Sterilization & Decontamination
Pharmaceutical sterilization is a validatable process aimed at rendering a product free from viable micro-organisms.
Impact of the new EU GMP Annex 1 on sterilization processes: the new EU GMP Annex 1 has updated the guidelines for sterilization processes. Here is a review of these changes, following a reminder of the definitions and operating principles of sterilization.
What is a sterilization process?
According to ISO, a sterilization process is a validated process aimed at rendering a product free from viable micro-organisms. The objective is to achieve sterility — i.e. the measured absence of any contaminating agent (including spore-forming organisms) — which permits a product to be placed on the market with legal accountability.
Several key points must be highlighted before proceeding:
- A single 6-log reduction of the bioburden or initial concentration is not sufficient
- Special case for injectables: the Probability of a Non-Sterile Unit (PNSU) must be < 10⁻⁶ (Ph.Eur.)
- Sterilization is a matter of probability and can never reach zero
- It is not an all-risk guarantee: sterilization does not degrade pyrogens or prions (TSE agents)
- A validation supported by design, installation, operational and performance qualifications (SAL, reproducibility, homogeneity…) is required
- Sterility is an absolute state, ensuring the absence of viable micro-organisms, statistically demonstrable (EN 556-1:2001, definition 3.4)
- Normative reference: EN 285 / ISO 17665
Further reading
Steam: Heat transfer properties
Steam has several phases: wet steam, saturated or dry steam and superheated steam. Discover the phase diagram.
Sterilization methods
Various methods are referenced in the international guides on Good Manufacturing Practices (GMP) appended to the Pharmacopoeias.
Learn more >
Sterilization value
The sterilization value "Fo" is expressed in units of time and is used to quantify the effect of a sterilizing treatment during a decontamination process.
Regulatory approach: focus on EU GMP Annex 1
Chapter 8: Specific manufacturing and technologies — Sterilization
- 8.34: Addition of detail on sterilization in its final container, using a controlled and validated process
- 8.34 & 8.37: Addition of a line giving preference to thermal treatment over other processes
- 8.35: Entire paragraph adding detail on the choice of equipment and process based on scientific principles, as well as control mechanisms for a sterilization cycle demonstrating repeatability and reliability
- 8.38: Addition of a validity check of the process in the event of a change in product packaging, load configuration (min/max), equipment modification (revamping) or parameter changes
- 8.39: Periodic (annual) requalification, worst-case parameters and load; reference to the CCS for others
- 8.40: All current operating parameters must be established and adhered to (previously only the load plan was mentioned)
- 8.42/43: Biological Indicators (BIs) considered as an additional control method but controlled (number and viable spore identity) + positive control on each cycle (if used in support of validation) and precaution regarding contamination introduced by BIs. Verification of D & z values for new lots.
- 8.44: Addition of detail regarding the flow and storage of sterilized products (classification to be respected, no crossing, double-door autoclave…), distinction between sterilized and non-sterilized loads
- 8.45: Addition of detail regarding the transfer of sterilized equipment, materials or components to an aseptic zone (double door on the sterilizer)
- 8.45: Single cycle report, compliance determined according to a procedure (standardisation of release criteria)
- 8.50: Thermal sterilization cycle: monitoring and recording systems must be independent of the control system
- 8.51: Validation studies must be conducted to demonstrate the adequacy of the control system and the location of probes
- 8.54: Addition on parametric release: reference to Annex 17 describing the review of process monitoring documentation (temperature, pressure, sterilization time, etc.) — Real-Time Parametric Release (RTPR)
- 8.50: Each heat sterilisation cycle should be recorded (e.g. by the use of duplex/double probes connected to independent control and monitoring systems) → Direct reference to EN 285
Moist heat sterilization
- 8.57: Systematic inspection of sterilized products for porous loads and dryness > Load integrity → traceability in the sterilization report
- 8.58: For SIP systems: temperature control at the drain point recommended during sterilization > Identification of cold spots → drain point accepted as a reference indicator
- 8.59: Requirement to take into account equilibration time, exposure time, P/T correlation and temperature range; control of these parameters during validation and routine controls → Reference to EN 285: equilibration time for all probes and start of count. Spatial and temporal homogeneity.
- 8.61: In cycles including an air purge, loads must be designed to allow effective air extraction and free drainage of condensate → Process/machine consideration, but also direct reference to packaging selection (which is not universal but specific to the load/process)
- 8.62: Avoid distortion and damage to flexible containers (particularly BFS and FFS) during terminal sterilization through parameter adjustment → Care in cycle development/optimisation with respect to the load: no "one-size-fits-all" cycle
- 8.63: Sterilization systems must be designed and validated so that everything is subjected to treatment at critical points and treatment reproducibility is demonstrated → QbD & Design Qualification + Qualification
- 8.64: For superheated water processes, it is necessary to demonstrate that all required contact points are covered → QbD & Design Qualification + Qualification
Dry heat sterilization
- 8.68: Use of endotoxin loads for validation: specific Fh and required 3-log₁₀ reduction
- 8.69: Control of time, pressure, heat penetration and uniformity, and exposure temperature with verification of reproducibility within pre-established tolerances for depyrogenation ovens and those used for initial, intermediate or final sterilization → Increased control and detailed use of depyrogenation tunnels (for details see Annex 1, 8.65)
- 8.70: Oven/Tunnel: critical parameters to be monitored: temperature, exposure time, chamber pressure, air velocity and quality, heat penetration and uniformity, load configuration — HEPA filters
Radiation sterilization
- 8.71: Addition of a reference to a directive in EU GMP Annex 12 (specific to radiation) and removal of detail on the use of BIs or irradiation doses
- 8.71: UV not accepted as a sterilization method
- 8.72: Consideration of variations in load density
Ethylene oxide sterilization
- Addition of EO pressure as a parameter to be monitored
- Aeration may take place in the sterilizer chamber and/or in a separate aeration chamber. The aeration phase must be validated
Further reading
Lethality table
Pharmaceutical autoclave sterilization is subject to numerous controls. Discover the lethality table used in the pharmaceutical industry.
Sterilization standards
AFNOR and European Pharmacopoeia sterilization and disinfection standards related to STERIGENE's activities.
Learn more >
Regnault table
Discover the empirical formula giving the latent heat of vaporisation of water (saturated steam) as a function of temperature and pressure.