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Angie Drakulich was editorial director of Pharmaceutical Technology.
After five years in the making, the official pharmaceutical quality system is here. All three parties to ICH adopted a final version of Q10 and agreed to implement the guideline through their individual regulatory bodies.
Fully known as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH finalized the concept of Q10 Pharmaceutical Quality System in late 2005 with the aim of facilitating innovation and continual improvement, and strengthening the link between pharmaceutical development and manufacturing activities, according to the guideline's business plan. Incorporating the concepts behind ICH Q8 Pharmaceutical Development and ICH Q9 Quality Risk Management, Q10 provides a model for "a pharmaceutical quality system that can be implemented throughout the different stages of a product life cycle" (1–3). Q10 rounds out the ICH "trio" and paves the way through harmonized understanding of quality systems for industry and regulators to reap the benefits of process understanding and risk management fostering industry management of change, continual improvement, and better, more efficient regulatory oversight.
PHOTOGRAPHY: ROINE MAGNUSSON, LAUREN NICOLE/GETTY IMAGES
The final version, to be published in the Federal Register this summer and now available on the ICH website, contains new and expanded language compared to its May 2007, Step 2, draft. The changes include new and expanded sections about outsourced activities, purchased ingredients, change management, and knowledge management, based on feedback received during Step 3 of the harmonization process (the consultation and comment period), which took place May 2007–June 2008.
ICH Q10 is meant to complement and enhance existing regional current good manufacturing practices (CGMPs), but as a guideline, it is not enforceable. However, as industry leaders move farther into the use of quality-by-design (QbD), manufacturers large and small across the globe will find that the components and tools recommended within Q10—and its sister ICH quality guidelines—are going to be considered standard best practices by all ICH-region regulators, including the US Food and Drug Administration, European Commission, European Medicines Agency, and Japanese Ministry of Health, Labor, and Welfare.
Pharmaceutical Technology and SGS, an inspection, verification, testing, and certification company, held a webcast titled "Quality Systems in the Global Marketplace" on June 12, focused on Q10's adoption. Participating panelists included Joseph C. Famulare, deputy director of the Center for Drug Evaluation and Research at FDA (Famulare also led the Expert Working Group (EWG) that moved Q10 through to Step 4 of harmonization); Gerald Migliaccio, vice-president of Global Quality and Environmental Health and Safety Operations at Pfizer (Migliaccio also served as the ICH Q10 rapporteur, leading Q10 through Step 2 of harmonization); Karen Ginsbury, president of PCI Pharmaceutical Consulting Israel; Zena G. Kaufman, divisional vice-president for Abbott Quality & Regulatory, and a member of the ICH Q10 Expert Working Group for the Pharmaceutical Research and Manufacturers of America; Nicholas Cappuccino, PhD, chief scientific officer for Eagle Pharmaceuticals and member of the ICH Quality Implementation Working Group (IWG) representing the International Generic Pharmaceutical Alliance; and Jacques Morenas, PIC/S chairman and European Commission representative to the ICH Quality Working Group. The event was moderated by consultant and editorial advisory board member Susan J. Schniepp (4).
This article, based on excerpts from the webcast, provides insight into the expectations and challenges that come with ICH Q10 implementation.
Evolution and concepts
If you think back to the early 2000s, industry was very vocal about the challenges of operating a global business in an environment where GMP regulations were regional. There was a strong desire to have some form of harmonized view of these practices. So in July 2003, an informal ICH working group agreed on a quality vision: to develop a harmonized pharmaceutical quality system (PQS) that's applicable across the life cycle of a product, emphasizing an integrated approach to quality risk management and science. Q8, Q9, and Q10 have all evolved from the statement. Q8 is the science, Q9 is the quality risk management, and Q10 is the quality system which all of this operates within.
In 2005, the ICH steering committee assembled another informal working group to come up with a concept paper on PQS. I led the group, and we agreed that a quality-system guidance had to follow contemporary, modern principles, and align with the International Organization for Standardization's (ISO) quality management-system principles.
The committee also agreed that a guidance had to focus on the product life cycle. GMPs were focused on commercial manufacturing, but we have all learned that it's the linkage between development and commercial manufacturing that is critical to the successful introduction of a product and successful transfer of the knowledge, or process understanding, around that product. The way industry interpreted GMP back then was that once you had a process approved, you didn't change it. This interpretation inhibited innovation and continual improvement.
In the end, the Q10 EWG wanted to augment regional GMP regulations and move from GMP compliance to robust processes and adequate process understanding, which is where knowledge management comes in. Q10 defines knowledge management as a "systematic approach to acquiring, analyzing, storing, and disseminating information related to products, manufacturing processes and components." Knowledge management, knowledge transfer, and technology transfer are key aspects of the final version of Q10. Industry will find very little reference to these concepts in GMPs, but they are critical to the success of each company.
