by Stéphanie Peika
(Editor’s note: This is the second half of a two-part article series that will focus on quality risk management and the pharmaceutical quality system in the pharmaceutical industry. The first half appeared in The Auditor’s September–October 2010 issue.)
An organization’s control strategy is designed to ensure that it consistently produces quality products. The elements of the control strategy should describe and justify how in-process controls and the controls of input materials (drug substance and excipients), container closure system, intermediates, and end products contribute to final product quality. These controls should be based on product, formulation, and process understanding and should include, at a minimum, control of the critical parameters and attributes.
A comprehensive pharmaceutical development approach will generate process and formulation understanding that identifies sources of variability. Critical sources of variability that can lead to product failures should be identified, appropriately understood, and managed or controlled. Understanding sources of variability and their affect on downstream processes or processing, intermediate products, and finished product quality can provide flexibility for shifting of controls upstream and minimize the need for end-product testing. This process understanding, in combination with quality risk management, will support the control of process parameters so that the variability of raw materials can be compensated for in an adaptable process to deliver consistent product quality.
This process understanding enables an alternative manufacturing paradigm in which the variability of input materials might not need to be tightly constrained. Instead, it’s possible to design an adaptive process step (a step that is responsive to the input materials) to ensure consistent product quality. Enhanced understanding of product performance can justify the use of surrogate tests or support real-time release in lieu of end-product testing. For example, disintegration could serve as a surrogate for dissolution for fast-disintegrating solid forms with highly soluble drug substances. Unit dose uniformity performed in process (e.g., using weight variation coupled with near-infrared assay) can enable real-time release and provide an increased level of quality assurance compared to the traditional end-product testing using compendial content uniformity standards.
Elements of a control strategy can include, but are not limited to, the following:
- Control of input material attributes (e.g., drug substance, excipients, primary packaging materials) based on an understanding of their affect on processability or product quality
- Product specification(s)
- Controls for unit operations that have an effect on downstream processing or end-product quality (e.g., the effect of drying on degradation, particle-size distribution of the granulate on dissolution)
- In-process or real-time release in lieu of end-product testing
- A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models
A control strategy can include redundant or alternative elements, if justified. For example, one element of the control strategy could rely on end-product testing, whereas an additional or alternative element could depend on real-time release using process analytical technology (PAT).
Product life cycle management and continual improvement
Throughout a product’s life cycle, companies have opportunities to evaluate innovative approaches to improve product quality. For example, once approved, a design space provides the applicant flexibility to optimize and adjust a process as managed under the organization’s quality system. A design space isn’t necessarily static in nature and should be periodically reassessed to ensure that it’s working as anticipated to deliver expected product-quality attributes.
For certain design spaces using mathematical models (e.g., chemometrics models of near-infrared assay) periodic maintenance could be essential to ensure the models’ performance (e.g., checking calibration), or to update the model based upon additional data. Expansion, reduction, or redefinition of the design space could be desired upon gaining additional process information.
Continual improvement and the pharmaceutical quality system
The International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use’s (ICH) Q10 standard lists many activities that should be conducted to manage and continually improve a pharmaceutical quality system. But in the new Quality by Design (QbD) approach, the pharma industry is finally implementing some of the tried-and-true initiatives of other industries. Implementing the appropriate quality systems should include, at a minimum:
- The pharmaceutical quality system should be well structured and clearly facilitate common understanding and consistent application.
- The elements of ICH Q10 should be applied in a manner that is appropriate and proportionate to each of the product life cycle stages and recognize the different goals of each stage.
- The size and complexity of the company’s activities should be taken into consideration when developing a new pharmaceutical quality system or modifying an existing one. While some aspects of the pharmaceutical quality system can be companywide and others site-specific, the effectiveness of the implementation of the pharmaceutical quality system is normally demonstrated at the site level.
- Outsourced (contracted) activities should be within the scope of the pharmaceutical quality system.
- Management responsibilities should be identified within the pharmaceutical quality system.
- The pharmaceutical quality system should include the following elements: Process performance and product quality monitoring; Corrective and preventive action; Change management and management review
- Key performance indicators should be identified and used to monitor the effectiveness of processes within the pharmaceutical quality system.
