Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

As part of its transparency initiative, which began in June 2009, FDA launched a website during the first week of January 2011 that addresses basic questions for industry about regulated products. The 

 addresses questions, such as, “How do I know if my product is regulated by FDA?” and “What should I expect during an inspection?” 

  The site also provides resources and contacts for drug manufacturers just getting into the business, or perhaps for those who manufacture outside the United States and want to sell their products in the US, and thus, be approved by the agency. For example, a list of frequently asked questions and educational resources is part of the site, as is a page that reviews the drug application and review process. 

  The site is separate from the FDA Basics webpage that the agency launched in January 2010. That site includes key questions and answers about the agency, including short videos that explain agency activities, and recorded conversations with officials about the work of their offices. The agency 

 notes that, as of Nov. 30, 2010, 957,008 visitors had viewed the FDA Basics site and left 8781 comments.

  The new site includes a video message from Commissioner Margaret Hamburg about communication with the agency. The site is one of 19 action items called for in the agency’s 

, “FDA Transparency Initiative: Improving Transparency to Regulated Industry.”  Other action items still to be tackled include: 

Setting an agencywide expectation that questions emailed to FDA involving the regulatory process will, whenever possible, receive an answer within five business days, or a response stating when an answer can be expected

Making agency presentations at key meetings widely available

Developing and executing a project to promote uniform processes and procedures across field districts.

Articles

As part of its transparency initiative, which began in June 2009, FDA launched a website during the first week of January 2011 that addresses basic questions for industry about regulated products.

FDA Launches Industry Basics Website

In mid-2008, the Pharmaceutical Research and Manufacturers of America (PhRMA), the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), and other research and development pharmaceutical associations, established the Global Health Progress (GHP) initiative. Supported largely by biopharmaceutical companies around the world, GHP is built on the concept that improving healthcare in the developing world requires multifaceted approaches and solutions and that therefore, partnerships and collaborations are the best way to tackle the growing challenge of providing access to medicines and improving health in less developed countries. 

Today, GHP's work with governments, public health leaders, universities, foundations, and other stakeholders, is underpinned by more than 300 innovative programs worldwide, backed by R&D pharmaceutical companies. Each program is aimed at finding sustainable solutions to improving healthcare in the developing world. Specifically, GHP member company programs focus on four core areas: strengthening healthcare systems, combating neglected tropical diseases (NTDs)*, pursuing innovative solutions (e.g., R&D efforts), improving access to medicines, and fighting the spread of HIV/AIDS, malaria, and tuberculosis. Member company programs, based in almost 150 countries, currently reach more hundreds of millions of people each year and help to train more than 50,000 healthcare workers annually, according to the GHP website. 

For example, one program that falls under GHP is EPIVAC, taken from the words epidemiology and vaccinology. The one-year program focuses on providing professional training for doctors in West Africa. Sanofi Pasteur, the vaccine subsidiary of sanofi-aventis, is a major supporter.  

Since its establishment, GHP has also helped to develop a large number of case studies for global health stakeholders. With partners such as the Bill & Melinda Gates Foundation and the TDR Tropical Disease Research organization (the UNICEF/UNDP/World Bank/WHO Special Program for Research and Training in Tropical Diseases), among others, the case studies provide best practices on subjects such as disease prevention and strengthening healthcare systems. The case studies are available online at 

.  GHP is also working with the UN Economic and Social Council and World Health Organization on various educational forums and programs. 

The greatest challenges in improving health outcomes in the developing world are "the sheer scale of the task, the numbers of people involved, and the poverty of the affected countries," says Guy Willis, director of communications for IFPMA.  

For example, biopharmaceutical companies have donated medications for NTDs valued in the hundreds of millions of dollars, and in sub-Saharan Africa, these donations have provided more than 600 million courses of treatments and helped to lower the residual cost of an effective program to fight NTDs to less than $0.40 per person per year, according to GHP. Still, more funds and medications are needed daily. 

"Our industry's contribution, although substantial, has to be set alongside other major contributions, from intergovernmental bodies, national governments of rich, poor, and middle income countries, philanthropic foundations, and other NGOs," explains Willis. "Where each party contributes, it usually does so in ways that make sense. While the overall effort is unprecedented in its size and ambition, there are still unmet needs and the approach is fragmented, being built largely on disease-specific foundations." 

Going forward, Willis notes that it may be worth looking at how resources are allocated across different health needs. Mark Grayson, of PhRMA's international issues office, adds that, "Many programs from governments, foundations, and companies overlap but do not necessarily match exactly the health agendas that each country has set out. We need to continue to search out better ways to coordinate programs so that they will benefit as many people as possible and not put excessive burdens on country health ministries."

With so many programs around the world, the GHP website (

) allows users to search by disease, country, or organization all of the global healthcare efforts underway by the biopharmaceutical industry. 

