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
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.
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
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) |