Implementation of updates to ISO 14644 Parts 1 & 2 (2015)

Information for manufacturers of sterile therapeutic goods

4 January 2017

The ISO 14644 series of standards outline the requirements for the design, operation, classification and monitoring of clean rooms and clean air devices. The ISO 14644 series of standards are explicitly referenced in the manufacturing principles applicable to the manufacture of sterile medicinal products and aseptically prepared medical devices, which means those manufacturers are required to demonstrate compliance to the ISO 14644 standard.

Parts 1 and 2 of ISO 14644 were updated and reissued in December 2015 and these updates include several changes. It is important that affected manufacturers review the changes to the ISO 14644 series of standards to ensure continued compliance.

The following text summarises the interpretations an inspector adopts during the inspection of the manufacture of sterile therapeutic goods.

Key changes and interpretation

The key changes to ISO 14644 Part 1 are:
Change TGA expectations
Removal of the requirement to perform classification of clean rooms that are ≤ISO 5 or lower using the 5.0µm particle limit.

Manufacturers should ensure that:

  • For classification of ≤ISO 5 areas, the airborne particles ≥0.5µm should be measured.
  • For classification of clean rooms >ISO 5, the airborne particles should be measured for particles ≥0.5µm and ≥5.0µm.
  • Classification of clean areas should be performed to represent both "at-rest" and "in-operation" occupancy states.

During routine monitoring, measurement should be performed for particles both ≥0.5µm and ≥5.0µm.

Changes to the method for the determination of the number and location of samples. Manufacturers should follow the updated requirements.
The tests that manufacturers are required to perform prior to classification are now referenced in "Annex A" of ISO14644 Part 3.

The following tests should be performed prior to area classification:

  • Installed filter leakage*
  • Airflow measurement*
  • Air pressure difference measurement*
  • Airflow direction and visualisation
  • Temperature
  • Humidity
  • Recovery
  • Containment leak* 1

Items marked with an * should be verified before each subsequent re-classification event.

Tests should be performed in a logical and defined sequence as agreed between the licensed manufacturer and certifying authority.

1Where relevant to the design/operation of the installation.

Specified requirements for the preparation and calibration of instrumentation, namely ISO 21501-4:2007.

Zero count checks should be performed for each counter prior to use as described within the standard.

Particle monitoring equipment should be calibrated in accordance with ISO21501-4:2007.

Reduced statistical treatment of measurement data. Manufacturers should follow the updated requirements.
The key changes to ISO 14644 Part 2 are:
Change TGA expectations
Changes to prescribed reclassification intervals

Manufacturers should ensure that:

  • For ≤ISO 5 areas, the maximum time interval for requalification is 6 months. The 6 month time interval may be extended to 12 months when the area is equipped with a continuous monitoring device, and providing the results of continuous monitoring remain within specified limits.

For >ISO 5 areas the maximum time interval for requalification is 12 months.

Additional guidance regarding conduct of risk assessments for monitoring Manufacturers should ensure that the updated requirements are addressed within their quality management system, (QMS)
Reduced guidance regarding the circumstances following which re-classification may be required.

Manufacturers should ensure that requalification of the installation is undertaken after any of the following.

  • Completion of remedial action implemented to rectify an out-of-compliance condition.
  • A significant change from the current performance specification, such as a change in operational use. The significance of a change should be determined through change management processes.
  • Any significant interruption of air movement which affects the operation of the installation. The significance of a change should be determined through change management processes.

Special maintenance which significantly affects the operation of the installation, (e.g. change of final filters). The significance of a change should be determined through change management processes.

12 month implementation period

The TGA has proposed a formal implementation period of 12 months from the date of this notice following which; full compliance (as indicated above) shall be expected.

In the interim period:

  • Existing qualifications performed under the ISO14644-1 (1999) and ISO 14644-2 (2000) standards remain valid and will be acceptable to the TGA.
  • Manufacturers are encouraged to review the updated standards and perform a gap analysis of how the changes to qualification and monitoring may affect them.
  • Manufacturers may elect to begin certification in accordance with the 2015 standards should they wish to.

Feedback

The TGA welcomes feedback that helps processes be improved. Any feedback regarding these changes or their implementation may be given to the TGA via the email gmp@tga.gov.au. Any feedback will be used to improve inspection procedures and training.