Introduction—Why Choose to Try Quality by Design?
Quality by Design can impart strong added value to the overall control strategy of your process and product. While this can take a certain degree of up-front time and cost input, the quality dividends in terms of robustly delivering a process and product that more consistently meets quality expectations and release criteria can easily make up for this primary investment. Quality by Design doesn’t just stop here, however— additional advantages include validation options, facilitation of change control and post-license variations, and above all, the creation of a positive regulatory confidence with regard to chemistry, manufacturing, and control (CMC).
So why hasn’t Quality by Design hit the big time in the case of the pharmaceutical industry? This may be due to perceptions that Quality by Design is too difficult, too time intensive, or too costly to undertake. Some may think, “Why should I bother when minimum CMC may work and be much cheaper?”
This perception, however, is starting to change.
Quality by Design is becoming increasingly implemented in the case of small molecules (where chemistry lends itself to being more formulaically defined and recipe driven) and is beginning to be employed for more complex biopharmaceuticals by both large pharma and emerging biotech. Although the choice still depends on company preference, Quality by Design is starting to become mooted in certain circles as being smart design or, essentially, the modern application of good science. This isn’t too far from the truth; whereas traditional development is based on incremental empirical studies from the ground up, Quality by Design uses the clever systematic and logical design approach of “beginning with the end-point in mind” or, more specifically, asking, “What do we ultimately want our process and product to do?” and then accurately designing a focused and systematic development program back from this. Smart design indeed.
In fact, the FDA and EMA continually embrace the virtues of Quality by Design and have been running a “pilot programme for the parallel assessment of sections of applications that are relevant to quality by design”1,4 with industry to see exactly how this works in the real world and in achieving the end-point goal of regulatory sanctioned market approval. This has been undertaken to good effect. What, up until fairly recently, was a new discipline for the FDA and EMA is now an accepted and even “anticipated” approach.
At this point, one might ask, “So, it’s easy then?” Well, not quite. It still takes careful consideration, focused planning and management, and the tricky part is the outsourcing scenario, as the mindset and application for Quality by Design need to be correctly communicated and taken on board. Collective buy in—both internal and external—is paramount. So how, therefore, do we go about doing this? What is a surefire strategy for Quality by Design and how do we communicate and transfer this as well as manage our outsourcing partners to meet our expectations?
The purpose of this paper is to examine the strategic concepts of this.
The Quality Paradigm
Before we go further, it is worth noting a brief history lesson. ICH discussions in July 2003 (Brussels) agreed on a consensus vision:
- To “Develop a harmonized pharmaceutical quality system applicable across the life cycle of the product emphasizing an integrated approach to risk management and science”2
This gave way to modern Quality by Design which is defined as
- “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and Process Control, based on sound science and Quality Risk Management”2,3
This is a very powerful definition as it encompasses all of the necessary traits of quality design and development.
A good starting point for Quality by Design is therefore consultation of the ICH guidelines: this being ICH Q8 (R2)2,3 stated above, and ICH Q11 (Step 4),2,3 both of which cover process and drug substance/drug product development for small and large molecules. Although this makes insightful reading and is further supplemented by the FDA and EMA with complementary questions and answers covering general concepts and a focus on the more demanding requirements of Design Spaces, there is still a certain amount of extrapolation that is required from a few lines of regulatory text.
To properly embark on Quality by Design, a key take-home message is to ideally find an individual or a company who’s approached this before and therefore knows the “roadmap” and common pitfalls. More importantly is to ask for regulatory/scientific advice early on; this is strongly advised in order to check your intended approach to Quality by Design; the competent authorities will be more than willing to embark on the “QbD journey” with you—like you, regulators are scientists, so don’t worry if you get asked probing or challenging questions, this is normal scientific intrigue. Quality by Design is, after all, known as an enhanced approach so it is important to establish a 2-way open and constructive dialogue to communicate this “heightened” level of development.
Assembling a Quality by Design Strategy
So, what is a starting point “template” for Quality by Design and can we ever effectively hope to outsource this?
- Do some basic homework: examine Quality by Design on the EMA and FDA websites and use the relevant ICH guidelines for general assimilation of the principal facts.
