A new definition of pharmaceutical quality: Assembly of a risk simulation platform to investigate the impact of manufacturing/product variability on clinical performance (original) (raw)
Related papers
Journal of Pharmaceutical Sciences, 2011
The quality of pharmaceutical products is currently evaluated through a series of tests that do not explicitly communicate the clinical consequences of product variability. A previously published risk simulation platform was used to generate quantitative estimates of inefficacy and toxicity for 288 uniform lots of extended-release theophylline tablets displaying various levels of content uniformity and dissolution variability. These data were used to evaluate the univariate specifications utilized in the United States Pharmacopeia (USP) <711> and <905>. Simulation revealed that the specifications are too lenient for content uniformity, both in terms of inefficacy and toxicity, whereas the criteria for dissolution testing are too strict for inefficacy and inaccurate for toxicity. The USP tests also failed to pinpoint the clinical interaction between content uniformity and dissolution variability. Additionally, the simulation platform was used to define the underlying relationship between product quality attributes and clinical performance. Here, content uniformity and Weibull dissolution time constants were used as inputs to the design spaces, which were conditioned on quantitative estimates of inefficacy and toxicity. This methodology enhances the information content of the design space by omitting quality surrogates (e.g., dissolution, moisture content) that are utilized in current design space practices.
The Biopharmaceutics Risk Assessment Roadmap for Optimizing Clinical Drug Product Performance
Journal of Pharmaceutical Sciences, 2014
The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.
Journal of Pharmaceutical Innovation, 2008
For good reason, quality by design (QbD) has become a topic of significant interest within the pharmaceutical industry. Whereas regulatory agencies and standardsetting organizations are moving swiftly to establish QbD guidance relevant to the needs of pharmaceutical manufacturing, much of the core science of QbD was established long ago by Dr. Genichi Taguchi and other leaders in the field of quality management. In order for the pharmaceutical industry to fully capitalize on QbD, new methods for quantitatively assessing product quality need to be established. This perspective article presents a risk-based strategy for quality assessment which uses model-based simulation to link variation in drug product parameters and clinical performance. This work is intended to provide background and introduction for a series of manuscripts dealing with QbD based on probabilistic risk assessment.
International journal of pharmaceutics, 2016
Failures surrounding pharmaceutical quality, particularly with respect to product manufacturing issues and facility remediation, account for the majority of drug shortages and product recalls in the United States. Major scientific advancements pressure established regulatory paradigms, especially in the areas of biosimilars, precision medicine, combination products, emerging manufacturing technologies, and the use of real-world data. Pharmaceutical manufacturing is increasingly globalized, prompting the need for more efficient surveillance systems for monitoring product quality. Furthermore, increasing scrutiny and accelerated approval pathways provide a driving force to be even more efficient with limited regulatory resources. To address these regulatory challenges, the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration (FDA) harbors a rigorous science and research program in core areas that support ...
Understanding pharmaceutical quality by design
The AAPS journal, 2014
This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a commo...
Quality by design (QbD) approaches in current pharmaceutical set-up
Expert opinion on drug delivery, 2018
Quality by design (QbD) encourages the pharmaceutical industry to use risk management and science-based manufacturing principles to gain process and product understanding and thus assures quality of the product. With the objective to curb the rising costs for development and regulatory barriers to innovation and creativity, QbD is being widely promoted by Food and Drug Administration (FDA) and International Conference on Harmonization (ICH). Areas covered: This review describes the elements, different design and tools of QbD as well as multidimensional applications of QbD ranging from dosage form and method development to meeting latest regulatory requirements. Expert opinion: The understanding of a process is facilitated by proper identification of sources of variation, management of variability by process design, and prediction of product quality attributes using design space. The pharmaceutical industry is rapidly adopting the QbD principles for fabrication of safe, effective and...
AAPS PharmSciTech, 2015
Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level.
Saudi Pharmaceutical Journal, 2014
In July 2013, the World Health Organization (WHO) of the United Nations finalized the Annex 2 of the new Technical Report 981 that is the WHO guideline on the implementation of a Quality Risk Management system. In general, alignment of the WHO requirements with the harmonized guidelines means consensus with the harmonized European, US and Asian regulations. In this short communication some aspects and the role of quality risk management (QRM) in the pharmaceutical quality systems (PQS) are discussed.
An overview of established practices and parameters to ensure quality of a pharmaceutical product
2017
ii Abstract The quality of a pharmaceutical product is one of the most challenging considerations of the pharmaceutical industry because it is directly related to the patient health and safety. Every pharmaceutical product should be manufactured by a licensed pharmaceutical manufacturer according to the guidelines, which should be stringently monitored by the licensed pharmacist, in order to attain the target quality product. The guidelines that are followed in the pharmaceutical industry are several, such as the ICH guideline, WHO guideline, FDA guideline, etc. A systematic approach needs to be designed and developed with the ‘end’ in mind, in order to ensure quality where the product and process performance characteristics are scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches. The impact of starting raw materials and process parameters on product quality must surely be well understood, with an emphasis on product a...
The AAPS Journal
Recent changes in the pharmaceutical industry have led to significant paradigm shifts in the pharmaceutical quality environment. Globalization of the pharmaceutical industry, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible standards to complement these efforts. They also increasingly have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group ...