Combination Products analysis to comply with the new FDA requirement 21 CFR Part 4

With the new 21 CFR Part 4 “Current good manufacturing practice requirements from combination products” which came into effect on July 22, 2013, both the medical device manufacturers, as well as the (bio)pharmaceutical companies, face a lot of questions on how to comply with this new rule, which Quality Systems to apply (CGMP or QS regulation) and the associated required level of testing and documentation.

In a lot of cases, these unexpected impurities are – at first – not identified, as they are often initially detected with non-specific detectors in generic analytical methods, such as HPLC-UV Chromatography.

Three different types of combination products are described:

Single entity combination products: 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 (e.g. prefilled syringe).

Co-packaged combination products: 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 (e.g. insulin pen and insulin packaged together).

Cross-labeled combination products: two products, manufactured and marketed, but linked to each other through e.g. the instructions for usage (e.g. pen and associated pre-filled drug cartridges, not packaged together).

The 21 CFR Part 4 describes depending on the application, two possible approaches:

  • If pharmaceuticals or biologics are manufactured, then compliance with the drug cGMPs (21 CFR parts 210 and 211) needs to be demonstrated as well as the following provisions of the Quality System regulation (QSR) for medical devices: §820.20 (management responsibility), §820.30 (design controls), §820.50 (purchasing controls), §820.100 (corrective and preventive action), §820.170 (installation) and §820.200 (servicing)
  • If medical devices are manufactured, then compliance with the QSR for medical devices needs to be demonstrated, as well as the following provisions of the drug cGMP (21 CFR parts 210 and 211): §211.84 (testing and approval or rejection of components, drug product containers and closures), §211.103 (calculation of yield), §211.132 (tamper-evident packaging requirements for over the counter human drug products), §211.137 (expiration dating), §211.165 (testing and release for distribution), §211.166 (stability testing), §211.167 (special testing requirements), §211.170 (reserve samples).

At Nelson Labs Europe, two divisions work complementary towards the evaluation of Combination Products. The first division ‘Pharmaceutical services’, focusing on Drug Product quality, intends to investigate if the properties of the Drug Product are not negatively affected by the combination with the Medical Device. This division supports both the analytical (e.g. purity, pH, stability,..) and microbiological testing (sterility). The second division ‘Extractables and Leachables’, focuses on chemical compounds released under appropriate conditions from the Medical Device into the Drug Product. This combined approach results in optimized study design and cost-efficient budgeting.

As a Contract Research Organization, we are recognized for the analysis and control of pharmaceutical products by the Belgian Ministry of Health. Our laboratory is GMP inspected and recognized by the Belgian Federal Agency for Medicinal and Healthcare Products (FAMHP), GLP certified by the Scientific Institute of Public Health (IPH) (Identification number: T02), FDA registered (FDA Establishment Identifier (FEI): 3005742674) and ISO 17025 accredited by BELAC (Identification number: 363-TEST) and all testing is carried out according to European GMP Guidelines. Additionally, we are licensed to handle narcotic products. With this quality background, we support companies that decide to outsource their analytical and validation work to respect the EP/USP/ICH guidelines.


Mr. Kevin Breesch, MSc
Manager Business Development International Preclinical

Nelson Labs Europe | Combination Products