- Next, sketch out a simple framework; the best approach for Quality by Design is to aim to keep it:
- Realistic
- Sensible
- Achievable
- Focused
- Above all, make sure there is complete “company buy-in” from the scientific level up to the corporate level—this is essential in making sure Quality by Design is accepted and stays on track from a financial, resource, and time perspective. Commandeering support from individuals with proven experience in this field can help cement this.
A Basic Quality by Design Framework
Table 1 is a straightforward breakdown of Quality by Design that can be easily communicated.
Table 1. Quality by Design Flow Outline
The purpose of the outline presented in Table 1 is to provide a “quick start” outline in order to lift Quality by Design off the page and put the essential underpinnings into emerging action. It is then essential to back up each part of this process by what is stipulated in the guidelines and to get behind this as a fully coordinated team. In the case of a product being a new chemical entity, we will probably not have all of the information to start off with, so the Quality by Design parts will need to be periodically revisited in order to firm this up and this will also affect what Design of Experiments are chosen.
So can this elementary Quality by Design framework really be used “off the peg?” While this provides the basic starting point considerations of Quality by Design only (and upon which to actively build), it is important to realize that this is only a 2-dimensional list—a 3-dimensional project plan of delivery will need to be developed and managed in unison.
Quality by Design Strategies based on a ‘Modular Approach’
The highly flexible advantage of Quality by Design is that it is not necessary to do everything in Table 1 at once. It can be structured using a modular approach (ie, based on the most relevant, achievable, and logical parts selected from component parts 1 through 8), provided that it makes sense and still supports the final control strategy. This flexible advantage of Quality by Design is another key take-home message.
In fact, as an example, Quality by Design can quite easily be balanced with a traditional approach. Some companies, especially in the case of small- to medium-sized enterprises, do not have the luxury to pursue the full scope of Quality by Design due to lack of resources (capital and time, which is the most impactful). Therefore, these companies may, for example, choose to use certain enhanced QbD modules on the upstream part of the process but in fact use a standard traditional approach for the downstream process or vice-versa due to this making more “achievable,” “joined-up” sense—providing this is logical, and supports the control strategy, this is perfectly acceptable. This dual aspect approach is known as a combination approach and is perfectly valid from a regulatory perspective. This is where Quality by Design is, to a degree, “backward/cross compatible.”
Another strategic example is to choose to defer the modular part of the Design Space, including the accompanying and necessary validation at scale.
Table 2. Possible Scenario of Responsibilities (Based on the Development/Outsource Strategy)
Quality by Design and Outsourcing: Critical Factors
Having established a baseline strategy, let’s explore how we might take this forward. Inevitably, we will need to think about outsource development/manufacturing.
As outsourcing remains a strong option for development and cGMP manufacture, the challenge in maintaining Quality by Design and keeping it on track is paramount. So what are the principal issues and how can these issues be overcome?
The maintenance and maturation of QbD across the complete product development lifecycle needs to be controlled. Therefore, the philosophy and understanding of Quality by Design has to be imparted and managed with the outsource partner who may be unfamiliar with Quality by Design.
Conveyance of Quality by Design to the outsource partner will come at a commercial cost—notably money and time—in order to establish this. Additionally, outputs from the CMO will need to meet expected regulatory expectation.
Selection of Outsource Partner for QbD
Table 3. How do you best select and facilitate an outsource partner to undertake Quality by Design?
Regulatory Strategy and Compliance
The driving force behind process and product development in utilizing Quality by Design is the culmination of better aligned and focused regulatory approval. Early demonstration through scientific advice of a realistic Quality by Design approach and the establishment of a disciplined control strategy builds in important confidence by the competent authority. The benefit is being able to purposefully execute this and appropriately document the Quality by Design parts in the final dossier submission for regulatory assessment/approval. This is easier said than done, and though there is some guidance in ICH Q8 and Q11, the guidance is minimally presented. A tip here is to map out the QbD parts under the various sections which are indicated in the ICH guidance and then elaborate on these as necessary in a systematic and linked manner. The competent authority wants to see that you are decisive and logically structured in your approach and reasoning of Quality by Design and in the realization of the final Control Strategy through the constructive and joined-up compilation of the component parts. Key points will include clear relational linkages of the material attributes and critical process parameters to the critical quality attributes with appropriate control of risk, design space integration as a unity (not a selection of proven acceptable ranges), appropriate/ sensible validation at scale, and a unified, robust control strategy with a clear control strategy summary. This is essential in being able to assemble robust dossier sections on Quality by Design. Seriously consider an experienced regulatory partner who can make sure that you assemble the “right story” and data in the correct places in order to meet the expectations of the competent authorities.
