Quality by Design: A Contract Organization's Perspective

Quality by design (QbD) is based on sound science and quality risk management through which quality is built into products. Although the benefits of QbD are obvious, the industry has been relatively slow in adopting the concept because QbD often falls low on the list of immediate priorities. With product development and manufacturing increasingly being outsourced to contract development and manufacturing organizations (CDMOs), however, a strategic partnership between the sponsor and a CDMO can help realize the benefits of QbD. The author discusses how a CDMO helps in gaining process understanding and in developing robust, high-quality products and processes.

Whether the product and process is developed at one contractor's site, transferred from one contract developer to another, or transferred from a sponsor development unit to a contract development and manufacturing organization (CDMO), knowledge transfer, an in-depth process understanding, identification of critical process parameters, and determination of proven acceptable process ranges (PAR) are crucial to successful development. By failing to identify and correct the root causes of problems early in the design phase of the process- and product-development cycle, organizations risk quality, yield, and supply-chain issues. Quality by design (QbD) should be viewed as an opportunity that brings value and business benefits to both the sponsor and the CDMO.

QbD benefits offered by a CDMO

A CDMO supports the development of hundreds of molecular entities in different stages of clinical programs with small or large molecules in sterile and nonsterile processes. A wealth of knowledge and experience resides with a CDMO that could be leveraged by a sponsor for new projects. Drawing on knowledge gained from experience, a CDMO can move quickly in identifying critical steps, building a robust model to plan, and designing experiments to address problems. We often find that when sponsors have changed hands due to licensing of new chemical entities, some information and documentation does not get transferred. A CDMO can help the sponsor orle001anize information, determine gaps, and work to build the program to meet the quality and regulatory requirements. QbD requires a solid base of knowledge of the drug substance, its physicochemical properties, characterization, raw material and excipient interactions and variability, and how all these impact the dosage form design, target product profile, and shelf-life stability. A CDMO can leverage its inventory of knowledge and experience, work with a sponsor to lay out a plan, and apply the principles of ICH Q8, Q9, and Q10 to develop a QbD strategy that adds value to the sponsor's program (1–3).

Current state of QbD: a CDMO view

A CDMO develops products for virtual companies, biotech, specialty, mid-size, large pharma, and generic drug companies, and sees different philosophies and strategies adopted by sponsors in applying QbD to product development. As key players in industry, CDMOs need to move the QbD initiative forward by helping sponsors and clients see potential benefits, so they will give QbD a higher priority and understand the risks of not using the QbD toolbox.

The benefits of using QbD at various stages of development have been well documented. In a live poll conducted during a QbD conference, the majority of representatives from the industry felt that it is "never too late" to adopt QbD and generate data to get an in-depth process understanding (see Figure 1) (4).

Figure 1: When is it too late to adopt a quality-by-design approach to your product at a CDMO? (Ref. 4).

In a 2008 survey, 58% of the respondents said that their QbD initiatives were only in the ideas and vision stage (5). In 2010, at another QbD conference represented by the small, medium, large pharmaceutical, and generic drug sectors, results of a live poll, shown in Figure 2, indicated that more had moved on from this stage (6).

Figure 2: At what stage are quality-by-design initiatives in your organization? (Ref. 6).

Organizations have been slow in thinking about the best way to implement the principles of QbD in their development programs as a part of their corporate strategy. When asked about the biggest obstacles, poll respondents' answers, shown in Figure 3, indicated that pursuing QbD did not fit into the priorities of many organizations (6).

Figure 3: What is the biggest obstacle to pursuing quality by design in your organization? (Ref. 6).

Based on various discussions, Patheon has compiled comments from the sponsors' perspective as to reasons for not adopting QbD in their programs:

• "Our process is well developed and scalable. There may not be any need for additional process development to set appropriate design space."

• "We need to meet aggressive timelines to ensure continued funding. For virtual to small organizations, proof of concept and moving quickly to the next phase of the clinical program are of top priority."

• "Our goal is to have a product that will be successful in clinical trials. We can always optimize the process after the clinical phase is done."

• "This product will be partnered or sold post Phase 2b; why invest in QbD now?"

• "There are regulatory risks associated with conducting QbD experimentation and the risk of delays due to large experimentation and possible reformulation in the late stages of development. This could also lead to an additional bioequivalence study, which is costly and time-consuming."

• "We are reluctant to share development or proprietary information (e.g., filing or historical data)."

On the other hand, comments from CDMOs, compiled by Patheon from various discussions, offer a different perspective on why QbD is worthwhile:

• "Many transferred processes are not well defined. Selection of excipients and their levels are not scientifically justified. Processes are scaled up to provide larger quantities of clinical trial supplies without sufficient data."

• "The failure rate in clinical trials is high. Using sound judgment and a calculated risk-based approach, however, will help move the clinical program forward by balancing the scientific approach with capital investment."

