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Visual Inspection of Parenteral Products Part 5: Container Closure Integrity - From Regulations to Production

Commonly referred to also as "Leak Control/Testing", the CCIT (Container Closure Integrity Testing) is intended to test and confirm that each container is properly sealed and cannot allow the contamination or spillover of product inside.

Even though integrity test has been required for a long time by regulations and pharmacopeias, only starting from 90's it has become more clear how to implement it into drugs manufacturing because new technologies and control systems have developed enough to become effective and be validated and used in production lines.  

Definition

Container closure integrity (CCI) is the ability of a container closure system to maintain the sterility  and product quality and quantity of sterile final pharmaceutical, biological, and vaccine products throughout their shelf-life.

The above definition implies two different processes: the design and validation of the container and its closure system in the first place and the inspection of it after manufacturing then.



Design of Container and Closure System

The very first step to take is to choose and design the container and its closure system in such a way that they can guarantee the required stability and integrity not only after manufacturing, but for the whole shelf life of the product. This design should then be validated.

There are several factors involved in the design and validation of a good Container Closure System:

?            The material used for the container must be stable in time and in contact with the product inside without affecting its features, safety (i.e. sterility) and medical efficacy.

?            It must stop external gases, liquids, microorganisms and other foreign material to enter and get in contact with the product or the product to leak outside.

?            In case of photosensitive products, the container must be able to block most of the light, and specially its high-frequency component such as blue and ultraviolet to protect the product.

?       It must be also able to withstand the changes in temperature and mechanical handling, shacking and movements expected throughout the whole shelf life of the product including manufacturing, packaging, shipping, storage and use periods and phases.

?            The closure system of the container must be able to provide a similar level of integrity after product filling and final assembly.

?            Additionally, all interactions between container-closure and closure-product must be similarly analyzed and confirmed over the whole shelf life and range of storage and use of the product.

?            Both the container and the closure system should be economic  to produce and manage, easy to inspect for quality assurance, easy and safe to operate even by common people without special skills or knowledge and finally easy and safe to dispose after use.


If we assume a good design of the Container Closure System, that all materials involved in the primary packaging (i.e. in direct contact with dosage form) have the required characteristics and stability in time, that their coupling and assembly is also stable and resistant throughout product life and under all conditions then we can shift our attention to the Quality Control of CCS.


Closure Container Integrity Testing (CCIT)

The Testing of integrity of parenteral containers (also called Leak test or detection) has become more and more important during last decades.

This is due to two main factors: on one side the technological developments of new control systems more affordable, reliable and easy to integrate in the manufacturing process, on the other the criticality of this control and its direct connection with sterility.

The most critical requirement for the safety of parenterals is sterility.

A drug contaminated by microorganisms can seriously harm the receiving patient, therefore the real danger in case of integrity breach/lacking is that external microorganisms are allowed to enter the container and once there they multiply so much that when the drug is administered to patient the germs load can severely affect its health status.

This is way most regulators are moving quickly toward a mandatory 100% CCIT for all parenteral products, even though as of today this is required only for containers closed by fusion (glass or plastic ampoules) and samples of other containers should be checked for integrity according to appropriate procedures (to be defined and validated).

It is widely accepted that within next years the 100% integrity test requirement will be gradually extended to all kinds of containers and all pharmacopeias.

This way of reasoning has brought to the very first requirement ( USP<1> ):

Validation of container integrity must demonstrate no penetration of microbial contamination or gain or loss of any chemical or physical parameter deemed to be necessary to protect the product

Other European and Japanese pharmacopeias are similar and based as well on the prevention of microbial contamination. So the first step to do in order to fulfill this requirement is to understand the minimum size of hole/crack/leak which could allow dangerous microbial contamination to enter the container.


Similarly to what we have seen about the particles inspection where the pharma industry first and regulators then have found the way to move from "Visible particles" definition to practical technological measurement and systems that can be put in the production line and qualified, to implement and validate a CCIT it is necessary to find first of all a scientific, reasonable way to move from mCCI (microbiological container closure integrity) to pCCI (physical container closure integrity) requirement.

Once again, as for particle inspection, no real method is given within any Pharmacopoeia, no correlation between the mCCI and pCCI and no indication on how to perform and validate such test on 100% of production.

So the first step was to consider the smallest bacteria size and define the maximum allowed "hole diameter" accordingly. According to the size of smallest bacteria, it was initially considered that every hole / crack / leakage bigger than 0.6 um was big enough to endanger the sterility of the product and therefore needed to be found and rejected by CCIT.

Starting from 2000 however, more recent studies involving containers with calibrated holes immersed into bacterial culture baths have proven that this limit is far too low and unrealistic.


Those studies have shown that more realistically only holes bigger than 5μm start posing a risk for the sterility of containers in most cases.

At the same time other studies with very accurate laboratory systems (Helium spectrometer) have demonstrated that the diameter of a hole is not a reliable measure for leaks of gases, specially when the diameter of such hole is smaller than 30μm.

When the diameter falls below that limit, the features of materials such as glass, metal, rubber and other factors such as the thickness of the wall influence heavily the consequent leak.

We will see in the next part the full range of CCIT methods available today on the market. Some of them like Helium spectroscopy and Blue Dye can be very precise and sensitive but they're also by nature destructive, slow and expensive and therefore they can be used only on samples in laboratory controlled conditions.

Other technologies, such as High voltage, Pressure/vacuum decay, Head space laser and Visual inspection are on the other hand fast, non destructive and suitable to be implemented in production on 100% of products but they are also less accurate and often produce more qualitative then quantitative results.

There is therefore the need to correlate the precise measures obtained in the laboratory with the measurements obtained in line in order to validate them and this can be achieved much better by expressing leaks by flow rate instead of hole diameter. That's why today it is recommended to express leaks by mass flow rate instead of hole diameter.

In order to test and qualify every CCIT device it is necessary to produce samples with required (or at least measurable) leak flow rate.

Several methods are available, each of them with advantages and disadvantages.

Method

Features

Laser drilled holes

High costs, long preparation times, small holes can clog easily specially with highly viscous liquids.

Positive controls cannot be prepared directly on the product for stability testing purposes.

Copper wire

Undefined leak path and size with limited reproducibility.

Difficult sample preparation, assembled container closure system needs to be manipulated in order to introduce the artificial leak.

Micro pipettes

Very sensitive towards breakage, difficult to prepare.

Check of leak rate before and after testing highly recommended.

Complete seal around micro pipette is required.

Microcapillaries

Commercially available in a wide range of hole sizes (2-75 μm).

Well defined leaks through adjustment of length.

Possibility to prepare positive controls in a specific packaging format and for multiple products (e.g., syringes and vials)

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