EMA Guideline on the Development, Manufacture of Synthetic Peptides and Good Pharmacogenomic Practice

Modern medicines development increasingly sits at the intersection of advanced chemistry and genomic science. On one hand, synthetic peptides represent a fast-growing therapeutic class that bridges small molecules and biologics. On the other, pharmacogenomics is reshaping how medicines are developed, evaluated, and ultimately used in patients. Recognising these parallel advances, the European Medicines Agency (EMA) has recently published two key scientific documents: the Guideline on the Development and Manufacture of Synthetic Peptides and the Concept paper on the guideline revision on good pharmacogenomic practice.

Guideline on the Development and Manufacture of Synthetic Peptides

Synthetic Peptides:

EMA defines synthetic peptides as chemically synthesised sequences of amino acids that occupy a unique space between traditional small molecules and biologically derived proteins. Because of this hybrid nature, they raise specific quality, manufacturing, and control challenges that are not fully addressed by existing ICH guidelines for chemical or biological substances.

The synthetic peptide guideline, adopted by both CHMP and CVMP and effective from June 2026, is intended to close this gap by providing product-specific quality expectations across the entire lifecycle.

The guideline applies to both new and existing synthetic peptide active substances used in human and veterinary medicines, including post-authorisation changes and investigational medicinal products. Biological peptides produced by recombinant technology and radiopharmaceuticals are excluded, as they fall under separate regulatory frameworks.

Development and Manufacture: Controlling Complexity at the Active Substance Level

EMA places strong emphasis on manufacturing process understanding for synthetic peptides, particularly where solid-phase peptide synthesis, solution-phase synthesis, or hybrid fragment-condensation approaches are used. Applicants are expected to provide a clear, stepwise description of the synthetic process, supported by justified controls for critical steps such as coupling, deprotection, cleavage, purification, and pooling strategies.

Because peptide synthesis can generate a wide range of structurally related impurities—including deletion sequences, insertion sequences, stereoisomers, truncated peptides, and aggregation products—the guideline stresses early and thorough impurity profiling. Control strategies must consider impurity fate and purge, starting material quality, and the potential for degradation during manufacture and storage.

Characterisation expectations go well beyond molecular weight confirmation. EMA expects a combination of orthogonal analytical techniques, such as mass spectrometry, amino acid analysis, peptide mapping, NMR, circular dichroism, and where relevant biological assays, to confirm primary structure and assess higher-order structure. This comprehensive approach ensures that subtle structural changes with potential clinical relevance are detected and controlled.

Stability, Specifications, and Lifecycle Management

Stability testing for synthetic peptides must follow general EMA and ICH stability principles, while also addressing peptide-specific degradation pathways such as oxidation, deamidation, hydrolysis, aggregation, and disulfide exchange. The guideline highlights that many peptides require refrigerated or frozen storage, but stresses that stress conditions and short-term excursions must also be evaluated using stability-indicating methods.

Specifications for synthetic peptides are anchored to the European Pharmacopoeia general monograph “Substances for Pharmaceutical Use,” with defined reporting, identification, and qualification thresholds for peptide-related impurities. EMA makes clear that impurity control strategies must be scientifically justified and supported by batch data, not simply aligned to theoretical thresholds.

Synthetic Peptides Referencing Biological Products

A particularly important section of the guideline addresses development programmes where a synthetic peptide is compared against a biologically manufactured reference product. Although synthetic peptides cannot follow the EU biosimilar pathway, EMA expects applicants to apply biosimilarity-like principles, including extensive analytical comparability, impurity profile evaluation, and justification of any observed differences. This reflects EMA’s growing focus on analytical evidence as the foundation for regulatory decision-making.

Concept paper on the guideline revision on Good Pharmacogenomic Practice

EMA’s concept paper on the revision of the guideline on good pharmacogenomic practice acknowledges that since the original guideline’s publication, scientific understanding, sequencing technologies, and regulatory use of genomic data have progressed significantly.

The proposed revision aims to preserve the original guideline’s core principles while expanding and clarifying expectations in areas such as sequencing technologies, analytical validation, interpretation of genotype-phenotype relationships, and the use of pharmacogenomics throughout the product lifecycle.

EMA identifies several priority areas requiring revision. These include the use of modern sequencing technologies, particularly long-read sequencing, to resolve complex pharmacogenes with high polymorphism or structural variation. Special attention is given to enzymes such as CYP2D6 and the CYP3A4/CYP3A5 system, where substrate-specific effects and population variability have major implications for dosing and safety. For more information, please refer directly to the guidances using the links below.

• Guideline on the Development and Manufacture of Synthetic Peptides 

• Concept paper on the guideline revision on good pharmacogenomic practice.