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Real-time release testing: a review of global regulatory frameworks and application by the industry
Real-time release testing
Abstract
Real-time release testing is defined in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q8(R2) as “the ability to evaluate and ensure the quality of in-process and/or final drug product based on process data, which typically includes a valid combination of measured material attributes and process controls”.
The purpose of this review is to present the evolution of the real-time release testing regulatory framework, current health authority guidance and expectations, and possible regulatory burden and rationale of why the industry has been reluctant to more aggressively implement this concept. Overall, there remains a harmonized approach and wide acceptance of real-time release testing by global health authorities thanks to international cooperative agreements such as the Pharmaceutical Inspection and Convention Pharmaceutical Inspection Co-Operation Scheme (PIC/S). The most mature and successful application of real-time release testing remains the manufacturing of pharmaceutical tablets.
The literature mainly features hybrid approaches of real-time and traditional release testing, and often within the context of continuous tablet manufacturing. The implementation of real-time release testing for large molecule modalities remains a challenge, as the limitations in current in-line, on-line, or at-line analytical technologies would likely not support all biologic CQA testing resulting in hybrid real-time/conventional release testing. Additional potential causal factors toward the industry’s slow implementation include the challenging regulatory issues managing out of specification results, analytical technology limitations, the high data and modelling required to support regulatory approval, and the regulatory burden associated with maintaining the control strategy post-approval.
However, as analytical and modelling technologies continue to improve, these technical challenges may become less relevant. Continued discussion between industry and global health authorities will additionally drive new regulatory strategies to help implement these innovative technologies. For example, ICH is currently revising Q6A and Q6B (e.g., specifications) and may facilitate broader adoption of innovative approaches including real-time release testing. Additional discussions through United States Food and Drug Administration’s (US FDAs) Emerging Technology Program (ETP), the European Medicines Agency (EMAs) Quality Innovation Group (QIG), and Japan’s Pharmaceutical and Medical Devices Agency (PMDAs) Innovative Manufacturing Technology Working Group (IMT-WG) remain promising forums for further discussion.
Introduction
Real-time release testing is the concept of utilizing in-process data instead of end-product testing to confirm product quality, safety, and efficacy. To accomplish real-time release testing, the quality target product profile (QTPP) needs to be defined and critical quality attributes (CQAs) identified. Once the CQAs have been identified, then the process parameters and material attributes that impact the CQAs need to be measured during the manufacturing process. Additionally, it is important to understand the relationship between in-process data and conventional end-product testing to determine the where and how in the manufacturing process the CQAs should be evaluated and qualified to ensure product quality. Thus, the development of an appropriate manufacturing process and control strategy utilizing the science and risk-based principles defined by Quality by Design (QbD) and Quality Risk Management (QRM) remain a fundamental aspect of real-time release testing. The potential positive features of real-time release testing include a) faster batch release/shorter manufacturing lead times, b) reduced manufacturing costs (e.g., less laboratory testing), c) early detection of deviations (e.g., excursions identified while production is occurring), d) data driven product release decision making, and e) greater manufacturing flexibility.
The concepts of real-time release testing have been strongly supported by global health authorities for decades, with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), United States Food and Drug Administration (US FDA), European Medicines Agency (EMA), Japan’s Pharmaceutical and Medical Devices Agency (PMDA), Health Canada, and Pharmaceutical Inspection and Convention Pharmaceutical Inspection Co-Operation Scheme (PIC/S) publishing multiple guidance documents on this topic. Despite the potential upsides and global regulatory support, a robust endorsement and application of real-time release testing by the pharmaceutical and biopharmaceutical industries remains slow. However, there has been an impressive growth of publications featuring the process development, control strategies, and analytical advancement needed to support real-time release testing (e.g., especially toward pharmaceutical tablets). This review presents the evolution of the real-time release testing regulatory framework, current health authority guidance and expectations, implementation case studies, and the possible rationale of why the industry has been reluctant to more aggressively implement this manufacturing concept.
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Results and discussion
The first steps toward real-time release testing – parametric release
IIn 2010, the US FDA published guidance that defined parametric release as a “a sterility assurance release program where demonstrated control of the sterilization process enables a firm to use defined critical controls, in lieu of the sterility test, to fulfill the intent of 21 CFR 211.165(a), and 211.167(a)” (US Food and Drug Administration 2010). The US FDA first approved this concept of releasing terminally sterilized products based upon meeting defined sterilization parameters and not on performing an approved sterility test on individual units in 1985 for certain large volume parenteral drug products (US Food and Drug Administration 2012), based upon the justification that the parametric release process can provide greater assurance that a batch meets sterility requirements. The challenges of individual unit sterility testing included the small number of samples required for testing which restricts the ability to capture those microorganisms dispersed in a large volume and the limited ability of the prescribed culture media to stimulate growth of all potential microorganisms. Thus, the analysis of in-process control data from the sterilization process could provide a more accurate understanding of product sterility (US Food and Drug Administration 2010). However, it should be noted that parametric release was originally developed for terminally sterilized products utilizing a single well understood sterilization process. Applying parametric release concepts to non-sterile products creates numerous challenges since these manufacturing processes do not feature an equivalent single, validated process that ensures all CQAs.
The control strategy needed to support parametric release relies upon an in-depth knowledge of the sterilization process, product, process impact on the product, and potential microorganisms associated with the process to determine the critical process parameters to ensure product quality from the sterilization process. Regulatory considerations toward submission and health authority approval include a risk-based assessment and description of the control strategy for the terminal sterilization program, including methods, critical process parameters, acceptance criteria, container closure system, production loading patterns and microbiological monitoring plan.
In 2001, EMA published a note for guidance on parametric release testing (The European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products 2001). In this guidance, EMA introduced the concept that while medicinal products must comply with authorized release/shelf-life specifications, this did not mean all tests in the specification had to be carried out on the finished product before release. The principles for parametric release in this guidance also included sufficient process understanding, such as adequate validation, control, relation between end-product testing and process monitoring, acceptance criteria, procedures for approval/rejection, and Good Manufacturing Practice (GMP) compliance during inspections. Assessment of new market authorizations or variations includes a risk analysis of the sterility assurance system between assessors and GMP inspectors.
In 2007, the PIC/S published guidance on parametric release (Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-operation Scheme 2007). PICS/S is a non-binding, informal co-operative arrangement between Regulatory Authorities in the field of GMP and currently comprises of 57 participating authorities from all over the world (e.g., Europe, Africa, America, Asia and Australasia) and has contributed to the global harmonization efforts of parametric release expectations. This document provided guidance to global health authority assessors and GMP inspectors to jointly approve applications containing parametric release.
Source: Arnarsdottir, I., Chang, A., Do Viderø, T. et al. Real-time release testing: a review of global regulatory frameworks and application by the industry. AAPS Open 12, 55 (2026). https://doi.org/10.1186/s41120-026-00188-w
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