Container Closure Integrity Test (CCIT)
Container Closure Integrity Test, abbreviation of CCIT, which is a method of evaluating whether a drug packaging system can prevent contamination of drugs by microorganisms, gases and other substances. CCIT is an important part of drug quality control, which can ensure that sterile drugs are not affected by external factors during production, storage and transportation.
1, Those Regulations about CCIT you should know!
USP <1207> chapter ‘Package integrity evaluation – sterile products’ implemented in August 2016
New EU Annex 1
‘Manufacture of Sterile Medicinal Products’ revision – significant new language on container closure (deadline for implementation 25 August 2023) Pharmaceutical Inspection co-operation Scheme (PIC/S) and the World Health Organization (WHO) participated in finalizing requirements.
Technical Guide for Research on Tightness of Chemical Injection Packaging System (Trial)-CDE
The chapter on the verification of Container closure integrity testing methods points out that it is necessary to pay attention to the investigation of method sensitivity, and it is necessary to set up negative and positive control samples. Positive control refers to packaging containers with known defects created by laser drilling, micropipette/capillary, etc.
2, Move on from probabilistic methods to deterministic methods.
CCIT has various methods, which can be divided into probabilistic methods and deterministic methods. Probabilistic methods are based on statistical principles, which perform destructive tests on a certain number of samples, and then infer the integrity of the entire batch. This method has many limitations, such as sample loss, long test time, inaccurate results, etc. Common probabilistic methods include dye immersion method and microbial immersion method.
3, What are the deterministic methods? which one fit your products.
Deterministic methods are based on physical principles, which perform non-destructive tests on each sample, and then obtain quantitative and predictable results. This method is more reliable, faster and more cost-effective. The United States Pharmacopoeia (USP1207) issued guidance in 2016 recommending the use of deterministic methods rather than probabilistic methods. Common deterministic methods include vacuum decay method, HVLD （High voltage discharge method）, Laser head-space analysis, etc.
CCIT is a constantly developing and innovating field. With the diversification and complexity of drug packaging systems, it is necessary to develop more advanced and adaptable testing technologies. CCIT is of great significance for ensuring drug quality and safety.
4, What is positive control samples & positive control samples comparison.
A positive control sample is a package with a known, intentional defect that is used for comparison with a negative control sample (package without defect) .
The role of the positive control in CCIT is to verify the sensitivity and reliability of the test method and to check whether the test system is functioning properly.
Depending on the method used to make positive control samples, they can be divided into the following types:
Laser drilling method: using a laser on the packaging container manufacturing small pore and pore size can be precisely controlled.
Micropipette/capillary Pierce law: the use of tubes or capillary Pierce a hole on the container, and seal it.
Crack/scratch method: the use of mechanical or chemical methods in packaging container manufacturing cracks or scratches on.
Comparison of positive control samples
5. Laser drilling micro holes on the container
Laser drilling is the closest way to a natural defect; High tolerances are possible in most materials and thicknesses; Hole Diameter: Ranging from 1 micron to 100 micron; Able to drill all materials like rigid package like glass ampoules, vials, pre-filled syringes, cartridges, moulded glass, Polymers: IV bags, PP/PE bottles, BFS plastic ampoules, COC/COP vials, etc
Laser drilling technology is the authoritative positive sample preparation technology which is the most close to the natural defects recommended by FDA and cited by USP1207. It is also highlighted in the draft of the CDE Technical Guideline. Laser drilling can be applied to the verification of packaging CCI test methods such as dye method, microbial challenge method, vacuum decay method, pressure decay method, HVLD method as well as the calibration of leak detector.
