As of March 1, the pharma industry finally has comprehensive guidance in the form of USP <1790> Visual Inspection of Injections, which becomes effective in August 2017.
The Inspection Life-cycle’s principle is characterization, classification, and trending of particle defects after a 100% visual inspection on a scientific basis for continuous process improvement. The basis for the trending is building and continuously updating a library for defect particulates. The goal is to develop a knowledge base and trained inspectors for reliably grouping and trending those defects.
The holistic model and life cycle approach for defect prevention and control is monitoring of each potential source of particulate matter. This includes particle burden control of primary packaging materials, such as elastomers and glassware, but also periodical inspection from gowning, handling, and cleaning materials to the filling environment, tubings, and pumps. Supplier acceptable quality limit (AQL) on particulate matter levels from primary packaging components to active pharmaceutical ingredients (APIs) and the control of critical process steps such as cleaning in place (CIP) are control requirements.
Visual Inspection: 100% /AQL Inspection
Component and Packaging: Primary Packaging (glassware and elastomers) as well as API, Excipient Testing and Acceptance
Handling and Filling: Component Preparation, Filling, Handling
Special Samples: Stability, Retention, Customer Complaints
By this approach, it becomes possible to build quality into each step of the process and minimize particulate matter rejects.
To establish this robust and scientific approach, the operators for visible inspection and characterization need to be continuously trained with actual defects. Properly trained, they are able, by means of quick visual characterization (Level 1), to investigate a large number of samples in little time. Atypical [never seen before] particles need to be isolated and analyzed with a microscope (Level 2) and further characterized by means of spectroscopy (Level 3) to populate the library of defect. With this life cycle approach, the library of defects is then populated and continuously updated with thoroughly investigated particulate matter – on the molecular scale by means of Raman EDS and on the atomic scale by means of LIBS.
By establishing Alert and Action Levels, the right measures lead to better control and improvement of your manufacturing processes.
With these high quality in situ images and thorough spectroscopic information, the library of defects is populated, and training sets can be put together to train operators in the life-cycle concept outlined in the USP <1790>.
General particle materials classification can be made in these groups:
Inherent particulates are made entirely of components of the formulated product, arising from the product itself. These particles are related to the product formulation (e.g., API proteins, API suspensions, aluminum salts) which are intentionally present. These particles are not the focus of USP <790> and other compendial guidance on visible particulates and are characterized by other particle size distribution analysis methods such as laser light scattering or image analysis.
Intrinsic process related particles include product contact materials from the manufacturing process or primary packaging components (e.g., glass, stainless steel, elastomeric closure, polymeric tubing, process related fibers from sterilization bags or wrapping materials, and silicone lubricant). These process related intrinsic particle types are typically controlled as a major defect at the time of batch release. They may also indicate product stability from the result of product-contact or interaction over time, such as plasticizers, from package deterioration or due to formulation change.
Particulates that are introduced from foreign or external sources. Any particulate not sourced from product contact materials and/or particles of a biological source (e.g., non-process related environmental natural and synthetic fibers, hair, and insect parts). Due to their unknown origin or sterilization pathway, these particles should be treated as a critical defects, or definitely with more concern than other foreign particle categories.