For the first time since 2001, the European Commission (EC) is updating its guidelines for pharmaceutical qualification and validation.

The update to EurdraLex Volume 4, Annex 15: Qualification and Validation goes into effect on 1 October 2015. The new version accounts for significant changes in the regulatory environment and will align with guidelines from the International Conference on Harmonisation (ICH).

Background

Annex 15 contains the requirements for qualification and validation of processes, equipment and locations used to manufacture pharmaceutical products. These requirements are part of the good manufacturing practice requirements established in EudraLex Volume 4 and require manufacturers to ensure that “critical aspects” of their operation are validated throughout the product lifecycle. This includes any changes that could impact a product’s quality.

Major Changes

The new version of Annex 15 places greater emphasis on risk management than the previous document, and adds new requirements to reflect changes in the manufacturing and regulatory environments.

One of the significant changes to Annex 15 is the addition of principles developed in ICH guidelines Q8, Q9, Q10 and Q11:

• Q8: Pharmaceutical Development
• Q9: Quality Risk Management
• Q10: Pharmaceutical Quality System
• Q11: Development and Manufacture of Drug Substances

In the past, companies were able to validate their cleaning methods by conducting three consecutive successful cleaning procedures. The updated guidelines now require companies to conduct a risk assessment to determine the appropriate number of times a cleaning procedure must be performed.

The section on “Process Validation” is updated to include provisions for ongoing process verification during a product’s lifecycle. Companies should demonstrate that “a state of control is maintained throughout the product lifecycle,” and periodically assess the “extent and frequency of ongoing process validation.”

Addition Sections

The new version of Annex 15 also adds four sections which were not including in the 2001 version of the document. These sections are:

• Verification of Transportation:
• Manufacturers are instructed to transport products according to the product’s marketing authorization, label or “as justified by the manufacturer.”
• Manufacturers should define routes and take into account “variable factors” such as weather.
• Manufacturers should conduct a risk assessment for such variable factors and their impact on “controlled or monitored” conditions.
• For products sensitive to environmental factors, companies should monitor and record conditions inside the vehicle.
• Validation of Packaging:
• Companies should qualify all primary and secondary packaging equipment to ensure packaging functions as intended.
• This qualification should be done at the “minimum and maximum operating ranges” of the equipment.
• Qualification of Utilities:
• Manufacturers should confirm the quality of utilities used during manufacturing, e.g. water, air, gas.
• Seasonal variations should be accounted for if they have the potential to impact the utility.
• Companies should conduct a risk assessment on utilities’ direct or indirect contact with the product.
• Validation of Test Methods:
• Test methods should be validated per EurdraLex Volume 4, Chapter 6.
• Methods for microbial testing should be validated to ensure the product “does not influence the recovery of microorganisms.
• Test methods should be validated to ensure that cleaning products do not affect the recovery of microorganisms.

EudraLex, Volume 4, Annex 15 (New Version), (Current Version)