Quality by Design in Solid-Dosage Manufacturing

The quality-by-design (QbD) initiative, which focuses on building quality into a product from early on in the development process, has created a shift in the way pharmaceutical companies develop and produce drug products. With a focus on patient safety, QbD helps drug manufacturers incorporate a risk-based approach to development and production. “Many firms leverage the understanding gained from adoption of QbD principles to implement innovative manufacturing approaches, such as continuous manufacturing and real-time release testing. Furthermore, QbD is a continuum approach that supports demonstration that a manufacturing process is always in a state of control and capable of consistently manufacturing desired quality product throughout its lifecycle. Consequently, manufacturers implementing the QbD paradigm are implementing a science-  and risk-based lifecycle approach that allows for continuous improvement,” states an FDA spokesperson.

The industry has become accepting of QbD, and companies have worked to implement it into their processes.  “The introduction of QbD has triggered a paradigm shift in drug development and manufacturing and provided a new toolbox of quality principles with several opportunities for the pharmaceutical industry. QbD is applied widely in drug development today and represents the leading and most favored principles where applicable and appropriate,” says Sven Stegemann, director for pharmaceutical business development at Capsugel. And Brian A. C. Carlin, director Open Innovation, FMC Health & Nutrition and Chair of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) QbD Committee, believes that “the FDA Quality Metrics Initiative will further drive QbD manufacturing and quality approaches.”

According to Siegfried Schmitt, principal consultant, PAREXEL, “QbD … requires intensive studies prior to the validation batches, resulting not only in higher success rates for validation, but an overall better controlled process during commercial manufacture. QbD therefore enhances control, understanding, and continuous performance.”

Barriers to QbD implementation
Although many have adopted QbD, others are limited by what they see as barriers. Pharmaceutical Technology’s annual manufacturing and equipment survey found that while 28% of respondents stated they fully use QbD in process development/optimization for solid-dosage manufacturing and 56% apply QbD to some extent, 16% said they do not use QbD. Respondents indicated that a lack of knowledge, training, and clarification from regulators contributed to their reluctance to use QbD. Cost and time also factored into the decision to not incorporate QbD into their processes (1).

But are these real or imagined barriers? “The barriers are in the peoples’ minds. They can no longer simply rely on a set of tight rules, but must use their powers of deductive reasoning rather than their memories (to paraphrase Leonardo Da Vinci),” says Chris Moreton, partner at FinnBrit Consulting and active member of the IPEC-Americas QbD Committee.

According to an FDA spokesperson, several International Conference on Harmonization (ICH) guidelines were developed to help the industry implement QbD (2–5) as well as several Q&A documents drafted by the Implementation Working Group to answer industry questions and clarify guidance documents. “It has been the agency’s observation that there is some confusion amongst the manufacturers. There is currently an ongoing QbD pilot program with the European Medicines Agency (EMA), which has identified enhancements to the regulatory assessment process. The first and third Q&A documents from the FDA-EMA pilot clarify the agencies’ expectation regarding criticality and level of detail in submissions. Additionally, this topic is addressed in the just published FDA draft guidance on Established Conditions: Reportable CMC Changes for approved Drugs and Biologic Products (6). Additionally, the agency published the Manual of Policy and Procedures (MAPP), ‘Chemistry Review of Questions-based Review (QbR) Submissions,’ which provides transparency regarding the agency’s expectation for the submission of abbreviated new drug applications (ANDAs),” says the FDA spokesperson.

Applying QbD to solid-dosage manufacturingPharmaceutical Technology spoke with Carlin, Moreton, Schmitt, Stegemann, and FDA about the benefits and challenges of incorporating QbD into solid-dosage manufacturing.

PharmTech: What specific aspects of the solid-dosage product lifecycle are most affected by implementation of QbD? Can you provide examples?

