FDA publishes Draft Guidance on Visual Inspection of Parenterals

It has been known for some time that the US FDA is working on its own guide on the visual inspection of parenterals. Now the draft has been published as a 15-page document.

The new guide "Inspection of Injectable Products for Visible Particulates" is intended for use in development and manufacturing and is supposed to cover visual inspection, particle identification and measures to be taken if particles are found. Sub-visible particles are not included in the paper.

The FDA references the USP Chapters <1> and <790> with the requirement that injectables be "essentially free" of particulates. Likewise the authority writes that compliance with the USP Chapter requirements alone is not sufficient to achieve GMP compliance. The USP chapter <790> first defined the requirement "essentially free from particulates" via an AQL of <= 0.65. Depending on the risk, the FDA sees the possibility that a product must meet stricter standards than those described in the pharmacopoeias.

Risk Assessment

The FDA continues to see a major patient risk from particles in injections. The risk is influenced by the route of administration, the patient population, the material of the particle, its size and shape, the number of particles and thus the possible impact on cell tissue (immunogenicity, infectivity, carcinogenicity). The FDA cites case reports from 2012 and 2014 here, where in connection with injected particles are described: Infections and venous and arterial embolisms as well as microembolisms, abscesses and granulomas in visceral organs. Venous inflammation, granulomas and local infections have been reported at injection sites.

As early as in the development stage, the manufacturer should identify the particles typical for the production process, their size distribution and their composition, and describe the risk for each type of particle. Likewise, analytical methods to monitor the particles and strategies to reduce their load should be defined.

The FDA distinguishes three types of particles: intrinsic (the product itself or originating from the formulation), intrinsic (originating from the process), and extrinsic (from outside the process, i.e., the manufacturing environment).

• Inherent particles should not lead to rejection of the product, insofar as they are a property of the product and the release criteria are met in this regard. For products that are difficult to inspect, such as emulsions, the manufacturer should develop/implement additional test methods to address this.
• Intrinsic particles originate from the process or the product contacting parts of containers or equipment (glass vials, glass delamination, rubber stoppers, piping, filters, valves). The medicinal products manufacturer is supposed to use development studies to determine how and where these types of particles originate in their process and establish device/equipment life spans.
• Extrinsic particles originate from the process environment and come from sources where product contact is not intended. These particles pose a higher risk of microbial contamination of the product. For the FDA, the presence of extrinsic particles in the final product means deficiencies in environmental control, equipment design, age or maintenance of equipment, etc.

Visual Inspection

For the FDA, the 100% visual inspection of parenterals is only one part of a larger program to ensure that products are "essentially free from particles," as envisioned in USP Chapter <1790>.

The visual inspection program is intended to fit the product and manufacturing process. Thus, if there are changes in, for example, batch size or the manufacturing process, it may be necessary to revise inspection and/or statistical methods. In addition to visual inspection, a particle control program shall include employee training and qualification, discrepancy investigation, root cause analysis, and CAPA measures. In addition to 100% visual inspection, statistical sampling and testing shall be performed by the Quality Unit (AQL Testing). The 100% inspection should take place at the time when the probability of detecting particles is highest, e.g. before labeling product containers.

The FDA lists all three types of 100% visual inspection. Manual inspection, semi-automatic inspection, and automatic inspection. Automatic control can be used as part of an examination in the inspection process, as a substitute for manual inspection, or as an additional quality assurance step. In automatic inspection, different wavelengths or sensors can be used to better inspect products that are difficult to inspect visually. The FDA specifically mentions cameras, diode array, X-ray, near-field radar, UV and NIR spectroscopy.

Medicinal product manufacturers should conduct statistically sound studies on the detection of visible particles, the duration of the inspection of a unit, the illumination and the time frame for fatigue of the (manual) operators. The conduct of the visual inspection must be fixed in writing. Parameters such as swirling, inversion, distance from the light source) and the maximum duration of inspection without rest (for manual inspection) should be described  there.

For Large Volume Parenterals (LVPs), the FDA sees a greater risk to the patient in terms of particles, as the large volumes administered increase the likelihood of particles appearing. Therefore, these products should be subject to the same level of inspection as small volume products. The drug manufacturer should take appropriate measures to ensure adequate 100% control in this area as well. Additional destructive testing may be appropriate.

Opaque products and containers (e.g., freeze-dried powders, suspensions, dark containers) are also difficult to inspect visually. The above technologies (X-Ray, NIR, etc.) can help, as can additional destructive testing after 100% inspection. However, additional destructive testing may not be warranted if it has been validated that the technology used meets or exceeds human inspection requirements.

Statistics and AQL

After 100% control, the manufacturer should use statistically sound sampling plans, validated control methods, and appropriate acceptance criteria to ensure that each batch of product meets a pre-determined AQL for visible particles. Here, FDA concurs with the USP chapters <1> and <790>. However, for higher risk products, FDA believes that more stringent criteria may be appropriate. Sampling plans should consider any defect classification or quality characteristic to be tested.

Extrinsic particles found in the 100% inspection or AQL of the batch, indicating major sterility or GMP compliance issues, may result in product rejection even if the acceptance criteria of AQL testing are met. Similarly, the presence of multiple visible particles (extrinsic or intrinsic) in a single product container may indicate manufacturing problems and should trigger increased batch testing.

Training and Qualification

With regard to the training requirements for manual inspection staff, the FDA paper does not contain any news. In terms of equipment, a distinction is made between the three types of inspection. For manual inspection, the specific background and light intensity used should be qualified. Semi-automatic inspection equipment should be calibrated and rotated for a specific speed with the container and should be qualified with respect to belt speed and illumination. Qualification/validation of fully automatic equipment should be based on comparison with and equal to or better than human inspection capability. This can be qualified using test kits or artificial intelligence. Test kits should be approved by quality assurance. As a rule, the percentage of defective units in a test kit should not exceed 10-20%.

Procedures in case of deviations

Deviations from the inspection process, in quality control tests or through complaints should aim to identify the particles and categorize them in terms of intrinsic or extrinsic. This may result in exacerbated sampling plans and investigation of the particle origin. Investigations should be conducted when individual or sum defect limits are exceeded and when a batch fails to meet AQL limits.

Atypical trends should also be investigated, as should the occurrence of units with visible particles not commonly observed.

The FDA also makes statements regarding reinspection. Thus, reinspection of a batch is generally possible if scientifically justifiable. This should be done according to approved SOPs with tightened acceptance criteria. The FDA also recommends not more than one reinspection of batches found to have atypical defects. Samples that failed the AQL reinspection should be included in the calculations along with rejections from other testing of the product (e.g., from the 100% inspection and from the original visual AQL inspection) to account for all unit batches.

The new FDA Guide, "Inspection of Injectable Products for Visible Particulates," was published in December 2021, and comments can be submitted until 15 February 2022.