Sandi Schaible and Britt Jones, WuXi AppTec02.01.24
Stability testing refers to evaluating a drug product’s quality and performance over time based on various environmental factors, including temperature, humidity, and light. In biopharmaceutical development, ensuring the stability of drug products (DP) and drug substances (DS) is paramount for maintaining their safety, efficacy, and quality.
Stability testing for drug products must also consider factors including potential degradation and the stability of the product in various formulation and packaging configurations. This robust testing is essential to overcome these challenges, providing the necessary data to support product labeling and guidelines for storage, transport, and handling.
Exploring the inherent challenges associated with stability testing drug products, the myriad roles played by extractable and leachable testing (E&L) and the opaque regulatory environment will highlight the importance of rigorous, repeatable stability testing.
Multiple analytical techniques are needed to fully assess the inorganic and organic compounds that could potentially put biopharmaceuticals at risk. Commonly used analytical methods include:
Extractables and leachables: a regulatory overview
Manufacturing processes play critical roles in determining biopharmaceutical product stability. The intricate process of material creation, molding and shaping commands a meticulous approach to safeguard the integrity and stability of these products. As such, the conditions in which these products are created matter.
Current good manufacturing practices (CGMP)1 ensure a drug product’s identity, strength, quality, and purity. Biopharmaceutical manufacturers must adequately control manufacturing operations, including:
CGMP requirements are designed to be flexible so manufacturers can define the processes and procedures that make the most sense for their products. However, the “C” in CGMP stands for “current,” meaning manufacturers’ technology must be relatively recent to stay compliant. “Systems and equipment that may have been ‘top-of-the-line’ to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today’s standards,” the guidance reads.
It is important to remember that despite its patchwork appearance, the regulatory landscape has numerous checks to ensure safe products are developed, distributed, and marketed to consumers. For example, pre-submission meetings offer a unique opportunity to gain informal yet valuable feedback on a product’s testing plan. Engaging in these meetings can significantly streamline manufacturing, curtail expenses to prepare formal submissions and mitigate the potential for patient risk.
These meetings are a staple in U.S. Food & Drug Administration (FDA) submissions, but global counterparts like the EU’s MDR, China’s NMPA, and Japan’s PMDA also engage in similar interactions with biopharma manufacturers. Experienced lab testing partners often have technical or regulatory experts on staff who closely monitor evolving regulatory trends. These efforts help them stay abreast of new guidance and anticipate changing regulatory expectations. Here is a brief overview of the current regulatory structure for biologic drugs:
Regulatory bodies are government organizations empowered to create, implement, and monitor compliance with laws and guidelines to ensure public safety, ethical practices, legal adherence, and quality standards.
• U.S. FDA
U.S. FDA guidance “Container Closure Systems for Packaging Human Drugs and Biologics”2 was published in 1999. It focuses on E&L’s potential impact on product quality and patient safety. The agency recognizes the need for robust analytical methods to detect, identify and quantify E&L compounds, ensuring they are within acceptable limits. The FDA emphasizes a risk-based approach, including route of administration, dosage form and patient population to customize testing protocols.
• European Medicines Agency (EMA)
The EMA offers detailed guidance on testing and evaluating the compatibility of drug products and packaging materials. The agency’s “Chemical and pharmaceutical quality documentation concerning investigational medicinal products”3 from 2022 includes directives on examining the potential migration of substances from packaging materials to ensure product safety and quality. The ICH Q74 guidance on good manufacturing practices (GMP) for active pharmaceutical ingredients provides supplementary information about the EMA’s expectations for E&L testing.
The regulatory initiative called the International Conference on Harmonization (ICH) is a collaborative effort between regulatory authorities and the pharmaceutical industry in Europe, Japan, and the United States. Its primary goal is to harmonize the scientific and technical aspects of drug development and registration, streamlining the process while ensuring efficacy, quality, and patient safety. The ICH reduces the need for duplicate testing in different regions and speeds up global access to new medicines.