FDA: QbD is a patient-centric approach that encourages manufacturers to design a product and a process that always meets the needs of the patient. This starts with first identifying the product’s quality target profile such that it meets the need of the patient and then identifying critical quality attributes (CQAs) (i.e., measurable attributes) of the finished product that would ensure that the product always meets the desired quality target profile. Thereafter, a science- and risk-based approach is used to design a manufacturing process and control strategy that ensures that the product consistently meets the desired CQAs. For example, one of the aspects of solid oral-dosage manufacturing that has evolved since adoption of the QbD approach is delineating risks of each manufacturing step and then designing a control strategy that ensures that the risks are appropriately mitigated. Additionally, QbD has spurred implementation of novel approaches. For example, we have come across use of near infrared (NIR)-based procedures that include: identification testing of raw materials, blend uniformity monitoring, detection of blending end point, measuring moisture content in tablets/granules, detection of drying end point, detection of polymorphic forms, and measuring active content of tablets. Also, many solid oral-dosage manufacturing firms are looking to implement continuous manufacturing. In a recent interview, Dr. [Janet] Woodcock [director, Center for Drug Evaluation and Research (CDER), at FDA] commented that though making the switch from batch to continuous manufacturing may be difficult, costly, and time consuming, pharma manufacturers and CMOs should begin to consider the switch, because in the long-run it will end up saving companies time, money, and space (7).

Stegemann (Capsugel): A fundamental understanding of the solid-dosage product and processes can be achieved by applying QbD principles early in development. This understanding can be augmented as development progresses and QbD is utilized to simplify the formulation and process development. During scale up, QbD can be applied to enhance product quality by determining and managing the critical product and process parameters. The knowledge gained through a QbD development program enables the shift from a batch-based process to a continuous process, increasing manufacturing efficiency and flexibility. QbD can also support technology transfer into regional manufacturing sites. Finally, monitoring the critical quality attributes and parameters can be used to ensure continuous commercial supply.

Carlin (FMC Health & Nutrition): Design and development (and regulatory filing) have so far been the aspects of the solid-dosage product lifecycle most affected by QbD due to the increasing requirements to scientifically justify the product and process design. An interesting raw material example is the request for applicants to justify their reliance on pharmacopeial or supplier specifications.
New manufacturing and analytical technologies are evolving in response to QbD. A good example is the rise of continuous manufacturing. The Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers University has recently agreed to help FDA draft guidance on continuous manufacturing.

Moreton (FinnBrit): All aspects of the solid-dosage form lifecycle are potentially affected by QbD, from pre-formulation through to commercial manufacture. The objective of QbD is to ensure we make the correct decisions based on good science, and that this translates into robust medicinal products where performance may be any combination of consistency in process output, stability, and/or in vivo performance.

Challenges in solid-dosage manufacturingPharmTech: What challenges have pharmaceutical companies overcome in incorporating QbD into the manufacturing process for solid-dosage products? What challenges do they still face?

FDA: The agency often observes that the main barrier to change is often internal to the company. For more than a decade now, FDA has been encouraging modernization of manufacturing. We have had countless public discussions on the topics and individual meetings with industry. The agency encourages continued dialogue with applicants to help lower their anxiety toward change.

Schmitt (PAREXEL): In production, it is essential to maintain a high level of automation with integrated feedback loops to exercise process controls in real time. It is also critical that expertise at the personnel level reaches across the R&D/commercial production divide to assist with technology transfer and troubleshooting. Another ongoing challenge includes the difficulty in finding regulatory professionals with appropriate expertise to put the QbD approach into expert dossier filings.

Carlin (FMC Health & Nutrition): The promised reduction in ‘extensive regulatory oversight’ in return for QbD has yet to be realized and may have to await quality culture/risk stratification. Reviewer interest and learning in QbD is to be welcomed but not on an applicant’s critical path. It may be difficult to justify investment for QbD in older legacy products.

Incorporating QbD into the manufacturing process for solid-dosage products not only requires internal alignment, but should involve all stakeholders, including suppliers.

Moreton (FinnBrit): The biggest challenge is the corporate mindset, particularly in my experience in regulatory affairs groups, but also in development and manufacturing. This type of resistance can only gradually be broken down. It may take another 5-10 years before the benefits of QbD are broadly seen.

