Understanding “Local Protection /Grade A Air Supply (LP/GAAS)” in Aseptic Manufacturing

Background

The terms, local protection and Grade A air supply, have appeared in several regulatory documents. In 2004, the FDA guidance [4] introduced the terms “Local Class 100 (ISO 5) protection” and “local protection”. Similarly, in 2008, the EU GMP Annex 1 [1] introduced the term “Grade A air supply”.

The following definition is provided by both EU GMP Annex 1[2] and PICs Annex 1 2022 [3];

Grade A air supply; Air which is passed through a filter qualified as capable of producing grade A total particle quality air, but where there is no requirement to perform continuous total particle monitoring or meet grade A viable monitoring limits. Specifically used for the protection of fully stoppered vials where the cap has not yet been crimped.

Local Protection/Grade A Air Supply (LP/GAAS); These systems have become increasingly common in aseptic manufacturing facilities over the past few decades.

While Grade A unidirectional airflow (UAF) zones have traditionally been used for critical operations, LP/GAAS provides an alternative way to create a localized Grade A environment where for certain unit operations without the costs/constraints of a full Grade A room. LP/GAAS systems provide a localized ISO 5/Grade A environment for critical operations in the manufacturing of sterile products. This allowed manufacturers to better target environmental controls. [5]

Airflow patterns generated by HVAC should be compared to the equipment layout to ensure that turbulence or dead spots are not created in critical zones and to locate areas where product contact surfaces may be contaminated [5]

Some common applications of LP/GAAS;

• Protection of open product containers/components during processing steps like capping, material additions, and component transfers.
• Protecting sterilized items during cooling after autoclave/oven unloading.
• Providing clean air for parts preparation/wrapping before sterilization.
• Manipulations, such as open aseptic assembly of pre-sterilized equipment, should be performed under.  
• ISO 5/Grade A environment conditions or LP/GAAS, as indicated by risk assessment.

Unidirectional Airflow Grade A vs LP/GAAS;

• Grade A zones use unidirectional HEPA-filtered air in a room/enclosure
• LP/GAAS uses HEPA filters to create a localized Grade A zone just where required.
• Grade A requires stringent gowning and is intended for extended operations.
• LP/GAAS allows less rigorous gowning for localized, shorter duration work.

Examples of LP/GAAS Applications;

Some examples of LP/GAAS applications are shown in the table below;[5]

* Although many regulatory agencies whose requirements are based on EU & PIC/s Annex 1 2022 [2,3] allow a Grade D background environment, the US FDA [4] requires a minimum background environment which can achieve ISO 8 conditions “in operation”. Therefore, for a global facility, an ISO 8/Grade C may be the most appropriate. A Grade D environment which is classified as ISO 8 “in operation” as well as “at rest” is also possible. [5]

** An LP/GAAS system that has been properly designed should be capable of significantly reducing the amount of particles (by 90%, or a "1-log reduction") below the "in operation" background limit. The "in operation" background limit refers to the average level of particles present while the system is functioning. [5]

*** Although many regulatory agencies whose requirements are based on EU & PIC/s Annex 1 [2,3] allow a Grade D background environment for isolators, the US FDA guidance [4] requires a minimum background environment which can achieve ISO 8 conditions “in operation”. For a global facility, therefore, the ISPE designated background ISO 8/Grade C is considered most appropriate. A Grade D environment which is classified as ISO 8 “in operation” as well as “at rest” is also possible. [5]

Environmental Monitoring (EM);

Designing HVAC systems for LP/GAAS environments is relatively simple and easy to understand., establishing appropriate environmental monitoring limits for Low Particulate / Grade A Air Supply (LP/GAAS) environments is a critical task, but many people do not pay adequate attention to it or disregard it entirely.

The following principles should be considered when establishing LP/GAAS EM limits:

• Monitoring/testing of LP/GAAS zones should include measurement of total and viable particulates proximate to the work zone for the process.

• “At rest” monitoring/testing is primarily useful as a pre-check of overall system performance and to establish limits for recovery during qualification testing.

• LP/GAAS air supply should generally meet ISO 5 requirements for 0.5 µm and 5.0 µm particles, when measured 100 – 150 mm below the filter face or grille, under all conditions.

• While particulate levels in the work zone are a function of the LP/GAAS configuration, airflow rates, sanitization, and rate(s) of particulate generation (which is heavily influenced by gowning), a well-designed LP/GAAS should be capable of achieving a 1-log reduction in total particulates, below the “in operation” background limit.

• Care should be taken to establish appropriate viable limits where LP/GAAS is used in classified areas below ISO 7/Grade B. Viable particulate limits should be consistent with the less rigorous gowning and sanitization requirements for these areas. A careful review of the specific manipulations required to expose and collect EM plates should also be performed.

• For initial qualification purposes, viable particulate limits 1/2 to 1/3 of the background environment limits are recommended. At the completion of qualification testing, historical EM data should be reviewed and limits adjusted, as appropriate, using statistical analysis.

Recommended initial qualification EM limits are shown in the table below;

Conclusion;

By understanding LP/GAAS applications, differences from Grade A zones and proper monitoring, we can leverage this valuable tool for enhanced environmental control in aseptic manufacturing.

Reference

1)     Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use; Annex 1 Manufacture of Sterile Medicinal Product Brussels, 2008 (rev.)

2)     Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use; Annex 1 Manufacture of Sterile Medicinal Product Brussels, 2022

3)     PIC/S Revised Annex 1 Manufacture of Sterile Medical Products to guide to good Manufacturing Practice for Medical Products; PS/INF 26/2022 (Rev. 1), 2022

4)     US-FDA, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, 2004

5)     ISPE Baseline® Guide: Volume 3, Sterile Product Manufacturing Facilities, Third Edition, 2018