The European Medicines Agency’s Human Medicines Division has published a Q&A document addressing the technical and organizational measures that manufacturers should evaluate to prevent microbial contamination of non-sterile medicinal products. The document is issued under reference EMA/INS/GMP/161750/2026 and is dated 13 July 2026.
Although the text itself is limited to two questions, a short background section, and a consolidated reference list, it addresses a longstanding interpretive gap in the EU GMP guide. Chapter 5, section 5.10 requires that products and materials be protected from microbial and other contamination at every stage of processing, but it does not define what constitutes adequate control in a non-sterile manufacturing context. This Q&A is the first EMA publication to set out that expectation in operational terms.
The background section identifies the regulatory driver directly: individual cases of multi-resistant microorganisms detected in non-sterile antibiotic products. This is a significant framing choice.
It establishes, at agency level, that microbial contamination in a non-sterile product is not solely a product quality consideration but a potential patient safety hazard, whether through opportunistic organisms present in the final formulation or through organisms carrying multi-antibiotic resistance.
EMA directs manufacturers to apply the same quality risk management discipline set out in sections 5.17 to 5.22 of the EU GMP guide, Part I, when assessing this category of risk, and identifies cleaning validation, in particular, as an area warranting close attention. Critical cleaning procedures are expected to be defined in SOPs, executed as written, and supported by documented verification.
Technical Measures
The first question addresses the technical dimension of contamination control. EMA’s response identifies facility and equipment design, material flow, microbiological control of process characteristics, and cleaning processes as the categories that should be evaluated against established limits, with the outcome of a documented quality risk management process serving as the basis for implementing technical measures.
Manufacturers are also directed to consider adapting Contamination Control Strategy principles drawn from Annex 1, notwithstanding that Annex 1 is written primarily for sterile manufacture. This is a notable point of regulatory convergence: EMA is signaling that CCS methodology, developed for the sterile manufacturing environment, has direct applicability to non-sterile risk assessment when appropriately scaled.
Beyond this general framework, EMA specifies a number of measures that should be considered where supported by the risk management outcome:
- Suppliers of cleaning agents and detergents should be incorporated into the formal supplier qualification programme rather than managed outside the quality system.
- Where a deviation involves microbial growth, a phenotypical identification strategy should be considered as part of the investigation, so that the organism’s identity, not merely its presence, informs the impact assessment.
- Expiry dating should be established and controlled for prepared solutions of cleaning agents and detergents, and the preparation process itself should be controlled to ensure it does not introduce contamination.
The Q&A also reiterates a set of expectations already present in EU GMP Part I that manufacturers should incorporate where relevant. Cleaning validation studies should include microbiological sampling of surfaces in direct contact with the drug product, with sampling locations and techniques documented to a level sufficient to demonstrate cleaning success.
See Also: Types of Sampling Methods in EM
The validation exercise should extend to other parameters of the cleaning cycle, including the drying step, to address the risk of microbial contamination arising from residual moisture retained in equipment.
Validated methods should be applied to microbial testing of active substances, excipients, water, primary packaging materials, equipment, the manufacturing environment, and finished product. Water used in manufacture should be demonstrated to be suitable for its intended use in accordance with applicable guidance.
Where microbial contamination is identified, validated cleaning or disinfection methods should be applied, and the suitability of the detergents or disinfectants used, whether as part of a scheduled programme or in response to a specific contamination event, should be demonstrated.
Organisational Measures
The second question addresses the organisational and personnel-related controls expected to support microbial contamination prevention. EMA specifies that appropriate gowning, including gloves and facemasks, should be in place for critical operations, and that glove disinfection should be considered prior to entry into critical areas.
As with the technical measures, these expectations sit alongside existing requirements under EU GMP Part I that manufacturers are expected to apply where relevant to their operations:
- Personnel involved in gowning and cleaning activities should receive regular practical training with documented assessment of competence; production personnel training should specifically address correct behavioural practices during production and other critical activities;
- Personnel hygiene and health status should be subject to ongoing monitoring and review;
- Environmental monitoring programmes should be maintained to confirm that the facility remains suitable for manufacture and that no unmanaged contamination risk is present.
Regulatory Implications for Manufacturers
This Q&A does not introduce a new legal requirement. Every measure it references traces back to an existing provision in EU GMP Part I, Annex 1, or Annex 15. Its significance lies in consolidation and interpretation: it establishes, for the first time in an EMA-issued document, a defined baseline against which the general obligation in section 5.10 can be assessed for a non-sterile manufacturing site.
Inspectors are likely to use this document as a reference point during GMP inspections of non-sterile facilities, particularly where the product portfolio includes antibiotics, other products with documented microbial contamination history, or products where microbial quality is a recognised critical quality attribute.
Manufacturers should treat the publication as a prompt to review, rather than rebuild, existing contamination control documentation. Practical points for a gap assessment include verifying that cleaning agent and detergent suppliers are formally qualified within the supplier management programme, confirming that cleaning validation protocols include microbiological sampling and address the drying step explicitly, reviewing deviation investigation procedures to confirm that phenotypical identification is triggered appropriately for microbial excursions, and confirming that gowning, glove disinfection, and personnel training records for non-classified but critical areas are current and defensible.
Sites that have applied Annex 1 Contamination Control Strategy principles in sterile operations may find it efficient to extend that same methodology, scaled appropriately, to their non-sterile lines rather than developing a parallel framework.