PharmTech: Are there specific challenges for companies working in international markets? Are the guidelines for QbD different in different markets? If yes, how are manufacturers addressing these differences?

FDA: Basic principles of implementation of the QbD approach are based on ICH guidelines, which have been adopted in Japan, Europe, and the United States and are widely followed by other health authorities. For the countries in the ICH, there is an ongoing effort to harmonize regulatory expectations regarding implementation of the QbD approach.  The FDA-EMA QbD pilot program that was started in March 2011 is an example of one such initiative. This pilot program provides a platform for the regulators to engage in dialog with their global counterparts regarding new QbD-based concepts. One such example is implementation of continuous manufacturing for manufacture of solid oral-dosage forms. Additionally, the pilot has led to the publishing of  three Q&A documents. For example, the Q&A on design space verification explains  the similarities and differences between FDA and EU on this topic (8).

Stegemann (Capsugel): The application of QbD will support a global product launch and secure product quality in the case of technology transfers or production changes. Nevertheless, there are still different regulatory opinions that might restrict filings solely based on QbD principles in product -development.

Carlin (FMC Health & Nutrition): Not all regulatory authorities have adopted QbD, so companies working in international markets have to employ a mix of QbD and traditional filings.

Schmitt (PAREXEL): Though QbD is part of the international regulatory harmonization effort, many regulators are not equipped to professionally review QbD applications. Unlike FDA, few other regulators have put such emphasis on the benefits of QbD, and staffed their offices accordingly.

Impact of QbDPharmTech: How has QbD improved the solid-dosage product supply chain? Are excipient manufacturers, API producers, and other material suppliers applying QbD to their processes?

Stegemann (Capsugel): QbD has put more emphasis on quality and variability of excipients in pharmaceutical manufacturing, leading to some QbD projects at supplier levels and the recognition that QbD principles can be applied to the same extent to excipient manufacturing. Some suppliers have taken responsibility and provided QbD data on their excipients for use in drug product development. For example, the variability of critical product parameters of hard capsules across a two-year manufacturing period was recently published to help companies make a science-based risk assessment in their capsule development program. Moreover, any regulatory quality initiative should trigger a reflection on suppliers’ own quality systems, leading to advancements. A good example is the development of enhanced and tighter process capabilities, which reduce the product variability, build better quality into the product and the process in order to reduce reject rates at the finished product manufacturing level. These enhancements in capsule manufacturing provide the means to move from AQL quality assurance scale to a Six Sigma scale and level. Producing capsules at Six Sigma quality levels for pharmaceutical product manufacturing will become the new quality standard due to the value it offers to pharmaceutical manufactures. Further, as industry leaders, Capsugel works to stay ahead of regulatory requirements to provide the highest quality products to its customers.

Schmitt (PAREXEL):  Where a raw material, such as an API, is sold to clients who may not be willing to take on the additional expense, suppliers are very reluctant to invest without guaranteed payback. Excipient manufacturers are often reluctant to even apply GMP as their customer base may not require such controlled standards. Therefore, QbD is most successfully applied in vertically integrated enterprises where at least R&D, API, and drug product manufacture are all managed in-house. Achieving the same result with outsourced services is still a significant challenge.

Carlin (FMC Health & Nutrition): QbD has increased awareness that greater understanding of excipients is required beyond the specification or certificate of analysis. QbD as a pharma concept has been applied to both APIs and drug products, but one could criticize the disjointed approach where the quality of APIs (generally very pure crystals) is not related to their fitness for purpose in pharmaceutical manufacturing (insoluble, poorly compactible, and non-flowing). Regulatory uncertainty has hindered incorporation of excipients into composite APIs with optimized manufacturability. Is a co-crystal an API or drug product intermediate?

Most high-volume pharmaceutical excipients have been manufactured continuously, decades before pharmaceutical industry awareness of QbD or continuous manufacturing. The level of material and process understanding required for excipient continuous manufacturing is essentially QbD, but may not be congruent with the QbD for a specific pharmaceutical product, especially if the major markets for that excipient are non-pharmaceutical.