Conclusion
Quality by Design is a powerful development approach that offers a number of technical, quality, and regulatory dividends. To the uninitiated it may feel, at the outset, to be burdensome, but its advantages soon become obvious in achieving built-in quality, a decisive control strategy, and regulatory flexibility. Quality by Design can impart better process/product understanding to allow for a more focused, streamlined, and hence a prospective faster development approach and in the realization of a more commercially robust control and validation strategies. It can also facilitate regulatory flexibility (ie, development options) and regulatory agency confidence via increased product understanding, therefore helping reinforce regulatory submissions. The modular aspect of Quality by Design means that it doesn’t all have to be done at once and this modularity, in order to assemble as a “best fit” approach is advocated.
More and more contract manufacturing partners are becoming knowledgeable in Quality by Design. Where they are not isn’t necessarily a showstopper providing they can readily accumulate the concepts, but this needs to be strongly planned and closely project-managed.
Gaining access to regulatory support (with a demonstrated QbD track record) is advantageous in initially setting up Quality by Design, managing expected outputs with outsource partners, and in assembly of the final dossier from raw data and reports. In addition, obtaining early scientific advice from the competent authorities is an essential step in order to obtain a “reality check” and “buy in.”
Following market approval, Quality by Design really comes into its own from an operational Technical/Quality point of view. Providing Design Space validation has been performed, out of specifications during production batches can be more realistically dealt with and more clearly justified; change control of the process for any reason can be more readily incorporated and post-license variations more confident as they are backed with extensive and broad data.
So the outcome is that Quality by Design and outsourcing can certainly be made to work. This requires more constructive planning and a strong project management interface, but given the right buy-in from the outsource partner is in place, the beneficial outputs can lead to the establishment of a strong relationship and the positive realization of the process and product with quality being effectively built in by design.
References
- European Medicines Agency (EMA). Human Regulatory. Quality by design guidance page. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/ document_listing/document_listing_000162.jsp&mid=WC0b01ac058076ed73. Accessed October 27, 2014.
- European Medicines Agency (EMA). Human Regulatory. Scientific guidelines. ICH: Quality page. ICH Guidance Q8-Q11. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000431.jsp&mid=WC0b01ac0580029593. Accessed October 30, 2014.
- U.S. Food and Drug Administration. International Conference on Harmonisation – Quality page. Updated October 15, 2013. ICH Guidance Q8-Q11 Available at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htm. Accessed October 30, 2014.
- U.S. Food and Drug Administration. Conclusions of FDA-EMA Parallel Assessment of Quality-By-Design Elements of Market Applications page. Updated November 4, 2013. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm365524.htm. Accessed October 30, 2014.
Dr. Richard Dennett is responsible for the management of projects involving the development of Chemistry Manufacturing and Control (CMC). He provides scientific, technical, and regulatory expertise for a broad range of activities, including, but not limited to, Quality by Design (QbD), Technology Transfer/Comparability, and cGMP compliance/validation. He has 17 years of biopharmaceutical industry experience, including 8 years in construction and operational roles at a UK CMO. Dr. Dennett has actively advised on 2 successful FDA and EMA NDA/MAA submissions, each with QbD content, for a small molecule and a biologic, respectively. Dr. Dennett has first-hand experience of process/product development from concept through to regulatory market authorization as well as being a leading, recognized regulatory consultant in the field of Quality by Design. Dr. Dennett earned his PhD in applied biochemistry at Liverpool John Moores University in the UK.
Romain Le Deun is an 8-year experienced biotechnology engineer with significant experience in the management of regulatory files and all the CMC information required to ensure compliance of innovative biotechnology and medicinal products worldwide. Mr. Le Deun holds an Engineering Masters’ Degree in Biotechnology and Biochemistry from the ‘Institut National des Sciences Appliquées’ (INSA) in Lyon, France.