Real-Time Release Testing Promised Faster Drug Batch Release, Yet Industry Adoption Stays Slow

Pharmaceutical manufacturers have long been promised a way to release drug batches without waiting for slow end-product laboratory testing, yet a new review concludes that the industry has largely failed to embrace the concept. The review, published on 20 August 2026 in the open-access journal AAPS Open, traces the evolution of real-time release testing (RTRT) across global regulatory frameworks and examines why, despite decades of health authority support, implementation by pharmaceutical and biopharmaceutical companies remains limited. The authors, led by Iris Arnarsdottir with contributors including Andrew Chang, Tin Do Viderø and Scott W. Roberts, find that the most mature and successful application of RTRT remains the manufacturing of pharmaceutical tablets, and that the literature mainly features hybrid approaches combining real-time and traditional release testing, often within continuous tablet manufacturing.

Real-time release testing is defined in the International Council for Harmonisation (ICH) Q8(R2) guideline 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. In practice, this means using in-process data instead of end-product testing to confirm product quality, safety and efficacy. To accomplish it, manufacturers must define a quality target product profile, identify critical quality attributes (CQAs), and measure the process parameters and material attributes that affect those attributes during manufacturing. The review stresses that developing an appropriate manufacturing process and control strategy using the science- and risk-based principles of Quality by Design (QbD) and Quality Risk Management remains fundamental to the approach. Potential advantages include faster batch release and shorter manufacturing lead times, reduced manufacturing costs through less laboratory testing, early detection of deviations while production is occurring, data-driven release decisions, and greater manufacturing flexibility.

The regulatory history stretches back further than many in the industry might expect. The review notes that the concept of leveraging manufacturing in-process data to support testing and release dates to the 1980s with parametric release of terminally sterilized products. The US Food and Drug Administration first approved releasing terminally sterilized products based on defined sterilization parameters rather than an approved sterility test on individual units in 1985 for certain large volume parenteral drug products, on the justification that parametric release could provide greater assurance that a batch meets sterility requirements. Individual unit sterility testing suffered from a small sample size that restricted the ability to capture microorganisms dispersed in a large volume, and from the limited ability of prescribed culture media to stimulate growth of all potential microorganisms. In 2010, the FDA published guidance formally defining parametric release as a sterility assurance release program in which demonstrated control of the sterilization process enables a firm to use defined critical controls in lieu of the sterility test.

Other regulators followed with their own frameworks. In 2001, the European Medicines Agency’s predecessor published guidance introducing the idea that while medicinal products must comply with authorized release specifications, not all tests in the specification had to be carried out on the finished product before release, provided there was sufficient process understanding, validation, control and a demonstrable relation between end-product testing and process monitoring. In 2007, the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S), a non-binding cooperative arrangement currently comprising 57 participating authorities from Europe, Africa, America, Asia and Australasia, published guidance to help assessors and GMP inspectors jointly approve applications containing parametric release. The review credits these international cooperative agreements with maintaining a harmonized approach and wide acceptance of RTRT by global health authorities.

The modern RTRT framework took shape in the early 2000s. In 2002, the FDA recognized that the pharmaceutical industry was hesitant to adopt innovative manufacturing strategies because of regulatory uncertainty, and launched the Pharmaceutical Current Good Manufacturing Practices for the 21st Century: A Risk-Based Approach initiative, with its final report published in 2004. Soon after, the FDA issued guidance on process analytical technologies (PAT), defining PAT as a system for designing, analyzing and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials, with the goal of ensuring final product quality. The guidance described three measurement strategies: at-line, where a sample is removed and analyzed near the process stream; on-line, where the sample is diverted and may be returned; and in-line, where the sample is not removed from the process stream at all. In 2009, ICH Q8(R2) codified the definition of real-time release testing still in use today.

Subsequent guidance has refined expectations in ways that matter operationally. EMA revised its parametric release guideline in 2012 to include RTRT, adding discussion of handling deviations, Certificate of Analysis generation and submission expectations. Notably, the guidance states that if real-time release testing results fail or trend toward failure, batch release decisions cannot be substituted by end-product testing; failures must be investigated and release decisions made on the results of that investigation. Stability-indicating methods are required regardless of the means of release testing. Attributes indirectly controlled by approved RTRT must still appear on the Certificate of Analysis, marked as complying if tested and footnoted as controlled by approved real-time release testing. In 2018, PIC/S updated its Annex 17 to align with the EU version, after which Health Canada adopted it into its GMP guide. Japan’s PMDA has created specialized teams, including the Innovative Manufacturing Technology Working Group, to support continuous manufacturing and RTRT approval, while China’s Center for Drug Evaluation approved technical guidelines for continuous manufacturing of oral chemical drug preparations in 2023 to support localized implementation of ICH Q13.

