Ensuring Product Quality, Safety, and Potency for Pharmaceutical Manufacturers
The U.S. Food and Drug Administration (FDA) defines a reference-standard material as a “highly purified compound that is well characterized.” Reference standards are a cornerstone of the pharmaceutical industry, critical to assessing product quality, safety, and potency during product development. Throughout the drug development process, properly characterized reference standards are required to ensure quality control in critical areas such as the release of new product batches and stability evaluation.
A typical drug product may require a reference standard for not only the active pharmaceutical ingredient (API), but also any number of degradation products, process impurities, metabolites, or resolution components. For new drugs where compendial standards are unavailable, it is the responsibility of the sponsor to synthesize and characterize these materials. This work can include analytical testing necessary for the qualification of these different standard types, with a focus on maintaining industry guidelines such as the FDA’s current good manufacturing practices (cGMP) and the International Council for Harmonisation (ICH).
Reference standards are also required for a wide range of development activities that impact clinical research, including manufacturing, stability testing, and toxicology. With an increased reliance on both domestic and international contract laboratories to perform critical research functions, storage and distribution of standards to collaborating organizations has become more critical than ever. Failure to properly characterize reference standards and maintain them in a qualified state can lead to significant delays in project timelines and increased costs.
Reference standards can be divided into the following general categories:
- API—used to determine potency for active pharmaceutical ingredients (APIs)
- Degradation products—used to identify and/or quantitate degradation products
- Process impurities—used to identify and/or quantitate process-related compounds
- Metabolites—used to identify and/or to quantitate substances generated in vivo through a metabolic process
The level of characterization required depends on the intended use of the reference standard. A reference standard used to determine potency of an API requires full identity and purity characterization. A reference marker or impurity marker used for identification only or as a resolution component may require no more than identity confirmation.
For additional expertise on this topic, MRIGlobal’s John Cobb, program manager, and Audrey Ingram, Ph.D., senior chemist, offered a free webinar on essential insights into the qualification and distribution of reference standards, and the importance of developing a formal program for reference standard management. You can watch the webinar recording at “Reference Standard Management for Pharmaceutical Development.” You can also read about some of the questions we received about reference standards at “Reference Standards in the Pharmaceutical Industry.”
From their acquisition and qualification to their application in maintaining product quality and regulatory compliance, it is critical to understand the importance of reference standards in ensuring high-quality pharmaceutical products through development. Here are four keys to reference standard management that all pharmaceutical manufacturers should know:
- Acquisition and Qualification of Reference Standards for New Drugs
For development programs involving novel chemical compounds, reference standards will not be available from compendial sources such as the U.S. Pharmacopeia (USP). Reference standards, therefore, must be synthesized by the sponsor or a contract manufacturer and properly characterized before use. Typically, a portion of an early batch of drug substance is set aside for use as the primary API reference standard. As the program develops, the need for standards of process impurities, degradants, or key metabolites may arise. These related compounds may be obtained from the API manufacturing process or by a custom synthesis. Qualification should be appropriate for each material’s use case, with more rigorous testing required for primary assay standards for which accurately known purity is of utmost importance. Uncalibrated reference standards that are used for identity confirmation only may not be as extensively characterized and may not have an assigned purity.
- Challenges in Reference Standard Management and Strategies to Mitigate Them
After an initial qualification, reference standards must be continually evaluated at regular intervals to ensure no significant changes have occurred. Most development projects will require several different standards, and it is important to track the status of these numerous materials using a rigorous inventory management system and qualification schedule. Consider a centralized reference standard program to help maintain consistency and reduce risks associated with decentralized management. Having an organized system will ensure that the correct standards are always available in a qualified state for the laboratories that need them.
- The Critical Role of Reference Standards in Product Quality and Project Timelines
Reference standards must be evaluated and retested at regular intervals to maintain their qualified status. After qualification, each reference standard is assigned a retest date with a requalification period based on available stability data. If requalification testing is not performed prior to the retest date, standards will fall out of qualification status and cannot be used until requalification is completed. This can lead to major delays in critical processes that depend on reference standards such as product manufacturing and release. Proper planning is necessary to ensure that all reference materials remain in a qualified state at all times.
- Best Practices for Storage and Distribution of Reference Standards to Collaborators and Vendors
Reference standards are required for a wide range of development activities that impact clinical research, including manufacturing, stability testing, and toxicology evaluation. With an increased reliance on both domestic and international contract laboratories to perform critical research functions, storage and distribution of standards to collaborating organizations has become more critical than ever. Materials should be stored in a secure facility at appropriate, controlled storage conditions. The storage location should be monitored by a validated monitoring system that provides real-time tracking, historical data, and automatic system alerts if an out-of-range event occurs. When distributing reference standards to international laboratories, care must be taken to comply with both domestic export controls and import regulations of the destination country.
In summary, the best way to prepare for these and other challenges and risks associated with reference standards is by planning ahead with a comprehensive reference standard management program. The program should include procedures for material procurement, initial and requalification testing, storage, and distribution to third parties. Validated inventory software is used to track amounts of each standard, with threshold notifications enabled to alert the team when a material is running low. A successful reference standard management program ensures that standards are always in a qualified state and available to those who need them.
GETTING STARTED AT MRIGLOBAL
Contact MRIGlobal for further information about our work in pharmaceutical sciences. Through a multidisciplinary approach, we provide customized pharmaceutical development solutions for government and commercial organizations. This includes expertise in pharmaceutical analysis, API manufacturing, clinical research support, repository management, and bioanalytical chemistry.
To discuss how we can help your project be successful, contact us today.
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