For example, Q10 can help improve data management. Those in the industry that have adopted techniques such as Six Sigma have found that they can convert their data into process understanding. At that point, they're well on their way to achieving the kind of process control and quality that is called for in Q10. It's really about promoting the tools within Q10 to convert data into knowledge you can do something with.
Within the ICH working group, there was always the fear that we were taking commercial GMP requirements and forcing them upon development and clinical-manufacturing activities. So we made it clear that the elements of Q10 are to be applied in a manner that is appropriate and proportionate to each product life-cycle stage, recognizing that the goal of development is different than the goal of commercial manufacturing. Q10 is not meant to apply commercial standards to the development arena.
Q10 also does not replace regional GMP regulations but rather is to be used with the regulations. Regional GMPs don't explicitly address all stages of the product life cycle nor do they promote innovation or continual improvement. So the quality system that we defined in the final Q10 guideline, including its management responsibilities, encourages the use of science and risk-based approaches at every stage of the life cycle and therefore promotes continual improvement across the product life cycle.
—Joseph C. Famulare
During the consultation and comment period for Q10 (Step 3), we received 300 estimated individual comments. One of the most important issues was management of change in ownership of the product. It was noted that when product ownership changes or certain transfers occur, that the change of ownership doesn't always follow the transfer of all the necessary things and responsibilities to ensure quality.
So we added section 2.8, Management of Change in Product Ownership, to the final Q10 document. Section 2.8 states that when product ownership changes, management should ensure "the ongoing responsibilities are defined for each company involved" and "the necessary information is transferred." The hope for regulators is that this new section will address some past experiences in which these issues were not well coordinated or addressed until quality concerns surfaced.
Another issue identified was management of outsourced activities and purchased materials. Everyone should be aware that the process of manufacturing pharmaceutical products is more complex today than ever in terms of having many activities, operations, and materials outsourced. Pharmaceuticals are manufactured globally and materials used in the manufacture of pharmaceuticals are obtained from global sources. Section 2.7 of the Q10 document was expanded to address this, as follows [and is further explained in the next section]:
"The pharmaceutical quality system, including the management responsibilities described in this section, extends to the control and review of any outsourced activities and quality of purchased materials. The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials. These processes should incorporate quality risk management and include:
(a) Assessing, prior to outsourcing operations or selecting material suppliers, the suitability and competence of the other party to carry out the activity or provide the material using a defined supply chain (e.g. audits, material evaluations, qualification).
(b) Defining the responsibilities and communication processes for quality-related activities of the involved parties. For outsourced activities, this should be included in a written agreement between the contract giver and contract acceptor.
(c) Monitoring and review of the performance of the contract acceptor or the quality of the material from the provider, and the identification and implementation of any needed improvements.
(d) Monitoring incoming ingredients and materials to ensure they are from approved sources using the agreed supply chain (3)."
The third issue identified during Step 3 called for a diagram that would illustrate the major principles of Q10 (see Figure 1). The diagram demonstrates some of the major features of the Q10 guideline, showing the relationship to GMP over the life cycle of the product, and how quality systems extend even further back than development, further than GMPs. The important elements are featured here, which include management responsibilities for the quality system, the actual elements in terms of process performance and product quality monitoring systems, the corrective-action and preventive-action (CAPA) system, the change-management system, and management review.
Figure 1: Diagram of the ICH Q10 Pharmaceutical Quality System model.
One of the final discussions we had in Portland involved suggestions for the IWG [to help carry out Q10 in all three ICH regions], some of which included training. In terms of implementation within FDA, I think it will work very much in line with IWG. Certainly, integration between the review, the compliance, and the inspection will continue here in the US, and...strong importance will be placed on integration between assessors and inspectors.
Issues that will be discussed going across the ICH quality documents (Q8, Q9, and Q10) will involve a good integration of design space, control strategy, and real-time release and criticality. Knowledge management will be important as to how it will look in actual practice, and how we will understand that as regulators and be able to make, hopefully, better regulatory decisions based on knowledge management and actual knowledge gained over the life cycle of the product and process. The opportunities for both industry and regulators are summarized in Annex 1—the opportunity for industry to take ownership of quality and continual improvement and better use of resources by regulators for more effective and efficient review and inspection processes (e.g., management of movement within the design space by the quality system). IWG is key to having these things implemented on a regional basis and more harmoniously.
Outsourced activities and purchased materials
As demonstrated in sections 1.7(d) and 2.7 of the final Q10 guideline, the ICH Q10 Expert Working Group took into account the fact that the pharmaceutical world has changed and there's a lot more outsourcing of activities for any pharmaceutical company than in years past. Whether we're talking about the largest multinational or the smallest start-up, certain aspects of companies' operations and PQS are given to others to undertake. The management of those activities is very important from a quality perspective and from a business perspective.
