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Pharmaceutical Technology Outsourcing Resources August 2012

Quality by Design: A Contract Organization’s Perspective
By Anil, Kane, Ph.D.

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a CDMO can move quickly in identifying critical steps. and determination of proven acceptable process ranges (PAR) are crucial to successful development. Q9. and supply-chain issues. large pharma. and how all these impact the dosage form design. A CDMO can help the sponsor organize information. target product profile. PhD and MBA. The author discusses how a CDMO helps in gaining process understanding and in developing robust. raw material and excipient interactions and variability. Canada. tel: 905. and work to build the program to meet the quality and regulatory requirements. With product development and manufacturing increasingly being outsourced to contract development and manufacturing organizations (CDMOs). We often find that when sponsors have changed hands due to licensing of new chemical entities. organizations risk quality. and generic drug companies. yield. A CDMO can leverage its inventory of knowledge and experience. ON L5N 7K9. A wealth of knowledge and experience resides with a CDMO that could be leveraged by a sponsor for new projects. work with a sponsor to lay out a plan.Quality by Design Quality by Design: A Contract Organization’s Perspective Anil Kane Overcoming Obstacles to Implementing QbD Quality by design (QbD) is based on sound science and quality risk management through which quality is built into products.6874. P h a r mTe c h . mid-size. transferred from one contract developer to another. Drawing on knowledge gained from experience. characterization. some information and documentation does not get transferred.and product-development cycle. an in-depth process understanding. ION-BOgDAN DUMITRESCU/gETTy IMAgES W hether the product and process is developed at one contractor’s site.812. c o m Pharmaceutical Technology OutsOurcing resOurces 2012 . biotech. high-quality products and processes. Quality by design (QbD) should be viewed as an opportunity that brings value and business benefits to both the sponsor and the CDMO.kane@ patheon. identification of critical process parameters. Current state of QbD: a CDMO view A CDMO develops products for virtual companies. or transferred from a sponsor development unit to a contract development and manufacturing organization (CDMO). QbD benefits offered by a CDMO Anil Kane. QbD requires a solid base of knowledge of the drug substance. email: anil. specialty. a strategic partnership between the sponsor and a CDMO can help realize the benefits of QbD. determine gaps. and designing experiments to address problems. knowledge s20 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. and shelf-life stability. Mississauga. and Q10 to develop a QbD strategy that adds value to the sponsor’s program (1–3). is executive director of global science and technology for pharmaceutical development services at Patheon. its physicochemical properties. building a robust model to plan. Although the benefits of QbD are obvious. and apply the principles of ICH Q8. By failing to identify and correct the root causes of problems early in the design phase of the process. 2100 Syntex Court. the industry has been relatively slow in adopting the concept because QbD often falls low on the list of immediate priorities. however.

10% Sharing of proprietary information. 5% Initial implementation. 68% After commercial launch. 13% Cost. 14% Rolled out across organization. 8% Most people don’t know what it is. After preformulation. 15% Figure 3: What is the biggest obstacle to pursuing quality by design in your organization? (Ref. Patheon has compiled comments from the sponsors’ perspective as to reasons for not adopting QbD in their programs: s22 • “Our process is well developed and scalable. medium. 9% All of the above. 58% of the respondents said that their QbD initiatives were only in the ideas and vision stage (5). 5% Never too late. 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. There may not be any need for additional process development to set appropriate design space. 4). 12% Too many other things to do. Selection of excipients and their levels are not scientifically justified. 14% and sees different philosophies and strategies adopted by sponsors in applying QbD to product development. Roadmap development. and generic drug sectors. indicated that more had moved on from this stage (6). compiled by Patheon from various discussions. 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). 18% Ideas & vision. so they will give QbD a higher priority and understand the risks of not using the QbD toolbox.g. Based on various discussions.” • “Our goal is to have a product that will be successful in clinical trials. Processes are scaled up to provide larger quantities of clinical trial supplies without sufficient data. comments from CDMOs. 40% Initial implementation. This could also lead to an additional bioequivalence study. shown in Figure 2. which is costly and time-consuming.” • “This product will be partnered or sold post Phase 2b. offer a different perspective on why QbD is worthwhile: • “Many transferred processes are not well defined. In a 2008 survey. In 2010. indicated that pursuing QbD did not fit into the priorities of many organizations (6). c o m ALL FIgURES ARE COURTESy OF THE AUTHOR . Delays in project timeline. 6). shown in Figure 3.” Pharmaceutical Technology OutsOurcing resOurces 2012 P h a r mTe c h . We can always optimize the process after the clinical phase is done. proof of concept and moving quickly to the next phase of the clinical program are of top priority. In a live poll conducted during a QbD conference.” On the other hand. 20% Figure 2: At what stage are quality-by-design initiatives in your organization? (Ref. 4). CDMOs need to move the QbD initiative forward by helping sponsors and clients see potential benefits. filing or historical data). 10% Enrolled participants.” • “We are reluctant to share development or proprietary information (e. large pharmaceutical. 6). 36% Lack of contractor’s expertise. Roadmap development. 10% People resources. results of a live poll. 29% Not started. 8% After validation.Quality by Design Figure 1: When is it too late to adopt a quality-by-design approach to your product at a CDMO? (Ref. 1% After clinical phase 2b.. poll respondents’ answers. 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. For virtual to small organizations. As key players in industry. When asked about the biggest obstacles. The benefits of using QbD at various stages of development have been well documented. 18% Not compatible with company culture.” • “We need to meet aggressive timelines to ensure continued funding. at another QbD conference represented by the small. 43% Figure 4: What is the biggest concern you have in conducting a quality-by-design approach using a CDMO? (Ref.

