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There continues to be much interest within industry and FDA about the future of the GMPs. Discussion groups have been spawned within professional organizations and at FDA to reevaluate the aging GMPs and associated guidance documents to ensure that the government does not impede technological progress, focuses its resources effectively, and upholds its mandate to protect the public.
There continues to be much interest within industry and FDA about the future of the GMPs. Discussion groups have been spawned within professional organizations and at FDA to reevaluate the aging GMPs and associated guidance documents to ensure that the government does not impede technological progress, focuses its resources effectively, and upholds its mandate to protect the public. Although this trend is largely fueled by FDA's budgetary constraints, good things happen when we are reminded to focus on the essentials.
The present struggle within industry and among regulators is to sort out how best to grasp the essentials. FDA must grasp the essentials in order to translate them into regulations and guidance, and industry must grasp the essentials in order to translate them into best practice and consistent behaviors. So far, there have emerged several key themes. We can expect this lively dialog to lead to changes in how we answer the question: "Compliance with what?"
The following is a brief discussion of these key themes that are changing how we think about compliance and several practical examples to elucidate the "mindful compliance" we seek to achieve. Beyond simple compliance with regulations, mindful compliance entails aligning our operations to ensure a data-driven state of control.
Process knowledge is the collective awareness and experience of science and operations technology that ensure a product is manufactured and delivered in a manner consistent with its intended design. The more knowledgeable we are about our processes, the more we are able to control them and evaluate the impact of changes.
Consider the example of a medical device manufacturer that was proud of its progressive approach to managing its component suppliers. Suppliers were certified by facility audits and inspections of incoming attributes on the first ten lots received. Having cemented partnerships with its suppliers, the manufacturer accepted future shipments on the basis of the suppliers' certificates of analysis. However, when an investigation into field complaints for failing devices implicated a certified component, the supplier would not refund the manufacturer because the component met all of the agreed-upon inspection tests.
The manufacturer failed to recognize that qualification of the supplier was not based on anything related to the component's performance in the final product. The manufacturer knew nothing about the supplier's process variability or statistical control. The manufacturer had not communicated requirements in terms that related to the functionality for this critical component. The qualifying audit was too general and largely relied on the fact that the supplier was ISO-certified. Additionally, the incoming attribute inspection was an ineffective predictor of the component's actual performance in use.
The manufacturer had — and followed — a procedure for qualifying its suppliers. However, mindful compliance is based on process knowledge that is data-driven and statistically treated. In this example, loss to the manufacturer in terms of revenue and customer confidence could have been avoided by acquiring process knowledge and making a technical assessment of the supplier's capabilities.
Risk knowledge is the collective awareness and experience of causes of unacceptable effects such as personal harm and financial loss, controls that eliminate risk or reduce it to acceptable levels, and metrics that detect trends toward failure. The more knowledgeable we are about risk, the more we can focus on the most critical aspects of the process and apply more rigorous process development, technical transfer, monitoring, and control.
Consider the example of a drug manufacturer of a liquid suspension. The manufacturer retrofitted the processing equipment of a decommissioned true-solution production line, which seemed like a cost-effective alternative. Mixers were added to all the tanks to ensure even distribution of the suspension in all mixing and holding vessels. The process was readily validated as the firm applied its long-standing process knowledge of liquid manufacturing.
Just days before the new product launch, a uniformity problem emerged. Batch records confirmed continuous tank mixing, and laboratory records confirmed that all testing was in control. Yet, across-the-lot sampling revealed portions that were subpotent and portions that were superpotent.
The manufacturer failed to recognize that tanks were not the only place where even distribution of the suspension was necessary. Upon further investigation, it was discovered that there were periods when filling was stopped to deal with downstream filling issues. Although mixers kept the suspension adequately mixed in the tanks, there was no in-line mixing for the long process lines connecting the equipment train. Although process lines were thought to account for a relatively small proportion of the total volume, the settling of the suspension in the lines during lengthy down times effectively redistributed the active ingredient across the filled containers.
The manufacturer complied with its policy to validate its manufacturing processes. However, mindful compliance is based on identifying and controlling risks. Critical control points of the process are identified and validated, and data from these points are monitored in routine production to ensure continuous control. In this example, loss to the company and the potential for a patient adverse event could have been avoided by a disciplined approach to identifying and controlling risk based on process knowledge.
Quality systems knowledge is the collective awareness and experience of designing, integrating, and implementing written business process instructions that drive consistent behaviors to meet requirements effectively and efficiently. A quality system stabilizes operations by ensuring that required practices are performed consistently and predictably yield the intended result.
