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Lack of Compendia Harmony for Visible Particles Causing Confusion

Dan Berdovich, Micro Measurement Laboratories and James Melchore, Melchore Consulting

The major compendia require sterile injectable and ophthalmic drugs to be prepared in a manner that is designed to exclude particulate matter (1-4). In the United States, this requirement is satisfied by testing for subvisible particles in the laboratory (USP Chapters <788> and <789>) and 100% inspection of all containers for the presence of visible particles (USP Chapter <1>).

For subvisible particles, there is harmonization across the major pharmacopeia. For visible particle inspection (aka, “visual inspection”), harmony does not exist, and this is causing confusion in the industry.

Background

Inspection for visible particles is performed in the operations area using one of three methods. Manual inspection is based on human visual acuity, the ability of the inspector to distinguish between conforming and nonconforming containers and remove nonconforming units. Semi-automated inspection is a variation of manual inspection, in which a roller conveyor handles and presents the containers to the human inspector. Fully automated inspection systems perform handling, inspection and rejection of defective containers. All inspection methods must meet the compendial requirement for sterile drug product to be “essentially free” of visible particulates.

Given the random occurrence of particles within the batch, visual detection of a particle in an individual container is probabilistic. The probability of detection for a specific particle is affected by many variables that include product attributes, container size and shape, particle composition and size, and inspection capability. The challenge set is a useful tool to assess the particle detection in product, and it may also be used to evaluate detection of container/closure defects. While the importance of a well-designed challenge set is not always recognized or understood, it serves as the cornerstone for qualification and/or validation of all inspection methods. This article is intended to provide useful information for the design, composition and use of container challenge sets for particulate inspection studies.

Inspection of product in the operations area is primarily focused on container/closure defects and particulate matter in product. Both type defects present potential harm to the patient; the circumstances surrounding their detection and rejection, however, are very different. Most container/closure defects are easier to detect than particulate matter in product and guidance provided by PDA and the U.S. FDA has enabled companies to create clearly defined acceptance criteria and disposition for each type container/closure defect (5-7).

Harmony and Disharmony

The major compendia have harmonized the testing methodology and acceptance criteria for subvisible particles (1-4), however, the absence of a harmonized guidance for visible particles has led to confusion in the global industry.

Harmonization for subvisible particulate matter has been in place since 2007, with USP <788>, USP <789>, which describes two different methods, light obscuration and microscopic membrane. Recommendations and guidelines are described in USP Chapter <1788>, which describes equipment qualification and sample preparation methods. Unlike subvisible particulate matter testing, visual inspection of containers is probabilistic. Regardless of the method performed, it requires a human baseline to connect any method to human vision, which is probabilistic.

The wording in the major compendia for visual inspection, however, varies. At best, the pharmacopeias share only the vague expectation for injectable and ophthalmic products to be “essentially free” of visible particulate matter. This expectation is based on human visual acuity, which is subjective and can be affected by many variables.

Many questions and issues arise in discussions about the various uses of challenge sets and even more confusion exists as to what particles should be included. Also, there is a good deal of disagreement on how these sets should be utilized for qualification and training of inspectors, as well as validation and qualification of automated systems. What uses are served best by challenge sets that include real rejects and which uses can be better served with challenge sets that contain spherical particle standards? Which challenge sets must be NIST traceable? Should the challenge set contain only absolute rejects and blanks? How many reject level containers, how many blanks. Should there be “grey zone” containers? Many of the answers to these questions are further complicated by the attributes of the container as well as the formulation, especially for many biologics. What constitutes a suitable challenge set? Particle size which might be suitable for clear vials will not be the same as those for amber vials or ampoules or even syringes or administration bags. Packaging technology is moving forward and new containers are being considered that reduce cost and allow improved administration. New (often complex) formulations are being introduced along with very small volume containers for ophthalmics. Some products are viscous.

In the search for a quantitative approach to validation, much attention has been given to particle size as the criterion that contributes to particle detection, but studies show that other particle attributes including shape, composition, reflectivity, color, contrast, density and particle behavior (such as during spinning and inspection) must also be considered.

Because of the considerable differences between products, packages and formulation attributes, there are many issues that regulatory agencies will need to deal with if specifications are going to be adopted for the industry as a whole. The authors would like to suggest that the regulatory bodies consider an interim means to reduce and/or eliminate much of the current confusion through two key areas:

  1. Introduce a high-level (guidance) document containing recommendations that affect key areas of the inspection process
  2. Provide guidelines for the design and uses of challenge sets for visual inspection of most products. This would provide the manufacturer of each product/package to develop the information and practices under this framework.

[Authors’ Note: In the absence of a harmonized guidance, we are preparing a review article which is based on published studies and experience gained in the design and use of challenge sets for particulate matter studies. We believe this article will shed some light on many issues in the inspection process. It describes differences in various challenge sets as well as their use as a means to achieve better agreement and harmonization in visual inspection. The manuscript is currently going through the peer review process for the PDA Journal of Pharmaceutical Science and Technology, though there is no guarantee as of yet that it will be published in that Journal.]

References

  1. Particulate Matter in Injections, <788>; Particulate Matter in Ophthalmic Solutions <789>; Methods for the Determination of Particulate Matter in Injections and Ophthalmic Solutions, <1788>. USP 34-NF 29; United States Pharmacopeia: Bethesda, Md. 2011.
  2. Particulate Contamination: Sub-visible Particles; Method 2.9.20, 6.0, 1, 302. European Pharmacopeia: 2011.
  3. Appendix XIII B. Particulate Contamination: Visible Particles; Ph. Eur. Method 2.9.20, I, A322. British Pharmacopeia: 2011.
  4. Insoluble Particulate Matter Test for Injections: The Ministry of Health, Labor and Welfare Ministerial Notification No. 285, 15, 6.07, 110. Japanese Pharmacopoeia: 2007.
  5. Guidance for Industry, Container Closure Systems for Packaging, Human Drugs and Biologics, Chemistry, Manufacturing and Controls Documentation. U.S. Food and Drug Administration: May 1999.
  6. PDA Technical Report No. 43: Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing. PDA: 2007.
  7. PDA Technical Report No. 27: Pharmaceutical Package Integrity Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing. PDA: 1998.

About the Authors

Dan Berdovich started Micro Measurement Laboratories (MMLabs) in February of 1998 to expand his focus on particulate matter testing and particle size analysis by offering his experience through contract testing. Today, the lab provides several analytical and problem solving services, using a wide variety of the latest, state of the art, instrumental, microscopic and imaging techniques. Dan has over 20 years experience in, and a reputation for, solving particle-related problems found in formulations, ingredients, medical devices as well as many types of package components. He has developed and validated hundreds of methods and assisted manufacturers in regulatory submissions related to dozens of particle related issues.

James Melchore Jr. is the Principal Consultant for Melchore Consulting. He has over 30 years experience in pharmaceutical/biotechnology operations and has specialized in validation and training in the areas of inspection and cleaning methodologies. He offers evaluation of existing inspection programs, corrective actions, creating new programs and writing supporting documentation to include protocols, reports, SOPs and Validation Master Plans. Prior to consulting, he was an associate director of validation/process engineering for Enzon Pharmaceuticals Inc. Prior to that, he was the director of technical operations for Bracco diagnostics. From 1971 through 1997, he worked for big pharma, first for Novartis (1971-1986), then with Bristol-Myers Squibb (1986-1997).

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