In Stage 2. which has impact on the cost of goods and security of supply. respondents are concerned about project delays. Using sound judgment and a calculated risk-based approach. design appropriate QbD strategy to build of experiments quality into the product being developed. Patheon has seen an increase in the number of sponsors/clients asking for QbD. c o m . 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. s24 CDMOs will typically have worked with a larger variety of complex processes and challenging molecules than their counterparts in individual sponsor organizations. however. and chemically stable drug product. and conduct the criticality analysis. Stage 1).. A combination of prior knowledge and experimental assessment during development were used to identify performance requirements (i. As more and more product development is outsourced to a CDMO. 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. 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. stable product developed using sound QbD principles adds value to robust development. or even failing due to a variety of developmental reasons. process analytical technology Life-cycle management • “The failure rate in clinical trials is high.e. cost. taking longer.” • “A well-understood. A case study illustrates the QbD process wherein Sponsor X developed a drug product and process in partnership with Patheon. In recent years. it is important for the CDMO and sponsor to jointly build a business. however. such as the possibility of the project costing more. and the product is more attractive to potential partners for out-licensing. efficacious. and the expertise of the contractor (4). develop process understanding. De ne initial quality target product pro le Prior knowledge Assign criticality (critical quality attributes) Identify critical process parameters Risk assessment Establish design space Knowledge space and control space Develop control strategy For example. will help move the clinical program forward by balancing the scientific approach with capital investment. Figure 6 depicts the overall QbD strategy that was used. by using QbD principles to ensure desired safety. when considering conducting QbD with a CDMO. 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).” • “Often there is no time to optimize products in later phases.” The live-poll results in Figure 4 show that. 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.” • “Failed batches and additional regulatory scrutiny will cause more delay than doing a systematic study correctly now. An initial risk assessment was performed in Stage 3 to determine which process steps and materials could control product CQAs. and quality of the product.Quality by Design Figure 5: Steps in the quality-by-design process. Process failure mode and effect Building a business case A QbD case study at Patheon Pharmaceutical Technology OutsOurcing resOurces 2012 P h a r mTe c h . It is not always possible to put a financial value on everything we do. critical quality attributes (CQAs) of the drug product were defined. A CDMO can help in performing an in-depth scientific risk assessment that will help in justifying the investment in a QbD exercise. sponsors will have to partner with CDMOs in pursuing the QbD strategy. information sharing. There also are business risks to this investment. Because the financial investment in QbD to a small or medium sized organization can be huge. An experimental plan should conserve API and consider time and cost. efficacy. 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. A CDMO can design a phaseFor example.

6. 2011). followed by continuous verification and improvement during commercial operation (Stage 7). OH. key. PT Pharmaceutical Technology OutsOurcing resOurces 2012 P h a r mTe c h . Using the above systematic approach based on sound science and quality risk management. 2. J. Q9 Quality Risk Management (2005). Closs. S. and the product has been successfully launched in the marketplace. Due to the wealth of knowledge gained by working on multiple. ICH. 4. design space. 3. processes. 21 (12). clinical. c o m . and material attributes DP CQAs Stage 5 Intermediate CQAs Perform process failure mode and effect analysis Drug substance CQAs Stage 7 Continuous process veri cation and improvement Stage 6 Conduct process validation analysis (FMEA) was conducted (Stage 5) prior to validation (Stage 6). Kane. CDMOs are well positioned to support the sponsor in building a business case.Quality by Design Figure 6: Quality-by-design process flow for a drug product (DP). the CDMO will play a critical role in jointly developing a QbD strategy to develop robust processes and quality products. and commercial programs. ICH. and products. 42–47 (2008). Q8 Pharmaceutical Development (2009). Sponsor X filed a QbD-based new drug application that was subsequently approved. OH. Risk assessment Amplitude of the effect. Stage 1 Identify performance requirements Stage 2 Identify critical quality attributes (CQAs) Stage 3 Identify potentially critical process steps and input materials Stage 4 De ne critical and key process parameters. CQA is critical quality attribute. challenging molecules. justifying the investment. A. s26 References 1. operations in-process parameters. presentation at FDA/Xavier University Global Outsourcing Conference (Cincinnati. A detailed criticality analysis was conducted on each material attribute. BioPharm Intl. Figure 7: Criticality analysis process flow. Each aspect of the material was designated as critical. ICH. 2010). closeness of design space to edge of failure YES Signi cant potential to impact a CQA NO High risk Noncritical YES NO Conclusion Critical Key As pharmaceutical companies partner with CDMOs for development. or noncritical based on its potential to impact a CQA as illustrated in Figure 7. Neway. normal operating range vs. presentation at FDA/Xavier University Global Outsourcing Conference (Cincinnati. and applying risk assessment to drive QbD implementation. 5. Q10 Pharmaceutical Quality System (2008).