Pharmaceutical Sterilization

Some points are very important to highlight before moving on:

• Simply reducing the bioburden or initial concentration by 6 logarithms is not sufficient.
• Special case for injectables the PSMO (Prob Survival Micro Organism) must be <10-6 (PhEur).
• Sterilization is a notion of probability without ever reaching 0
• This is not all-risk insurance: sterilization does not degrade pyrogens or prions (ATNC)
• Validation supported by design, installation, operational and performance qualifications (SAL, reproducibility, homogeneity, etc.) is necessary.
• Sterility is an absolute state, ensuring the absence of viable microorganisms, statistically demonstrable (EN 556-1: 2001 def 3.4)
• Normative reference EN 285 / ISO 17665

REGULATORY APPROACH: FOCUS ON ANNEX 1 OF EU GMP

 

Chapter 8: Production and Specific Technologies – STERILIZATION

• 8.34: Addition of detail on sterilization in its final packaging, using a controlled and validated process
• 8.34 & 8.37: Addition of a line which favors heat treatment over other processes
• 8.35: entire § on the addition of details on the choice of equipment and process based on scientific foundations followed as well as control mechanisms of a safety cycle demonstrating repeatability and reliability
• 8.38: Addition of a process validity check in the event of a change in product packaging, load configuration (Mini / Maxi), modification of equipment (revamping) or parameters,
• 8.39: Periodic (annual) requalification, parameters & worst case load; referral to the CCS for others
• 8.40: All current operating parameters must be established and respected (previously only the load plan was mentioned),
• 8.42/43: BIs considered as an additional method of control but controlled (number and viable identity of spores) + control on each cycle of a positive control (if used to support validation) and precaution on contamination caused by Bis. D&z value verification for new batches.
• 8.44: Addition of detail concerning the flow and storage of sterilized products (class to be respected, no crossing, double door autoclave, etc.), distinction between sterilized and non-sterilized loads
• 8.45: Addition of detail regarding the transfer of sterilized equipment, materials or components to an aseptic area (double door on the sterilizer),
• 8.45: Single cycle report, compliance determined according to a procedure (standardization of discharge criteria)
• 8.50: Thermal sterilization cycle, monitoring and recording systems must be independent of the control system.
• 8.51: Validation studies must be carried out to demonstrate the adequacy of the control system and the location of the probes.
• 8.54: Addition on parametric release: reference to annex 17 describing the review of documentation relating to process monitoring (temperature, pressure, sterilization time, for example) – Libé Para Ana Temps Real: LPATR
• 8.50 Each heat sterilization cycle should be recorded […….] (e.g. by the use of duplex/double probes connected to independent control and monitoring systems). -> Direct reference to EN285

Moist heat sterilization

• 8.57: Systematic inspection of sterilized products, for porous loads & dryness > Integrity of the load -> traceability in the sterilization report
• 8.58: For SIP systems: temperature control at the drain point recommended during the inspection, > Cold point search -> drain point admitted as indicator,
• 8.59: Request to take into account equilibration time, exposure time, P/T correlation and temperature range [….] control of these parameters during validation and routine checks, > Reference to EN285: Time balancing all probes AND starting the countdown. Spatial & temporal homogeneity.
• 8.61: During a cycle including an air purge, the loads must be designed to allow efficient extraction of air and free drainage of condensates, > Process / machine but also direct reference to the choice of packaging (which is not universal but ad hoc for load/process)
• 8.62: Avoid distortions and damage caused to flexible containers (notably BFS and FFS) in the terminal sterilization phase by adjustment, > Care in the development/optimization of cycles with respect to the load: no “goes everywhere” cycle
• 8.63: Sterilization systems must be designed and validated so that everything is subject to treatment [….] at critical locations and the reproducibility of the treatment. > QbD & Design Qualification + Qualification
• 8.64: For superheated water processes, need to demonstrate that all required contact points are covered > QbD & Design Qualification + Qualification

Dry heat sterilization

• 8.68: use of endotoxin loads for validation: Fh ad’hoc and required reduction 3log10
• 8.69: Control of time, pressure, penetration and uniformity of heat as well as exposure temperature with verification of reproducibility within pre-established tolerances for depyrogenation ovens and those in initial, intermediate sterilization or final, > Increased control and details of use of depyrogenation tunnels (for details see appendix 1 8.65),
• 8.70 Furnace / Tunnel: critical parameters to monitor: 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 Annex 12 of the EU GMP (radiation specific) and deletion of detail concerning the use of BIs or irradiation doses.
• 8.71: UV not accepted as a sterilization method
• 8.72: Taking into account variations in load density

Sterilization with ethylene oxide

• Added OE pressure as a parameter to track
• Aeration can take place within the sterilizer enclosure and/or in a separate aeration chamber. The aeration phase must be validated