Control of Abnormal Visual Particles in Microcrystalline Cellulose Excipients

Background and Terminology

Abnormal Visual Particle (AVP): A visibly different particle that can be seen with the naked eye that is inherent in the raw material, manufacturing process, or product and does not represent a risk to patient safety.

The matter concerning discernibly distinct particles present in excipients is a significant concern within the pharmaceutical sector. However, the existence of these particles can alter the appearance/description of tablets. This is especially true with uncoated tablets.

Technically Unavoidable Particles are defined as particles that naturally exist in the pharmaceutical manufacturing process. They are considered “technically unavoidable” because they are often inherent consequences of the manufacturing procedures or the materials used. Complete elimination of these particles is not always feasible. Examples of these particles are:

• Black Particles
• Black Specs
• Dark Particles
• Off -Colored Particles
• Charred Particles
• Atypical Particles

Source of Abnormal Visual Particles

As defined by IPEC 2015 guidance, Technically Unavoidable Particles can be product or process-related:

• Intrinsic components derived from raw resources (mined or natural goods).
• Colour variance is inherent to the product.
• Particles stained by heat (e.g., burnt particles).
• Misshapen or morphologically different particles.

Risks Associated with AVPs

These particles have always been found in excipients, but attention and concern about their existence have grown. FDA inspectors issued many Form 483s (adverse findings from an FDA inspection) to pharmaceutical companies for insufficient or incomplete investigations of uncommon, visible particles, which is a major source of concern. These 483s did not prohibit these technically unavoidable particles but rather addressed the inadequacy of the inquiry process. IPEC, USP, and regulatory bodies have not addressed this issue, hence materials are rejected unnecessarily. As a result, both users and manufacturers devote considerable resources to researching particles that are technically unavoidable and pose no risk to patient safety. In many cases, the identity and origin of these particles are already known and have been thoroughly researched by the excipient maker to demonstrate that they pose no harm to the end user.

Risk Assessment

Excipient makers who are aware that their goods (from raw materials to packaging) may contain these types of particles should have conducted a risk assessment to determine which types of particles may be present. Several risk assessment models can be used for this purpose, as detailed in ICH Q9 - Quality Risk Management. Excipient manufacturers should be willing to communicate the outcomes of their risk assessment. Where the excipient manufacturer considers this information confidential, the means of sharing it is negotiated and agreed upon between the maker and the user and is beyond the scope of this publicly available guidance.

Controlling Measures

To keep black particles to a minimum, not only should quality wood pulp be sourced, but a suitable manufacturing process should also be implemented. It can also be part of the specification for the Microcrystalline Cellulose (MCC) release Certificate of Analysis (CoA). This will assist drug product manufacturers in implementing a control strategy and ensuring consistent drug product quality characteristics.

Abnormal Visual Particles Detection Methods

Chemfield Cellulose has studied and evaluated a variety of well-established and widely accepted methods for detecting abnormal visual particles in pharmaceutical excipients, ensuring compliance with industry standards for quality control. These methods include visual inspection through sieve analysis, visual inspection through an illuminated magnifier and surface area count through the glass plate method.

By leveraging a deep understanding of these detection methodologies and aligning with diverse customer requirements, Chemfield Cellulose has developed an in-house AVP technology. This technology ensures comprehensive capture and precise quantification of black particles across all visible size ranges, adhering to the latest IPEC Technically Unavoidable Particle Profile (TUPP) guidelines. This approach helps maintain the highest standards of visual particle control and quality assurance in excipient production.

The detailed AVP detection methodology can be made available to customers under a confidentiality agreement. The Primecel^® range of grades from Chemfield Cellulose consistently exhibits a lower incidence of black particles compared to industry benchmarks. This commitment to quality is clearly demonstrated in the CoA, where black particle counts are carefully recorded to ensure transparency and guarantee high standards of excipient quality.

Investigation Measures for Particle Profiling

• Collecting the samples of Abnormal Visual Particles and measuring the particle dimensions
• Capturing digital photographs for recording purposes.
• Analyzing the particle chemistry based on FT-IR, DSC and other relevant techniques
• Analysis of current and future trends in periodic particle types, with an emphasis on their use in risk assessment and decision-making
• Understanding the materials used in the production process and components such as lubricants, gasket materials, sealants, and other consumable maintenance items
• Heat sources include frictional and added heat sources (drying, distillation, etc.)
• Discuss the continual improvement strategy/processes related to technically unavoidable particles and their formation

Conclusion

The objective of this guide is to help excipient users understand the different forms of normal, inherent, and technically unavoidable particles. This article has defined the expectations for the exchange of information during an investigation that leads to the appropriate disposition of the affected excipient. When the observed particles fall within the range of normal or usual particles expected to be observed with the excipient, the disposition should not result in material rejection.

References

1. Technically Unavoidable Particle Profile (TUPP) Guide. Retrieved May 23, 2024, from https://ipec-federation.org/wp-content/ uploads/2024/05/2024-IPEC-TUPP-Guide-Revision-FINAL.pdf.
2. IPEC, Technically Unavoidable Particle Profile (TUPP) Guide. Retrieved May 23, 2024, from https://ipec.org/sites/default/files/ files/TUPP_GUIDE_2015.pdf (2015).

Author Details

Upendra Reddy, Technical Director - Chemfield Cellulose Pvt Ltd.

Publication Details