The same amount of due diligence that goes into, for example, the financial arrangements in developing contracts between the parties regarding outsourced activities should also be put forth toward the quality aspects of those contracts. This is really what's new in the final version of the Q10 guideline versus earlier drafts.
According to section 1.7(d), "The pharmaceutical quality system should include appropriate processes, resources, and responsibilities to provide assurance of the quality of outsourced activities and purchased materials as described in section 2.7." Outsourced activities, according to Q10, include "activities conducted by a contract acceptor under a written agreement with a contract giver" (3).
Although the definition of "outsourced activities" is broad, the intent is clear. Companies should have a written agreement between the firm that's ultimately responsible for the pharmaceutical and the firm that's going to do the work for that pharmaceutical concern.
Section 2.7 also addresses purchased materials. A PQS therefore involves active pharmaceutical ingredients as well as inactive ingredients and components, or in some cases, pharmaceutical intermediates that could be purchased by a particular pharmaceutical company.
A key concern in this context is management responsibility of the PQS. It must be very clear in written quality agreements or contracts which party is responsible for certain activities. It also should be clear that it's the firm that is outsourcing these operations that is ultimately responsible for the product. Companies cannot point to the provider of an outsourced activity and say it's their responsibility if there's a problem with a product.
These types of outsourced activities, in my view, do not just apply to the commercial realm but also to research and development (R&D) activities (see next section). In a properly designed PQS, companies should account for outsourced activities throughout the entire product's life cycle.
Quality systems for R&D
As previously discussed, it's important not to force commercial requirements on development, but industry definitely needs a PQS in the development arena. Because ICH Q10 is a guideline and therefore voluntary, some in industry are not sure whether they should adopt it or not. Furthermore, many are unclear how best to persuade management to implement the guideline, particularly in the area of R&D.
In the US, the clinical supply chain is rarely inspected. In the European Union, the situation is different because investigational drug inspections are a legal requirement. Nevertheless, all reputable companies recognize that there is both a legal and ethical requirement to enforce GMP standards on any product intended for human use. Life-cycle management covers early research and discovery, proof of concept, and preclinical studies—none of which are covered by GMPs. These early phases need some kind quality system because they are feed items: they provide data and a solid basis for Phase I, II, and III as well as product commercialization.
This is where Q10 comes into play—the elements of Q10 can be applied in an appropriate, proportionate manner to each life-cycle stage (see Figure 2). If one looks at legacy products with regard to quality systems, they are only looking at a small part of the product's life cycle. From discovery through commercialization, the average time for an innovative product is about 15 years. That leaves around 7–15 years of commercial life at most for a novel product. If a company wants a good return on investment, it needs to invest in a quality system that is appropriate in the earliest stages in order to have rapid approval and smooth production.
Figure 2: The various stages of a productlife-cycle management, including the introduction of a legacy product change.
Approximately 50% of a product's life cycle is spent in the R&D stage. Can we still argue that because regulators don't require a formal quality system (prior to human use of products), we are wasting company resources and stifling innovation if we implement any kind of quality system in our company? I don't think so.
With legacy products, Q10 is needed primarily for change management (see next section). Industry has been dealing with change management for years and they're pretty good at it. But if we look at Q10 in terms of R&D, then change is inherent to the process. We can use risk-assessment tools to mitigate potential harm to patients. We can adopt design-of-experiment tools to accelerate process understanding and to develop control strategies.
In cases where we make changes to new products, where a PQS is involved in early R&D, we're talking about a kind of "light quality system," similar to diet products if you will. It shouldn't be something burdensome. The quality system should be different to the commercial system, but there are issues that need to be addressed.
For example, there are many small start-up companies that have never come into contact with GMPs and don't know what a quality system is. When they go to an outsourcing company, they don't know what to ask for or how to define their requirements clearly enough to get what they're looking for (see a suggested checklist at pharmtech.com for auditing a quality system within a contract relationship). They need a quality system, especially when it comes to transferring data into knowledge and then transferring that knowledge to stakeholders.
Change management and CAPA systems
—Zena G. Kaufman
Within ICH Q10, the phrase "change management" rather than "change control" is used. The new terminology speaks to the fact that as an industry, we've been reluctant to embrace change. We've been controlling change and where we, both the regulators and industry, need to move is to managing change using appropriate science and risk-based approaches.
Imagine we're designing a change-management system. The first thing to do is try to understand the purpose of the change-management system—it's not to control change but rather to improve processes and products, and assure conformance to registration, including avoidance of unintended consequences. Some of the inputs to a change-management system include innovation, continual improvement, and the output from analysis of performance indicators and a company's CAPA system.
