Regulatory Considerations in Biologic Therapies Packaging

Biopharmaceuticals differ from conventional (synthetic) drugs due to the “bio” component that uses living cells, proteins, or organisms to create the formula. Biologic therapies present unique regulatory considerations because of their complex nature and susceptibility to degradation.

Currently, the FDA refers Investigational New Drug and Biologics License Application candidates to its May 2002 Guidance Document, Container Closure Systems for Packaging Human Drugs and Biologics — Questions and Answers, PLR 2006, and Biological Products Specific Labeling Resources for packaging and labeling.

Regulatory Framework

The highly sensitive nature of biologics calls for new content to be conveyed on packaging and labeling. Knowing how the FDA is managing this market explains what to expect when developing and packaging a biopharma product. The FDA regulates conventional drugs under 21 CFR and the Federal Food, Drug, and Cosmetic Act (FDCA). Biologics are regulated under the Public Health Service Act (PHSA). Within the FDA, Centers for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) are the two branches that have regulated product and packaging. Today, the Centers are assigned incoming biologics applications as follows:

CDER

• In vivo monoclonal antibodies
• Protein therapies (excluding vaccines and blood products)
• Immunomodulators
• Growth factors that act on cell production (in vivo)

CBER

• Human cellular and tissue-based products (HCT/Ps)
• Vaccines and related products
• Blood products components and plasma derivatives
• Gene therapies
• Antitoxins, antivenins, and venoms

It’s worth noting that some biologic therapies are developed in conjunction with some element of a medical device or conventional drug, making it a “combination product.” Regulatory governance for combination products will be assigned to CDER or CBER based on “the products’ primary mode of action.”

Regulatory Pathways

The regulatory path for a new biological product (and certain conventional new drugs) begins with an Investigational New Drug (IND) application. The IND must present detailed safety data, clinical processes, supporting documentation, and manufacturing details. Successful review triggers the step of a Biologics License Application (BLA). Customers, suppliers and packaging partners work with the FDA’s assigned CDER or CBER investigator(s) to gather data and documentation for the application process.

Packaging and Labeling Requirements

USA-made biologics are subject to the same 2006 Physician Labeling Rule (PLR) content requirements and format followed by conventional drugs. The 2006 update sought to make product information easier for clinicians and healthcare practitioners to locate and utilize for making prescribing decisions. Labeling that is compliant with the 2006 PLR format is required for all biological products submitted to the FDA through NDA or BLA after the June 2006 effective date.

As of now, CFR Title 9 Sec. 112.1 and .2 (1973) remain the cornerstone for both conventional and biopharma labeling. Requirements are:

• The FDA-approved name of the biologic (as shown on the product license) must be prominently displayed on unit and packaging, and shown in identical manner across all container labels, carton labels, and all enclosures and accompanying resources.
• The language of CFR does not state whether this is required on labeling, but all packaging and labeling must be completed at a verified and licensed facility.
• The physical address and contact information for the maker. For exported U.S. product, no phone contact is required.
• Expiration dates and batch serial numbers must be printed on every unit.
• Storage conditions must be printed on every unit and carton, including minimum/maximum temperature (in both Celsius and Fahrenheit)
• Contraindications, safe use and warnings must be printed on all units and cartons
• Single-dose biologics distributed within the US must include a consumer phone contact on each individual container, carton, and enclosures.
• The number of single-dose units contained within a carton must be stated on the carton.
• More than one multi-dose unit of a biologic may be held in one carton unless the volume of required information requires an individual carton to hold it.
• Packaging label durability for biologics must be validated to remain fully legible through transit, shelf life, and use period.
• If a biologics label has any mark, alteration or illegible portion, the biologic product must be removed from use and destroyed.

Conclusion

The regulatory distinctions between making, labeling, and packaging conventional drugs and biologics are relatively few. This is likely attributable to the speed of innovation vs. the speed of regulation. This is where conversations with assigned CDER/CBER investigators will be important for makers and packaging professionals of emerging biologic products.

Sources

• https://pharmaceuticalmanufacturer.media/pharmaceutical-industry-insights/keeping-up-with-biologics/
• https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-packaging-human-drugs-and-biologics
• https://www.fda.gov/media/70788/download
• https://www.fda.gov/combination-products/jurisdictional-information/transfer-therapeutic-biological-products-center-drug-evaluation-and-research#:~:text=On%20June%2030%2C%202003%2C%20FDA,Evaluation%20and%20Research%20(CDER).
• https://www.fda.gov/drugs/laws-acts-and-rules/fdas-labeling-resources-human-prescription-drugs
• https://pubmed.ncbi.nlm.nih.gov/25868989/
• https://www.fda.gov/drugs/fdas-labeling-resources-human-prescription-drugs/biological-products-specific-labeling-resources
• https://ispe.org/pharmaceutical-engineering/september-october-2021/safeguarding-vial-container-closure-integrity
• https://www.sciencedirect.com/science/article/abs/pii/S0939641123002990
• https://www.outsourcedpharma.com/doc/packaging-of-biologics-and-biologically-derived-drug-products-0001
• https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-packaging-human-drugs-and-biologics-questions-and-answers
• https://www.fda.gov/about-fda/economic-impact-analyses-fda-regulations/summary-content-and-format-labeling-human-prescription-drug-and-biological-products-requirements#:~:text=For%20human%20prescription%20drug%20and%20biological%20products%20subject%20to%20the,that%20summary%2C%20and%20relevant%20information