Inundated Quality Systems and Personnel

This week, I will address the third of nine common CGMP Quality System shortcomings; Inundated Quality Systems and Personnel.

If your company is like most of the companies that I have encountered, the Quality Systems and Quality Personnel are pushed to their limits. Sometimes this is the result of working with a less than robust process and/or an unstable product, but often it is the result of an over extended Quality System. I once inspected a facility that had over 5,000 non-conformance investigations within one year. Can you image what it takes to adequately complete and manage that many investigations? It amazes me how a manufacturer can be content to tolerate such a large amount of investigations.

Yes, Quality Systems must have adequate product quality controls, but sometimes these controls can be so stringent and rigid that it becomes almost impossible to meet them consistently. An effective Quality Systems must be able to adequately control the process, product, and testing, while still provide sufficient flexibility to avoid redundant and/or needless investigations? Overly stringent requirements can quickly inundate a Quality System to where it becomes inefficient and non-functioning.

It is “the boy that cried wolf” syndrome. When everything becomes a crisis, then a real crisis may be lost in the busyness of the day. In biology, there is a term called “adaptation”, where organisms become desensitized to a regularly occurring event, stimulus, or condition. For example, if the fire alarm is constantly going off for no reason, then people start ignoring it and are not likely to react when the alarm goes off for a real fire.

One of those 5,000 investigations involved a detrimental product/container interaction that was not identified as such. I am convinced that this investigation was not given its due focus due to the overwhelming number of investigations being conducted on a daily basis.

To overcome this weakness, the Quality Unit needs to ensure procedures and processes have sufficient flexibility to allow for non-impacting variability and eliminate needless investigations. Monitoring parameters should be periodically adjusted to eliminate “background static” (i.e., non-essential alarms and/or notifications). Once the needless investigations and nuisance alarms have been eliminated, the Quality System can focus on addressing real issues and improving product / process robustness.

Un-Refined Quality Monitoring

This week, I will address the second of nine common CGMP Quality System shortcomings; Un-Refined Quality Monitoring.

When limited development information is available, Critical Quality Attribute (CQA) and specifications may have been established too loose or too tight. If set too tight, the CQA and/or specifications may be regularly exceeded, thus causing extensive investigations and/or product to be scraped, reworked, and/or released under questionable justifications. If the CQAs and specifications are set to loose, poor product quality may go undetected. Setting precise CQAs, specifications, and processing parameters can be difficult to achieve using limited small-scale and bench-scale data. During a typical technology transfer, a set of CQA parameters and specifications are inherited from the development group’s smaller-scale experiences. Often, these CQA parameters and specifications have not been exactly determined and tend to be a best guestimation. Critical processing parameters are established with the goal of meeting these CQAs and specifications. Phase III clinical lots are made using these processing parameters and specifications. If these clinical trials are successful, then the CQAs, processing parameters, and specifications become the gold standard for determining product quality. I have often heard people simply justify process deviations by stating specifications were met. This may be acceptable justification or it may not, depending upon the how the specifications were determined in the first place.

During commercial scale-up, process validation is typically completed in full-scale equipment using these processing parameters and specifications. Often, the limits of the processing ranges are not tested during process validation and sometimes not even tested with bench-scale studies.

CQA and specification ranges must be established to allow for inevitable processing and testing variability, but obtaining product quality and/or stability data at the range’s extremes is generally not obtained by the time of commercial manufacturing. Due to this limited processing/product knowledge at the start of commercial production and the learning curve associated with new processes, procedures, and assays, manufacturing management often experience difficulties with the product and/or process during the first year of production. As manufacturing works through these difficulties, significant process and product characterization knowledge is obtained. After several months of commercial manufacturing, process/testing variability typically settles into a more stable pattern.

To overcome this shortcoming, the Quality Unit should closely monitor all critical processing parameters using Statistical Process Control (SPC) to enhance their process characterization knowledge. To facilitate this endeavor, product reviews should be completed quarterly instead of annual for new production lines. Ideally, better product and process characterization should be completed prior to initiating commercial manufacturing with the goal of obtaining each critical processing parameter’s edge of failure.

Narrow-Focused Development Program

This week, I will address the first of nine common CGMP Quality System shortcomings; Narrow-Focused Development Program.

Current Pharmaceutical Quality Systems tend to inherit a process/product designed and developed by a completely different internal organization. The research and development groups are typically concentrating on the enormous task of finding a suitable molecule and developing it into a useful drug product.

Consequently, commercial manufacturing efficiency and robustness is not typically the primary objective on anybody's agenda. Due to the tremendous resource requirements to research and develop a product, extensive product/process characterization knowledge is not often obtained prior to commercial scale-up.

To compound the issue, commercial management is often not introduced to the new product/process until the initial stages of technology transfer. By that time, it may be difficult for value-added input to be provided.

With these development restrictions, the initial commercial scale-up of a product is often less than robust. The first several years of commercial manufacturing often involve working through the inherited product/process short-comings. This trial-by-fire experience is often clumsy and inefficient.

To overcome this shortcoming, the Quality Unit should take an early interest in the product development and characterization process and continue that investment through the life cycle of the product. The Quality Unit should view product reviews as an opportunity to provide continual product improvement and characterization input.

Typical Shortcomings of GMP Quality Systems

During my many years of reviewing and working with CGMP Quality Systems, I have encountered several reoccurring shortcomings. Although a given Quality System is not likely to have all of these shortcomings, most quality systems that I have evaluated have at least one of them.

Nine common CGMP Quality System shortcomings are:

1. Narrow-Focused Development Program
2. Unrefined Quality Monitoring
3. Inundated Quality Systems and Personnel
4. An “It’s Approved, Don’t Improve It” Mentality
5. Under Utilized Quality Tools
6. Poor Quality Leadership from Senior Management
7. Resistance to New Technological Advances
8. Meager Internal Auditing Program
9. Ineffective Training Programs

Over the course of the next nine week’s I will elaborate on each of these Quality System shortcomings and provide suggestions on how to overcome them.