*NTDs are primarily infectious diseases that thrive in impoverished settings, especially in the heat and humidity of tropical climates. More than 1 billion people are affected by one or more NTD, according to WHO. 

The Global Health Progress collaboration works to improve healthcare delivery in the developing world.

Global Healthcare on the Ground: Global Health Progress Initiative

In July 2010, the US Food and Drug Administration issued an enforcement strategy document signed by the heads of the key agency centers and offices. The strategy document states, "...some regulated entities will disregard even the clearest regulations..." and that, "All FDA components are committed to swift, aggressive enforcement actions to protect the public health." Since then, industry has been uncertain of exactly what FDA has planned and how enforcement actions may or may not change. 

talked to Rick Friedman, director of the Division of Manufacturing and Product Quality (DMPQ) within the FDA's Center for Drug Evaluation and Research, Office of Compliance, to get a better sense of the agency's thinking on enforcement, quality, and corporate responsibility. 	

In general, what changes should industry expect with regard to enforcement actions? Do you anticipate any new types of enforcement authorities/activities to be approved by Congress in the future? 

FDA will continue to pursue swift, aggressive, and effective enforcement to ensure consumers have access to safe, effective, and quality drugs. FDA expects to increase the number of risk-based surveillance inspections of certain drug manufacturing sites around the world, including those that make over-the-counter finished products. At this time, I cannot predict the legislative timeframe for modernizing the Food, Drug, and Cosmetic Act to allow more effective regulation of imported drugs. 

DMPQ, and FDA overall, is very involved with the International Conference on Harmonization's Quality Implementation Working Group (IWG) initiatives regarding quality systems and risk management. Now that the ICH IWG workshops are complete, do you think industry has a better sense of how to address and use the harmonized principles in its daily manufacturing? Also, what is the agency's goal in this area? For example, it's been noted that FDA officials and reviewers/inspectors are also on a learning curve when it comes to the ICH quality guidelines and how to implement them. 

The ICH IWG workshops were well-attended and promoted an understanding of the harmonized Q8-Q9-Q10 guidelines. Both regulators and industry attended these conferences to improve mutual understanding of an integral set of recommendations on development, risk management, and quality systems. FDA's ultimate goal for these guidance documents is to promote innovation and improve the quality assurance of pharmaceuticals for consumer use. We have made gradual progress toward cultivating an environment in which firms promptly identify and correct manufacturing deficiencies that may occur during the manufacturing life cycle. More training and interaction will help to promote awareness of the Q8–Q9–Q10 concepts, and continue to clarify terminology and expectations. With better understanding by both industry and regulators of the opportunities presented by the modern quality system, I think we will see broader implementation. 

Agency officials have increasingly noted "corporate responsibility" in various public statements and conferences during the past year. Can you explain why this issue is important, and to what extent the agency is willing to go to uphold corporate responsibility? 

Expecting corporations and their management to be accountable for the quality of the drugs they produce is not a new policy. Since the 1975 Park decision, courts have recognized that individuals who manage businesses that make and sell FDA-regulated products have an affirmative legal duty to ensure the safety of their products. Because corporate executives are in the position to prevent or correct drug quality problems, it is only logical that they are the ones ultimately held responsible if their firm produces poor quality drug products.

Since the agency has turned up the volume, so to speak, on its enforcement approach, has DMPQ seen any change thus far in industry feedback with regard to product quality and compliance? 

Industry is aware that FDA is placing more emphasis on swift and aggressive enforcement actions and encouraging modern quality systems and PAT approaches. While the results are only anecdotal at this point, we have seen some very promising developments. It will take some time before we can readily measure the overall trends. 

FDA has been successfully building its overseas presence for a couple of years to help train other national regulatory agencies and to increase inspections of foreign facilities. There is still a lot of grumbling that overseas audits are more lenient than domestic audits (e.g., companies outside of the US have advance notice of inspections, whereas US companies do not). Do you agree with the characterization? What will FDA do to level the playing field? 

We do not agree with that characterization. Foreign inspections do pose their own unique challenges. FDA only has explicit authority to take legal action on products in its jurisdiction (the United States). Although we do not have authority to seize products in foreign commerce nor enjoin foreign firms, we can administratively block adulterated products from entering the US by placing firms on import alert if we find significant violations during an inspection. This is a faster sanction than seizure or injunction, and is a strong one. 

There has been some talk of electronic inspections increasing—including at the ICH workshop in October 2010. Do you see this model growing in the future and if so, what advantages might it offer for industry and for regulators? 

