Poor Quality Leadership from Senior Management.

This week, I will address the sixth of nine common CGMP Quality System shortcomings; Poor Quality Leadership from Senior Management.

I strongly believe that a strong quality environment is cultivated from the very highest levels of management. If senior management cares about quality implementation, then all levels of the company tend to buy into “quality matters”.

Inversely, if senior management doesn’t fully appreciate the direct connection between quality management and the bottom line, then a sub-robust quality system is likely to materialize.

A Quality Director isn’t likely to successfully implement a Robust Pharmaceutical Quality System, if Senior Management views the quality function as simple overhead. That Quality Director is likely to meet resistance at every turn and not receive the resources necessary to establish and maintain a health and effective quality system.

Unfortunately, it is unlikely the Quality Director will have the necessary influence to correct Senior Management’s quality short-sightedness, but it probably is worth an attempt. If all else fails, then it is probably best to search out a new corporate quality culture.

Under Utilized Quality Tools

This week, I will address the fifth of nine common CGMP Quality System shortcomings; under utilized Quality Tools.

Modern Quality tools, such as SPC and PAT, can be very beneficial in establishing an effective Quality System. Ironically, many of the quality tools necessary to implement a Robust Pharmaceutical Quality System are already part of most Quality Systems. They just tend to be under utilized.

A significant under utilized tool is the Annual Product Review. I have found that most manufacturers complete this regulatory requirement simply to complete it, as opposed to completing it to gain product/process characterization knowledge. Most of the APRs I have read go something like this, “we produced “X” amount of batches, most batches meet specifications, root causes and corrective actions were completed for those that didn’t, and no negative trends were observed, therefore everything is beautiful and no process improvement is required. What a complete pencil whipping exercise.

Another under utilized tool is qualification/validation studies. These studies are often written to ensure that they pass. The functionality of these studies is to ensure all facilities, equipment, utilities, and/or processes are functioning sufficiently to ensure problems are minimized during commercial manufacturing. As a QA reviewer, I was often frustrated with change control requests that were submitted to fix problems with equipment or processes that recently passed validation activities. In these cases, validation activities were not completed appropriately.

To overcome this shortcoming, the Quality Unit should maximize the return from their established quality tools by complete more thorough and objective analyses and evaluations.

An “It’s Approved, Don’t Improve It” Mentality

This week, I will address the fourth of nine common CGMP Quality System shortcomings; an “It’s Approved, Don’t Improve It” Mentality.

I have found that many manufacturers have a resistance to improving their process because of a potential to impact market supply. Although regulatory hurdles associated with significant processing changes could create difficulties, not making changes for this reason can be short-sighted.

Immediately after licensing a product, most manufacturers shift their focus from gaining product approval to increasing market demand. Once successful, they often experience manufacturing capacity limitations due to their initial efforts to minimize capital start-up costs.

With an emphasis on increasing market demand and manufacturing capacity, proactive and continual product / process improvements are often minimized. When this focus shift is combined with limited initial product/process characterization, product quality can be put at risk.

It has been said that “the process is the product.” A sub-robust process can create significant issues for the most rigorous Quality System. When processing methods, techniques, and materials are not sound, then manufacturing difficulties are bound to surface. Likewise, if the product is sensitive (i.e., susceptible to oxidation), then a robust process becomes essential to assuring product quality.

To overcome this shortcoming, the Quality Unit should not lose sight of the importance of continually evaluating the product and process to achieve a better understanding and to increase the processes' robustness.

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.