FDA: QbD encourages manufacturers adopting this approach for product design to establish specifications for the incoming raw materials (API and excipients) that would ensure consistent manufacture of desired quality finished product throughout its lifecycle. This, in turn, would encourage API and excipient manufacturers to design their processes such that the manufactured API and excipients consistently meet the quality desired by the finished product manufacturer. QbD also encourages the manufacturers to identify the risks in the supply chain and to come up with appropriate risk mitigation techniques.

PharmTech: How can QbD be applied specifically to excipient manufacture, API manufacture, and ultimately final product manufacture?

Stegemann (Capsugel): Quality needs to be built into the product. This means that QbD must start at API and excipient manufacturing, as these are the components that go into the pharmaceutical product formulation and development process. The application principles do not differ if it is the API, excipient, or finished product being manufactured. The principles aim to provide product and process understanding targeted to ensure that the final targeted product profile is constantly met over the lifecycle.

Moreover, where the design space is limited by the excipient base properties, QbD can facilitate innovation through research initiatives. While gelatin capsules were the main polymers for capsules 10 years ago, additional capsule types are available today with gelatin-like properties, including hydroxypropl methyl cellulose (HPMC) capsules manufactured by thermal gelation and HPMC capsules with delayed-release properties.

Carlin (FMC Health & Nutrition): QbD is patient-centric, so QbD must necessarily focus on the final product. API QbD will reliably deliver consistent API but not necessarily be congruent with performance or manufacturability in finished product.

For excipients (and third-party APIs), the question is how can the suppliers support the final product QbD. This assumes they are made aware of the application, in which case they can advise:

• potential application-specific failure modes

• potential critical attributes (which may not be on specification)

• true variability of continuously produced material 

• process capabilities.

This will improve robustness, strengthen the risk analysis, and inform control strategy.

Schmitt (PAREXEL): Relative to the cost of the finished product, API costs are typically in the range of 1-5%. Very rarely are API costs really high, maybe 20% or higher. Given the low cost contribution of excipients and APIs to a finished drug product, price is and remains the driving force. This is in direct competition to scientific progress. Thus, QbD for these product categories remains mostly out of bounds for QbD approaches, except for cases where these are part of the same company (i.e., all being part of the same company quality philosophy).

Moreton (FinnBrit): QbD, as the concept introduced by Duran, can be applied to any product or service, and excipients are no exception. However, I would submit that excipient manufacturers have been applying their own form of QbD for many years in the form of process capability studies and process improvement projects. It is not recommended to build a plant capable of manufacturing thousands of tonnes of material per annum without having undertaken some serious development work. In addition, there is the lifecycle aspect, and the excipient manufacturers have been managing the lifecycle successfully for many years.

References
1. J. Markarian, PharmTech 39 (8) 24-28 (2015).
2. ICH, Q8(R2) Pharmaceutical Development (ICH, November 2009).
3. ICH, Q9 Quality Risk Management (ICH, June 2006).
4. ICH, Q10 Pharmaceutical Quality System (ICH, 2009).
5. ICH, Q11 Development and Manufacture of Drug Substances (Chemical Entities And Biotechnological/Biological Entities) (ICH, May 2012).
6. FDA, Draft Guidance, Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products Guidance for Industry (CDER, CBER, May 2015).
7. Z. Brennan, “FDA Calls on Manufacturers to Begin Switch from Batch to Continuous Production,” in-Pharma Technologies.com, May 1, 2015.
8. FDA, Guidance for Industry, Q8, Q9, and Q10 Questions and Answers(R4), (CDER, CBER, November 2011). 

Article DetailsPharmaceutical Technology
Vol. 39, No. 9
Page: 26–32

Citation:
When referring to this article, please cite it as S. Haigney, “Quality by Design in Solid-Dosage Manufacturing," Pharmaceutical Technology 39 (9) 2015.