• ICH Q1A(R2)
Published in 2003 and updated in 2018, the ICH’s “Stability Testing of New Drug Substances and Products”5 defines the stability data package needed to be compliant in Europe, Japan, and the U.S. The guideline was written to encompass a variety of scientific characteristics of the materials being tested. It also makes provisions for alternative approaches when they can be scientifically justified.
• ICH Topic Q5C
This is an annex to ICH Q1A(R2) that deals specifically with stability testing of biopharmaceutical products6 in which the active components are proteins and polypeptides—i.e., products susceptible to temperature changes, oxidation, light, ionic content, and shear—and how to store them to avoid degradation.
The professional group U.S. Pharmacopeia (USP) is a scientific, non-profit organization that sets standards for the identity, strength, quality and purity of medicines, food ingredients and dietary supplements worldwide. These standards are recognized and used in more than 140 countries. Adhering to USP standards helps ensure regulatory compliance, facilitates market access, and builds trust with healthcare professionals and consumers by assuring the quality and safety of their products.
• USP <661> and <1661>
These chapters address plastic packaging systems and materials of construction. They are under revision until December 1, 2025, but as an overview, USP <661> guides the use of plastic materials, components and systems used to package pharmaceuticals, biologics, and dietary supplements. It also defines the process of assessing the materials used in these components and systems. USP <1661> describes the plastic materials referred to in <661> and, once the revision is complete, will include four new polymer descriptions and discuss the importance of packaging systems assessment and qualification.
• USP <1663>
This general chapter addresses the design, justification, and execution of an extractables assessment for pharmaceutical packaging and delivery systems. As an informational chapter, USP <1663>7 does not establish specific extraction conditions, analytical procedures or mandatory extractables specifications and acceptance criteria. Nor does the chapter define every situation requiring an extractables assessment.
• USP <665> and <1665>
These chapters detail production equipment and patient safety protocols for plastic/polymeric components and systems used in biomanufacturing. USP <665>8 discusses the characterization of plastic components and systems used to manufacture biopharmaceutical DSs and DPs. USP <1665>9 outlines how to select and qualify plastic systems used to manufacture APIs, biopharmaceutical drug substances and biopharmaceutical and pharmaceutical drug products. As currently published, <1665> is an informational chapter, USP <665> is official and will become enforceable in May 2026.
Additional regulatory considerations that may provide valuable context for biopharmaceutical manufacturers include the BioPhorum Operations Group (BPOG) protocols.
• BPOG
The group published an updated extractables testing protocol in 202010 based on the extraction capabilities of various solvents over recommended time points. The protocol suggests methods for extractables studies, including sample preparation, extraction conditions, recording test article sample conditions, and reporting data from the analysis of extracts. Manufacturers following the most recent BPOG protocols are most likely compliant with the revised USP <665>, but a lab testing partner can confirm whether new data is necessary.
The presence of unwanted or unidentified compounds can lead to regulatory questions, product recalls, and, most importantly, risks to patient health. Complete chemical characterization is not always included in safety assessments due to the large amount of resources associated with this level of analysis. However, E&L testing with no unknowns reported is the most effective way to understand product quality and safety.
A common misconception is that a single round of testing is sufficient to ensure drug products are free from chemicals of concern. Changes in manufacturing, storage, transport, and packaging can introduce new risks, making continual evaluation of potential risks necessary. Drug manufacturers who do not possess this capability in-house are encouraged to find a trusted partner committed to E&L testing with no unknowns reported.
The numerous challenges emerging from the complex molecular structures of biologics to the extensive data management required for stability testing underscore the imperative for robust, comprehensive testing frameworks. Scientists and stakeholders in the biopharmaceutical industry must stay committed to stringent and continual testing. It is also important to remember that the rapidly evolving biopharmaceutical landscape—and the regulations governing it—demands an agile, proactive approach to stability testing.
