QUALITY-BY-DESIGN - Quality-by-Design: The Good, The Bad, The Inevitable

INTRODUCTION

To bring new ideas and innovations into the real world, science has to be made into something tangible. While that’s the fundamental mission for many pharmaceutical companies, that’s exactly where many drug development programs fall short – in the actual formulation, engineering, and production of new products. This is evident as the US Food and Drug Administration (FDA) continues to emphasize the “modernization of the regulation of pharmaceutical manufacturing and product quality.” Poised to be the key driver of that mission is Quality-by-Design (QbD).1

With proportionately smaller shares of product development investments going toward actual formulation and production, it’s all too easy to overlook the processes that are so critical to a product’s downstream approval and long-term market viability. A focus on upstream investigation to ensure the integrity of drug products is what QbD is geared to instill in development programs. In essence, QbD can be interpreted as a way to maximize time and cost savings by better understanding the components and processes necessary to optimize a drug product’s safety, efficacy, and quality at every stage in development.

UNDERSTANDING QBD

While the concept of QbD originated in the early 90s, it’s a much more recent phenomenon for pharmaceutical companies, having only been adopted and refined for end-to-end drug development programs throughout the past decade. Today, confusion exists as to whether or not the FDA expects QbD to become a standard part of all submissions in the near future. In short, the answer is yes; the FDA is demanding that components of QbD be provided in all submissions. Already, generics companies have felt the pressure as the FDA has moved beyond evaluating mere equivalencies of generics to reference drugs, especially as products increase in design complexity.2

The FDA continues to prepare inspectors to more capably accept and review QbD submissions, and there is an expectation that QbD will become standard practice for generics makers. In fact, the majority of ANDAs now include multiple QbD elements. At a presentation at the International Forum Process Analytical Chemistry meeting in January 2013, Daniel Peng, PhD, noted that in June and July of 2012, only about one in four ANDA filings contained multiple QbD elements, while more than 80% did at the time of the presentation.3 As of January 2013, ANDA applicants are being “strongly encouraged” by the FDA to apply QbD – deficiency letters will now explicitly cite the lack of QbD.4

While the rise of QbD is certainly evident and perhaps more pressing for generics, the number of new drug QbD submissions has also increased steadily, with just one in 2005, seven in 2008, nine in 2011, and six in less than the first half of 2012.5 While the FDA has noted lapses in QbD filings, both the FDA and drug makers are looking to normalize the application of QbD in submissions. While QbD does not directly reflect a change in regulatory requirements, it can provide opportunities for more flexible approaches to meet evolving regulations.6

From the FDA’s standpoint, QbD represents a schema or thought-process behind the development and manufacture of a product and adds a measure of accountability. The FDA wants drug makers to demonstrate that they’ve challenged raw materials and processes to ensure products are performing not only as intended, but as optimally as possible given the inputs. For example, the FDA wants to know: How has the formulation been deconstructed and reconstructed? Are these ingredients put together in the best way possible? What are the minimum/maximum target values set before testing, and how has the product fluctuated within those minimum and maximum values when different processes are used? QbD answers these questions.

THE FOUR PILLARS OF QBD

1. Define the Product Design Goal
Outline the quality target product profile (QTPP), and identify all the critical quality attributes (CQA) for the product. The QTPP includes factors that define the desired product, including the intended use of a product, route of administration, delivery system, dosage form, and dosage strength, among others. A CQA is “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.”7 By conducting experiments on different formulations (eg, gels, ointments, sprays) to characterize a substance’s solubility, compatibility, stability, etc, the QTPP and CQAs provide a framework for product design and understanding.

2. Discover the Process Design Space
ICH Q8 defines design space as an “established multidimensional combination and interaction of material attributes and/or process parameters demonstrated to provide assurance of quality.” Critical process parameters (CPPs) are identified by determining the extent to which any processvariation can affect the quality of the product.8 By defining the design space, issues can be anticipated and better control of the process can be achieved. Actual experimental data, product experience, or literature guidance can be used to define the extremes of the parameter sets to be refined.

3. Define the Control Space
Based on the process design space, a control space can be defined. This enables an understanding of processes in a way that ensures product quality from known variability of the production process. This approach will keep multifaceted production processes under tighter control. To illustrate the concept of a control space study, think of a reference product dataset with tightly clustered data points that represent the output of a tightly controlled process. Plotting the output of a process and comparing it to such a reference will indicate whether a process is in control. One technique to help avoid disparities is to conduct a design of experiments study on a product in the development stage. Considerable wasted effort can be eliminated, and root causes of unexpected adverse outcomes can be found sooner with such an approach.

