Primary packaging material (PPM) refers to the material in direct contact with a drug product, serving as the first barrier to external elements. For parenteral products, it includes containers such as polymer or glass vials, pre-filled syringes, cartridges, infusion bags, blow-filled seals, or ampules, along with components like stoppers, plungers, seals, and caps (Figure 1).
PPM ensures the drug’s stability, sterility, efficacy, and safety throughout its shelf life, including transport and storage. For combination products, the PPM must also enable functionality and usability.
Compendial requirements, such as those from the European Pharmacopoeia (Ph. Eur.), establish essential standards for primary and secondary packaging materials. Key chapters cover glass containers (3.2.1), plastics (3.2.2), and elastomers (3.2.9)1, with corresponding United States Pharmacopeia (USP) standards—USP <660> for glass, <661> for plastics, and <381> for elastomers.2
From December 2025, USP <382>2 “Elastomeric Closure Functionality in Injectable Pharmaceutical” is also available and refers to the elastomeric component quality requirements, such as fragmentation or penetration. Other standards and guidelines, including ASTM F2097-20,3 provide industry recommendations for designing and evaluating primary packaging for medical products. This standard emphasizes material performance, seal integrity, and mechanical properties, offering testing methods to assess durability and ensure compliance.
The selection of the PPM impacts multiple considerations throughout the product lifecycle and is associated with various technical requirements and challenges. Figure 2 illustrates the critical stages of this interconnected lifecycle.
Quality of PPM from the supplier
Quality is crucial to ensure the safety and efficacy of parenteral drug products. It becomes especially critical for ready-to-use (RTU) PPM: materials that are produced and sterilized by the PPM supplier, ready for filling at the GMP drug product manufacturing site. Since no additional cleaning or processing steps are conducted at the GMP fill-finish site, the quality of the PPM directly translates into the quality of the final drug product.
In general, suppliers must provide detailed specifications and Certificates of Analysis (CoA) confirming compliance with critical product attributes, such as dimensional requirements, which are related to processability during filling, container integrity (component fit), and functionality for combination products. Additionally, visual inspection must confirm the absence of critical defects.
Potential chemical contaminants must be controlled, e.g., ethylene oxide (ETO) residues and tungsten, as they can affect product stability and pose safety risks. For pre-filled syringes or cartridges, silicone oil levels should also be monitored to prevent unintended interactions with the drug product.
Most importantly, physical quality attributes, such as particulate matter, should be carefully specified, as particles originating from the PPM can cause safety concerns in patients and may lead to product rejects and batch losses. Visible and sub-visible particle limits are defined in pharmacopeias such as the European Pharmacopoeia (2.9.19 and 2.9.20)2 and the USP (<1>, <790>, <789>, <788>),3 though these apply only to the final drug product. However, they are often used for PPM specifications as industry guidance on particulate matter limits and adequate testing methods are lacking. Therefore, specifications for PPM should be much stricter (e.g., 10% of the final DP specifications) than those for the final drug product.
Additionally, for RTU formats, microbial contamination control is essential, particularly regarding bacterial endotoxins. For intravitreal administration, the maximum NOAEL of 0.01 endotoxin units/eye for non-human primates4 (translating into 0.2 EU/mL for an injection volume of 50 µL) is not currently met by all PPM.
Effective quality by design—including robust testing, qualification, and continuous monitoring—combined with strong collaboration between product developers and manufacturers to facilitate troubleshooting and continuous optimization, is essential to maintain high-quality primary packaging materials for parenteral drug products.
Fill-finish process fit
A successful fill-finish process depends on the effective implementation of the PPM. This typically requires dedicated format parts and process design, along with process optimization, including fine-tuning filling parameters, ensuring proper stopper setting, and implementing training sets and defect libraries for visual inspection. Additionally, batch size and volume demands must align with the capabilities of the fill-finish line.
During drug product manufacturing, the PPM is a key determinant for precise dosing and stopper placement, and hence, consistent headspace, all of which are critical for container closure integrity, product stability, regulatory compliance, and ultimately, patient safety.5
Successful integration of PPM into the fill-finish process requires close collaboration between packaging suppliers and drug manufacturers to ensure process compatibility, minimize risks, and achieve efficient, high-quality production.
Supply chain considerations
1. Compatibility & Stability
Compatibility between the PPM and the drug formulation must be carefully evaluated over a product’s shelf life. Material selection (glass vs. polymer syringes) and siliconization, particularly for functional containers to be used in drug/device combination products like prefilled syringes along with stopper configurations are key parameters determining product quality and stability. Stability of the API and interactions with formulation components, such as surfactants, and particulate formation must be assessed over the product’s shelf life. Additionally, extractables and leachables studies are essential.