At the heart of biopharmaceutical development is patient safety and product efficacy. To achieve these goals, developers must keep abreast of the latest regulatory guidance, continuously enhance stability testing protocols to encompass emerging challenges and employ novel analytical methods. Engaging with experienced lab testing partners can help ensure comprehensive, accurate and timely stability testing data.
References
Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization, and a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR42).
Britt Jones is the group manager of the chemistry and package testing services for medical devices, biologics, and combination products at WuXi AppTec. He serves on the ASTM Committee on Packaging (ASTM D-10) and is a member of and certified by the International Safe Transit Association (ISTA) and the Institute of Packaging Professionals (IoPP).
Stability testing for drug products must also consider factors including potential degradation and the stability of the product in various formulation and packaging configurations. This robust testing is essential to overcome these challenges, providing the necessary data to support product labeling and guidelines for storage, transport, and handling.
Exploring the inherent challenges associated with stability testing drug products, the myriad roles played by extractable and leachable testing (E&L) and the opaque regulatory environment will highlight the importance of rigorous, repeatable stability testing.
Challenges in stability testing for biopharmaceuticals
Navigating stability testing for biopharmaceutical systems involves grappling with a unique set of challenges. These stem from biologics’ complex molecular structures and plastic and polymer materials’ potential to interact with drugs. Even materials with a history of successful and safe clinical use can contain chemicals of concern that may contribute to their degradation. Tackling these challenges via advanced analytical methods that combine physical, chemical, and biological assays support safe, effective, and compliant products.Multiple analytical techniques are needed to fully assess the inorganic and organic compounds that could potentially put biopharmaceuticals at risk. Commonly used analytical methods include:
- Inductively coupled plasma (ICP) to detect and identify metals;
- Headspace gas chromatography-mass spectrometry (HSGC-MS) to detect volatile compounds;
- Gas chromatography-mass spectrometry (GC-MS) to detect semi-volatile compounds;
- Liquid chromatography-mass spectrometry (LC-MS) to detect semi- to non-volatile compounds. While effective, this method is challenging and resource-intensive, given that no commercial databases are available for these compounds.
Extractables and leachables: a regulatory overview
A comprehensive and rigorous assessment of extractables and leachables (E&L) is a cornerstone of pharmaceutical stability testing. Extractables are chemical compounds that can be drawn from materials when subjected to aggressive solvents under exaggerated conditions to generate “worst-case” data. Conversely, leachables are compounds that naturally migrate from the container closure or delivery system into the drug or the drug into the container closure or delivery system (under clinically relevant or “normal” usage conditions).
Manufacturing processes play critical roles in determining biopharmaceutical product stability. The intricate process of material creation, molding and shaping commands a meticulous approach to safeguard the integrity and stability of these products. As such, the conditions in which these products are created matter.Current good manufacturing practices (CGMP)1 ensure a drug product’s identity, strength, quality, and purity. Biopharmaceutical manufacturers must adequately control manufacturing operations, including:
- Establishing strong quality management systems;
- Obtaining appropriate quality raw materials;
- Establishing robust operating procedures;
- Detecting and investigating product quality deviations;
- Maintaining reliable testing laboratories.
CGMP requirements are designed to be flexible so manufacturers can define the processes and procedures that make the most sense for their products. However, the “C” in CGMP stands for “current,” meaning manufacturers’ technology must be relatively recent to stay compliant. “Systems and equipment that may have been ‘top-of-the-line’ to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today’s standards,” the guidance reads.
E&L testing on biologics and new modalities
Regulatory guidance around E&L testing on biologic drugs and cell and gene therapies also suffers from recency issues. The guidance is comprehensive, but it’s somewhat disjointed. The E&L landscape has changed significantly over the last 20 years, and regulatory bodies cannot always keep pace with the rising use of biopharmaceutical products or innovative scientific or instrumentation capabilities. Not all regulatory bodies require E&L data, but most reviewers expect to see it accompanied by a safety assessment/toxicological risk assessment.It is important to remember that despite its patchwork appearance, the regulatory landscape has numerous checks to ensure safe products are developed, distributed, and marketed to consumers. For example, pre-submission meetings offer a unique opportunity to gain informal yet valuable feedback on a product’s testing plan. Engaging in these meetings can significantly streamline manufacturing, curtail expenses to prepare formal submissions and mitigate the potential for patient risk.
