Clean Rooms for API, requirements
Is there a regulatory requirement for Class 1,00,000 clean room for APIs (bulk drugs). Any specific guidance suggest Class 1,00,000/Class D / ISO Class 8 clean rooms
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<p class=”MsoNormal”><span style=”font-size: 9.0pt; line-height: 107%;”>A clean room with only Temperature and Humidity control (without air classified as Grade D or Class 1,00,000 or ISO Class 8) provide operator comfort (to ensure operator remain fully gowned during operations) and product control. A Class 1,00,000 air classification significantly reduces risk of contamination due to dust / cross contamination due to recirculation of air. One should note that even an ISO Class 8 air is allowed to have upto 3,52,000 particles (0.5u) per cubic meter. Air not meeting the ISO Class 8 standard can have much higher number of particles per cubic meter. This can cause concern with regulatory auditors regarding potential contamination, especially where environmental air is dusty; and in multiproduct -multiline facilities. Also air with higher amount of dust particles in clean room can affect quality of the API especially when they are for use in injectable products (e.g filtration issues). </span></p>
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No regulatory guidance specify the Clean room classifications for bulk drugs or APIs. ICH Q7A specify facilities should be designed to minimize potential contamination (Section 4.10) and also specify adequate ventilation, air filtration, and exhaust systems to be provided and designed to minimise risk of contamination and cross contamination; specify equipment to control air pressure, dust, humidity, temperature with particular attention to API stage and require appropriate measures to control cross contamination if air is recirculated (Section 4.20). Other guidance’s also specify similar requirements (WHO Annex 2; WHO good manufacturing practices for active pharmaceutical ingredients; EudraLex – Part II – Basic Requirements for Active Substances used as Starting Materials, PIC/S GMP and so on). India’s Schedule M GMP requirements specify at least 5 micron filtered air with adequate air changes, humidity, temperature controls for non sterile oral products and bulk drugs (Schedule M Part 1B, 1C, 1D). However the controls specified – dust, contamination, cross contamination, air pressure, recirculation of air – would imply that the ventillation air need to be filtered, rooms to have flush doors and sealed windows and maintained at a higher pressure to external environment to avoid dust, operators will need to be adequately gowned to avoid contamination due to operator actions (hair, sweat, dust and so on), humidity and temperature need to be controlled for operator comfort and product control. When room is airconditioned to have control over temperature and humidity, air will be recirculated for energy savings. Recirculation of air causes concern of cross contamination and to have adequate control adequate filtration of air is necessary. Thus a Class 1,00,000 (ISO Class 8 or Grade D clean room) facility becomes a norm to meet all the regulatory expectations. This also has become more or less the defacto industry standard.
References:
Guidelines ICHQ7A, WHO Annexure 2, EudraLex – Part II (Refer Guidelines page / GMP Good Manufacturing Practices – Medicinal Products and Active Pharmaceutical Ingredients (APIs)
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<p class=”MsoNormal”><span style=”font-size: 9.0pt; line-height: 107%;”>A clean room with only Temperature and Humidity control (without air classified as Grade D or Class 1,00,000 or ISO Class 8) provide operator comfort (to ensure operator remain fully gowned during operations) and product control. A Class 1,00,000 air classification significantly reduces risk of contamination due to dust / cross contamination due to recirculation of air. One should note that even an ISO Class 8 air is allowed to have upto 3,52,000 particles (0.5u) per cubic meter. Air not meeting the ISO Class 8 standard can have much higher number of particles per cubic meter. This can cause concern with regulatory auditors regarding potential contamination, especially where environmental air is dusty; and in multiproduct -multiline facilities. Also air with higher amount of dust particles in clean room can affect quality of the API especially when they are for use in injectable products (e.g filtration issues). </span></p>
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No regulatory guidance specify the Clean room classifications for bulk drugs or APIs. ICH Q7A specify facilities should be designed to minimize potential contamination (Section 4.10) and also specify adequate ventilation, air filtration, and exhaust systems to be provided and designed to minimise risk of contamination and cross contamination; specify equipment to control air pressure, dust, humidity, temperature with particular attention to API stage and require appropriate measures to control cross contamination if air is recirculated (Section 4.20). Other guidance’s also specify similar requirements (WHO Annex 2; WHO good manufacturing practices for active pharmaceutical ingredients; EudraLex – Part II – Basic Requirements for Active Substances used as Starting Materials, PIC/S GMP and so on). India’s Schedule M GMP requirements specify at least 5 micron filtered air with adequate air changes, humidity, temperature controls for non sterile oral products and bulk drugs (Schedule M Part 1B, 1C, 1D). However the controls specified – dust, contamination, cross contamination, air pressure, recirculation of air – would imply that the ventillation air need to be filtered, rooms to have flush doors and sealed windows and maintained at a higher pressure to external environment to avoid dust, operators will need to be adequately gowned to avoid contamination due to operator actions (hair, sweat, dust and so on), humidity and temperature need to be controlled for operator comfort and product control. When room is airconditioned to have control over temperature and humidity, air will be recirculated for energy savings. Recirculation of air causes concern of cross contamination and to have adequate control adequate filtration of air is necessary. Thus a Class 1,00,000 (ISO Class 8 or Grade D clean room) facility becomes a norm to meet all the regulatory expectations. This also has become more or less the defacto industry standard.
References:
Guidelines ICHQ7A, WHO Annexure 2, EudraLex – Part II (Refer Guidelines page / GMP Good Manufacturing Practices – Medicinal Products and Active Pharmaceutical Ingredients (APIs)