The 2021 PDA FDA Joint Regulatory Conference (Sept 27 – 29, 2021) was a great opportunity to present a case study of the development of the Pfizer–BioNTech COVID-19 BNT162 mRNA Vaccine, a significant moment in science. The vaccine is stored and distributed in deep cold storage conditions using a conventional packaging system (i.e., glass vial, rubber stopper, crimp seal). The use of a conventional packaging system and the ability to ensure container closure integrity (CCI) at the ultracold temperatures enabled the mass production and distribution of the vaccine to meet public health needs.
Of great interest to the participants of the conference was the application of a holistic science-based approach utilized in the CCI program. The presenters were Michael Edey and Anna (Abriana) Rozentsvayg from Pfizer and Derek Duncan, from Lighthouse Instruments.
The presentation given was focused on a case study based on the BNT162 mRNA vaccine covering the following topics:
- Application of a Quality Risk Management (QRM) approach using Quality by Design (QbD) principles for robust and rapid package development of the BNT162 mRNA vaccine
- Generation of robust science-based data to ensure CCI of the BNT162 mRNA vaccine
- Use of Data Analytics for Attributes and Dimensional Reports for BNT162 mRNA vaccine Primary Packaging Components
- Supply Constraints and FDA Guidance for Industry for Container Closure System and Component Changes
Significant enthusiasm for the holistic science-based approach was generated during the panel discussions. Besides the authors, the panel members included Susan J. Schniepp, Distinguished Fellow, Regulatory Compliance Associates Inc., and Patricia F. Hughes, PhD, Sr. Scientific Advisor, U.S. FDA.
This panel discussion centered on the holistic science-based approach to CCI. Panelists discussed how the generation and presentation of good quality data may support decisions about the process. Additionally, that such data as presented makes a convincing case, especially if it’s well-controlled data and has accompanying analytics.
The holistic science-based approach presented the use of a validated deterministic CCI test method, application of QbD to produce a test plan, the use of container closure integrity testing (CCIT) on empty containers, and residual seal force (RSF) for qualification of the vial sealing process in manufacturing. Additionally, it advanced the concept of limited or exclusion of CCI sampling in the manufacturing phase of a product’s lifecycle based on the generation of robust CCI development and validation data as well as a control strategy. All these controls and rationale for decisions were documented in a risk assessment.
Lighthouse and Pfizer collaborated on the project, which was focused on how to demonstrate CCI maintenance during ultracold chain storage and distribution, given that CCI testing cannot be performed at the ultracold chain conditions. The risks of leakage during deep cold storage resulting in headspace gas exchange was explained as part of the detailed presentation as follows:
- The BNT162 mRNA vaccine uses readily available conventional primary packaging components: Vial/Stopper/Flip off Aluminum Seal. Stoppers may lose elasticity below their glass transition temperature (Tg) and shrinkage of the components may lead to potential interface gaps between the vial and the stopper, resulting in a potential loss of CCI.
- Any sealing failures caused by deep cold temperatures are temporary as resealing occurs when the vials are returned to ambient conditions after deep cold storage. In an ultra-chain distribution process, dry ice is often used for handling and transport. In the case of a CCI failure, CO2 gas enters the vial headspace. The cold dense CO2 gas trapped inside when the vial is taken off dry ice can expand as the temperature rises, creating overpressure and other potential risks such as a pH shift in the formulation.
Test methods deployed were:
- Laser-based headspace analysis for CCIT which is a nondestructive deterministic CCIT technique that measures gas ingress into the headspace due to a leak.
- Residual seal force (RSF) testing to measure quality of the vial sealing process. RSF is the strain a compressed elastomeric stopper flange exerts on the vial sealing surface after crimping of the aluminum seal. It is a seal quality test, not a leak test (USP <1207>). Sufficient stopper compression is essential to seal integrity, especially for products requiring deep cold storage
Questions to the panel included:
What is the risk if CCI is lost during ultracold storage in general applications?
Answer – Potential for ingress of CO2 gas, pH shift and an overpressure in the vial. When the syringe is used to draw product from the stopper, the plunger could be pushed upwards in the syringe; product in the vial can spray out of the syringe puncture hole in the stopper as a result of the overpressure. The deep cold storage conditions represent a lower potential for sterility issues.
Does the regulator require CCIT in manufacturing for product needing deep cold storage?
Answer – A Risk Assessment along with input from robust CCI data generated in development can be used to determine the testing approach.
Of further interest, Derek Duncan closed his segment stating:
- The Pfizer primary packaging project team took a very robust data-driven approach for defining the primary packaging solution for the BNT162 mRNA vaccine.
- A coordinated network-wide CCI strategy was defined.
- QbD principles and risk management approaches were used to define packaging component studies, process validation studies, transport validation, and control strategies.
- The project was very data-driven; tens of thousands of data points were generated on the primary packaging components and the vial sealing process (headspace CCIT, RSF).
The authors look forward to wider engagement on this topic and the broader adoption of the holistic science-based approach to CCI at the upcoming PDA Annual Meeting in Dallas Texas on April 04 – April 06, both as part of a presentation at the conference and Packaging Science Interest Group sessions.