Home > Events >Tofflon Interpretation: Development of Inspection for Lyophilized Product :PART 2 What is visual inspection and why it is required

Tofflon Interpretation: Development of Inspection for Lyophilized Product :PART 2 What is visual inspection and why it is required

Visual inspection of injections (parenteral) was originally developed and it’s still mainly targeted in order to find and remove products containing unwanted particles. This is necessary to minimize the risk of introducing such particles to patient’s body during the delivery of injectable medications.

The same visual inspection is also used to find and reject containers whose integrity and consequently sterility has been compromised. This is again aimed to protect patient’s health from introduction of non-sterile or corrupted drugs and liquids.

Finally, more and more attention is put on minor defects often called “Cosmetic defects” which don’t affect directly safety and efficacy of the injection, but can cause worrisomeness and concern to the final user about perceived quality and safety of the product.

Visible and subvisible particles

The requirements for “Particulate Matter in Injections” are divided into visible and sub-visible particles, and they prescribe that control is performed by completely different ways for those two categories.


Visible particles

The requirements for visible particles can be found in USP General Chapter <1> Injections.

It is required that every container is visually inspected before being released “to the possible extent” and that every container showing “observable foreign and particulate matter” is rejected.

It is further required that “the inspection process shall be designed and qualified to ensure that every lot of parenteral preparations is essentially free from visible particulates.”

Even if there are still significant differences in USP, EP and JP pharmacopeias, they all agree on two essential points:

  • 100% of containers of each batch/lot must be visually inspected under controlled conditions.
  • the inspection process is intrinsically probabilistic.

Visual Inspection of lyophilized products

Being parenterals, lyophilized and sterile powder products are still subjects to the same requirements as liquid Injectables about undergoing 100% Visual Inspection and being "essentially free from foreign particles".

However, because of their nature only the outer surface can be visually inspected, no matter whether by human eye or the camera of an automatic system. The presence of foreign particles can hence be observed only whenever they lie on the outer surface of the product and they exhibit enough contrast against the product cake or powder bulk. In other cases the particles won't be visible nor detectable.


In order to overcome these limitations and achieve a better degree of Quality Control, a certain number of samples is taken out of each batch and reconstituted with pure WFI then visually inspected and checked for particles. Special care must be taken to avoid contamination of the sample by the water or during the reconstitution process, then the detection of particles can be reliably associated to the manufacturing process.


What is “visible” and what is not?

Theoretical resolution of human eye should allow 11mm particles detection but several tests have shown that only particles bigger than 150mm have a significant (>70%) Probability of Detection (PoD) in normal conditions. In this case “normal conditions” refers in reality to “optimal conditions”, the same described in USP.

Any difference in container and product features or observation conditions will affect the PoD of same sized particles (i.e. increase the size of particles with PoD>70%).

Smaller particles can still be occasionally detectable by human eye but their PoD decrease quickly and becomes essentially negligible below 50mm.

Figure 1: PoD of particles under Manual Visual Inspection according to size

Classification of foreign particles by source

Particles can originate from many different sources, sometimes even difficult to identify.

It is common practice to classify them in the following two main categories according to their origin:

Extrinsic (coming from exterior)

Particles that are not part of the manufacturing process.

Common examples are: hair, fibers not related to process, starch, insect parts.

Extrinsic particles are generally one-time occurrence and are considered to be the most dangerous to  the patient because of their non-sterile origin.

 Intrinsic (coming from the process)

In this case particles are coming from processing equipment or primary packaging materials.

Common examples are: glass, plastic or rubber, stainless steel or aluminum, fluid transport tubing, lubricant.

Another source of intrinsic particles is related to the aging and interaction of the product with the container. In this case the particles can appear inside the sterile container after some time or because of movement or temperature changes.

Even if they’re still a risk for patient’s health, they are usually sterile. Furthermore their interaction with the product is more studied and well known than extrinsic particles, consequently they are usually considered less dangerous and critical for patient’s health.


Classification of defects based on their risk level

Another important way to classify defects for pharmaceutical containers is based to the risk and effect they can have on the patient’s health and drug’s effectiveness.

This classification is not limited to particles but includes all other kinds of defects which can affect the sterility and safety of the product (such as a passing crack of the container or a bad sealing) or the dosage of the drug and the appearance of the container.


Critical defects: Defects that may cause a lack of sterility and container integrity that can cause harm to the patient.

Major defects: Defects that may alter or reduce the content or the function of the product/drug.

Minor defects: Defects that do not affect patient health or product functionality but can affect the perception of quality of the product by final user.

Obviously definitions of this kind allow a lot of space to different interpretations and need to be evaluated and set on a QRA (Quantitative Risk Assessment) base case by case and product by product.

For example, a partial meltback of the freeze dried cake can cause incomplete or difficult dissolution of the drug into water and therefore reduce the potency of the treatment. A deformed sealing of a vial can be considered a minor (cosmetic) defect only when it doesn’t affect the proper closure and sealing of the container and the sterility of the product.

 The Risk-based classification of defective containers is essential because many steps related to Quality are based on these three categories of defects and the associated detection rates (for example the criteria for Batch Release or for the Qualification of an Inspection system are based on maximum allowed number of Critical/Major/Minor defects found/not found) 

End of Part 2