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The concept of design space has started a minor revolution in our industry.
Today's global marketplace challenges the pharmaceutical industry to deliver quality medicines to patients under a fractured regulatory environment. Managing regulations, inspections, approvals, and other requirements can be overwhelming. Recently released guidance documents from the International Conference on Harmonization (ICH), which are based on solid scientific principles, have the potential to simplify the drug registration process.
For example, at the Parenteral Drug Association (PDA) meeting in Paris in December 2004, Dr. Emer Cooke, head of the EMEA Inspectorate, remarked, "Risk concept is mentioned 90 times and in 20 documents in EU GMP legislation and guidance."1 Cooke cited the phrase "unless otherwise justified" as direct linkage to Quality Risk Management. In other words, current regulations support good science. In addition, greater emphasis is being placed on guidances based on international harmonization. This article focuses on the most recent quality guidances developed by the International Conference on Harmonization (ICH), both finalized: ICH Q8, Pharmaceutical Development; and ICH Q9, Quality Risk Management. A third document, ICH Q10, Pharmaceutical Quality Systems, is under development. These documents realize the consensus vision statement developed and adopted by all parties and observers involved at the ICH meeting in Brussels in July 2003:
Develop a harmonized pharmaceutical quality system applicable across the life cycle of the product, emphasizing an integrated approach to quality risk management and science.2
ICH is an organization that includes regulatory and industry representatives from Japan, the United States, and the European Union. ICH operates by consensus; the underlying goal is to apply good scientific principles to pharmaceutical regulation. Canada, along with other countries and the World Health Organization, has observer status in ICH; however, this involvement has not prevented these countries from developing their own guidances that conflict with those of ICH.
The work to date on the above-mentioned trio of documents has been extraordinary. The scope of the work was first envisioned as a harmonized quality system describing a life cycle approach. Now we are at the stage when we are beginning to realize the benefits of two of the three documents. With the anticipated addition of Q10, the entire suite of documents will provide the basis for the full benefits to be realized.
The ICH Q8 guidance document, Pharmaceutical Development, was originally intended to provide details of the expected content for the subsections of section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of module 3 of the Common Technical Document (ICH guideline M4). This part of ICH Q8, Pharmaceutical Development, is logical, educational, and didactic. Embedded within the document is a gem of a concept: design space. These two words and their associated definition have started a minor revolution in our industry. Here is the definition excerpted from the document:
Design Space: the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters demonstrated to provide assurance of quality. Working within the design space is not considered a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval."3
The definition of design space takes into account raw materials, components used in processes, operating parameters of equipment, and the interactions among them. It also implies the need to carry out a rigorous, science- and risk-based approach (based on ICH Q9) to development studies. Carefully chosen words such as "working within the design space" start to lay the groundwork for firms who invest in understanding their processes to manage continual improvements within their own quality systems. The overall principle, the extent of knowledge obtained by the firm and shared with the regulator, defines the extent of a flexible regulatory approach applied to affecting changes without prior regulatory approval.
The concepts embedded in Q8 transcend its application solely to drug products. Most of the comments to the docket for the version posted as FDA guidance suggested expanding the applicability towards drug substances and larger molecules. ICH Q8 is now being revised to clarify its revolutionary concepts. Discussions are under way within ICH about extending the concepts to active pharmaceutical ingredient (API) development, including both new chemical entities and biotechnology drug substances.
Q9 is the repository for the risk-management tools to be applied both in Q8 and Q10. John Berridge, who is vice president for Pfizer Global Research and Development and the rapporteur for the initial stages of Q8 and now its revision, described Q9 as a collection of tools, drawing the comparison between wrenches, pliers and hammers, which can be used, per the guidance, to put a car together (development) or to maintain a car (commercial manufacturing). Risk Management tools are commonly used in many other industries, most notably the insurance industry, to analyze, evaluate, and manage risks. The guidance describes examples of how to apply the tools to a variety of pharmaceutical systems.
When first faced with implementing Quality Risk Management, one could become paralyzed with indecision about which tool to use in a given application. Unlike statistical analysis, where it is necessary to understand the data (normality, randomness), in quality risk management there is no wrong tool to use, since there are no statistical rules to violate. The correct tool is the one the user feels most comfortable with. In the total absence of experience, one can look at other applications of Quality Risk Management. For example, a recent FDA white paper, which discusses applying risk management to determining inspectional priorities, is an excellent example of risk ranking and filtering.4 Quite often, failure mode effect analysis (FMEA) works well in conjunction with a six-sigma approach.
One must be cautious, however, about applying risk management to justify an incorrect decision. For example, Quality Risk Management does not mean risk can be accepted and used to justify the release of a batch that should be rejected. Bad risk analyses should not be used as a basis for poor decisions.
Rather, Quality Risk Management can be used to facilitate consistent decisions. The risk-management process encourages a multi-disciplinarian approach to bringing different experiences to bear on risk analysis. Quality professionals bring unique experiences to their daily work. By creating a process where collective experiences can be used in a structured approach, the resulting decisions will be stronger than decisions based on limited experience or knowledge would be.
Since Quality Risk Management is flexible, there will be many applications for its use. As a scientific process, it can be used in many quality systems both in development and commercial manufacturing. However, there is no reason to create a separate Quality Risk Management Department; this would probably discourage the wide usage of Quality Risk Management envisioned by the authors of the guidance document. Instead, Quality Risk Management should be a tool used by many diverse disciplines and departments.
Each firm will need to define the documentation requirements for informal and formal risk management processes. These requirements will depend on the depth of the risk management process, and its criticality and role in supporting current good manufacturing practices (GMP) activities. Proper GMP record keeping and documentation will still be a cornerstone in the application of Quality Risk Management.