The inspection of a facility's conditions and practices are done on site. It is analogous to buying a house. You want to see it before you buy it. Indeed, you even do a final walk-through. A manufacturing facility is extremely complex, and CGMP audits require one to observe numerous manufacturing practices like sanitation (such as personal hygiene), state of repair of equipment, whether personnel practices match what is written in SOPs and staff are qualified, contemporaneous completion of batch records, whether operations are being supervised, laboratory conditions and controls, how a firm deals with deviations, etc. With that said, we obtain and leverage electronic information on facility statuses quite routinely these days, particularly when collaborating with our international regulatory counterparts. 

Are there any major new guidances affecting drug manufacturing that industry should look for in 2011? 

We expect FDA's guidance on process validation will publish as final in 2011. In addition, CGMP regulations and guidance for Positron Emission Tomography drugs will go into effect in December 2011. We are also working on other guidances that should enhance industry's understanding of regulatory expectations regarding drug manufacturing and product quality. 

Industry executives share insight into the future direction of drug manufacturing and the supply chain.

FDA Discusses Current and Future Take on Compliance

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.

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. 

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. 

To help prevent manufacturing deviations, manufacturers can put into practice key points from the International Conference on Harmonization's quality-trio guidelines (Q8 

), 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). 

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 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 

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.  

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.  

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. 

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. 

Industry experts offer their best practices for dealing with deviations. This article contains online bonus material.

Preventing and Troubleshooting Manufacturing Deviations

After five years of discussions, the US Food and Drug Administration is joining the Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical Inspection Cooperation Scheme (PIC Scheme), known together as PIC/S. The agency submitted its application in September 2005 and will be an official member as of Jan. 1, 2011. 

PIC was established in 1970 and the Scheme was launched in 1995. Together, the two bodies serve as the foremost international collaborative body on pharmaceutical manufacturing inspections and as a major supporter of GMP training and harmonization. The organization, which now has 39 members, functions as a cooperative arrangement among global regulatory and health authorities. Other PIC/S activities and benefits are listed on the organization’s 

The PIC/S Audit team gave FDA an approval during a follow-up visit to the agency’s Silver Spring, Maryland, headquarters in August 2010. In November 2010, at the organization’s leadership meeting in Malaysia, FDA’s accession to PIC/S was formally accepted. The Ukraine’s State Inspectorate for Quality Control of Medicines is also becoming a new member as of January 2011. 

According to the PIC/S website, the application-review process includes a detailed assessment to determine whether the regulatory authority is able to apply an inspection system comparable to that of current PIC/S members. The assessment involves “an examination of the authority’s GMP inspection and licensing system (or equivalent), quality system, legislative requirements, inspector training, etc. It is followed by a visit by a PIC/S delegation to observe in particular inspectors carrying out routine GMP inspections.” The full guidelines for joining PIC/S are 

It typically takes two to three years for a membership application to be completed, with a maximum allowable timeframe of six years. Many European regulatory authorities are members. The European Medicines Agency, European Directorate for the Quality of Medicines, UNICEF, and World Health Organization are partners with PIC/S. Of interest, the regulatory agencies of Japan, China, and India are not yet members.

In November 2007, former FDA Commissioner Andrew C. von Eschenbach 

 to Congress that the agency was in the process of joining PIC/S to ultimately “enable the exchange of inspection reports and other inspection information with regulatory authorities.”  It’s hoped that PIC/S membership will help fill a gap in the number of overseas inspections conducted by FDA.

 provides a detailed look at FDA’s application process with PIC/S.

Inside PIC/S: South Africa's Accession to PIC/S

Inside PIC/S: Implementing Quality Risk Management

After five years of discussions, the US Food and Drug Administration is joining the Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical Inspection Cooperation Scheme (PIC Scheme), known together as PIC/S.

FDA to Officially Join PIC/S

The European Medicines Agency launched on December 20, 2010, a public 

 about small and medium-sized enterprises (SME)  that includes information about SME-registered companies. The goal is to facilitate interaction among these types of companies. For now the, website includes details such as company contact information, activities, and number of employees. In March 2011, according to an EMA press 

, the registry will also include information about company products, including what’s in the pipeline. To be included in the registry, companies must be based in the European Economic Area and have submitted to the agency an SME declaration per the European Commission Directive 2003/361/EC.

  “This initiative is in line with the overall transparency policy of the Agency,” says the EMA release. The idea is to provide more information to the pubic and, in turn, to increase support for the 20 million SMEs located throughout the European Union. 

  EMA also has a dedicated SME Office, which provides assistance to companies regarding the development and authorization of drug products. For example, the agency offers help with regulatory procedures, translations, fee reductions, exemptions, and deferrals, says the EMA release. There is also a helpful Question and Answer section on the new registry for SMEs needing more information.

The European Medicines Agency launched on December 20, 2010, a public registry about small and medium-sized enterprises (SME) that includes information about SME-registered companies.