• "Often there is no time to optimize products in later phases, which has impact on the cost of goods and security of supply."

• "Failed batches and additional regulatory scrutiny will cause more delay than doing a systematic study correctly now."

• "A well-understood, stable product developed using sound QbD principles adds value to robust development, and the product is more attractive to potential partners for out-licensing."

The live-poll results in Figure 4 show that, when considering conducting QbD with a CDMO, respondents are concerned about project delays, cost, information sharing, and the expertise of the contractor (4). As more and more product development is outsourced to a CDMO, however, sponsors will have to partner with CDMOs in pursuing the QbD strategy.

Figure 4: What is the biggest concern you have in conducting a quality-by-design approach using a CDMO? (Ref. 4).

In recent years, Patheon has seen an increase in the number of sponsors/clients asking for QbD. Sponsors would like to know what strategy a CDMO would propose to proceed with this exercise and the experience level of the CDMO in designing a QbD work plan. More organizations are now conducting statistical design-of-experiment (DOE) studies to understand the design space for critical process steps in solid oral and sterile dosage manufacturing operations.

Building a business case

CDMOs will typically have worked with a larger variety of complex processes and challenging molecules than their counterparts in individual sponsor organizations. The knowledge base gathered during many years and the experience gained in resolving complex problems can immensely help the sponsor through the steps in the QbD process (see Figure 5).

Figure 5: Steps in the quality-by-design process.

A CDMO can design a phase-appropriate QbD strategy to build quality into the product being developed. An experimental plan should conserve API and consider time and cost. A CDMO can help in performing an in-depth scientific risk assessment that will help in justifying the investment in a QbD exercise.

Because the financial investment in QbD to a small or medium sized organization can be huge, it is important for the CDMO and sponsor to jointly build a business. It is not always possible to put a financial value on everything we do. There also are business risks to this investment, such as the possibility of the project costing more, taking longer, or even failing due to a variety of developmental reasons.

A QbD case study at Patheon

A case study illustrates the QbD process wherein Sponsor X developed a drug product and process in partnership with Patheon, by using QbD principles to ensure desired safety, efficacy, and quality of the product. Figure 6 depicts the overall QbD strategy that was used.

Figure 6: Quality-by-design process flow for a drug product (DP).

A combination of prior knowledge and experimental assessment during development were used to identify performance requirements (i.e., Stage 1), develop process understanding, and conduct the criticality analysis. In Stage 2, critical quality attributes (CQAs) of the drug product were defined. An initial risk assessment was performed in Stage 3 to determine which process steps and materials could control product CQAs. Stage 4 included a detailed criticality analysis which evaluated the functional relationship between critical and key process parameters and CQAs to establish the design space. The design space included the control ranges of the key processing parameters and in-process parameters (IPCs) used to meet the CQAs for a safe, efficacious, and chemically stable drug product. The design space defined by normal operating ranges (NORs) and proven acceptable ranges (PARs) in conjunction with material and product CQAs formed the basis of manufacture of the drug product. Process failure mode and effect analysis (FMEA) was conducted (Stage 5) prior to validation (Stage 6), followed by continuous verification and improvement during commercial operation (Stage 7).

A detailed criticality analysis was conducted on each material attribute. Each aspect of the material was designated as critical, key, or noncritical based on its potential to impact a CQA as illustrated in Figure 7.

Figure 7: Criticality analysis process flow. CQA is critical quality attribute.

Using the above systematic approach based on sound science and quality risk management, Sponsor X filed a QbD-based new drug application that was subsequently approved, and the product has been successfully launched in the marketplace.

Conclusion

As pharmaceutical companies partner with CDMOs for development, clinical, and commercial programs, the CDMO will play a critical role in jointly developing a QbD strategy to develop robust processes and quality products. Due to the wealth of knowledge gained by working on multiple, challenging molecules, processes, and products, CDMOs are well positioned to support the sponsor in building a business case, justifying the investment, and applying risk assessment to drive QbD implementation.

Anil Kane, PhD and MBA, is executive director of global science and technology for pharmaceutical development services at Patheon, 2100 Syntex Court, Mississauga, ON L5N 7K9, Canada, tel: 905.812.6874. email: anil.kane@patheon.com

References

1. ICH, Q8 Pharmaceutical Development (2009).

2. ICH, Q9 Quality Risk Management (2005).

3. ICH, Q10 Pharmaceutical Quality System (2008).

4. S. Closs, presentation at FDA/Xavier University Global Outsourcing Conference (Cincinnati, OH, 2011).

5. J. Neway, BioPharm Intl. 21 (12), 42–47 (2008).

6. A. Kane, presentation at FDA/Xavier University Global Outsourcing Conference (Cincinnati, OH, 2010).