The output of the change-management system would be a changed process, or a new piece of equipment, or new specifications. All these would include a documentation of the change. As with any system, there needs to be a defined process owner of the system. Typically, the quality department has been the system owner for a company's change-management system. As industry moves forward with Q10, it may become more effective for the technical services group, which is usually charged with innovation and continuous improvement, to be the system owner.
To execute and improve a current change-management system, there must be defined metrics. There usually are key performance indicators and metrics against the "logistics" (e.g., cycle time, the number of deviations open over 30 days, trending of the system). One can always recite the number of open change controls or the time a change control has been open, but moving into this new paradigm, industry is going to have develop metrics which measure the effectiveness of a given change and evaluate the return on investment (ROI) of that change.
The ROI of a change transcends beyond dollars and cents to a clear improvement in the quality/control of the product. There are tangible as well as intangible benefits from implementing change. Sometimes we make a change because there's been a change in regulatory expectation due to emerging regulations or the "C" in CGMPs or because regulations are being interpreted a little bit differently globally. We must also look at these perspectives in terms of the ROI of a change.
Companies also need to review how they improve the change-management system. In my experience, change-management systems are often overloaded with way too many change controls being processed. Rather than managing the change control, industry should ensure that the system itself supports the business process.
With the change-management system, one of the inputs is the CAPA system, which can include deviations to procedures, nonconformities, etc. Other inputs come from internal audit reports, inspection observations, and regulatory findings. Also to be considered are product quality complaints and trending of a company's process monitoring. Most companies understand that a CAPA system helps them to assess the risk of releasing a deviant batch to market, but a CAPA system also can help prevent the recurrence of a deviation. A most excellent CAPA system goes beyond addressing the impact to a single batch to develop meaningful corrective and preventive action to prevent recurrence. The CAPA system is not a tool for facilitating or justifying release of nonconformance materials.
With Q10 in mind, industry needs to move into the quality and effectiveness of a CAPA system. Rather than applying a quick fix such as retraining the operator, a more robust quality system asks: Is that the most effective CAPA I can think of? This approach may lead to a more effective corrective and/or preventive action.
Overall, the elements of ICH Q10 and the aspects of a PQS really are at the center of integration, effectiveness, and the global nature of these systems. And by global, I mean not only global operations but also the life cycle of a product.
Global quality inspections
Although Q10 can be used to create a quality system for an entire manufacturing site or many different sites, GMPs are dedicated to the manufacture of investigational medicinal products and commercial finished products. Even though certain GMP guidelines such as those of the EU and the Pharmaceutical Inspection Cooperation Scheme (PIC/S) contain information related to quality management or quality assurance, it is important to remind industry that GMPs mainly concern systems for finished products, not the life cycle of these products .
To explain, in a manufacturing site inspection, a quality-management system should be considered a normal part of the GMP-inspection process. At the EU level, we are not considering the development of a Q10-specific certification scheme inspection. Inspecting the quality-management system in a manufacturing site will be considered routinely, and will be quoted in the GMP certificate issued at the end of the inspection (based on GMP compliance evidence). It will be noted that the quality-management system was inspected and found to be in compliance with GMP. In a development site, inspecting quality-management systems will be considered on a case-by-case basis, depending, for example, on requests coming from the assessor.
Looking ahead, the IWG for Q10, as well as Q8 and Q9, will address notably the need to train inspectors on the Q10 document. At the EU level, we will likely develop this summer a work plan for introducing Q10 elements dedicated to GMP into the EU's GMP guide. In addition, the EU, with the help of PIC/S, may develop a guide for inspection of quality systems in both manufacturing and development sites.
Overall, ICH Q10 Pharmaceutical Quality System provides a roadmap for product control. And in today's market, with growing supply chains and additional outsourcing, control is vital to end-product quality. As FDA's Famulare put it, "We've come together with industry that this is a direction and a way we'd like to see the industry go.... We've become all too accustomed to reacting to problems, issues, and crises...we hope that Q10, with the other ICH documents, will serve as a basis and a way to prevent some of those incidents and to, in a global way, have quality medicine products available where and when they're needed."
1. ICH, ICH Q8 Pharmaceutical Development (Geneva, Nov. 10, 2005).
2. ICH, ICH Q9 Quality Risk Management (Geneva, Nov. 9, 2005).
3. ICH, ICH Q10 Pharmaceutical Quality System (Portand, OR, June 2008).
4. S.J. Schniepp, Moderator, Quality Systems in a Global Market webcast, Hosted by Pharmaceutical Technology and Sponsored by SGS (June 12, 2008), available at pharmtech.com.
For more on this topic, seePharma Quality systems