Auditing in a QbD context
Audits are important for keeping design spaces updated and risk management techniques as accurate as possible. Because QbD is a new concept in the pharmaceutical industry, auditing for QbD is a new challenge for auditors. Not only must the auditor have many years of audit experience in the industry, the auditor needs to be knowledgeable of many other aspects, namely:
- The design space being audited. The auditor needs to have access to the history of the product development and the risk analyses that were performed at the time; he or she needs to be knowledgeable of design space requirements and the related attributes and variables.
- Risk evaluation and management techniques. The auditor needs to be able to evaluate if the risk was evaluated correctly during development, if the risk is being managed adequately during the product life cycle, and if a new risk analysis is required based on all the process understanding information available.
- Measuring techniques. Because QbD involves many different measurement techniques, not the least often being PAT, the auditor must have extensive experience in the production area and quality control areas to evaluate whether the techniques used are adequate and to determine whether the results obtained confirm the design space or add new knowledge to the process.
- The auditor needs to be aware of and familiar with all the documentation used to consign the information within the design space and all the information used in the knowledge management process.
- Continual improvement. Expansion, reduction, or redefinition of the design space happen upon gaining new process information, so the auditor needs to be familiar with continual improvement techniques to understand the evolution of the design space and know which parts of it need to be audited on which schedule. Corrective and preventive actions requested during the audit of a design space need to be elaborated upon with continual improvement methods to gain additional knowledge and improve the design space.
- The pharmaceutical quality system. The auditor needs to know the scope and application of the quality system and the goals of its implementation. He or she needs to understand the organization’s structure, the system’s structure, and the established key performance indicators (KPI) to properly evaluate their appropriateness and implementation.
- The regulations. As in any other industry, the auditor needs to be familiar with the applicable regulations (Good Manufacturing Practices as defined in the Code of Federal Regulations in the United States or their international equivalent) and their interpretation and applications.
Table 1 outlines the differences between traditional audit items, and what an auditor should look for when auditing a pharmaceutical design space in a pharmaceutical quality system.
Table 1: Pharmaceutical quality system: Auditing approaches (Traditional vs. QbD)
|Aspect||Minimal approach||Enhanced QbD approach|
|Overall pharmaceutical development||
|Life cycle management||
Enhancing science- and risk-based approaches
The auditor, along with the quality, manufacturing, and regulatory departments, has many opportunities to improve product and process knowledge and redefine the design space. Table 2 illustrates a few of these opportunities.
Table 2: Pharmaceutical quality system: Improvement opportunities
|Old approach||Potential opportunity|
|1. Comply with GMPs.||Compliance—status quo|
|2. Demonstrate effective pharmaceutical quality system, including effective use of quality risk management principles (e.g., ICH Q9 and Q10).||Opportunity to:
|3. Demonstrate product and process understanding, including effective use of quality risk management principles (e.g., ICH Q8 and Q9).||Opportunity to:
|4. Demonstrate effective pharmaceutical quality system and product and process understanding, including effective use of quality risk management principles (e.g., ICH Q8, Q9, and Q10).||Opportunity to:
Essentials of QbD
QbD requires complete understanding of the product and the manufacturing process to control the critical steps to avoid batch failure. The design space must be developed through a proper study that reflects the degree of confidence in the process and the possible regulatory flexibility. The identification of critical factors and the use of control tools to monitor and control them to reduce variability and avoid failure is performed through the design of experiments. QbD requires operating within a design space that could be completely independent of batch size, equipment (size, etc.), manufacturing site, etc. The design space created will dictate the degree of regulatory flexibility. Industry and regulatory agencies have to build mutual trust to share vital information. Ultimately, if the patients are assured of good quality products, everybody wins.
About the author
Stéphanie Peika is an ASQ certified quality auditor and a certified manager of quality and operational excellence. She is director of quality systems at Paladin Labs Inc., a Montreal-based pharmaceutical company.
Tags: risk management, quality by design, QbD, pharmaceutical quality system.