[Edaily Reporter Minji Son ] The U.S. Food and Drug Administration (FDA) is conducting a comprehensive revision of its guidance on drug containers and packaging for the first time in 27 years. This revision is being made to align with the current market environment, where combination products—such as prefilled syringes and autoinjectors—that integrate drugs with medical devices have become widespread. Consequently, this is expected to impact not only South Korean companies selling self-injectable biosimilars in the U.S. but also those seeking to enter the U.S. market with obesity treatments, vaccines, and blood products.

Guidelines Updated for the First Time in 27 Years… Reflecting Drug-Device Combination Products

According to the pharmaceutical and biotech industries on the 21st, the U.S. FDA recently released a draft of the “Guidance for Industry: Container Closure Systems for Human Drugs and Biological Products.” The deadline for public comment is October 13.

If this guidance is finalized, it will mark the first comprehensive revision of the basic guidelines for drug containers in 27 years, since 1999.

CCS refers to components that contain pharmaceuticals and protect them from the external environment. This includes everything from the container bodies—such as ampoules and vials—to lids, stoppers, sealing materials, cushioning materials, and protective packaging that seal the pharmaceuticals.

The key point of these guidelines is that they encompass all container, device, and packaging components that store and protect pharmaceuticals while also performing administration functions. Evaluation criteria for the safety and suitability of containers already existed in the previous guidelines. However, at that time, the focus was on traditional packaging forms, such as vials. It is believed that the decision to revise the guidelines stemmed from the judgment that the existing guidelines alone could not adequately reflect recent product forms as new products with combined functions have emerged.

For example, a prefilled syringe—which contains the drug pre-filled in the syringe—serves both as a container for the drug and as a device for administering the drug to the patient. The FDA classifies such products as drug-device combination products and requires an evaluation not only of the drug’s quality but also of the device’s drug delivery performance and whether it maintains its intended function.

The new guidelines in the draft explicitly state that one should not assume that a Container-Closure System (CCS) suitable for a specific drug product is automatically suitable for other drug products. This means that even if containers have the same specifications and materials, the compatibility of the combination must be verified for each individual drug product. The explanation notes that even subtle differences in drug formulations can affect leachables—substances that migrate from the container into the drug.

Potential risks arising from an incompatible container-drug combination include degradation and precipitation of active ingredients, changes in pH and appearance, glass delamination, and the generation of microparticles. The guidelines also note that substances leached from the container may react with proteins, altering their tertiary structure and potentially affecting the safety and efficacy of biologics.

For sterile products, the Container Closure Integrity Test (CCIT)—which verifies that the container remains sealed without external contact—is also given significant attention. The FDA recommends using CCIT in place of sterility testing during stability evaluations.

Transportation and storage processes are also included in the scope of evaluation. The guidelines require an assessment of container performance during drug transport in response to shock, vibration, and temperature changes, as well as verification that refrigerated and frozen drugs maintain appropriate temperatures throughout the entire transport duration.

Korean Companies Entering the U.S. Market Also Affected… ‘Opportunity vs. Risk’ Coexist

If these guidelines are finalized, Korean companies that have entered or are preparing to enter

the U.S. market

may face increased burdens in the quality control process for drug containers. Companies such as Celltrion and Samsung Bioepis, which sell biosimilars in pre-filled syringe and autoinjector formats in

the U.S.

, are also affected.

Celltrion’s autoimmune disease treatment “Uplima” is supplied in the U.S. in both prefilled syringe and autoinjector forms. In addition, Celltrion uses the prefilled syringe formulation for several other biosimilars, including “Stekima” and “Omriclo.”

Samsung Bioepis’ autoimmune disease treatment “Hardima” is also sold in the U.S. in prefilled syringe and autoinjector forms. Last year, the FDA designated Hardima’s autoinjector and high-concentration prefilled syringe as biosimilars interchangeable with the originator drug.

Companies developing treatments for obesity and diabetes, such as Hanmi Pharmaceutical, may also be affected if they enter the U.S. market with autoinjectors or similar devices as their final commercial dosage forms. A biotech industry official stated, “It will be necessary to thoroughly demonstrate not only the quality of the drug itself but also whether the delivery device reliably delivers the prescribed dose,” adding, “Since changes to container or device components must be evaluated for their impact on the product as a whole—including drug delivery performance—the validation of delivery devices may become even more critical in the approval process.”

The guidelines apply not only to drug-device combination products but also to vial-based products. GC Green Cross’s blood product “Aliglo,” sold in the U.S., is a single-dose vial product, making the seal integrity of the glass vial and cap, as well as long-term stability, critical factors. In addition, SK Bioscience, which develops vaccines, and other Korean companies seeking to enter the U.S. market with botulinum toxin products will also need to review these standards during future U.S. approval processes.

A pharmaceutical and biotech industry official stated, “It is highly likely that the burden of testing and documentation will increase for companies,” adding, “Additional costs and time may be required for supply chain management, and since comparative data with previous products must be provided when changing containers or device components, barriers to entry will rise.”

Some analysts suggest that this could actually present an opportunity for companies with prior U.S. approval experience and a sufficient accumulation of data by dosage form. Since they have already identified component characteristics and potential risks, they can respond more easily than companies new to the U.S. market.

Additionally, a pharmaceutical and biotech industry official noted, “This could also enhance the competitiveness of Contract Development and Manufacturing Organizations (CDMOs) that possess validated container platforms and analytical capabilities,” adding, “Companies that have already accumulated experience with U.S. approvals and product-specific test data will be able to adapt relatively easily even if the guidelines are revised.”