Preventing and Troubleshooting Manufacturing Deviations - Pharmaceutical Technology

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Preventing and Troubleshooting Manufacturing Deviations
Industry experts offer their best practices for dealing with deviations. This article contains online bonus material.


Pharmaceutical Technology
Volume 35, Issue 1

Consider new approaches

In September 2009, the Global Harmonization Task Force (GHTF), which is essentially an ICH-like entity for the medical-device industry, released a draft guidance on quality-management systems (QMS) that addresses corrective actions, preventive actions, and related processes. The document, which was published as final in November 2010, has gained quite a bit of attention across the drug-manufacturing sector because of its unique interpretation of QMS and corrective and preventive actions (4).

For background, GHTF was established in 1992 to achieve greater uniformity between national medical device regulatory systems with two primary goals: enhance patient safety and increase access to safe, effective and clinically beneficial medical technologies around the world. Membership includes industry and regulatory authorities, including the organization's five founding members: the European Union, United States, Canada, Australia, and Japan. These members rotate chairmanship.

"I remember the first time I read the GHTF document," recalls Valerie Welter, senior director of quality management for Teva Animal Health (St. Joseph, MO), a subsidiary of Teva USA, "and it was like a light at the end of a dark tunnel. For years, I, like many quality professionals, struggled with defining a preventive action as a requirement to close every CAPA. Procedures were based on defining a single definitive root cause, at least one corrective action and at least one preventive action. The GHTF document provides a logical escalation process associated with the evaluation, investigation, verification, implementation and effectiveness determinations associated with negative quality events as defined in the measurement, analysis, and improvement sections of the device QMS regulation."

The GHTF document was created because device manufacturers were "failing to understand or fully implement the International Organization for Standardization (ISO) 13485:2003 QMS-based processes related to corrective actions and preventive actions," says Egan Cobbold, chair of the task force's Study Group 3 on quality systems. As a result, these systems were often cited in FDA inspection reports. "The guidance is therefore meant to improve the medical-device industry's understanding of basic corrective and preventive principles and lead to greater compliance with QMS requirements," he says.

The guidance includes a few concepts that may be considered innovative to the pharmaceutical sector. For example, the document states that preventive action as continuous improvement is not necessarily "CAPA." GHTF omitted the term "continuous improvement" from the guidance because it felt that the "continuous improvement of processes should be driven by organizational or business forces and not by medical-device regulations," explains Cobbold. "ISO 13485:2003 requires manufacturers to maintain an effective QMS not continually improve it.

The document also separates "preventive action" from "corrective action" by avoiding use of the CAPA acronym. The idea, says Cobbold, was to "highlight the need for the reader to understand the definitions of these terms which comes from the ISO definition (ISO 9000:2005).... That is, a corrective action is an action taken by a manufacturer to prevent the recurrence of a nonconformity, while a preventive action is an action taken by a manufacturer to prevent the occurrence of a nonconformity. These are two separate activities." A second reason for not using the CAPA acronym was to stress that when a "corrective action" is taken by a manufacturer in response to a nonconformity, it cannot by definition be followed by a "preventive action," says Cobbold.

Finally, the GHTF guidance talks about the difference between being preventive and being reactive. The document uses the term "data source" to identify sources of information that a manufacturer could use to monitor a product, process, or QMS. "Data sources could be considered as being reactive or proactive depending on how the information associated with the data source is used by the manufacturer," says Cobbold. "An example of a reactive data source could be returned nonconforming product. The manufacturer 'reacts' by taking corrective action such as redesigning the device to prevent the recurrence of the nonconformity.... An example of a proactive data source could be the manufacturer's risk-management process. The manufacturer identifies unacceptable product risks during the initial design phase of a new device and acts proactively by using this information to take appropriate risk-control measures to prevent unacceptable product related safety risks from occurring in the device.

Comments Welter, "A good way, if not a best way to interpret prevention versus reactive is the source of the knowledge...If the knowledge/input to your quality system is the result of an event that is happening within your quality system, it is reactive...You have knowledge and you are reacting to it by initiating a CAPA. An example may be a sister site is issued a 483, and you recognize the same vulnerability in your quality system...You are reacting. Conversely, if you gain knowledge through a source that something will or may affect your quality system in the future, an example may be a regulation that will be changing in 2012. You initiate within your quality plan an improvement in your quality system such that you are compliant when the regulation changes in 2012; this is preventive."

Overall, Welter believes that these concepts make perfect sense for the pharmaceutical secctor. "CAPA by definition is a reactionary program—inputs to the CAPA program are typically associated with negative events. Preventive actions are proactive, not based upon a negative event. In my opinion, it makes the most sense to fully separate those positive quality initiatives from those that are a result of a negative event. Additionally the processes associated with DMAIC [i.e., the major component of a Six Sigma manufacturing program] problem solving really do not meld well with a continuous improvement plan. ... Remember too that most continuous improvement initiatives are longer range types of projects, which is inconsistent with the urgency related to CAPA corrective actions.

Regardless of the type of data source, the guidance document advises a manufacturer to measure, monitor, and analyze the information about real or potential nonconformities coming from within and across data sources. These fundamental processes (e.g., planning, measurement and analysis, improvement, and management review) should be easily transferable to other industry sectors—including the pharma sector—that voluntarily operate or are regulated to operate an ISO 9001-based QMS to help prevent and control manufacturing deviations, says Cobbold. The concept of data sources should also be easily transferable.

According to Welter, the GHTF document "simplifies the overall investigative process [for when manufacturing deviations occur] and provides clear, concise and helpful information reflective of current FDA thinking.

Regardless of the type of data source, the guidance document advises a manufacturer to measure, monitor, and analyze the information about real or potential nonconformities coming from within and across data sources. These fundamental processes (e.g., planning, measurement and analysis, improvement, and management review) should be easily transferable to other industry sectors—including the pharma sector—that voluntarily operate or are regulated to operate an ISO 9001-based QMS to help prevent and control manufacturing deviations, says Cobbold. The concept of data sources should also be easily transferable.

According to Welter, the GHTF document "simplifies the overall investigative process [for when manufacturing deviations occur] and provides clear, concise and helpful information reflective of current FDA thinking.


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