GMP, ISO and USP Cleanrooms Guidelines

The EU GMP Annex 1 outlines the European Union’s standards for good manufacturing practices (GMP) concerning sterile medicinal products for both human and veterinary use. It details specific requirements for producing sterile medicinal products, including guidelines for cleanroom and clean zone design, personnel qualifications, and environmental monitoring. The main goal is to enhance the quality and effectiveness of products while safeguarding patient safety by reducing the risks of microbial, particulate, and endotoxin/pyrogen contamination through stringent manufacturing and environmental controls.
 

The EU GMP Annex 1 is a set of guidelines established by the European Union to ensure good manufacturing practices (GMP) for sterile medicinal products intended for both human and veterinary use. These guidelines outline specific requirements for the production of sterile medicinal products, including:

• Cleanroom design: principles for designing areas where sterile products are manufactured.
• Personnel qualifications: standards for the experience and training of personnel involved in the manufacturing process.
• Environmental monitoring: procedures for monitoring the manufacturing environment to prevent contamination.

The primary goal of Annex 1 is to enhance the quality and potency of products while safeguarding patient safety by minimizing risks of microbial, particulate, and endotoxin/pyrogen contamination through stringent manufacturing and environmental controls.

After years of development, the final draft of the EU GMP Annex 1 was published in August 2022 and came into effect on 25 August 2023. The revised EU GMP Annex 1 introduces several significant changes aimed at enhancing the quality and safety of sterile medicinal products. GRIFOLS can help you to ensure its correct implementation.

United States Pharmacopeia (USP) Chapter <795> provides standards for compounding quality nonsterile preparations to help ensure patient benefit and reduce risks such as contamination, infection, or incorrect dosing. As of 2020, the 2008 revision is currently official. Non-sterile compounding must occur in a separate space from sterile compounding.

USP <797> provides minimum practice and quality standards for CSPs of drugs and nutrients, based on the current scientific information and best sterile compounding compliance practices at the time of revision. USP pertains to the compounding of both hazardous and nonhazardous drugs. As of 2020, the 2014 revision is currently official.

For full allowable beyond use dating (BUD,) the currently enforceable chapter requires an ISO Class 5 PEC (“hood”) in an ISO Class 7 buffer area (“cleanrooms”) accessible via an ISO Class 7 or 8 ante-area. The ante-area minimum classification is defined by the differential pressure between the buffer area and the ante area: ISO Class 8 for a positive pressure buffer area used only for non-hazardous compounding, or ISO Class 7 for a negative pressure buffer area which allows hazardous compounding.

ISO 14644-1 also defines temperature and humidity ranges (16°C - 19°C, 55% - 65%.) USP <797>, 2014 does not apply these ranges and rather states that facilities typically include “a temperature of 20°C or cooler”1 without reference to compounding area humidity.

Though not currently enforceable, the most recent revision of USP <797> recommends “the cleanroom suite should be maintained at a temperature of 20°C or cooler and a relative humidity below 60%.“2 USP commentary responses have stated that “the chapter recommends a temperature of 20°C or lower and a relative humidity below 60%”3 but do not require it. While maintaining the cleanroom within those parameters is safe, if it is not reasonable for that facility, “facilities must determine the appropriate temperature and relative humidity for the compounding area, which can be verified through microbial air and surface sampling.”3

1 USP 797 2014
2 USP 797 2019
3 USP 797 Commentary 2019

USP <800> describes hazardous drug handling related to the receipt, storage, compounding, dispensing, administration, and disposal of both sterile and nonsterile 15 products and preparations. As of 2020, USP <800> is official but informational only, some states are enforcing parts of the chapter.

Hazardous cleanroom suites must include a negative pressure ISO Class 7 buffer room and a positive pressure ISO Class 7 ante-room. Hazardous compounding, preparation, and storage areas must be externally vented.

USP Chapters <1> - <999> are enforceable in the United States by the Food and Drug Administration (FDA) per section 503A(b)(1)(B) of the FD&C Act.

ISO 14544-1 is not enforceable by section 503A. USP Chapter <797>, 2014 adapts ISO 14644-1:1999 to define compounding cleanrooms air quality. The chapter also defines air quality by Federal Standard 209e. 209e was officially cancelled in 2001 but the FE “class” terminology is sometimes still used. Compounding cleanrooms air quality is defined using ISO Class terminology by limits in particle of 0.5 μm and larger per cubic meter and does not require or allow certification based on other particle sizes defined by ISO 14544-1.