Publications

Incorporating Industrial Forensics into a Quality by Design Approach

Publication Information:

Wolfe, Julianne, Karen Smith, Linxian Wu, “Incorporating Industrial Forensics into a Quality by Design Approach for Foreign Particulate Matter Characterization”, Pharmaceutical Manufacturing, November/December, 2011.

Year: 2011

Topics: Biopharmaceuticals, Laboratory Services, Materials Characterization, Medical Devices, Particle Characterization, Quality Control

In the life science industries, Foreign Particulate Matter (FPM), sometimes simply called Particulate Matter (PM), frequently is referred to as the contaminating components existing in solid forms in final pharmaceutical and biopharmaceutical products. This particulate matter can exist in many different sizes, shapes and chemical compositions. Most pharmaceutical and biopharmaceutical products are specified to be essentially free of visible particulates and are obligated to meet specifications limiting the number of subvisible particulates (USP/EP/JP).

FPM can affect product efficacy, but more importantly product safety. While data from controlled humanstudies are not available due to ethical considerations, numerous animal studies have been conducted to evaluate the potential adverse effects and the possible destinations of intravenously injected particles. The concerns for the adverse effects of FPM on humans have been clearly articulated for likely having triggering effects on aspects of both toxicity and immunogenicity The critical importance of the investigation and characterization of FPM in the manufacturing processes has been highlighted by recent legal and the regulatory actions taken by the FDA against some of the most established pharmaceutical, biopharmaceutical and healthcare firms in the United States.

In addition, numerous recent product recalls have also been initiated due to FPM contamination issues. These actions clearly point out that new methods are needed to efficiently characterize FPM and reduce lost product while increasing safety and particulate in final products. These quality control mechanisms would typically be employed at the end of the production cycle. It is not unusual that visibility of the FPM would occur only after the products are released and shipped to the customer destination to be reported by the customers. Presumably, under those circumstances, the visible FPM in the products could derive from the sub-visible particulate due to aggregation, agglomeration, precipitation or settling during the transportation processes. This type of outcome particularly poses specific challenges to the current inspection mechanisms in controlling FPM contamination. Furthermore, none of the existing compendial methods employed for analyzing FPM calls for the characterization of potential contaminating materials which would facilitate source identification.

All pharmaceutical and biopharmaceutical firms follow compendial testing requirements which set standards for inspection of visible particulate, and also for examining the size and quantity of sub-visible

It may not be unrealistic and unreasonable, in our opinion, to consider the current FPM inspection and examination methods as reactive “Quality by Inspection” methods. During recent years, the concept of “Quality by Design” (QbD) has been gaining momentum in its acceptance and adaptation. The application of the concept into the life science industries has been well explained and established by the FDA (sometimes referred as Pharmaceutical Quality by Design).

More and more drug manufacturers are participating in the FDA’s CMC (Chemistry, Manufacturing, and Control) pilot program for product submission. This program requires the incorporation of QbD into the product by accomplishing process design and development in a different and specific way.

The QbD concept places emphasis on systematically understanding and determining the critical quality attributes (CQAs) related to the process, risk assessments for those critical attributes and the associatedmcontrol strategies. Due to the critical importance of FPM contamination, we believe that a systematic approach in understanding, monitoring and characterizing FPM will enhance the product quality as a whole because these preventive procedures will increase understanding and decrease FPM variability.

This proactive approach parallels QbD concepts more readily than the reactive approach of current compendial methods described above.