In today’s pharmaceutical manufacturing environment, companies face increasing pressure to respond to changing demands across the global medicines supply chain while still maintaining the quality of their drug products. The U.S. Pharmacopeia (USP) understands the importance of evolving and expanding our standards to adapt to new practices and approaches, thereby ensuring a beneficial impact on the quality of medicines.
The conventional approach to drug product manufacturing involves a complex series of steps, including testing of the batch to ensure that it complies with safety and quality regulations. Over the past decade, regulators and industry have been gradually embracing Quality by Design (QbD) principles as an alternative to conventional, quality-by-testing and compliance-driven approaches, previously the only strategies for ensuring quality. As a result, quality paradigm shifts are currently underway in which QbD is being hailed as a modern and innovative approach that offers key advantages over conventional approaches and helps promote continuous quality improvement.
QbD can help prevent supply disruptions
Poor-quality drug products can cause supply disruptions and even drug shortages. The unexpected drop in supply can put patients’ access to essential medicines at risk. However, if substandard medicines are not removed from the market and patients take them, different adverse outcomes may occur. The drug may be ineffective in treating the patient’s medical problem, or the drug may harm the patient because it contains contaminants or adulterants. If antibiotics are substandard and are only partially effective, this can exacerbate antimicrobial resistance, a global health crisis in which widely used and needed antibiotics are becoming ineffective against the microbes they previously killed.
A paradigm shift to QbD may offer some relief from supply disruptions and other adverse effects of poor-quality drugs by strengthening the drug supply and promoting continuous quality improvement for medicines. In contrast, the traditional quality-by-testing approach typically does not provide a systematic strategy for continuous quality risk management because quality problems cannot be predicted. This makes the supply chain more vulnerable and raises the odds of shortages.
Quality culture transformation: QbD and the product life cycle
Sound science and quality risk/knowledge management are the key enablers of QbD, where emphasis is placed on acquiring an in-depth understanding of the relevant manufacturing processes and products. With QbD, process control is critical throughout the steps and stages of drug production so that quality can be built into the drug product from the beginning. Risk-based principles can be applied to prevent a wide range of quality issues, helping increase confidence when answering common questions about product quality such as “Is the genotoxic impurity below the safe upper limit?”
The concept of a “pharmaceutical product life cycle” has emerged as an approach to help pave the way of quality culture transformation and promote continuous quality improvement of medicines. Along with the evolution of process validation concepts, traditional analytical procedure validation has also been evolving to a life cycle risk-based approach. Several guidelines and pharmacopeial standards have been published in recent months highlighting the Analytical Procedure Life Cycle (APLC). This is considered an alternative, enhanced approach driven by Analytical Quality by Design (AQbD), where QbD principles are applied within the APLC framework to help build quality into the design of procedures and ensure procedure fitness for use along the entire procedure and product lifecycle.
Pharma 4.0 and increased complexity of the manufacturing process
Traditional medicines have been evolving into more complex, sophisticated drug products, dosage forms, and advanced therapies. In parallel, manufacturing technologies (including adoption of artificial intelligence, advanced computing, etc.) have been progressing and are challenging the traditional approaches for manufacturing pharmaceuticals and ensuring their quality. A fundamental piece of Pharma 4.0 (pharma industry efforts to implement the technological advances and adapt to the new era of digital transformation) is the concept of quality in which traditional validation practices require necessary redesign, often driven by QbD principles.
The APLC and AQbD principles provide a framework to ensure quality data and provide increased confidence when deciding whether a product is of the expected quality. Compared with the conventional procedure validation approach, the AQbD approach has additional advantages. These include improving productivity, helping to develop more robust procedures, providing regulatory flexibility for post-approval changes, and increasing reliability when deciding whether a product conforms to requirements. Together, APLC and AQbD support innovation and drive continuous quality improvement in pharmaceutical development.
USP scientists promote quality
The USP Measurement and Data Quality Expert Committee, chaired by Jane Weitzel, is advancing USP’s mission of promoting medicine quality while creating compendial approaches and providing technical expertise to industry and other stakeholders. In a related series of two articles on the Evolution of Analytical Procedure Validation Concepts — Part I and Part II — the authors note in Part I that “the concept of analytical procedure validation has also been evolving to a life cycle, risk-based approach. Current validation practices often focus on satisfying regulatory requirements rather than understanding and controlling sources of variability.” The main reason the life cycle approach is adopted is to ensure that the reportable value is fit for use and will remain so.
