QA/QC

Choosing Tolerance Intervals: A Framework To Use in Setting Specification Limits Based on Manufactured Drug Lot Data

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As defined in ICH Q6A, a specification is a list of tests, references to analytical procedures, and appropriate acceptance criteria that take the form of numerical limits, ranges, or other criteria for the tests described (1). They establish the set of criteria to which a new drug substance or product should conform to be considered acceptable for its intended use. Ideally, specifications are established based on demonstration of quality attribute levels that make drugs safe and efficacious during toxicology and…

Identifying False Metabolite Measurements During Cell-Culture Monitoring Effective Application of the Multivariate Hotelling’s T2 Statistic

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Upstream process scientists and engineers actively monitor bioreactor metabolite levels during cell culture using off-line blood-gas analyzers (BGAs) and related instrumentation. But such tools introduce inherent variability into metabolite measurements. The magnitude of that variability depends on the measurement range. Mammalian cells are sensitive to concentrations of one such metabolite: dissolved CO2. In cell cultures, CO2 levels often are reported as partial pressure (pCO2) in millimeters of mercury (mmHg). Available literature frequently reports that elevated pCO2 concentrations have adverse impacts…

A Parenteral Permissible Daily Exposure for Inactivated Therapeutic Proteins: An Approach Based on Literature Review

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In multiproduct biopharmaceutical manufacturing facilities, cross-contamination with pharmacologically active proteins must be controlled in a good manufacturing practice (GMP) environment (1, 2). Although guidance on control strategies exists for solvents and small-molecule pharmaceutical impurities, that is not directly applicable to inactivated (e.g., denatured and/or degraded) therapeutic proteins (TPs) occurring as impurities in a drug substance (DS) and/or drug product (DP). Small-molecule drugs and TPs differ in their molecular structures, pharmacological mechanisms of action, hazards, and potential impurities, so their cross-contamination…

October 17, 2023

Cell Culture Media Fingerprinting: A Three-Tiered Approach

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Cell culture media range from simple components to complex chemically defined mixtures. They may contain a number of chemical components, each with individual chemical properties — and any variation in which ingredients can affect cell culture processes and biological products being manufactured. Although simple substances can be identified easily using well-known classical methods such as Fourier-transform infrared spectroscopy (FTIR), analysis becomes more challenging when dealing with complex mixtures. Section VII-3-C of the Q7A guidance from the International Council for Harmonisation…

September 19, 2023

Validating Prefiltration Dirty-Hold Times for Upstream Media and Feed Solutions: Implications for Establishing In-Process Microbial Control

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Biopharmaceutical manufacturing processes require that prepared raw materials and product intermediates be held at different stages. During hold times, however, process and product intermediates are susceptible to microbial risks from bioburden, endotoxins, and exotoxins. Such risks arise from multiple sources, including bioproduction facilities, equipment, operations, and raw materials. Even a prepared intermediate can help microbes to grow. The US Food and Drug Administration’s (FDA’s) guidance on Sterile Drug Products Produced By Aseptic Processing states that “the time limits established for…

September 19, 2023

Establishing Microbiological and Particulate Controls When Reworking a Sterile Drug Product

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Reworking of finished sterile-product batches requires particular attention to maintaining microbial and particulate control. The strategy is permitted with regulatory agreement and observation of regulations such as 21 CFR 820 (1). Note that reworking is distinct from reprocessing. Under ICH Q7, reprocessing is confined to intermediates, whereas reworking is reserved for finished products (2). Reworking includes steps that were not part of an initial biomanufacturing process. The reworked steps are process elements that are designed either to bring an out-of-specification…

September 19, 2023

Continued Process Verification: A Multivariate, Data-Driven Modeling Application for Monitoring Raw Materials Used in Biopharmaceutical Manufacturing

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Biologics manufacturing entails multiple complex unit operations across three key process areas: cell culture, purification, and sterile fill–finish (Figure 1). Numerous raw materials are used to formulate reagents that are vital to those processes. For example, bioreactors require cell-culture media, and buffer solutions are used during both drug-substance filtration and drug-product final formulation. Changes in raw-material properties can introduce variation in the performance of intermediate processes and in product quality attributes. Therefore, raw-material properties must be monitored to help ensure…

June 26, 2023

Specification Limits for Biomanufacturing Processes: Comparing Tolerance-Interval and Process-Capability Methods

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Critical quality attributes (CQAs) such as safety, efficacy, purity, and identity must be monitored and controlled in biopharmaceutical products to meet predefined specification limits. Setting such parameters is critical but challenging. Unduly narrow specification limits increase risks for rejecting good product batches, whereas overbroad limits can lead to acceptance of bad batches (1). Limited sample sizes, homogeneous results obtained from testing of raw materials exhibiting scant variability, and variability inherent to testing methodologies can add up, encouraging quality teams to…

June 26, 2023

The Future of Virtual Audits and Audit Success

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Audits are a vital quality-management tool in the biopharmaceutical industry. Whether the activity is verifying supplier or partner qualifications, contributing to corrective and preventative actions (CAPAs), or fulfilling regulatory requirements, proactive auditing is key to successful operations. Over the past couple of years, virtual audits — also known as remote or distance audits — have enabled biopharmaceutical companies to maintain compliance and quality-assurance (QA) demands despite COVID-19–related travel restrictions and social-distancing protocols. Now that the world is opening up again,…

May 23, 2023

Pharmaceutical Manufacturing Quality Assurance Programs: Transitioning from Research and Development to the Clinic

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On average it can take or even exceed US$1 billion to get a pharmaceutical product to market, and nine out of 10 products developed never make it to commercialization (1). As technology advances, more potential therapies and preventatives are being developed and optimized by virtual companies. They are typically small, newly formed organizations that build their momentum on programs for novel products. Because many of the program activities are outsourced, virtual start-up companies developing pharmaceutical products raise concerns about ensuring…

May 23, 2023