Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

Myth versus Reality: What does ICH Q10 implementation really mean for my company?

conflict with good manufacturing practices (GMPs) and the International Organization for Standardization's (ISO) quality management systems. 

They really work together and augment each other. There are certain areas that GMPs don't specifically mention or if they are implicit, Q10 brings them out. What we have announced in the US Food and Drug Administration is an incremental approach to updating our GMPs, not a wholesale change of them. As shown in the ICH Q10 PQS model, GMPs are to be used in conjunction with the pharmaceutical quality system (PQS)....[the diagram] puts in place a way to follow GMPs and to have more holistic coverage because GMPs have always been represented as a minimal standard. ISO 9001 and Six Sigma principles are also consistent with the Q10 document. The important thing to keep in mind is that Q10 was written for pharmaceutical products. 

—Joseph C. Famulare, deputy director of the Center for Drug Evaluation and Research, FDA

My company outsources the bulk of its production, so we don't need a full PQS. 

The sponsor has the ultimate responsibility [of the pharmaceutical product] and the agreement as to how [that product's] quality functions will be carried out and ensured will have to be worked out by the sponsor. An important passage of Q10 indicates that we will look at it as being applied to sites that manufacture products or do whatever part of that manufacturing. So Q10 is applied to sites, but holistically, if you're contracting the entire operation out, you're going to have to ensure that those quality elements are put into place, either through a whole system in your own company or through an agreement to have those systems put in place for you. 

This is in fact true. ICH Q10 is a guideline in all ICH regions. If you choose to implement Q10, you're implementing something that regulators and industry from the three ICH regions have agreed is a sound approach to a PQS. Q10 is not creating new regulation..., but it does provide guidance on ways companies can better carry out their work. 

—Gerald Migliaccio, vice-president of Global Quality and Environmental Health and Safety Operations, Pfizer

ICH Q10 does not relate to good laboratory practices or preclinical testing of materials. 

The guideline can be applied to preclinical testing in the same way it applies to commercial manufacturing, but with an appropriate quality system approach to each stage. [Note: There are charts in the Q10 document that refer to the appropriate level of quality system implementation in the development stage.] 

—Karen Ginsbury, president of PCI Pharmaceutical Consulting Israel

Quality systems do not apply to biologics or medical devices. 

With regard to inspections from a US perspective, Q10 applies equally to drugs, biologics, and new products. It is not applicable to device inspections, however, it serves to make the approaches more parallel. 

My company has not caught up with Q8 or Q9, we can't possibly start implementing Q10. 

While Q8, Q9, and Q10 are intended to be a trilogy, it is possible to implement Q10 without having implemented Q8 (i.e., a company could decide not to adopt quality-by-design [QbD] but to still have a modern, effective quality system with management commitment to quality, policies for risk management, and oversight of outsourcing activities and knowledge management, CAPA, etc). Looking ahead, Q11 

Development and Manufacture of Drug Substances

, has entered the harmonization process. Q11 is an "enabler" for Q8 

. If active pharmaceutical ingredient manufacturers do not adopt QbD, it is going to be almost impossible for the drug product manufacturer to do so. 

Source: The above questions and responses were compiled from the June 2008 Quality Systems in a Global Market webcast (4) as well as from questions posed to the webcast panelists after the event. 

Articles

Myth versus Reality: What does Q10 implementation really mean for my company?

Pharmaceutical Quality Systems

Fully known as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH finalized the concept of Q10 

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 

, 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 

 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. 

 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. 

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. 

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 

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.  

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 

 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. 

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.

All Roads Now Lead to Quality Systems

The European Medicines Agency (EMEA) recommended strengthening the warnings for oral moxifloxacin medicines and concluded that these drugs should only be prescribed to treat acute bacterial sinusitis, acute exacerbation of chronic bronchitis, and community-acquired pneumonia when other antibiotics cannot be used or have failed. 

Moxifloxacin is a fluoroquinolone antibiotic. Earlier this month, EMEA’s US counterpart, the US Food and Drug Administration, asked manufacturers of fluoroquinolone antimicrobial drugs to add black box warnings to their these products due to increased risk of tendonitis and tendon rupture (see 

EMEA’s Committee for Medicinal Products for Human Use (CHMP) reviewed information on the safety of moxifloxacin-containing medicines for oral use, following concerns over their liver safety, according to an EMEA press release.

CHMP concluded that “the benefits of oral moxifloxacin medicines continue to outweigh its risks.” However, due to safety concerns, mainly related to an increased risk of adverse hepatic reactions, CHMP recommended restricting their use in these indications. CHMP also recommended that the warnings of oral moxifloxacin-containing medicines be strengthened concerning the risk of diarrhea, heart failure in women and older patients, severe skin reactions and fatal liver injury. 

The European Commission will now consider the committee’s recommendation and decide whether to apply it to all authorized oral moxifloxacin-containing medicines in the European Union. 

The European Medicines Agency recommended strengthening the warnings for oral moxifloxacin medicines and concluded that these drugs should only be prescribed to treat acute bacterial sinusitis, acute exacerbation of chronic bronchitis, and community-acquired pneumonia when other antibiotics cannot be used or have failed.

