Preventing and Troubleshooting Manufacturing Deviations

As we enter 2011, the pharmaceutical industry has quite a reputation to repair. Throughout 2009 and 2010, some of the most trusted and well-branded drug manufacturers were forced to issue major recalls and explain a series of poor choices. Johnson & Johnson (New Brunswick, NJ) and its McNeil Consumer Healthcare unit, for example, recalled hundreds of millions of bottles of popular over-the-counter pain and cold and allergy products, including many children's medications, because active ingredients were tainted or otherwise compromised. The company also allegedly hired contractors to buy up products off the shelves before issuing a formal recall. Amgen (Thousand Oaks, CA) recalled certain injectable products for treating anemia because of delaminated glass vials, and Abbott (Abbott Park, IL) issued recalls of infant formula because of contamination by beetle larvae.

IMAGE: INFLUX PRODUCTIONS, PHOTODISK, GETTY IMAGES

The flurry of recalls, along with a series of contamination and adulteration events caused by weak links in the pharmaceutical supply chain (e.g., heparin and melamine) have placed a spotlight on the pharmaceutical industry's management of quality control and systems. Congress has begun to question more intensely the accountability of industry as well as the effectiveness of the US Food and Drug Administration. And the US Government Accountability Office has issued more than one report suggesting that FDA needs to strengthen its oversight (1, 2). Indeed, FDA issued in July 2010 a strategy document that conveys its intent to strengthen its enforcement actions (3) (see FDA Discusses Current and Future Take on Compliance Q&A in this month's Cover Story, "Outlook 2011").

For its part, industry is paying a lot of attention to supply-chain management, including the way in which it audits suppliers and shares information. Manufacturer-led consortiums such as Rx-360 are promoting innovative programs, including audit sharing. Standard-setting organizations such as the International Pharmaceutical Excipients Council are broadening their international efforts to harmonize best practices for safe raw materials and distribution. To avoid another series of recalls, industry also seems to be looking for ways to strengthen its management of quality systems and of manufacturing deviations. Companies are exploring better ways to detect problems during manufacture and are seeking best practices for handling situations when something does go awry.

For example, as a result of the released FDA enforcement strategy document, some drug companies are identifying additional process issues to monitor, says Jim Prutow, healthcare partner at PRTM, a global management-consulting firm based in Waltham, Massachusetts. These include:

• Harmonizing key operational processes across facilities (e.g., corrective and preventive action [CAPA], management review, investigations, supplier management, and change control)

• Improving communication across facilities with such actions as periodic cross-facility reviews

• Interchanging key personnel (particularly high-potentials) to further foster knowledge sharing and harmonization

• Adopting common metrics and performance indicators

• Investing in enterprise-level tools to facilitate communication and global information exchange.

Pharmaceutical Technology spoke with experts involved in these issues to gain a sense of how industry is changing the way it prevents and handles manufacturing deviations. The following sections provide a look at some forward-thinking tactics.

Understand and integrate systems

For starters, it is important that companies understand the difference between a CAPA system and a deviation system and how they work together. The CAPA system is intended to manage the correction or prevention identified to resolve the deviation, whereas the deviation system is to be used for the identification of a variation and the subsequent investigation, explains Judy O'Hara, senior consultant at Parexel Consulting, a business unit of Parexel International and a global consultancy serving the biopharmaceutical and medical-device industries .

"Resolving an issue identified through the deviation system begins with the discovery of an issue and ends with the identification of the root cause(s)," she says. "The CAPA system picks up from there. Too many times, there is a disconnect between the deviation, the root cause, and CAPA. It is important that the department responsible for the investigation, along with the Quality department, make certain that the root cause addresses the deviation and that the CAPA addresses the root cause.

Adds William (Al) Kentrup, vice-president of manufacturing and supplier quality assessments at Pfizer (New York), "In some simple cases, a simple corrective action may be all that is warranted. However, in most cases, there is typically a one-to-one or one-to-many type of relationship between corrective and preventive actions." An automated CAPA process can help link and categorize deviations in such situations on a more consistent basis, explains Kentrup. Then, the events can be trended to direct further preventive actions such as financial investments, revalidation activities, or personnel training.

It's also important to be aware of the cross-functionality of global sites and systems, says O'Hara. FDA's enforcement strategy document has highlighted this connection. The agency is "evaluating the impact of manufacturing deviations on other sites and performing a systematic review to ensure that the same issue is not occurring or does not have the potential to occur. Any identified gaps result in actions to prevent or reduce the probability of occurrence.

Incorporate guidelines and standards

To help prevent manufacturing deviations, manufacturers can put into practice key points from the International Conference on Harmonization's quality-trio guidelines (Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System), advises Parexel's O'Hara. "I would suggest that companies take the time to understand the guidelines, train their staff, and have a good implementation plan," she says. "The deviation system is just one of many valuable Quality system tools a company should use to encourage continuous improvement, which helps not only the compliance of the company but also the bottom line.

The ICH quality-trio guidelines are also pushing drug manufacturers and regulators to focus more on corporate responsibility when it comes to managing risk and potential manufacturing deviations, according to PRTM's Prutow. A key message from ICH Q8, Q9, and Q10, says Prutow, is that "quality, safety and compliance should not to be limited to the domain of the quality unit and compliance organizations. Rather, the ICH tripartite emphasizes that executive management must be effective at preventing risks from spreading. Furthermore, the tripartite takes risk well beyond the product itself to the broader supply and business domains making an enterprise risk approach more important for all pharmaceutical companies, especially when they face threats in areas that may not have originally been expected (i.e. wooden pallets causing issues at Johnson & Johnson).

