Octobre 2023
La Vague n°79
Spécial Congrès 2023 : Annexe 1, Maitrise des procédés, environnement
Sommaire
- EU GMP Annex 1 (2022) : Aseptic Process Simulation (APS). De nouveaux ‘‘challenges’’ pour l’industrie pharmaceutique ?
- Introduction au procédé de remplissage des systèmes à double chambre (DCS)
- Mise en oeuvre des procédés de décontamination en industrie pharmaceutique
- Container Closure Requirements in the New EU GMP Annex 1 - Enabling Compliance with a Holistic Science-Based Approach
- Comment évaluer le risque pyrogène dans un process pharmaceutique injectable ? Outil d’aide à la décision
- Améliorer l’efficacité & la fiabilité de la qualification AVI : Détermination du nombre optimal de runs avec la méthode KNAPP
- Case Study: Effective Sterile Powder Transfer for Parenteral Drug Products
Container Closure Requirements in the New EU GMP Annex 1 - Enabling Compliance with a Holistic Science-Based Approach
The new EU GMP Annex 1 contains new requirements for the container closure of sterile pharmaceutical products. These requirements are triggering new best industry practices in the area of container closure integrity (CCI). This article will review the new requirements and describe an industry case study in which a holistic science-based container closure strategy was executed that enables compliance.
EU GMP Annex 1
The new EU GMP Annex 1, published in Eudralex Volume 4 on the 25th of August, 2022, details the rules governing medicinal products in the European Union and describes current Good Manufacturing Practice for medicinal products for human and veterinary use. The document itself describes the scope of the Annex as follows:
“The manufacture of sterile products covers a wide range of sterile product types (active substance, excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units), processes (from highly automated systems to manual processes) and technologies (e.g. biotechnology, classical small molecule manufacturing systems and closed systems). This Annex provides general guidance that should be used in the design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products applying the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product.”[1]
The deadline for the new Annex 1 coming into operation is the 25th of August, 2023 which is one year from the publication date in Eudralex Volume 4.
1. New container closure requirements in Annex 1
Requirements for container closure in the new Annex 1 can be found in sections 8.21 to 8.25 as well as in section 8.28. Some of the requirements are specific while other requirements are conceptual and put the burden of defining and justifying container closure integrity practices on the manufacturer. In general, it is clear from the new text that the regulator expects the application of QRM principles and a product life cycle approach when defining container closure integrity practices. It is also clear that the regulator is looking for robust approaches for assurance of good container closure by not only emphasizing appropriate validation of container closure integrity testing (CCIT) methods but also the monitoring of processes that can affect container closure. These conclusions can be confirmed by examining the language in each of the sections:
Figure 1 shows a slide from a recent A3P workshop on the container closure requirements in the Annex 1.[2] The text is from section 8.21 and very simply states that container sealing processes should be appropriately validated. A common example would be the capping and crimping process for vials. Current industry practice often includes a visual inspection of the crimp and a manual ‘twist’ test of the operator to check if capping is ‘tight’. These practices are clearly subjective and should not be used to justify an appropriately validated sealing method. Instead, section 8.21 motivates an approach in which capping and crimping settings should be robustly correlated to and validated for producing good container closure integrity.
Figure 2 shows the text from section 8.22 of the new Annex 1. Please note that the bold in the text is from the workshop and was used to emphasize that the new language on container closure motivates a science-based approach for making risk-based decisions about CCIT. We will discuss later in this article that ‘science-based’ includes generating analytical CCI data to gain knowledge and understanding of the container closure system. The text in this section also emphasizes the monitoring of parameters critical for seal integrity, gives specific requirements for the CCIT of containers closed by fusion, and stresses that visual inspection is not an acceptable integrity test method.
Figure 3 shows the text from section 8.23 which gives the requirements for CCIT of container systems other than those closed by fusion. This section can be considered to be the general container closure integrity testing requirements section. The section is not prescriptive, does not include specific requirements, and clearly puts the burden for defining and justifying CCIT practices on the manufacturer. The text does emphasize the use of integrity testing using methods that are (appropriately) validated. This section also stresses a product life cycle approach following the recommendations found in USP <1207> Sterile Product Packaging – Integrity Evaluation.[2] Manufacturing needs container closure data and knowledge from development and risk assessment input to define a CCIT strategy per product.
Figure 4 displays the text of section 8.24 and specifically addresses sterile product that is packaged under vacuum. Sterile products are sometimes packaged under vacuum to either ensure proper reconstitution for administration (e.g. vacuum in lyophilized products enables proper mixing of the diluent into the container), or to protect the drug product from reactive gases. This section requires checking for maintenance of vacuum in these products prior to certification/ release and during shelf life.
Figure 5 shows the text of section 8.25 which requires including CCI in the transport and distribution testing/validation if there are transportation or shipping requirements that can negatively impact the integrity of the container. Two situations which have recently received attention from the regulator and industry are a) the potential movement of prefilled syringe plungers due to decompression during air freight shipment, and b) risk to CCI that is introduced by the extreme temperatures of an ultracold chain for storage and transport of frozen product.
