Inspection of Lyophilized Products: From Regulations to Implementation and Production (part 4)

We have discussed in previous part 3 the main regulations and requirements about visual inspection covered by USP, EP and JP pharmacopoeias.

It is crucial to point out that in most cases such regulations and requirements do not actually explain in detail which systems, procedures and technologies should be used in order to achieve the required results such as “Essentially free of visible particles" or “The packaging system should be closed or sealed in such a manner as to prevent contamination or loss of contents”.

Furthermore, not only the choice and implementation of actual systems and technologies to be used is left to the manufacturer, but even more importantly and critically it is also manufacturer's duty to prepare and provide the necessary documents to prove that the whole manufacturing process is under control and able to fulfill all quality and safety requirements.

This situation has always put a lot of pressure on drug manufacturers in the struggle to find the way to close this gap and be able to produce and sell their products to the market while fulfilling requirements.

Let's check how this gap has been closed in lyophilized products inspection first and then in container closure.

Visual Inspection for foreign particles

In order to fulfill the fundamental statement “There should be no visible particles” inside containers it is necessary to define first of all:

  1. What we consider “particles”

  2. How we define “visible” (and consequently non visible)

The term “particle” (or equivalent terms “particulates” or “particulate matter”) was initially defined as "mobile undissolved particles, other than gas bubbles, unintentionally present in the solutions” and we already discussed how they can be classified in part 2.

Inspection in lyophilized products compared to transparent liquids

From quality standpoint it does nt make any difference whether the product to be inspected is in liquid, transparent or non-transparent form or is a freeze dried cake or powder. They are all parenterals and their final destination is equally to be injected into the patient and therefore they all undergo the same quality requirements as far as contamination concerns.

From production and quality control standpoint however the situation is very much different and much more difficult in case of non-transparent liquid products because spotting and detecting foreign particles is much easier and reliable when based on their movement.

This approach has been effectively used since the very beginning for manual inspection of transparent liquids and more recently adapted to semiautomatic and fully automatic inspection systems. This is because small particles present into containers are much easier to spot if they are moving. Non-moving particles are much more difficult to be identified because there is no easy way to distinguish them from small defects or features on the container's external wall (which are common and completely acceptable).

To make things even more difficult, in the case of freeze dried and powder products only the outer surface is visible and therefore eventual particles hidden in the bulk of the product cannot be detected by any kind of visual inspection.

Because of those two critical limitations related to the nature of the product itself, the visual inspection of lyophilized products or powders is limited to the following three approaches:

1.- 100% visual inspection of the outer surface

No matter whether by human operator or automatically by cameras, the outer surface of the cake or of the bulk of powder is visually inspected to detect visible foreign bodies (glass, rubber, metal chips or black particles mostly). The probability of detection is increased by inspecting carefully bottom and top side of the product along with the sidewall and is related to the contrast of the particle with the product and to the uniformity and quality of the cake. On the opposite, lower contrast defects such as white fibers and non uniform cakes will reduce the probabilities and capabilities of detection.

2.- 100% inspection by X-rays

Another solution which has been in use for some time already is the use of x-rays images to be able to inspect the whole bulk of the cake or of the powder. Apparently this approach can solve the limitation of inspecting the outer surface only, but in reality x-ray systems have their own weaknesses and limitations as well. First, x-ray imaging is sensitive to the density of the matter so for example a piece of metal with a very different density will show up even if in small size. On the opposite, a foreign body with density similar to the product will show up with minimal contrast and detection possibility even if large in size. Second, the use of x-rays systems poses a series of issues and concerns related to the safety of the staff working around the equipment and the stability and safety of the product itself.

3.- Destructive reconstitution and visual inspection of samples

The last resort currently used to assess and confirm the quality of lyophilized products is a sampling plan of the final containers. Samples collected from batch and are carefully reconstituted first with sterile water and visually inspected then.

Gradually all international pharmacopeias and regulations have been evolving and adapting more and more to such new topics and technologies. More recently the concept of Acceptable Quality Level AQL has been introduced and added to the procedures recommended to further insure the quality level of visual inspection. The number of samples to be taken and the maximum number of acceptable bad among them is calculated according to ANSI/ASQ Z1.4-2003 or ISO 2859 tables.

This final test, once again purely statistical, is intended to confirm that the previous inspection process was correct and that the whole batch is "Essentially free of visible particles". If this last sampling and analysis complies with requirements, the whole batch can then be released.

Visual Inspection for cake appearance and other items

Besides the presence of particulate matter, other defects can occur during freeze drying process which could affect the drug delivery and efficacy. Most of those items are therefore usually checked during visual inspection:

Cake volume and integrity

The cake volume and appearance are important to assess not only the quantity of the drug, but also the correctness of the freeze drying process. Incomplete or missing drying is related to presence of moisture, for example because of total capping during the drying phase, that can cause degradation of the drug before its use.

Cake meltback, color cast and moisture

Again incomplete removal of all water can cause cake meltback and presence of moisture or liquid in the capped vial. Meltback cakes are much more difficult to be dissolved in water during reconstitution therefore this is a critical functional problem. Cake color different from normal can also indicate some issues during lyophilization process or incomplete capping/sealing afterwards.

Cake breakage, displacement

These are less critical defects, often classified under "cosmetic defects" category, as they don't affect severely the functioning and efficacy of the drug. Nevertheless they can indicate some problem in the handling of the containers.

It's important to recall once more how the development and update of official regulations and pharmacopeias has always been much slower than the production practices and the available technologies and since 90's the first automatic inspection machines and systems have begun to be available on the market. Even though at the beginning the automatic visual inspection machines were primitive and based on basic cameras, computers and lights, the potential and advantages of this technology was immediately clear and a lot of work was made in order to validate such systems and improve their performances.

About Author: Mr. Stefano Arletti, since 2013, he has joined Tofflon introducing and developing Automatic Inspection Machines Development. He is responsible for automatic vision inspection machines to worldwide Pharmaceutical Industry. He has developed several new ideas patented under Italian and European Patent Offices.