EMEA Raises Warnings for Moxifloxacin Drugs

The  US  Food and Drug Administration issued a final rule on July 18, 2008 that exempts early  Phase I investigational drugs from certain good manufacturing practice (GMP) regulations. The new regulation, 

Current  Good Manufacturing Practice and Investigational New Drugs Intended for Use in  Clinical Trials

 210.2, exempting certain  investigational drugs (including biological drugs) for use in a Phase I clinical trial from compliance with Part 211. However, according to the rule, these  drugs remain subject to the statutory requirements under section 501(a)(2)(B)  of the act (i.e., current GMP or CGMP).

Exemption from compliance with Part 211 does not apply to an  investigational drug that a manufacturer has made available for a Phase II or  III clinical trial, or has lawfully marketed, and is being used for a  Phase I trial. Such investigational drug products used for a Phase I trial must  comply with Part 211. FDA  will continue to oversee the manufacture of these drugs through its general  statutory CGMP authority and review of investigational new drug (IND) applications. 

 recommends an approach for complying with CGMP  statutory requirements such as standards for the manufacturing facility and  equipment, the control of components, testing, stability, packaging, labeling, distribution, and record keeping.

“We are tailoring the CGMP requirements to make them appropriate to the earliest  stages of drug development,” said US Health and Human Services Deputy Secretary  Tevi Troy in an FDA news release. “This approach will ensure that these  investigational products can be developed as efficiently as possible with the  highest level of patient protection.”

 Parts 210 and 211, which covered drugs and biologics, the agency stated that the regulations applied to all types of pharmaceutical production, but that it was considering proposing regulations more appropriate for the manufacture of drugs used in investigational clinical trials. According to the news release, certain  requirements in Part 211 are directed at the commercial manufacture of products  and may be inappropriate to the manufacture of investigational drugs used in  Phase I clinical trials. The guidance describes an approach manufacturers can use to implement manufacturing controls that are appropriate for Phase I clinical trials.   

Under  the guidance, pharmaceutical manufacturers still must submit detailed  information about relevant aspects of the manufacturing process as part of  their IND  applications. FDA may inspect the manufacturing operation, suspend a clinical  trial by placing it on “clinical hold,” or terminate the IND if there is evidence of inadequate  quality control procedures that would compromise the safety of an  investigational product.

The  rule takes effect 60 days after being published in the 

The US Food and Drug Administration issued a final rule on July 18 that exempts early Phase I investigational drugs from certain good manufacturing practice regulations.

FDA Reissues Exemption for Phase I Testing

The US Food and Drug Administration published a 

Draft Guidance for Industry on Providing Regulatory Submissions in Electronic Format 

in the Federal Register on July 11. The draft guidance establishes a pilot program for the industry to voluntarily submit drug-establishment registration and drug-listing information in an electronic format. The e-format ideally will allow the agency to process, review, and archive information more easily and quickly. 

The draft guidance is based on a proposed rule issued in August 2006 to revise 21 

 Part 207 and on the FDA Amendments Act (FDAAA) of 2007, passed last fall. FDAAA requires electronic submission by domestic and foreign establishments of registration and listing information, unless a waiver is granted. FDA initiated the voluntary pilot program as a transition period to test the submission, receipt, and processing of electronic documents before electronic submissions are required starting in June 2009. The agency intends to issue a final guidance before June 2009.

The standard for electronic submissions will be extensible markup language (XML) in a standard structured-product labeling (SPL) format. The draft guidance explains how companies can transition from paper to an SPL format. The document also discuses how companies can submit additional, useful but not required information that is often included in paper submissions. FDA does not anticipate much new cost associated with electronic submission. According to the draft guidance, free software to create an SPL document will be available and a minor $20.00 electronic-submission-gateway-certificate fee to submit the file will be necessary.

FDA estimates that it may take an additional two hours to prepare an SPL-format submission, according to the draft guidance. The agency also predicts, however, that the burden will decrease over time as companies become familiar with the format. In addition, the new SPL format will allow for multi-establishment and multidrug submissions instead of individual forms currently used with the paper format system.

Comments on the draft guidance, including its adequacy and usefulness, are due Sept. 9, 2008 and can be submitted in writing to the Office of Critical Path Programs (HF-18), Office of the Commissioner, FDA, 5600 Fishers Lane, Rockville, MD 20857 or online at 

The US Food and Drug Administration published a Draft Guidance for Industry on Providing Regulatory Submissions in Electronic Format in the Federal Register on July 11.

Draft Guidance Issued for Electronic Regulatory Submission

-The US Food and Drug Administration is seeking volunteers from the pharmaceutical industry to participate in a pilot program involving the submission of quality information for biotechnology products. Focused on chemistry, manufacturing, and controls information, the Expanded Change Protocol will be consistent with the principles of quality by design (QbD) and risk management.

The purpose of the pilot program is to gain more information about QbD and to facilitate agency review of QbD and risk-based approaches for manufacturing biotechnology products, according to a July 2 notice. The pilot program will focus on those products reviewed by FDA’s Office of Biotechnology Products, which operates in the Office of Pharmaceutical Science at the Center for Drug Evaluation and Research. The agency hopes the program will assist in the development of guidance for industry on QbD and risk management. 

The program is open to original submissions of and supplements to biologic license applications and new drug applications, according to the 

. Requests to participate in the pilot program are due Sept. 30, 2009. Comments on the pilot program are due Dec. 31, 2008. All correspondence can be sent to: Division of Dockets Management (HFA-305), FDA, 5630 Fishers Lane, Room 1061, Rockville, MD 20852, or submitted online at 

The US Food and Drug Administration is seeking volunteers from the pharmaceutical industry to participate in a pilot program involving the submission of quality information for biotechnology products.