Phase 3, ongoing process verification: Guide to validation of terminal sterilization process of drugs (GUI-0074)

On this page

• Routine release
• Monitoring results
• Periodic review and revalidation
• Change management system

Routine release

You should:

• approve sterilization records as part of the batch-release procedure (should be available for each sterilization run)
• ensure that the records are reviewed and approved by the appropriate personnel and by the quality department

For more information on reprocessing and reworking, consult:

• Good manufacturing practices guide for drug products (GUI-0001)

For guidance on parametric release, consult:

• Guidance on parametric release - Pharmaceutical Inspection Co-operation Scheme (PIC/S)

Monitoring results

You should:

• monitor the sterilization process and its parameters routinely to ensure the specified process conditions are met
  • document these results in the processing records
• include maintenance of equipment in your routine control
• perform maintenance in conjunction with calibration

Include in the validation protocol the requirement for and adherence to effective, routine process-monitoring procedures.

You should also:

• document biological challenges for moist heat and ethylene oxide sterilization performed in routine process monitoring procedures
  • include the location, number, type and lot number of the challenge in the records, along with the actual test results (if applicable)
• obtain samples from each batch (bioburden-based approach) or periodically (overkill approach) of a drug for ongoing bioburden testing and data collection
  • use the data to determine the limits of species and number of organisms so you can document and control for seasonal/operational variations
• document deviations from defined processing conditions
  • investigate and assess the impact on the product and on process objectives
  • consider previously processed loads if your requalification indicates the process can no longer achieve the required SAL
• perform root cause analysis of procedural, process or equipment failure so that the risk to product is correctly understood and suitable corrective and preventative actions (CAPA) are implemented

Note: Sterilization has not been achieved if there is a growth of any biological challenge organisms after moist heat and EO sterilization, including documented change control evaluation runs. If this occurs, you must evaluate the process parameters. If you cannot find a processing error, you must consider the sterilization process unacceptable.

Periodic review and revalidation

You should:

• review the process and change control history at scheduled intervals, at least once a year to ensure nothing has changed inadvertently and to determine the extent of requalification that may be necessary
  • physical and microbial requalification of a sterilization process must take place at least once a year, in accordance with specified acceptance criteria and documented procedures
• perform periodic review/requalification according to a written procedure
  • should list information/systems to be reviewed and activities that should be performed
• make sure the appropriate personnel and the quality department review and approve the records of requalification

Change management system

An effective change management system involves evaluating, approving, implementing and documenting sterilization systems or product changes. Include documentation of any testing required to ensure the qualified state of control.

You should:

• use change control procedures to pre-authorize changes to equipment, sterilization system, sterilization or process parameters, load configuration and/or product, material and packaging components
• define the product/material before introducing a new or altered product, package or loading pattern
  • for example, evaluate changes to primary or secondary packaging, in package or case configuration, case composition
  • these changes may have an impact on sterilization and will require additional studies
• undertake microbial performance qualification (MPQ) when there are changes to equipment, process parameters or bioburden (based on seasonal variation or routine monitoring)
• for moist heat sterilization, consider temperature distribution, heat penetration and/or microbiological challenge studies for modifications made to the sterilizer chamber, changes to product carrier/tray design, sterilization medium supply/distribution system or sterilizer operation/control mode
• revalidate when significant modifications or changes are made

Note: You may not need to revalidate the modified sterilization process if you can demonstrate the product/material, packaging, load configuration, equipment or process equivalence. The process is considered equivalent if it runs within the defined, validated process limits.

You must conduct a technical review that compares the modification candidate with the product/material, packaging, load configuration, equipment or process used to validate the existing sterilization process. You must then document the outcome of this review and include the rationale for any decisions made as a result.