The sterility assurance level, abbreviated SAL, describes the probability that a viable microorganism remains on or in a product after sterilization. In medical device law, this parameter is not purely a microbiological concept but rather a normative prerequisite for labeling. EN 556-1 requires a SAL of no more than 1 × 10⁻⁶ for a medical device sterilized in its final package to be labeled as “STERILE”. Regulation (EU) 2017/745 does not specify a numerical value; it requires validated procedures in Annex I Chapter II Section 11.5, the target value of which is specified by the harmonized standards. The statistical foundations are presented in the entry Sterility Assurance Level and Terminal Sterilization.
EN 556 as a Bridge Between Parameter and Labeling
The EN 556 series of standards connects the calculated parameter with product labeling. Part 1 governs products sterilized in their final package, Part 2 governs products manufactured aseptically and therefore marked with a separate addition to the sterility symbol. Anyone who writes “STERILE” on the label thereby declares compliance with this standard requirement for each individual product in the batch, not for an average value. Because a SAL of 10⁻⁶ cannot be directly verified by measurement, it is established exclusively through validation of the procedure, knowledge of the initial bioburden, and routine process control. A sterility test on the final product does not replace this verification.
Process Standards and Their Different Verification Pathways
Each sterilization process has its own process standard with its own verification pathway. EN ISO 17665 governs the development, validation, and control of moist heat processes, EN ISO 11135 governs ethylene oxide sterilization, and EN ISO 11137 governs radiation sterilization. For moist heat and ethylene oxide, the SAL is typically demonstrated through inactivation kinetics and biological indicators, in conservative cases through an overkill approach. For radiation, a sterilization dose is determined instead, or a preselected dose of 25 kGy or 15 kGy is confirmed as sufficient for a SAL of 10⁻⁶ using the VDmax method of EN ISO 11137-2. The verification design is therefore process-dependent and not transferable.
Bioburden and Microbiological Routine Monitoring
Every SAL verification requires reliable knowledge of the initial microbial count. EN ISO 11737-1 specifies the procedures for determining bioburden, including extraction method, recovery rate, and sample size; EN ISO 11737-2 describes sterility tests as part of validation. If bioburden increases due to changed suppliers, materials, manufacturing steps, or cleanroom conditions, the basis of the verification shifts. Therefore, periodic bioburden determinations and, for radiation sterilization, regular dose audits are part of maintenance. These data are part of the technical documentation and become the trigger for revalidation when changes occur.
Role of the Notified Body in the Sterilization Aspect
If a Class I product is placed on the market in a sterile condition, Article 52(7) of Regulation (EU) 2017/745 requires application of the procedures under Annex IX Chapter I and III or Annex XI Part A. The involvement of the Notified Body remains limited to aspects related to the establishment, assurance, and maintenance of sterile conditions. It is precisely within this framework that the SAL verification is reviewed: validation reports, bioburden data, routine parameters, indicator or dosimetry data, release rules, and change control. For higher-class products, the same verification is part of the more comprehensive conformity assessment but appears alongside clinical and product-related assessments.
Distinction from the Pharmaceutical Law Understanding
The parameter is identical, the legal framework is not. In the pharmaceutical sector, the SAL is embedded in GMP requirements for sterile manufacturing and results in batch release by the Qualified Person; the entry Sterility Assurance Level and Terminal Sterilization describes this context. In medical device law, there is no batch release by a qualified person, and there is no pharmaceutical manufacturing authorization procedure. Instead, the SAL verification is an element of the quality management system according to EN ISO 13485 and the technical documentation, procedurally anchored through the process standards and the packaging standards of the EN ISO 11607 series. The legal consequence of a deviation is therefore not a refused batch release but rather an unsubstantiated labeling claim.
Relevance for clinical trials
Investigational products are frequently provided sterile before CE marking is available. The sponsor must then maintain the same depth of verification for the investigational batches as for market products: validated procedure, documented bioburden, routine parameters, and a justified SAL. Authorities and ethics committees evaluate this information as part of product safety in the application; incomplete validation data are a common reason for additional requests. If investigational batches are manufactured in small lots or in pilot production, it must be specifically justified how the transferability of the validation to these lot sizes is ensured.
During the course of the study, changes are critical: a new sterilization service provider, a changed packaging material, or a modified starting material shifts the bioburden and thus the verification basis. Such changes must be evaluated, revalidated if necessary, and documented in a traceable manner in the clinical investigation plan or as a notification of amendment. Full-service CROs such as Mediconomics support sponsors and manufacturers in compiling and evaluating sterilization verifications for application documents, in coordinating change evaluation and study documentation, and in medical writing for the clinical investigation plan, investigator’s brochure, and clinical investigation report.
Frequently Asked Questions (FAQ)
Does the MDR Mandate a SAL of 10⁻⁶?
Not literally. Annex I Chapter II Section 11.5 requires validated procedures; the numerical value originates from EN 556-1 as a prerequisite for the “STERILE” labeling. Through the harmonized standard, it becomes de facto binding.
Can the SAL Be Demonstrated Through a Sterility Test?
No. A sterility test according to EN ISO 11737-2 has insufficient statistical power to confirm a probability of 10⁻⁶. It serves validation and investigation, not demonstration of the level.
When Is Revalidation Required?
When there are changes to the product, material, packaging, loading, equipment, or manufacturing site, as well as deviations in bioburden. For radiation sterilization, periodic dose audits according to EN ISO 11137-2 are added.
Regulatory References
- Regulation (EU) 2017/745, Annex I Chapter II Section 11 and Article 52(7)
- EN 556-1 and EN 556-2 – Requirements for medical devices labeled as “STERILE”
- EN ISO 17665, EN ISO 11135, EN ISO 11137-1 to -3 – Process standards
- EN ISO 11737-1 and EN ISO 11737-2 – Bioburden and sterility testing
- EN ISO 13485 Section 7.5.7 – Validation of sterilization processes