4. Target the Operating Space
The operating space is the best set of parameters, determined statistically, which enable accommodation of any natural variability in CPPs and CQAs. For generics, the operating space should be within the control space and should allow a reference product to be tested with the same set of parameters. For new products, the operating space should be within the design space and compliant with regulatory guidelines. Innovators can gain a competitive advantage by thoroughly exploring the design space, including testing numerous batches of formulations to truly refine their product.

THE CASE FOR QBD

While regulatory agencies anticipate that products will be developed using QbD, drug makers should see it as more than regulatory decree; QbD is a methodology that formalizes product design, automates labor-intensive testing, and simplifies troubleshooting. By taking a systematic approach to understand the compatibility of a product with all of the components and processes involved in the manufacture of the product, drug makers are better equipped to safeguard product integrity.

Rather than conventional end product testing that relies on reproducibility, which can be costly on both ends of a development pipeline, QbD compels drug makers to assess processes and components earlier to grasp how they influence quality, safety, and efficacy. In short, QbD calls for thorough early investigation and more capable follow-through. On the commercial end, QbD ensures that the more information generated about the influence of a component or process on a product’s quality, safety, or efficacy, the more business flexibility is created. QbD also represents a bridge between developers and manufacturers, and better alignment among all parties involved in the design of a new drug – from concept to commercialization – to make the development process a concerted effort.

QbD is essential to preformulation and formulation stages, in which the goal is to identify risks – from environmental factors to shelf-lifespan – that may affect the final drug product. The extent of examinations is variable at this stage. For example, informal stability testing may also take place to evaluate packaging compatibility. Beyond physical testing, chemical and microbiological tests may also be conducted. By understanding how API degradation, mixture uniformity, viscosity, etc, may affect a product’s performance downstream, the in-process testing that QbD necessitates serves as both a framework for in-process improvement and future-proofing.

Consider the fallout of an out of specification (OOS) result: Insufficient data and/or in-process testing can lead to a seemingly endless search for the root cause(s). In fact, even a four- to nine-fold increase in testing could be required to remediate an OOS event.9 Potentially, huge external costs during and after product development can also come as a result of:

• Delayed product launch and/or approval
• Failure to achieve or maintain regulatory compliance, resulting in severe actions, such as consent decrees
• Misused raw materials and redundant manufacture of scrap batches
• Suboptimal manufacturing processes, and the resulting investigation and remediation when issues and deviations are found10
• Failure to successfully scale up an end product

The proactive investigation and intervention QbD incorporates can yield significant business benefits, including:

• Fewer lost batches, which could cost $250,000 to $500,000 per batch
• Fewer manufacturing deviations, saving hundreds of hours and $10,000 to $15,000 per deviation
• Faster time to market and more reliable supply, when each day on the market could mean $100,000+
• Fewer inspections of manufacturing sites
• A many-fold increase in ROI via cost savings and improved revenue

QBD ISN’T A QUICK FIX

While QbD’s downstream time and cost savings have proven significant for many development programs, there is still an initial investment to implement QbD. In general, developers are focused on getting their product to a manufacturing plant as early as possible. But implementing QbD – and designing and executing studies, then analyzing them to make sense of findings – can take up to 4 months or more before manufacturing. As off-putting as this is for many developers, there are other factors that compound the challenge.

QbD can be especially difficult to implement across the board when operations are fragmented, either geographically or functionally. Even when a QbD system is in place, technology, and knowledge transfers can be problematic when new personnel are being introduced without any prior guidance, for example, when a product is making the transition from development to manufacturing. While QbD is a systematic approach and can be implemented systematically into business operations, it’s important that everyone involved with a research program understand the concept of QbD before implementation. Putting QbD practices in place is only the beginning – the entire line of personnel with hands on a product must demonstrate a sustained commitment to continuous improvement that QbD demands.

QbD requires an investment of time and labor at each stage of development. Moreover, QbD necessitates adequate technologies and expertise be in place. Additionally, there are secondary matters to appraise (eg, data management, regulatory/filing preparation, internal management buy-in, and governance). While some companies may feel the pressure to get on board with QbD, careful consideration and planning are vital. As one consultant put it, “QbD can be significantly less daunting if the organization understands clearly what is most important, where there are critical gaps and what must be done to close them.”11

Within the FDA, reviewers vary in levels of understanding and adoption of QbD. While that looks to become more standardized, interactions with the FDA may still pose problems, as with any new practice that involves unique principles and lexicon. The three following observations were made in a recent QbD-based ANDA filing that highlight issues with the adoption of QbD:

1. Exhaustive information was presented with no justification or interpretation (no conclusions) of data
2. Basic QbD terminology, such as CQAs, CPPs and, in particular, process design space, was misused
3. Prior knowledge was often presented without necessary context or justification for its use12

CONCLUSION

From scientific and business standpoints, the case for implementing QbD is becoming stronger. QbD is a form of investment that certainly takes time and money to establish, but the ultimate costs are negligible and enable more efficient use of development funds. QbD is not just a methodology for mitigating risk and variability – it’s a viable means to discover insights upstream throughout your development process. It’s evident that the FDA sees QbD as a way to optimize the quality of drug products for everyone involved. From developers and manufacturers, to regulators and patients, QbD drives more consistent, high-quality drug products that meet safety and efficacy requirements. Today, the FDA expects the following QbD components in all submissions: the QTPP; lists of CQAs, CPPs, and critical material attributes of the drug and excipients; and the control strategy that ensures the product meets its predefined objectives.

While QbD can establish singularity in the development of a drug product, adopting QbD can prove overwhelming and, if misapplied, inefficient and expensive. A knowledgeable partner – one that has demonstrated successful QbD implementation – is a must for companies looking to adopt QbD.

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REFERENCES

1. US Food and Drug Administration. Pharmaceutical Quality for the 21^st Century a Risk-Based Approach Progress Report. U.S. Department of Health and Human Services. 2007. (http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobaco/CDER/ucm128080.htm).
2. Raw AS, Lionberger R, Yu LX. Pharmaceutical Equivalence by Design for Generic Drugs: Modified-Release Products. Pharm Res. 2011;28(7):1445-53. (http://www.ncbi.nlm.nih.gov/pubmed/21387150).
3. Peng D. Presentation at the International Forum Process Analytical Chemistry (IFPAC) meeting. Baltimore, Maryland. 2013. (http://www.lachmanconsultants.com/fdastudy-on-the-status-of-qbdimplementation-in-the-genericindustry.asp).
4. Rosencrance S. QbD Status Update Generic Drugs. North Bethesda, Maryland. 2011; s 9.  (http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/abbreviatednewdrugapplicationandagenerics/ucm292666.pdf).
5. Miksinski SP. Regulatory Assessment of Applications Containing QbD Elements — FDA Perspective. Silver Spring, Maryland. 2012; s 3. (http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM341173.pdf).
6. Nasr MM. Implementation of Quality by Design (QbD) – Current Perspectives on Opportunities and Challenges. 2011; s 13.  (http://www.fda.gov/downloads/Adviso…dClinicalPharmacology/UCM266751.pdf.
7. US Food and Drug Administration. Guidance for Industry, Q8 (R2) Pharmaceutical Development. U.S. Department of Health and Human Services. Rockville, Maryland. 2009.
8. Erni F. Design Space and Control Strategy. Presentation at European Federation of Pharmaceutical Industries and Associations. 2006; s 25. (http://www.pharma.gally.ch/pdf/design_space_and_control_strategy.pdf).
9. Lanese JG. OOS: The Last Resort. Pharmaceutical Formulation and Quality. 2011; p 30. (http://www.pharma.gally.ch/pdf/design_space_and_control_strategy.pdf).
10. Shanley A. From the Editor: The Cost of Poor Quality, Too High a Price? Pharmaceutical Manufacturing. 2012. (http://www.pharmamanufacturing.com/articles/2012/033/).
11. Schmidt B. Implementing Quality byDesign: Are You Ready, or Not? pharmaqbd.com. 2010. (http://www.pharmaqbd.com/schmidt_ready_for_qbd/).
12. Jain S. Quality by Design (QbD): A Comprehensive Understanding of Implementations and Challenges in Pharmaceuticals  Development. International Journal of Pharmacy and Pharmaceutical Sciences, Vol 6, Issue 1, 2014. 2013; p 34.  (http://www.ijppsjournal.com/Vol6Issue1/8108.pdf).

Michael Lowenborg is Manager of R&D Formulation and Process Development, DPT Laboratories. With nearly 20 years of experience in the industry working on semisolid and liquid formulations, primarily topical skin treatment products, he has been with DPT Laboratories for more than a decade. Before joining DPT, he served as development chemist for Estee Lauder and as formulation scientist for Avon. Mr. Lowenborg frequently speaks at industry events and presents on the implementation and use of QbD. He is a member of the AAPS as well as the Society of Cosmetic Chemists. Resources authored and presented by Mr. Lowenborg, including white papers, articles, webinars, and more, are available at dptlabs.com/resource-center.