The new paradigm, QbD, is enabling scientists to pursue modernization and innovation in drug manufacturing, and USP’s laboratories in the U.S. and India are starting to explore and implement the AQbD concepts. With the support of the USP laboratory management team, USP scientists Surendra Babu, Suresh Pachamuthu, Pravin Agrawal, Sushant Patil, Qiyao Li, Grace Albert, and Shane Tan have been building case studies, exploring AQbD principles, and generating data to support the development of monographs, which may contain AQbD elements in the future. USP scientists and their colleagues are also developing resources and educational courses about AQbD to assist industry and other sectors.
USP helps pave the way for quality culture transformation
In response to stakeholder needs, USP has taken many steps to support and promote the transition to QbD and the APLC. Some highlights include:
- USP created an Expert Panel in 2013 to focus on the future of analytical validation concepts. Originally named the USP Verification and Validation Expert Panel, this group evolved to become the Analytical Procedure Life Cycle Expert Panel, functioning today under the USP Measurement and Data Quality Expert Committee.
- Six relevant USP Stimuli articles were published in Pharmacopeial Forum (PF) from 2013 to 2019. These articles built upon QbD principles previously described by the International Conference on Harmonisation (ICH) and several associations.
- PF 39(5) Lifecycle Management of Analytical Procedures, 2013
- PF 42(2) Fitness for Use: Decision Rules and Target Measurement Uncertainty, 2016
- PF 42(5) Analytical Target Profile, 2016
- PF 42(5) Analytical Control Strategy, 2016
- PF 44(1) Measurement Uncertainty for the Pharmaceutical Industry, 2018
- PF 45(6) Distinguishing the Analytical Method from the Analytical Procedure to Support the USP Analytical Procedure Life Cycle Paradigm, 2019
- USP developed and published the new General Chapter, <1220> Analytical Procedure Lifecycle, which describes a holistic approach for APLC management and serves as a useful resource for industry and other stakeholders alike.
- USP developed a course on USP <1220> and AQbD. An article on Ongoing Procedure Performance Verification (USP <1220> stage 3) was published in Pharmaceutical Technology Europe.
- USP published Stimuli articles on Analytical Instrument Qualification and its connection to APLC.
- PF 48(1) Analytical Instrument and System (AIS) Qualification, to support Analytical Procedure Validation over the Life Cycle, 2022
- PF 48(2) Measurement Uncertainty Evaluation Relevant to Analytical Instrument and System (AIS) Qualification - The Role of Measurement Uncertainty Concepts within the AIS, 2022
- PF 48(5) Analytical Instruments and System (AIS) Qualification: The Qualification Life Cycle Process
Currently, USP is working on:
- New publications that will provide additional guidance on 1) how to establish routine monitoring programs (including statistical procedure performance control techniques and performance indicators), 2) the role of measurement uncertainty within the APLC framework, 3) Method Operable Design Region (MODR) design and validation, 4) life cycle-based monographs, and 5) AQbD and the greenness of procedures.
- Organization of a hybrid workshop
- Additional training materials
Stakeholders support QbD acceptance
The transition to QbD impacts the pharmaceutical industry most directly, but other stakeholders are also affected and have important roles to play.
- Many regulatory agencies are encouraging the pharmaceutical industry to adopt QbD for drug manufacturing. The U.S. FDA has played a pivotal role in transforming quality culture.
- The ICH has released two draft guidelines that describe QbD principles for analytical procedure development (ICH Q14) and procedure validation [ICH Q2(R2)].
- QbD principles are aligned with concepts described in ISO guidelines (e.g., ISO/IEC 17025:2017).
Different pharmacopeias, including USP, are developing compendial approaches that will help support industry in adopting the risk-based APLC approach.
Looking ahead
USP has been a leader in the efforts to improve medicine quality for more than 200 years. During the current transformation of quality culture, USP will continue to help drive progress by working to reduce supply chain disruptions and thereby protect global public health. Fortunately, innovative approaches such as AQbD and APLC have the potential to improve global access to quality medicines, and USP will work diligently alongside stakeholders to reach this goal. For more information, please visit: https://www.usp.org/our-science.
