In-Process Control and Real-Time Release Testing in Modern GMP Facilities

Modern pharmaceutical manufacturing no longer relies solely on end-product testing to ensure quality. Instead, the focus has shifted towards in-process control (IPC) and real-time release testing (RTRT) — two strategies designed to detect and correct deviations during production, rather than waiting until the final stage.

This evolution is driven by Quality by Design (QbD) principles and supported by regulatory frameworks such as ICH Q8-Q10, reinforcing the idea that quality should be built into every stage of the manufacturing process.

In this article, we explore how IPC and RTRT function in GMP settings, their role in maintaining consistent product quality, and the technologies enabling their implementation.

What Is In-Process Control (IPC)?

In-process controls refer to a set of tests and measurements carried out during the manufacturing cycle to monitor critical process parameters (CPPs) and ensure they remain within predefined acceptable ranges. IPC helps manufacturers:

• Identify and correct issues in real time
• Maintain batch consistency
• Avoid costly rework or product rejection at the final stage

Examples include:

• Tablet weight and hardness checks during compression
• pH monitoring during solution preparation
• Granule moisture content testing in drying processes
• Viscosity or particle size in emulsions or suspensions

These controls are crucial for ensuring intermediate stages do not deviate from validated norms, which could otherwise affect bioavailability, stability, or patient safety.

Real-Time Release Testing (RTRT): A Step Beyond

RTRT is an advanced quality assurance strategy that allows for the release of a batch without traditional end-product testing, based on continuous or predictive data collected during manufacture.

According to the ICH Q8(R2) definition, RTRT refers to “the ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically includes a valid combination of measured material attributes and process controls.”

This relies on technologies such as:

• Process Analytical Technology (PAT): Using tools like NIR spectroscopy, Raman spectroscopy, and in-line HPLC to monitor CQAs (Critical Quality Attributes) in real time
• Multivariate Data Analysis (MVDA): Interpreting complex datasets to flag deviations early
• Automated feedback loops: Adjusting process variables dynamically to maintain product specifications

Benefits of IPC and RTRT in GMP Facilities

• Faster batch release: Reducing time to market and warehousing requirements
• Enhanced process understanding: Allowing root cause analysis and continuous improvement
• Increased manufacturing efficiency: Lower rejection rates and reduced resource wastage
• Regulatory compliance: Aligning with global GMP expectations and improving audit outcomes

These methods also support continuous manufacturing — a model increasingly promoted by regulators and industry to replace traditional batch production in suitable scenarios.

Regulatory Perspective and Validation

Implementing RTRT doesn’t mean a relaxation of standards. In fact, it requires even greater validation and process control. Companies must demonstrate to regulators (e.g. MHRA, EMA, FDA) that their process:

• Is well understood through QbD principles
• Has validated, reliable PAT tools and data models
• Can consistently deliver products meeting all quality specifications
• Is supported by a robust quality system and change control processes

RTRT is often used in combination with traditional release testing initially, with the intention of scaling up once process capability is proven.

Conclusion

In-process control and real-time release testing represent the future of pharmaceutical manufacturing — enabling faster, smarter, and more reliable production without compromising on quality. These approaches reflect a shift from quality by inspection to quality by design, empowering manufacturers to be proactive, rather than reactive.

As technology advances and regulatory confidence grows, RTRT will increasingly become a standard expectation in modern GMP environments — particularly in continuous manufacturing, biologics, and high-volume production.