EMA Guidance: Chemistry of Active Substances and GMP for Additive Manufacturing (3DP)

The European Medicines Agency (EMA) has introduced two significant guidance updates in 2026, focusing on active substance chemistry requirements and the emerging use of additive manufacturing (3D printing) in pharmaceuticals.

These updates aim to strengthen quality, control strategies, and innovation, while ensuring that pharmaceutical development and manufacturing remain scientifically robust and patient-focused.

Guidance: Chemistry of Active Substances

Scope and Regulatory Basis

The guideline defines the data requirements for the manufacture and control of active substances used in medicinal products. It follows the ICH Common Technical Document (CTD structure) and applies to both new and existing active substances, excluding biological, herbal, and radiopharmaceutical products.

The purpose of this guideline is to set out the type of information required for the manufacture and control of active substances (existing or new chemical entities) used in a medicinal product. The differences in requirements for new or existing active substances are clarified in the relevant paragraphs of the guideline where applicable.

It also recognises regulatory submission pathways such as the Active Substance Master File (ASMF) and Certificate of Suitability (CEP), while maintaining consistent expectations regardless of the submission route.

General Information (3.2.S.1)

This section establishes the identity of the active substance through detailed information on nomenclature, chemical structure, and physicochemical properties.

It includes identifiers such as INN, IUPAC names, and CAS numbers, along with structural representation including stereochemistry. Physicochemical characteristics such as solubility, polymorphism, partition coefficient, and pKa are also described, as these directly influence safety, efficacy, and performance.

Manufacture (3.2.S.2)

The manufacturing section represents the applicant’s commitment to the process and must provide a comprehensive description of the synthesis and controls.

This includes graphical representations and sequential narratives covering all steps, materials, and conditions involved in the process. Critical process parameters such as temperature, pH, pressure, and reaction time must be clearly defined, particularly for steps that impact the quality of the active substance.

The guideline also addresses reprocessing and recovery practices. Reprocessing must be justified and controlled, while recovered materials must be evaluated through risk assessment, especially with respect to impurity carryover.

The selection of starting materials is critical and must be scientifically justified, ensuring that they are structurally defined and appropriate for the intended synthesis.

Control of Materials and Impurities

All materials used during manufacturing, including solvents, reagents, and catalysts, must be clearly defined and controlled through appropriate specifications.

The guideline places strong emphasis on impurity control, particularly the risk of carry-over from starting materials and the formation of mutagenic impurities such as nitrosamines. A scientifically justified control strategy must be implemented based on risk assessment and process understanding.

Characterisation (3.2.S.3)

Characterisation ensures a thorough understanding of the active substance. Structural confirmation must be supported by analytical techniques such as infrared spectroscopy, nuclear magnetic resonance, and mass spectrometry.

The guideline highlights the importance of polymorphism, as different solid-state forms can affect dissolution, stability, and bioavailability. Additional properties such as solubility, particle size, and physicochemical behaviour must also be evaluated.

Control Strategy and Specifications (3.2.S.4)

A well-defined control strategy is essential to ensure consistent product quality. This includes establishing specifications for identity, assay, and impurities, supported by validated analytical methods.

Batch analysis data from representative production batches must be provided to demonstrate consistency. Specifications should be justified using clinical, non-clinical, and manufacturing data, and aligned with pharmacopoeial standards where applicable.

Stability and Container Systems

Stability studies must assess degradation pathways, storage conditions, and retest periods or shelf life.

The container closure system should be suitable to protect the active substance from environmental factors such as moisture, light, and contamination. Compatibility between the substance and packaging materials must be demonstrated.

Guidance: GMP for Additive Manufacturing (3DP)

Introduction to 3DP in Pharmaceuticals

Three-dimensional printing (3DP) is an emerging pharmaceutical manufacturing technology that enables the production of dosage forms through a layer-by-layer approach using digital designs.

This technology supports patient-centric treatment by enabling personalised medicines with flexible doses, shapes, and combinations, making it particularly valuable for special patient populations.

Scope of the Guidance

The guidance outlines quality and GMP considerations for the use of 3DP in manufacturing solid oral dosage forms. It applies to both authorised medicinal products and investigational products used in clinical trials.

It should be applied alongside existing EU GMP requirements and relevant regulatory frameworks.

Pharmaceutical Development Considerations

The selection of 3DP technology depends on the properties of the active substance, formulation characteristics, and intended manufacturing scale.

Critical quality attributes such as uniformity, dissolution, disintegration, porosity, and stability must be defined during development. Intermediate materials, often referred to as pharma inks, must also be evaluated for stability and performance.

Process Validation and Control Strategy

Since 3DP is considered a non-standard manufacturing process, it requires robust validation using the intended production equipment.

A comprehensive control strategy should include in-process controls, specifications for intermediate and finished products, and real-time monitoring techniques such as spectroscopic tools. This approach supports consistent quality and may reduce reliance on end-product testing.

GMP Requirements for 3DP

The manufacturing process includes equipment qualification, preparation of materials, printing operations, quality control testing, and batch release.

Equipment, including software systems, must be properly designed, maintained, and validated in accordance with EU GMP principles.

Materials and Manufacturing Controls

Cartridges or syringes used in 3DP processes are critical components and must be appropriately controlled. Their stability, reuse potential, and impact on product quality must be evaluated.

Supplier qualification and material controls should follow a risk-based approach to ensure consistent quality and safety.

Quality Risk Management and Validation

Quality Risk Management should be applied throughout the manufacturing process to identify and mitigate risks.

Validation activities must cover process parameters, equipment performance, cleaning procedures, and software systems. Special attention should be given to data integrity and advanced technologies such as artificial intelligence where applicable.

For detailed regulatory information, refer to the official EMA guidance documents:

• Guidance: Chemistry of Active Substances

• Guidance: GMP for Additive Manufacturing (3DP)