Manufacturer 
   The company was made to understand that even though the syringe was obtained from an OEM, the ultimate responsibility for design control and V&V activities was that of the Legal Manufacturer (the Client). Hence, various supplier controls were put in place and implemented to ensure that the compliance and documentation requirements are met with the OEM.  
5. Design V&V – laying out the plan
   Elexes took the ownership to review the supplier’s design control data to determine what new questions would be raised by the use of the syringe with the drug, and assessed what additional design control activities may be needed. Elexes ensured that all design considerations for the combination product are addressed in accordance with 21 CFR 820.30.
   Elexes, with the involvement of Client’s engineering team, laid out a comprehensive design and development plan for the product such that verification and validation is traceable to risk and design input/output.
   Some tests recommended for the prefilled syringe were: 
   

Results

• The company making prefilled syringes could leverage OEM involvement and their established quality systems efficiently 
• The company was able to understand and implement all the compliance requirements
• The company confidently faced a surprise FDA inspection and passed
• Once the system was set, the company was able to maintain it with annual audit support from Elexes 

Key Takeaway

A combination product’s regulatory requirements say it is recommended complex and time-consuming. It is recommended to comply early on than to deal with non compliances later. Bringing a regulatory partner onboard sooner than later goes a long way.