In June 2010, with Annex 3 to TRS 957, the WHO published a new guide on the handling of hazardous or highly-active substances. This document is meant to be considered as a complement to existing GMP guides and national regulations and covers the research and manufacturing areas both of active pharmaceutical ingredients and of finished products. A detailed list of what is to be understood as a hazardous substance is not included in this document; the introduction merely mentions certain hormones, steroids or cytotoxins as examples. In any case, this wording leaves a lot of scope to the manufacturer.
The text recommends to keep these substances in closed systems. Manufacturing should generally be done in separate dedicated facilities, where a separate part of a building is enough to fulfil this definition. So, this wording does allow for exceptions. Examples for separation given in the guide are separate entrances and air-conditioning systems. The questions of whether the manufacturing steps fall within the scope of this guidance and to what extent the facilities should be separated from each other shall be answered on the basis of a risk assessment. This assessment shall take account of the different manufacturing phases, which can pose different levels of risk to the environment or to the personnel. Toxicological data, like OEL values (occupational exposure levels), should be considered.
Another complement that is worth mentioning is chapter 4.41 of Annex 2 to the same technical report (TRS 957), the WHO GMP guide on the manufacture of APIs. Here, dedicated manufacturing areas are only required if there are no established and validated procedures for inactivation and/or cleaning.
The use of personal protection equipment is permitted in case facility and equipment design do not provide sufficient operator protection. There is no further assessment between containment systems and protection equipment. However, personal protection equipment shall be available in case of a non-routine incident. Where central breathing air supply systems are used, the air should go through an H13 filter placed as close as possible to the operator, and a back-up system should be available in case of a main system failure, e. g. in the form of gas bottles with a supply lasting at least 5 minutes.
The chapter dealing with HVAC systems naturally requires a negative pressure cascade from the environment to the manufacturing area. The system shall trigger an alarm in case of pressure fluctuation, ensure the negative pressure also during start-up and shut-down and display the pressure in each room.
The decision to use return air or recirculated air should be made on the basis of a risk assessment.The use of an energy recovery system is admissible under the condition that the danger of air leakage or of contact between supply and exhaust air can be excluded.
The original text of Annex 3 to the Technical Report can be found here.
Dr Robert Eicher
On behalf of the European Compliance Academy (ECA)