Table 1 Additional 21 CFR Sections Applied to Combination Products with a Drug Constituent

21 CFR 211.84 Testing and approval or rejection of components, drug product containers, and closures

Provides detailed requirements for a manufacturer to sample, test, examine, and accept or reject drug product components, containers, and closures. It is interesting to note that combination device manufacturers only need to demonstrate compliance with this section for device constituent parts or materials if the device constituent part is also the drug container or closure or a part thereof (FDA 2015)

21 CFR 211.103 Calculation of yield

Requires actual yields and percentages of theoretical yield to be determined at various stages of the manufacturing process. Verification of the calculated results is also required

21 CFR 211.132 Tamper-evident packaging requirements for over-the-counter (OTC) human drug products

Applies to over-the-counter (OTC) drugs and how to demonstrate that they have not been tampered with before sale. OTC drug manufacturers must implement labels, tags, or other safety features that communicate that the drugs have not been modified or tampered with and remain safe and effective

21 CFR 211.137 Expiration dating

Helps ensure that drug products (or drug constituent parts) meet applicable standards of identity, strength, quality, and purity at the time of use. Expiration dating may be applied to the entire combination product or separately to the individual constituent parts of the combination product. For a co-packaged combination product with a single expiration date, the date is determined by the earliest expiration date (shortest shelf-life) for any constituent part. For the case of a drug-device combination product, the shelf-life is determined by the shortest estimated shelf-life of the following studies: drug stability, device aging, and packaging system (sterile barrier system) aging

21 CFR 211.165 Testing and release for distribution

Each drug product batch must be tested, conform to final specifications (including the identity and strength of each active ingredient), and be free of objectionable microorganisms before release. Any batch that fails to meet established standards or specifications must be rejected. Reprocessing is allowed, but the reprocessed material must meet the appropriate standards and specifications. For combination products, each batch must also be tested to ensure conformance to specifications for the drug constituent part. For single-entity combination products, laboratory testing must be performed on every batch of the combination product. In contrast, for co-packaged combination products, testing is only required for each batch of the drug constituent part

21 CFR 211.166 Stability testing

Requires a written stability program to assess the stability characteristics of drug products. The stability test results are used in determining storage conditions and expiration dates. Designing stability studies for combination products presents challenges as there may be vast differences in terms of stability requirements for drugs and devices. The selection of the number of batches, accelerated aging conditions, and the appropriate stability-indicating tests must be considered when establishing expiration dating for combination products. For a drug-device combination product, such as a drug-eluting stent, typical stability testing attributes may include appearance, assay/drug content, impurities/degradation products, drug release rate, particulate matter, and package integrity (FDA 2015). Matrixing and bracketing are encouraged; however, experience in this area is limited, especially with regions outside of ICH

21 CFR 211.167 Special testing requirements

Describes special testing requirements for drug products that are sterile and/or pyrogen-free, ophthalmic ointment, or a controlled-release dosage form

21 CFR 211.170 Reserve samples

Requires reserve samples to be included for every lot and sampled at twice the required quantity. For an active ingredient in a drug product, the reserve sample must be retained for one year after the expiration date of the last manufactured lot of drug product containing the active ingredient. Also included are special requirements for radioactive drugs and OTC drugs