Visual Inspection of Parenteral Products Part 8 Inspection of Different Kinds of Products / Containers

In the previous parts we discussed inspection of vials and ampoules because they are the most important containers by production numbers and because they were the first to be inspected by automatic inspection machines.

Even though more than 90% of automatic inspection systems are today sold and installed for such containers, we can't forget the wide range of other pharmaceutical containers which naturally require visual inspection and Quality Control as well.

As we will see, the main point is that the features of other containers make it more difficult to achieve an effective automatic inspection and this has slowed down the development and diffusion of automatic inspection for such kind of containers while manufacturers continue to rely more on manual inspection. Nonetheless we can be sure than this gap will gradually disappear because the same push to introduce automatic inspection and its advantages (higher speed, more stable and repeatable inspection level, much better data collection and precision) is there and newer technologies and designs become year after year available to solve technical problems.

Lyophilized Products (Lyo Cake)

According to most regulations, even lyophilized products must undergo the same 100% inspection as liquid products. However, after the freeze-drying and the capping process, the solid lyophilized cake becomes not transparent and the presence of particles can be detected only when they are located on the external visible surface. Furthermore to be effectively detected, particles must provide sufficient contrast with the lyo solid matrix, which usually is white or light yellowish color, because detection cannot be based on movement of particle such as in the case of liquid.

Because the external surface of the cake visible during inspection accounts for only a small fraction of the cake bulk volume there is a much higher probability of non-detection of non-visible foreign particles compared to liquids.

Because of these challenges in visual inspection, it is recommended that a small sample of units is reconstituted and inspected for visible particles in addition to the 100% inspection of the cakes for visible particles. Special care must be taken during reconstitution in order to avoid the contamination during the process and the false identification of the sample as a reject.

Since this is a destructive inspection, it must be limited to a sample set of every batch. As per liquid products AQL check, sampling according to ANSI/ASQ Z1.4 plans can be used.

If particles are detected in this relatively small sample, it is recommended to reconstitute more samples in order to investigate the overall quality and compliance of the whole batch.

Dry Powder Products

Similarly, to lyo cake, also powder filled products are difficult to inspect for particles because of powder flowing and the difficulty of spotting low-contrast particles in the drug itself.

Another common problem for powder products is when during container handling some powder ends up sticking to the inner sidewall of the container, reducing even further the inspection possibility.

Similarly, as described for lyo, sterile powders should also be sampled, reconstituted and inspected for visible foreign particles.

Automatic Inspection of F/D And Powder Products

With the development of newer and better automatic visual inspection technologies, several AVI machines have been gradually developed and introduced to inspect freeze dried and powder filled containers.

The main approach is to replicate the manual inspection by inspecting with several cameras the whole external surface of the cake or the powder looking for foreign particles.

Using this approach, the same automatic inspection machine is able to inspect both freeze dried and powder filled containers.

Despite the additional level of sophistication of these inspection systems, AVI for freeze dried and powder products are becoming more and more common because they have to be compared in performances to Manual inspection which has basically the same troubles and limitations with this class of products.

Emulsions and Suspensions Products

Other important categories of products where basically only the outer surface of content is visible for inspection are suspensions and emulsions.

They are subject to same requirements and similar inspection conditions as freeze dried products, except for the possibility to be spun before inspection to increase the probability of particles detection caused by liquid swirl.

X-rays

An alternative approach to inspect non-transparent products has been based on X-rays characteristic to travel through the matter.

By using X-ray sources and special, suitable cameras, the X-ray inspection system can obtain images which can be processed in rather similar way to conventional automatic inspection systems.

However, X-rays have some intrinsic limitations which limited the success and diffusion of this kind of machines: detection is basically possible only with foreign materials with density very different from product's and there are concerns about the safety of the operators working around the machine and the product itself.

Red/Dark/Amber Containers or Liquids

Manual Inspection of products contained into dark/amber containers or in red/dark is challenging.

Since these containers are still partially transparent to lower frequencies of light (usually red and near-infrared) higher brightness is recommended for manual inspection (8-10.000 lux instead of 2-3750).

It is however important to underline that the human eye is much less sensitive to red light in terms of resolution and contrast perception. Therefore the manual inspection of such category of containers can never be as effective as with conventional transparent containers and products.

On the contrary, in this context, automatic inspection is greatly advantaged and more efficient because cameras, lights and lenses can be optimized to work with the highest resolution and sensitivity in the region of the spectrum where the glass&product  are still most transparent. So with this kind of product automatic inspection can operate well and virtually unaffected in performances by dark color.

Translucent Plastic Containers / Blow Fill Seal (BFS)

Plastic translucent containers are more and more commonly used to compensate disadvantages of glass (easy to break, heavy, needs high temperature sterilization, etc.).

Similarly, to dark/amber containers, plastic is generally much less transparent of glass for visual inspection and therefore manual inspection is not so effective on this kind of products.

Once again, higher brightness is recommended for manual inspection as well as optimization of the lighting setup in accordance to the characteristics of the container.

Even in this case, automatic inspection systems can be better optimized to provide the best resolution and inspection efficiency of these containers, not only in the light and imaging part, but also in the processing software to compensate the lower transparency and contrast caused by the plastic container.

Large-Volume Containers (LVP)

Large-volume containers (usually denominated LVP when above 100 ml but most common in 500ml volume) are more difficult to inspect because they need longer time for spinning and inspection and are larger, heavier and more difficult and delicate to handle. They also more easily generate air bubbles in the liquid during transportation and spinning which we have seen interfering with both manual and automatic inspection and further reducing production and inspection speed.

In case of plastic containers, we have to add as negative factor we saw in the BFS category the reduced transparency of the container sidewall which reduces the ability to detect small particles and illuminate properly the liquid inside.

Despite of these extra-difficulties, automatic inspection machines have been available for this kind of products already for quite a long time and though optimizations and careful design have reached a level of performances generally equal or superior to manual inspection. Their main disadvantages compared to AVI for smaller volume are the bigger size of machine, higher cost and reduced inspection speed.

Soft-bags

The inspection of plastic soft bags can be considered as an extension of LVP containers with the addition of more difficult handling and imaging caused by their shape and construction.

While non-PVC new plastic films used for production are more and more transparent, the bags are often printed on the outer surface and the transparency quickly and easily reduces during sterilization and transportation.

Finally, handling and spinning them for inspection is quite difficult.

Because of all these issues, automatic inspection of soft bags is still very limited and can be considered one of new field of application for future automatic inspection machines.

Pre-filled Syringes (PFS)

The last family of containers to be inspected for injection products is PFS.

This is a rather new sector, where development of automatic processing machines has started only recently and consequently also regulations aren't yet complete nor clear.

In theory they are subject to similar requirements for foreign particles, filling level, capping and container closure system as other containers we checked before, so most manufacturers and designers of automatic inspection machines are trying to mimic the same range of controls.

Because of this, there is a rather wide range of automatic inspection systems already available for PFS heavily customized where controls and specifications also change a lot between machine and machine.

We can consider this field together with IV Soft bags a frontier area for Visual Inspection, where in the future we will see regulators and suppliers of machine work to define, regulate and develop standard criteria and inspection systems for Quality Control.