Developments in Container Closure Integrity Testing of Lyophilised Product

Container closure integrity plays an important role in maintaining the sterility and stability of sterile lyophilised products. Defects which causes a freeze dried by a visual inspection process. Examples of such defects are microscopic cracks and scratches in the glass, which causes a fall in the crimp. Increasingly, 100% automated container closure integrity testing (CCIT) is used to complement visual inspection for the quality of finished sterile products.

It has been made that the EU GMP Guidelines for the Manufacture of Sterile Medicinal Products Annex 1 will undergo a revision [1]. One of the revision topics is the container closure integrity (CCI) inspection of sterile product. In recent years, this has been and continues to remain a hot topic. Current EU Annex 1 regulations require 100% integrity testing of closed containers by fusion (ie ampoules) due to the inherent risk in these sealing processes. The requirements for other containers are vague and it is expected that revisions will address this issue.

Another section of the USP <1207> chapter on container closure integrity [2]. This section is scheduled for implementation in 2016. One of the items in the revised <1207> chapter is the identification of methods have CCIT Being probabilistic or deterministic. Traditional methods CCIT Such As microbial challenge tests or blue dye ingress tests are Described as methods associated with probabilistic outcomes That result in Findings In Some uncertainty as well as in Difficulties to quantitatively validate the method for the detection of critical leaks. Other CCIT methods That are based on analytical measurements, Such As helium leak testing, laser-based gas headspace analysis, or vacuum decay, are Described as methods That objective Produce, quantitative data That Enables the detection of critical leaks as well as analytically based validation .

These deterministic CCIT methods coupled with a risk-based approach can be used to generate statistical information. A recent White Paper from the BioPhorum Operations Group, a collaborative working group of the industry's leading biopharmaceutical companies, outlines a rational and risk-based approach for when and how to apply 100% CCIT [3]. The White Paper may also be more applicable.

For the specific case of sterile freeze dried product, CCI data is obtained from a statistical analysis of the state of the art. Recently, CCI benchmarking data from more than 15 million commercial freeze dried products were analyzed over five years ago [4]. The data shows that the freeze drying process introduces risk to the seal integrity of a freeze dried product to the complexity of the sealing process compared to the liquid filling process. The CCI benchmarking data Showed That It is not unusual for up to 0.5% of sales freeze dried product To Suffer from leakage. In the data analysed, more than 80% of the trading lyo batches contained at least one vial leaker. Some of These Were temporary leaks with the data analysis indicating indication que la vial Was leaking entre les lyo chamber and the capping and crimping machine. During this temporary leakage, the freeze dried vials lost Their (partial) vacuum and oxygen ingressed resulting and in loss of the initial nitrogen headspace.

Generating statistics CCI data might seem like a challenging task. However, CCI studies can be used to validate CCI studies. This can be particularly interesting for performing process studies on placebo test batches and validation batches produced during scale up and product launch, or for inspecting batches with suspected CCI issues to enable release of the product to the market. 100% CCI inspection as part of the commercial production and packaging process [3].

In summary, recent industry Developments in the area of ​​container closure integrity of sterile product again means clustering That Will Remain this topic one significant year in the coming year. The use of deterministic methods for CCIT Validating closure of packaging components, and the implementation of 100% for CCI inspection lyophilised product are two trends to look out for in the near future.

The container closure integrity plays an important role in maintaining the sterility and stability of lyophilized sterile products.
The causes that can cause a lack of integrity may not be detectable at a mirage operation. Common examples include micro-cracks and scratches of a glass container, hidden defects by the crimping operation, or temporary faults plug badly depressed type that lead to a temporary escape from the container. The pharmaceutical industry and regulatory agencies agree on this point today. The container closure integrity (ICC) is also relevant in the latest regulatory developments such as the revision of Annex 1 of Good Manufacturing Practices of the European Union, or the chapter of the USP <1207> on this subject. The revision of the chapter of the USP <1207> introduces a distinction between probabilistic methods as integrity test (methylene blue, challenge-test) and deterministic (test with helium, laser measurement of headspace, depression). Deterministic methods give objective analytical results, and can be used to validate critical leak detection quantitatively. The pharmaceutical industry has started to generate statistical data to identify risk process for product integrity. Increasingly, automated solutions to 100% of controls are implemented to complement the mirage to control the quality of sterile drugs.

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[1] Concept Paper on the Revision of the Guidelines on Good Practice - Manufacture of Sterile Medicinal Products, European Medicines Agency and the Pharmaceutical Inspection Cooperation Scheme, 8 January 2015 R
[2] Proposed Revisions to General Chapter Sterling Product Packaging-Integrity Evaluation <1207>, Pharmocopeial Forum, September 2014
[3] Scott Ewan, Min Jiang, Chris Stevenson, et al. White Paper: Container Closure Integrity Control versus Integrity Testing during Routine Manufacturing, PDA Pharm Sci and Tech 2015, 69 p.461-465
[4] Duncan, D .; 100% CCI Inspection Data for Lyophilized Product Vials: Lessons Learned. Presented at the PDA Parenteral Packaging Conference, Brussels, Belgium, March 2014 and PDA Packaging Conference, Washington DC, May 2014