Another concern related to PPM is glass delamination, a major quality-impact issue that has led to several product recalls in the past. The risk of delamination depends not only on the glass type and formulation but also the processing of the glass, including sterilization tunnel process conditions and terminal sterilization parameters.6
Microbiological quality is another key consideration, with container closure integrity (CCI) ensuring sterility throughout the product’s shelf life. The permeability of packaging components (e.g., rubber stopper or polymer containers) can impact the physiochemical stability of the drug or affect the moisture content by gas exchange. This may be important for oxygen-sensitive molecules exposed to oxygen from the air or residual VHP from isolator decontamination cycles.
For drug products intended for intravitreal delivery, external decontamination of the final drug product may be required for the U.S. market. This process is typically conducted using ETO or, in some cases, VHP or NO₂.7 It must be demonstrated that these decontamination methods do not impact product quality when penetrating the PPM components.
2. Functionality & usability
Besides stability considerations, selecting the appropriate PPM for a drug formulation is crucial for safe and convenient administration. For pre-filled syringes and cartridges (the latter typically combined with an injection device), break-loose and glide force must be carefully evaluated in combination with the formulation, as these factors influence injection performance, injection time, and user experience. They are primarily dependent on device design (e.g., inner needle diameter) and formulation viscosity, but also on the stopper/syringe combination and the presence or absence of lubrication. The choice of lubricants, such as silicone oil or alternative coatings, impacts plunger movement and overall functionality and, hence, usability. Accurate dosing must be ensured, and functionality tested over the product’s shelf life to match user requirements, particularly in cases of self-administration.8
Another technical challenge is the compatibility of the PPM with delivery devices such as autoinjectors or pen injectors. Factors such as dimensions influence smooth integration with these devices, ensuring proper functionality, in some cases implying exclusivity. It should be a given to integrate device development into drug product development and involve all relevant parties: the supplier, device manufacturer, pharmaceutical developer, and fill-finish/assembly site.8
Conclusion
The selection of PPM is a highly interconnected process with formulation development and DP manufacturing and, possibly, device selection. Each decision may impact product stability, manufacturability, and overall success. A successful product launch is only possible when all critical aspects are considered from the very beginning, ensuring seamless integration into development and manufacturing. A well-selected PPM, in combination with the formulation and manufacturing process, minimizes risks, supports regulatory compliance, and guarantees the safety and efficacy of the final drug product.
References
- European Directorate for the Quality of Medicines & HealthCare. (2025). European Pharmacopoeia (11.7th ed.). Council of Europe.
- United States Pharmacopeia. (2024). United States Pharmacopeia and National Formulary (USP-NF/PF 2024 Issue 3). United States Pharmacopeial Convention, Inc.
- ASTM International. (2023). Title of the standard. ASTM F2097-20. West Conshohocken, PA.
- Bantseev V et al. Determination of a No Observable Effect Level for Endotoxin Following a Single Intravitreal Administration to Cynomolgus Monkeys. J Ocul Pharmacol Ther. 2019 May;35(4):245-253. doi: 10.1089/jop.2018.0149.
- Allmendinger A, Mahler H-C, Behrendt P, “Addressing Intravitreal Product Manufacturing and Development Challenges”. ONdrugDelivery, Issue 157 (Mar 2024), pp 29–32.
- Ditter D et al. Impact of Vial Washing and Depyrogenation on Surface Properties and Delamination Risk of Glass Vials. Pharm Res. 2018 May 23;35(7):146. doi: 10.1007/s11095-018-2421-6
- Fujiwara S et al. Chemical-gas Sterilization of External Surface of Polymer-based Prefilled Syringes and Its Effect on Stability of Model Therapeutic Protein. J Pharm Sci. 2022 Jan;111(1):41-50. doi: 10.1016/j.xphs.2021.09.003.
- Allmendinger A, Adler M, Mahler H-C, “Integrated Drug Product Development and Manufacturing.” ONdrugDelivery, Issue 147 (May 2023), pp 44–50.
Andrea Allmendinger, PhD, is chief scientific officer at ten23 health and adjunct professor and professor at the University of Freiburg (Baden-Württemberg, Germany). Hanns-Christian Mahler, PhD, serves as CEO and board member at ten23 health. He also is a scientific expert at the European Directorate for Quality of Medicines & Healthcare (EDQM) and and an adjunct faculty member and professor at the University of Frankfurt/Main (Germany) and the University of Basel (Switzerland).