These meetings are a staple in U.S. Food & Drug Administration (FDA) submissions, but global counterparts like the EU’s MDR, China’s NMPA, and Japan’s PMDA also engage in similar interactions with biopharma manufacturers. Experienced lab testing partners often have technical or regulatory experts on staff who closely monitor evolving regulatory trends. These efforts help them stay abreast of new guidance and anticipate changing regulatory expectations. Here is a brief overview of the current regulatory structure for biologic drugs:
Regulatory bodies are government organizations empowered to create, implement, and monitor compliance with laws and guidelines to ensure public safety, ethical practices, legal adherence, and quality standards.
• U.S. FDA
U.S. FDA guidance “Container Closure Systems for Packaging Human Drugs and Biologics”2 was published in 1999. It focuses on E&L’s potential impact on product quality and patient safety. The agency recognizes the need for robust analytical methods to detect, identify and quantify E&L compounds, ensuring they are within acceptable limits. The FDA emphasizes a risk-based approach, including route of administration, dosage form and patient population to customize testing protocols.
• European Medicines Agency (EMA)
The EMA offers detailed guidance on testing and evaluating the compatibility of drug products and packaging materials. The agency’s “Chemical and pharmaceutical quality documentation concerning investigational medicinal products”3 from 2022 includes directives on examining the potential migration of substances from packaging materials to ensure product safety and quality. The ICH Q74 guidance on good manufacturing practices (GMP) for active pharmaceutical ingredients provides supplementary information about the EMA’s expectations for E&L testing.
The regulatory initiative called the International Conference on Harmonization (ICH) is a collaborative effort between regulatory authorities and the pharmaceutical industry in Europe, Japan, and the United States. Its primary goal is to harmonize the scientific and technical aspects of drug development and registration, streamlining the process while ensuring efficacy, quality, and patient safety. The ICH reduces the need for duplicate testing in different regions and speeds up global access to new medicines.
• ICH Q1A(R2)
Published in 2003 and updated in 2018, the ICH’s “Stability Testing of New Drug Substances and Products”5 defines the stability data package needed to be compliant in Europe, Japan, and the U.S. The guideline was written to encompass a variety of scientific characteristics of the materials being tested. It also makes provisions for alternative approaches when they can be scientifically justified.
• ICH Topic Q5C
This is an annex to ICH Q1A(R2) that deals specifically with stability testing of biopharmaceutical products6 in which the active components are proteins and polypeptides—i.e., products susceptible to temperature changes, oxidation, light, ionic content, and shear—and how to store them to avoid degradation.
The professional group U.S. Pharmacopeia (USP) is a scientific, non-profit organization that sets standards for the identity, strength, quality and purity of medicines, food ingredients and dietary supplements worldwide. These standards are recognized and used in more than 140 countries. Adhering to USP standards helps ensure regulatory compliance, facilitates market access, and builds trust with healthcare professionals and consumers by assuring the quality and safety of their products.
• USP <661> and <1661>
These chapters address plastic packaging systems and materials of construction. They are under revision until December 1, 2025, but as an overview, USP <661> guides the use of plastic materials, components and systems used to package pharmaceuticals, biologics, and dietary supplements. It also defines the process of assessing the materials used in these components and systems. USP <1661> describes the plastic materials referred to in <661> and, once the revision is complete, will include four new polymer descriptions and discuss the importance of packaging systems assessment and qualification.
• USP <1663>
This general chapter addresses the design, justification, and execution of an extractables assessment for pharmaceutical packaging and delivery systems. As an informational chapter, USP <1663>7 does not establish specific extraction conditions, analytical procedures or mandatory extractables specifications and acceptance criteria. Nor does the chapter define every situation requiring an extractables assessment.