Despite this regulatory scaffolding, the adoption data are striking. An analysis of PMDA review reports from 2009 to 2018 by Kajiwara and colleagues, cited in the review, showed that as the ratio of approved products containing a partial QbD submission to all approved products rose from 9 percent in 2009 to 71 percent in 2018, only a 3 percent increase was observed for real-time release testing over the same period. For small molecules, 10 products had been approved with RTRT as part of the drug product manufacturing process, and zero biologic products were approved over the reporting period. The authors of that analysis hypothesize possible causal factors: the extensive development data required for regulatory review combined with short development timelines, the verification needed to support manufacturing scale-up, and the reality that RTRT generally cannot be applied to all drug substance or drug product CQAs, resulting in hybrid real-time and conventional release testing.

The technical challenges are particularly acute for large molecules. Antibodies and complex proteins are manufactured from living cells, producing a much wider scope of complex attributes; whereas small molecule CQAs focus on purity and solid-state form, large molecule CQAs focus on biological activity, cellular impurities and higher-order structure. An assessment of monoclonal antibody CQAs and emerging analytical technologies reported by Jiang and colleagues suggests that limitations in current in-line, on-line or at-line analytical technologies would likely not support all biologic CQA testing, again pointing toward hybrid release strategies. The review also highlights the connection to data integrity: whereas standard release testing performs a limited number of laboratory quality control tests, RTRT combined with PAT technologies and digital models can leverage millions of data points, so quality decisions dependent on automated or computerized data must align with ALCOA+ principles and remain subject to GMP inspection.

Even in tablets, where RTRT is most advanced, regulatory hurdles persist. In 2023, the FDA published a special topic commentary on submitting continuous manufacturing and/or RTRT for dissolution, reporting anonymized case studies in which only three of eight dissolution RTRT submissions were approved. Common issues included inadequate dissolution methods, models predicting release only at a single time point rather than a complete profile, models based on batch-averaged mean values that cannot capture intra-batch variability, and insufficiently broad design-of-experiments studies. The review also cites an EMA assessment of Lazcluse (lazertinib mesylate monohydrate tablets), in which the Committee for Medicinal Products for Human Use initially issued a major objection because the RTRT strategy had not been adequately documented and justified, before the sponsor provided detailed control strategy information supported by substantial commercial-scale parallel testing data. Reported challenges include low-risk model updates requiring regulatory prior approval, lack of global harmonization, and an unfavorable environment for adopting new sensor technologies.

The review concludes that a continued disconnect remains between the regulatory burden of getting RTRT initially approved and maintained post-approval versus the gains in manufacturing efficiency. Yet the outlook may be improving: as analytical and modelling technologies continue to improve, the technical challenges may become less relevant, and ICH published a final concept paper in 2024 toward updating the Q6A and Q6B specifications guidelines, which may facilitate broader adoption of innovative approaches including RTRT. Ongoing discussions through the FDA’s Emerging Technology Program, EMA’s Quality Innovation Group and PMDA’s Innovative Manufacturing Technology Working Group remain promising forums, and opportunities to leverage platform technologies, prior knowledge and ICH Q12 lifecycle management concepts appear complementary to more efficient future implementation.

Subject of Research: A review of global regulatory frameworks for real-time release testing and the reasons for slow industry adoption

Article Title: Real-time release testing: a review of global regulatory frameworks and application by the industry

Article References: Arnarsdottir, I., Chang, A., Do Viderø, T., & Roberts, S. W. (2026). Real-time release testing: a review of global regulatory frameworks and application by the industry. AAPS Open, 12(1), Article 55. https://doi.org/10.1186/s41120-026-00188-w

Image Credits: AI Generated

DOI: 10.1186/s41120-026-00188-w

Keywords: real-time release testing, pharmaceutical manufacturing, ICH Q8, parametric release, process analytical technology, quality by design, FDA, EMA, PMDA, continuous manufacturing, tablets, biologics