The International Conference on Harmonization (ICH) guideline Q9 Quality Risk Management and the American Society for Testing and Materials (ASTM) Standard E2500-07, Standard for Specification, Design and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment, provide a science- and risk-based approach to commissioning and qualifying pharmaceutical and biopharmaceutical manufacturing systems and equipment. A key objective of these documents is to give industry flexibility in implementing the ASTM standard through the process of verification to demonstrate that pharmaceutical manufacturing facilities are fit for useand create products with the correct product-quality attributes. These approaches, in place of traditional qualification or integrated commissioning and qualification (C&Q) using impact assessment, can make projects and processes more efficient and help facility owners and designers ensure compliance, quality, and safety when defining acceptance criteria for their critical process systems and equipment.

In addition to standardizing terms and methods, the ASTM E2500 standard describes a risk-management system and helps lay the groundwork for verification C&Q planning and execution. ICH Q9 notes the following two primary principles of risk management:

• The evaluation of the risk to quality should be based on scientific knowledge and ultimately protect the patient.
• The level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk.

Although the standard addresses the traditional scope of qualification activities that prove equipment and systems are fit for use, ASTM offers organizations greater flexibility by allowing them to develop a verification plan following ICH Q9 principles for implementation according to their own specific quality goals, time and cost constraints, and internal roles and responsibilities.

New process paradigm
Under the ASTM model, principles of good engineering practice (GEP), risk management, design review, and change management influence each stage of a process, from compiling design requirements to final acceptance and release. The ASTM model has led some companies to realign their project-management teams and other resources to improve their verification processes.

Using C&Q as a foundation for system verification, the ASTM standard takes a comprehensive approach to assessing products’ and processes’ critical aspects for potential risk to product-quality attributes and patient safety. Equipment and systems that do not include critical aspects can be released for use after personnel determine that they conform to design intent, were created in accordance with GEP only, and did not require qualification activities.

To adopt the ASTM standard effectively, a company must define a systematic approach to verify that manufacturing elements—individually and collectively—are fit for their intended uses, properly installed, and operate correctly. All verification approaches must be documented to provide a level of detail commensurate with the elements’ risks to products and patients, their complexity, and their novelty. In contrast with traditional qualification methods, system verification involves a shift in emphasis from the quality-control mindset (i.e., approving every test case and respective acceptance criterion) to a broader quality-assurance perspective (i.e., approving the verification plan and the results of the completed verification execution activities).

Under ASTM, subject matter experts (SMEs) identify and document all process attributes (i.e., functions, features, abilities, and performance or quality characteristics) that are essential to maintaining consistent product quality. To ensure that all aspects of a facility conform to design criteria, companies should also implement a mechanism for communicating specifications and other relevant data with all design and manufacturing team members. In addition, SMEs should define acceptance criteria; develop and approve system-verification plans and specifications, including verification and test strategies; and ensure that all documentation and verification has been completed.

Impact versus risk assessment
The ASTM standard places new emphasis on risk management. In the past, companies relied heavily on impact assessment, which evaluates the effects of operating, controlling, alarming, and failure conditions on product quality. Impact assessment occurs after design development and focuses on systems and components rather than products and patients.

Risk management evaluates the chosen process design against a set of approved product and process user requirements. It is performed throughout design development to ensure that systems and other design and operating elements can monitor and control risks to the manufacturing process (e.g., process variability and contamination). The risk-management requirements are designated as critical and include all components, functions, and features of the design that control risks. The probability and severity of risks are evaluated to determine their effect on process variation, product quality, and safety.

In addition to risk assessment, the comprehensive ASTM approach promotes various other risk-assessment tools that are discussed in ICH Q9, including hazardous operation analysis, failure modes and effects analysis, and fault-tree analysis.

Conclusion
To determine the best approach for implementing ASTM verification, designers and manufacturers must define what they are trying to achieve. Potential goals include improving compliance, enhancing product quality, minimizing capital costs, and minimizing contamination risk. When these goals have been defined, a company can develop a request for proposal and initiate negotiations with qualified engineering experts who specialize in the complex commissioning and qualification process. In addition to saving owners time and capital, the ASTM approach can also help to optimize manufacturing processes and supporting quality systems, thus resulting in improved efficiency and compliance.

Steve Wisniewski is a senior associate and director of compliance at Integrated Project Services, 2001 Joshua Rd., Lafayette Hill, PA 19444, tel. 610.828.4090 x1254, swisniewski@ipsdb.com.