• USP <665> and <1665>
These chapters detail production equipment and patient safety protocols for plastic/polymeric components and systems used in biomanufacturing. USP <665>8 discusses the characterization of plastic components and systems used to manufacture biopharmaceutical DSs and DPs. USP <1665>9 outlines how to select and qualify plastic systems used to manufacture APIs, biopharmaceutical drug substances and biopharmaceutical and pharmaceutical drug products. As currently published, <1665> is an informational chapter, USP <665> is official and will become enforceable in May 2026.
Additional regulatory considerations that may provide valuable context for biopharmaceutical manufacturers include the BioPhorum Operations Group (BPOG) protocols.
• BPOG
The group published an updated extractables testing protocol in 202010 based on the extraction capabilities of various solvents over recommended time points. The protocol suggests methods for extractables studies, including sample preparation, extraction conditions, recording test article sample conditions, and reporting data from the analysis of extracts. Manufacturers following the most recent BPOG protocols are most likely compliant with the revised USP <665>, but a lab testing partner can confirm whether new data is necessary.
The presence of unwanted or unidentified compounds can lead to regulatory questions, product recalls, and, most importantly, risks to patient health. Complete chemical characterization is not always included in safety assessments due to the large amount of resources associated with this level of analysis. However, E&L testing with no unknowns reported is the most effective way to understand product quality and safety.
A common misconception is that a single round of testing is sufficient to ensure drug products are free from chemicals of concern. Changes in manufacturing, storage, transport, and packaging can introduce new risks, making continual evaluation of potential risks necessary. Drug manufacturers who do not possess this capability in-house are encouraged to find a trusted partner committed to E&L testing with no unknowns reported.
A final word on stability testing
Stability testing for biopharmaceutical products is a multifaceted process that includes meticulously evaluating extractables and leachables, overseeing manufacturing processes, ensuring adherence to CGMP and comprehensive final packaging testing.The numerous challenges emerging from the complex molecular structures of biologics to the extensive data management required for stability testing underscore the imperative for robust, comprehensive testing frameworks. Scientists and stakeholders in the biopharmaceutical industry must stay committed to stringent and continual testing. It is also important to remember that the rapidly evolving biopharmaceutical landscape—and the regulations governing it—demands an agile, proactive approach to stability testing.
At the heart of biopharmaceutical development is patient safety and product efficacy. To achieve these goals, developers must keep abreast of the latest regulatory guidance, continuously enhance stability testing protocols to encompass emerging challenges and employ novel analytical methods. Engaging with experienced lab testing partners can help ensure comprehensive, accurate and timely stability testing data.
References
- https://www.fda.gov/drugs/pharmaceutical-quality-resources/facts-about-current-good-manufacturing-practices-cgmp
- https://www.fda.gov/media/70788/download
- https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-and-pharmaceutical-quality-documentation-concerning-investigational-medicinal-products-clinical-trials-revision-2_en.pdf
- https://www.ema.europa.eu/en/ich-q7-good-manufacturing-practice-active-pharmaceutical-ingredients-scientific-guideline
- https://database.ich.org/sites/default/files/Q1A%28R2%29%20Guideline.pdf
- https://www.ema.europa.eu/en/documents/scientific-guideline/ich-topic-q-5-c-quality-biotechnological-products-stability-testing-biotechnologicalbiological-products_en.pdf
- https://doi.usp.org/USPNF/USPNF_M7126_03_01.html
- https://www.uspnf.com/notices-665-nitr-20220225
- https://doi.usp.org/USPNF/USPNF_M11136_02_01.html
- https://www.biophorum.com/resource/extractables-and-leachables/
Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization, and a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR42).
Britt Jones is the group manager of the chemistry and package testing services for medical devices, biologics, and combination products at WuXi AppTec. He serves on the ASTM Committee on Packaging (ASTM D-10) and is a member of and certified by the International Safe Transit Association (ISTA) and the Institute of Packaging Professionals (IoPP).