FDA cited a biologics manufacturer for an excessive number of open investigations of process deviations and customer complaints. There were hundreds of open investigations, many of which had been open for over 90 days and several over six months. The company promised in its response to FDA to triage the backlog to close out the most important investigations in 30 days and the balance in 60 days. The procedure for conducting investigations was revised to require future investigations to be completed within 30 days. The revised procedure was part of the company's response to FDA. To management's surprise, FDA reported that a subsequent inspection following a customer complaint revealed that the situation remained essentially the same. The open investigations may have been different ones, but the numbers were just as high.
The manufacturer failed to recognize that a revised procedure alone does not change behavior. Concerned about FDA enforcement action for the repeated citation, management conducted its own investigation into the failure to adhere to the new 30-day closure requirement. Many issues were discovered that required management's attention. Foremost was preponderance of the same deviations and complaints, pointing to a lack of thoroughness in investigations of the root cause of the problems. It was also noted that current protocols demanded the same degree of rigor for investigating a minor documentation error as a serious adverse event. Everything was given the same priority, and the system became clogged. Combined with administrative duplication and lack of accountability, it became apparent that the situation required far more attention than just a wording change in a procedure.
The manufacturer had policies and procedures constituting a quality system. However, mindful compliance recognizes that policies and procedures of the quality system live in relationship to each other and within an overall management context. In this example, the potential risk to the consumer and the enforcement risk to the manufacturer could have been avoided by looking beyond a single procedure. The process of conducting an investigation needed streamlining, and the rigor of the investigation needed to be based on risk. There were also training and accountability issues. Management realized it needed a means other than FDA inspections to learn that the quality system was not functioning well.
Management knowledge is the collective awareness and experience of applying the management arts in exercising its responsibility to adhere to applicable laws and regulations, meet customer expectations while economically controlling product quality, and provide dividends to stockholders. Management weaves together people and business processes that can acquire and utilize process knowledge, identify and control risks, and envelop the operation in a quality system.
Senior management of a drug manufacturer met offsite to review the state of the business and chart its future course. The finance, marketing, and sales departments gave presentations. Charts were projected and trends noted and explained. Data were compared to the previous quarter and year-to-date. The financial picture was less than optimistic, and this management group was tasked to respond. The company's quality improvement program suggested ways to reduce the cost of goods sold (COGS), accelerate the new product launch, and reduce associated costs. There was also the perennial challenge of reducing company headcount.
Many of the suggested changes were pushed through and rewarded in order to capture the savings in the next quarter. Cheaper suppliers along with a progressive approach to getting them on the approved supplier list quickly netted material savings and a reduction in headcount in the auditing group. Launch quantities of the new product were projected to be ready three months early as a result of retrofitting existing equipment and using existing validation templates. These and other changes were greatly facilitated by the use of planned deviations while the quality department caught up with procedure revisions and paperwork.
Management failed to recognize that it was creating the conditions for the loss of control — with financial and regulatory consequences far greater than the anticipated savings. Management lost touch with its process knowledge, risk knowledge, and quality system knowledge. Rather than directing its attention to achieving a greater understanding of the "sweet spot" where economic control of quality exists, suggestions were implemented without regard to the potential effects. Unfortunately, a perfunctory view of the quality system enabled the changes without challenging the effects of the changes and the probability of risk to the business. The quality system was viewed as a paper exercise. The financial loss from the delayed entry into the market was only exceeded by the long-term effect of being third to enter the market.
The manufacturer had a management process to review trends and to authorize and implement initiatives to respond to business needs. However, mindful compliance requires that management possess knowledge that enables it to facilitate product and process integrity and detect and control unwanted variation. To accomplish this requires professionals who can design a quality system that is an asset to the business. Quality professionals must be able to develop, present, and defend quality system metrics relevant to the business. They must be diligent and objective guardians of process and quality system changes, requiring data-driven and risk-assessed changes. And they will first seek to reduce cost by implementing an efficient quality system, eliminating nonconformance and capturing cost savings, and promoting intolerance for repeated deviations with the same root cause.
There is a shift to a compliance paradigm that is rooted in knowledge of process and risks. Arguably this may represent a swing to the middle ground between the historically science-based approach to inspections used by the biologics side of FDA and the more legalistic approach used by the drug side. This does not mean that one approach is right and the other is wrong, but it does mean momentum is building to grasp the essentials.
Good things happen when we are reminded to focus on the essentials. I say "reminded" because Deming, in 1931, said we need to continually search for better knowledge about materials, how they behave in manufacture, and how products behave in use. He proclaimed that economic manufacture requires statistical control of the process and measurements. Deming was a proponent for process improvement in every feasible way.
This then is a short definition of mindful compliance: where the business of medical product manufacturing and the promulgation of regulations and guidance find a common ground of scientific and technological operations knowledge.