Finally, Figure 6 displays the text of section 8.28 which is an example of process monitoring that is required in the capping and crimping process. All new capping lines are currently delivered with a missing/ raised stopper detection sensor. The objective of this sensor station is to detect vials that have missing or raised stoppers and reject these samples from the line. The new language in this section requires that the settings of the stopper height sensor be appropriately qualified. Data should be generated that qualifies the correlation between stopper height and good CCI so that an appropriate raised stopper height reject limit can be defined.
2. Industry case study
At the 2022 A3P International Congress in Biarritz, a presentation was given titled “Ensuring Container Closure Integrity of a COVID-19 Vaccine Product Requiring Ultra-Cold Chain Storage and Distribution: A Holistic Science-Based Approach”. [4] The project explicitly took the container closure requirements of the new Annex 1 into account (at that time, a draft version had been released for public comment) and a container closure strategy was defined aimed at compliance.
Figure 7 shows a summary of the science-based holistic approach that was used in the COVID-19 vaccine packaging development project. Important components of this approach included the use of a validated analytical deterministic CCIT method, a QbD approach to generate data in container closure studies early in the product life cycle, use of risk assessment to develop a test plan, and the use of seal quality measurements as part of a control plan. Both US and EU regulators have reacted very positively to this approach for container closure integrity assurance.
Studies had shown that ultracold storage temperatures can introduce risk to the container closure integrity (CCI) of vial-rubber stopper combinations traditionally used to fill sterile pharmaceutical products[5-7]. The project team decided to use risk assessment to help design robust container closure development studies to understand the CCI performance of primary packaging components considered for use for the vaccine.
Figure 8 shows the results of container closure studies that correlated the quality of the vial sealing process to the maintenance of container closure integrity during ultracold chain storage and transport for two different vial stopper combinations (combinations C and A). Vial seal quality was measured using residual seal force (RSF) measurements. RSF measures the stored energy or force in the compressed stopper – the higher the RSF value, the higher the stopper compression and thus the tighter the vial is capped. The RSF data points plotted in Figure 8 (scatter graph) show the measured RSF values in sample sets prepared with different capping settings and therefore over a wide range of RSF values. A headspace CCIT method based on CO2 ingress into a leaking vial was used to perform CCIT testing after ultracold storage.[8] Measured CO2 ingress is plotted in the bar graphs with failed vials as red in the RSF graph. It is clear from these results that there is a strong correlation between loose capping and CCI failure during ultracold storage for vial stopper combination C. The results for combination A show that these primary packaging components give good CCI performance over the full range of RSF values meaning that the process design space is much larger and risk of CCI failure much smaller. From a container closure perspective, one can conclude that combination A should be used over combination C.
Finally, Figure 9 shows how vial seal quality can be used as part of a control plan. Production lines were qualified with defined capping settings that produced a minimum RSF value for good CCI. RSF was then monitored during production and, if the values trended below the defined minimum, adjustments to capping were made as a correction. The data in Figure 9 show monitoring results and such a correction when RSF values trended under the defined minimum limit.
The results of this industry case study demonstrate an approach that uses robust generation of container closure data to enable compliance to the new Annex 1 sections 8.21, 8.23, and 8.25.
3. In conclusion
The revised EU GMP Annex 1 contains new language describing requirements for container closure. A holistic science-based approach that enables compliance can be summarized as follows:
- Implement a deterministic analytical method for container closure integrity testing.
- Use risk assessment to design packaging studies that generate robust science-based packaging data as required by the new Annex 1 using the deterministic (nondestructive) CCIT method.
- The knowledge built up about the primary packaging system through packaging and process studies can then be used to define and justify an appropriate testing strategy in manufacturing.
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Références
[1] European Commission. The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use – Annex 1, 2022
[2] Workshop ‘Meeting the Container Closure Requirements in the New EU GMP Annex 1’, Derek Duncan, A3P Lyophilization Conference, 4-5 April, Lyon, France
[3] U.S. Pharmacopoeia. USP 40 <1207>. Sterile Product Packaging – Integrity Evaluation. United States Pharmacopoeial Convention, Inc.: Rockville, MD, 2017.
[4] Presentation ‘Ensuring Container Closure Integrity of a COVID-19 Vaccine Product Requiring Ultra-Cold Chain Storage and Distribution’, Michael Edey, Derek Duncan; A3P International Congress, 11, 12, & 13 October, Biarritz, France
[5] Zuleger, B.; Werner, U.; Kort, A.; Glowienka, R.; Wehnes, E.; Duncan, D. Container/Closure Integrity Testing and the Identification of a Suitable Vial/Stopper Combination for Low- Temperature Storage at –80 °C. PDA J. Pharm. Sci. Technol. 2012, 66 (1), 453–465.
[6] Presentation ‘Ensuring container closure integrity of a gene therapy cancer vaccine needing deep cold storage’, Josine Wilmer, 2019 PDA Parenteral Packaging Conference, Venice, Italy
[7] Presentation ‘Correlating Vial Seal Tightness to Container Closure Integrity at Various Storage Temperatures’, Derek Duncan and Roger Asselta, 2015 PDA Parenteral Packaging Conference, Frankfurt, Germany2.
[8] Victor, K.; Caudill, A. A.; Veale, J. Container Closure Integrity Test Method Development on Vials Stored at −80°C Using Headspace Carbon Dioxide Analysis. PDA Journal of Pharmaceutical Science and Technology 2022, 76 (5), 395–415.
