Process Analytical Technology
When powders are blended together during drug production, the blending time is critical to the quality of the product. Ideally, it has been optimized to produce a uniform product (typically after 10-30 minutes). However, there is currently no method to detect uniformity during the blending process. As a result, the true optimum endpoint is rarely realized.
If blending is excessive, the particles will segregate (demix or deblend) based on particle size and mass. This deblending is undesirable, as agglomeration may occur and prevent the return to a homogenous state.
The goal of the industry is to assure that pharmaceutical manufacturers cease blending when a homogenous mixture is reached, so that the powder can be dispensed with equivalent dosages. The US Food and Drug Administration (FDA) formalized this objective through the introduction of Process Analytical Technology (PAT).
Non-PAT Environment: One Quality Measure
Current practice dictates that content uniformity analysis be conducted on batch samplings of finished tablets on the basis of active ingredient. Typically, this measurement is accomplished with HPLC (High Pressure Liquid Chromatography) or NIR (Near Infrared). If the tablets fall outside of the FDA recommendation, the entire batch is discarded at significant cost to the manufacturer. The goal in the new FDA draft PAT regulation is to supplement the content uniformity testing with a parallel measure – blend uniformity monitoring of the powder.
PAT Environment: Parallel Quality Measures
Blend uniformity is a function of the formulation as well as the mixing. Once the formulation is optimized from a theoretical process stand point, blend uniformity must be validated during piloting and scale up. Validation involves stopping the blender, extracting a sample and analyzing active ingredient content. After a blend time has been derived and adopted in production, it is typically only reevaluated after poor content uniformity has been detected.
Such variations from the determined ideal blend time are due to batch-to-batch fluctuations of the following influential factors:
- Environment temperature
- Feedstock grade
- Component particle size
- Component particle distribution
- Blender type
By adding uniformity monitoring at the blender, the goal is to catch these issues early and better control them. To address the challenge, the FDA’s Center for Drug Evaluation and Research (CDER) recommended in August 1999, that applicants of ANDAs establish in-process acceptance criteria for Blend Uniformity Analysis (BUA). This recommendation was later withdrawn in May 2002.
In November 2001, PAT was established to motivate incorporation of the following:“Tools and systems that utilize real-time measurements, or rapid measurements during processing, of evolving quality and performance attributes of in-process materials to provide information to ensure optimal processing to produce final product that consistently conforms to established quality and performance standards.”
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