Q10, Pharmaceutical Quality Systems, is currently at step 1 in the ICH process—the initial Expert Working Group is developing and drafting the document.
Within Q10, three elements have been discussed5 :
Quality management synthesizes all of the quality indicators that help to uncover systemic issues, determine priorities, and drive improvements. To comply with GMPs, a given site develops a set of standard operating procedures that define how the site will operate. These procedures detail requirements for such quality systems, such as deviations, complaint handling, training, internal auditing, validation, and change management. These concepts are irrespective of technology or national requirements but capture that intangible asset known as the "quality culture." Quality management synthesizes all of the quality systems to develop a comprehensive approach to address quality issues, make improvement, and create the quality culture.
Quality management is codified into tangible knowledge through a variety of documents, such as quality manuals and quality plans. These have been described in the Quality System Regulations (QSRs: 21 CFR 820)/ISO 9001 Quality Managment Systems—Requirements. The application of these documents in conjunction with quality risk management defines the site and the corporate quality culture. This concept will be applicable to both development and commercial manufacturing.
Product realization is the part of the life cycle described as the transition from the twinkle in the eye to product launch. It is an exciting time marked by success and failure and trial and error; along the way, a product is readied for market. A transfer of knowledge accompanies the technology transfer. The knowledge in developing, manufacturing, and testing a product is translated from the codified knowledge in laboratory notebooks, experimental reports, and other documents as well as intrinsic knowledge. This knowledge must be translated to a receiving site in a manner that assures successful commercialization, as opposed to a perfectly developed product impossible to manufacture.
Continual improvement describes the ability to enact incremental change in a rational and timely manner. It applies to both quality systems and manufacturing processes. Recent discussions about the "desired state" conclude that knowledge about the product and process increases exponentially during early commercial manufacturing. A corollary of in-creased knowledge is continual improvement. Sites that institute a way to measure and monitor, with the capacity to analyze data from production and quality systems, also have the ability to identify opportunities for improving the product and processes. This is an example of how the three guidances (Q8, Q9, and Q10) can supplement each other, when Q10 is completed. For companies demonstrating enhanced process and product understanding, working within the design space (as defined in Q8) can lead to implementing improvements without seeking prior regulatory approval.
This flexible regulatory approach can transcend regional differences and enable companies to implement continual improvement without the concern of differing regional interpretation. Thus can we realize the goal of using science to achieve harmonization.
Many of the basic concepts outlined in the three guidances are not new to the biotech industry. The opportunity for innovation they provide is demonstrated through how aggressively the industry pursues their combined synergies.
The Q8 concept of design space provides a common framework for the science of process development for biologics. Because of the challenges in characterizing complex proteins for routine Quality Control, the Q8 lesson to build in quality by design is already practiced to "consistently deliver the intended performance of the product." The fundamentals of demonstrating process control and capability, already in place in our industry, includes scientifically sound studies for:
Additionally, ICH Q6B, Specifications: Test Procedures and Acceptance Criteria for Biotechnological and Biological Products, includes guidance for product characterization through the design of product specs specifically aimed at controlling product heterogeneity. It allows for not testing certain impurities if supported by adequate process understanding and demonstrated impurity clearance.
The production of biologic products is inherently risky. Many controls are encoded into our processes and systems to avoid poor outcomes. Risk management analysis and control are typically centered around:
Good, solid science has always been a key element in the regulatory environment for biologic products. The adage historically applied to biologic products, "The process is the product," indicates process understanding is at least as important as product characterization, if not more so. Regulators expect we know a great deal about our molecule and the specific process controls, which assure its quality. Elements of risk-based decision-making are already defined by ICH for biologics in regard to raw material controls, viral safety, and specifications. Thus, Q8 and Q9 offer more structure and specific tools to support good scientific practices already in play for the development and control of biopharmaceuticals. The quality system elements under development in Q10 may represent an opportunity for significant advances in the quality culture and spirit of continual improvement.
This article has described recent quality guidances that could lead to greater harmonization. The concepts of design space, quality by design, process understanding, quality risk management, quality management, and continual improvement, all depend on a solid scientific foundation. The application of these concepts in the current and future environment of biopharmaceuticals was discussed.
There are several differences in the regulations. The specific and general requirements are somewhat consistent and differences can be viewed as minor. The real differences lie within the details and interpretation of the regulations. This is where the science embedded in the ICH Quality documents can help transcend regional differences and lead to scientific harmonization.
This is best captured in a quote attributed to the French microbiologist Louis Pasteur: "Science knows no country because knowledge belongs to humanity and is the torch which illuminates the world."
ZENA G. KAUFMAN is director of the Quality Center of Excellence, Corporate Regulatory & Quality Science, at Abbott Laboratories, 100 Abbott Park Road, Dept. 3QA, Bldg. AP6C, Abbott Park, IL 60064-6088, tel. 847.938.1750, firstname.lastname@example.orgDIANE BENO is director of Biologics Quailty Assurance.
1. Presentation by Dr. Emer Cooke at PDA Meeting December 2004, Paris, France.
2. Presentation by Dr. Joyce Ramsbotham, at PDA Meeting September 2003, Washington DC, USA.
3. International Conference on Harmonization Q8, Pharmaceutical Development.
4. FDA: "Risk-Based Method for Prioritizing cGMP Inspections of Pharmaceutical Manufacturing Sites—A Pilot Risk Ranking Model," September 2004.
5. Presentation by Mr. Gerry Migliaccio at PRPQA meeting, January 2006, San Juan, Puerto Rico.