Put knowledge management to use

The ICH quality-trio also incorporates the concept of knowledge management, an idea that has been the topic of many industry forums and conferences during the past several months. Information can be used to a drug manufacturer's benefit, according to experts. "Companies collect data, track and trend deviations and complaints, and monitor CAPAs, but in many cases, that's all that's done," says Parexel's O'Hara. Taking these data and actually analyzing them can yield valuable information. For example, a company might group deviations into similar problem types and root causes and use that grouping to determine whether a deviation is occurring in the same department, during the same shift, or when using a certain piece of equipment or certain part of the process, she explains.

"Applying the knowledge gained from analyzing the data helps in anticipating issues or potential issues, recognizing opportunities for improvements to processes and products, reducing rework and generating efficiencies," says O'Hara. "Individually, this is hard to see, but once data is tracked and trended as well as reviewed collectively, this is invaluable." (See sidebar, "In the case of recall," for information on how knowledge management can be useful in the case of recalls.)

In the case of a recall

In day-to-day manufacturing, an automated CAPA process can be interfaced with a knowledge management repository to maximize access to the data and minimize the need for re-entering data into multiple systems, recommends Pfizer's Kentrup. "A well-integrated CAPA system can be invaluable with regard to overall product-knowledge management by providing access to information regarding the issues that have been addressed in one central repository or via a single link."

Knowledge management can also play a role when a company is manufacturing multiple products that share specific components or processes, says PRTM's Prutow. "One best practice is the use of virtual dynamic centers of excellence, or user communities, which allow sharing of practices and opportunities across a specified area, such as validations or aseptic practices. The centers of excellence ensure knowledge of issues and best practices across the company," he explains.

Finally, involvement of management is crucial for several reasons, says Parexel's O'Hara. Management is ultimately responsible for how the company responds to risks and the actions taken has the authority and responsibility to provide the resources (e.g., financial, staff) to ensure that the company produces a product that is safe and effective (and in a safe and compliant environment) and can encourage the engagement of staff, which aids in ensuring success from the design of a product to a finished product. These three factors encourage staff to anticipate issues, and to voice their thoughts as to why or how a deviation occurred and aid in CAPA. Their knowledge and experience is invaluable in the deviation and CAPA systems processes.

Don't overlook the supply chain

Beyond the manufacturing floor, it's crucial for quality teams to pay attention to raw-material sources and potential supply-chain gaps at the international level. For example, explains Jian Liu, PhD, associate professor of the Eshelman School of Pharmacy at the University of North Carolina. Liu has researched extensively the heparin contamination of 2008, which was largely the result of a shortage of pigs (their intestines are used to manufacture the blood-treatment product).

It should not have been a surprise to drug companies that "the worldwide production of heparin exceeds 100 tons/year, which is isolated from 500 to 700 million pigs, and that the entire US pig production is only about 60 to 65 million/year," says Liu. When the pig shortage started to gain traction, manufacturers should have been looking for potential counterfeit problems. A key lesson learned from this incident, says Liu, is that, "Manufacturers must monitor the quality of products from suppliers and have adequate controls in place to prevent the counterfeits, especially those highly sophisticated counterfeit products (i.e., such as the oversulfated chondroitin sulfate used in the heparin contamination).

In order to reduce risks associated with material sources, industry and regulators might also consider enforcing "high purity standards," says Liu, For example, after the heparin crisis, FDA and the US Pharmacopeia worked to revise the heparin monographs to contain higher purity standards. Such standards, however, can be a double-edged sword, he says, because excessively high purity can narrow profit margin and hurt honest suppliers.

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.

Involve senior management

As a general best practice, experts believe that it's important to have management involved in CAPA programs, not just the Quality unit. Involvement of management is crucial for several reasons, explains Parexel's O'Hara:

• Management is ultimately responsible for how the company responds to risks and the actions taken

• Management has the authority and responsibility to provide the resources (e.g., financial, staff) to ensure not only that the company produces a product that is safe and effective, but also that the environment in which the product is produced is safe and compliant with trained, knowledgeable staff

• Management can encourage the engagement of staff and open communication with staff, which aids in ensuring success from the design of a product to a finished product.

"These three factors also encourage staff to anticipate issues, voice their thoughts as to why or how a deviation occurred and to aid in the corrective and preventive actions taken," says O'Hara. "In my opinion, their knowledge and experience of the management team is invaluable in the deviation and CAPA systems processes.

Adds Teva's Welter, "Management is ultimately responsible for the health and effectiveness of the firm's quality system. Having management participate in the CAPA process will ensure that management is aware and can communicate across the organization the issues that the firm is facing and will no doubt be supporting in any upcoming regulatory inspectional activities. It is crucial that ownership and accountability for corrective actions and effectiveness of those corrective actions be solidly with the organization owning the deviation.

References

1. GAO, FDA Could Strengthen Oversight of Imported Food by Improving Enforcement and Seeking Additional Authorities (May 6, 2010), www.gao.gov/products/GAO-10-699T.

2. GAO, Improved Monitoring and Development of Performance Measures Needed to Strengthen Oversight of Criminal and Misconduct Investigations (Jan. 2010), www.gao.gov/new.items/d10221.pdf.

3. FDA, Enforcement Strategy (Jul. 15, 2010), www.fda.gov/downloads/ICECI/EnforcementActions/UCM225183.pdf.

4. GHTF SG3, Quality Management System–Medical Devices–Guidance on Corrective Action and Preventive Action and Related QMS Processes (Nov. 2010), www.ghtf.org/documents/sg3/sg3_n18.pdf.