Visible particles inspection in powders for injections. Approaches to AQL level

N

norbus

Hi everyone,

considering the monograph which is claimed to be included to USP 37 <790> VISIBLE PARTICULATES IN INJECTIONS, my company is confused in applying proposed requirements to powders for injections. These monograph is aimed to give concrete description of the "essentially free from particles" or "practically free from particles".

There is a description taken from USP forum website:

All products intended for parenteral administration must be visually inspected for the presence of particulate matter as specified in Injections 1 . Dry solids, from which constituted solutions are prepared for injection, meet the requirements for Constituted Solutions under Injections 1 when they are prepared just prior to use. Where used in this chapter, the term essentially free means that when injectable drug products are inspected as described herein, no more than the specified number of units may be observed to contain visible particulates. Particulate matter is defined in Particulate Matter in Injections 788 as extraneous mobile undissolved particles, other than gas bubbles, unintentionally present in solutions. Examples of such particulate matter include, but are not limited to, fibers, glass, metal, elastomeric materials, and precipitates. However, some products, such as those derived from proteins, may contain inherent particles or agglomerates; in such cases, requirements for visible particulates are specified in the individual monograph or in the approved regulatory application.

Inspection Procedure
This procedure is intended for products that have been 100% inspected as part of the manufacturing process, but this procedure alone is not sufficient for batch-release testing. A complete program for the control and monitoring of particulate matter remains an essential prerequisite. Other procedures that have been demonstrated to achieve the same or better sensitivity for visible particulates can be used as an alternative to the one described below.

Inspected units must be free from visible particulates when examined without magnification (except for optical correction as may be required to establish normal vision) against a black background and against a white background with illumination that at the inspection point has an intensity between 2000 and 3750 lux. This can be achieved through the use of two 13-W or 15-W fluorescent lamps (e.g., F13/T5 or F15/T8). The use of a high-frequency ballast to reduce flicker from the fluorescent lamps is recommended. Alternative light sources (e.g., incandescent, LED) that provide illumination within the specified intensity range are acceptable. Higher illumination intensity is recommended for examination of colored solutions or product in containers other than clear glass.

Before performing the inspection, remove any adherent labels from the container, and wash and dry the outside. The unit under inspection should be gently swirled and/or inverted, ensuring that no air bubbles are produced, and inspected for approximately 5 s against each of the backgrounds. The presence of any particles should be recorded.

Batch-Release (Following 100% Manufacturing Inspection)
For batch-release purposes, sample and inspect the batch using ANSI/ASQ Z1.4 or ISO 2859-1) General Inspection Level II, single sampling plans for normal inspection with an Acceptable Quality Limit (AQL) of 0.65%. Alternative sampling plans with equivalent or better protection are acceptable. Not more than the specified number of units contains visible particulates.

Product in Distribution
If it becomes necessary to evaluate the product that has been shipped to customers (e.g., because of a complaint or regulatory concern), sample and inspect 20 units. If no particles are observed in the sample, the batch is considered essentially free of visible particulates. If available, additional units may be inspected to gain further information on the risk of particulates in the batch.

We work with active substances of well-known european manufacturers (such as Sandoz Industrial Products GmbH, Germany). I'll describe a specific case to explain what kind of problem do we have. Manufacturer claims in a specification for substance upper limit for visible particles content - 0.6 / g (this value is for one of the antibiotics powder) that theoretically results to 6 particles per 10 g and so on - in 100 g (1 g in each item - vial) we'll have 60 particles in the worst case. Heretofore we used obsolete state standard which required sample size of 8 vials (8 g) and not more than 15 particles to be found in these 8 vials (requirements for batch size less than 35 000). Our average determined on a finished product (contains only active substance) is 0.4 /g (3 particles per 8 g; but several batches showed 5 particles per g that results to 0.6 / g - which is the limit value stated by manufacturer). We tried to apply ISO 2859 Tables using Special Levels (to decrease sample size because of a destructive type of control - we need to dissolve a vial content in water to inspect the solution - so further this item will be out of the batch that is expensive) - and understood that we can't fullfill the requirement in acceptance number if AQL is taken 0.65 because the starting number of visible particulates is higher than that one which provides the compliance. But these substances are manufactured by one of the best european company so if they do so there must be a reason for that. Sure it's quite obvious that manufacturing of completely particle - free substance is utopia. But if we transform the requirements of ISO 2859 in acceptance number 0 or 1 (1- if the sample size will be increased) into real numbers of visible particulates which must give active substance manufacturers to obtain the needed vaue - the problem will appear.

Batch sizes of our product (powder for injections) starts from 10 000 vials (items). So even Special levels will give sample size from 20 vials. 20 vials=20 grams - if I have 0.6 in 1 g, in 20 g i'll have 12 particles as maximum. Minimum (if I'll take our average values) - 8 particles. It doesn't matter what will I count - nonconformities (visible particles) or nonconforming items (vials) - these values are to high to fulfill the requirements.

My question is - are the manufacturers so bad in what they're producing, or is this approach which recommends USP not applicable for such attribute as number of visible particles?

If someone had experience in solving such problem, please share :agree:
Maybe I misunderstood something about application of ISO or smth like that, so I'd be glad to hear any advice or opinion on this topic.

Thanks :)
 
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