Follow up activities after EM
After EM activities are completed during manufacturing activities, plates are incubated in appropriate temperatures and appropriate incubation periods. After incubation the results are read and recorded onto EM data sheets. Microorganisms recovered from the EM plates that reach the alert or action levels are identified. Vitek® Microbial Identification System is an example of ID system used in QC labs. Non-viable particulate air results should be printed out on the day of manufacturing and attached onto EM datasheets.
EM excursions higher than or equal to Alert levels are out of specifications (OOS). OOS results should be documented in deviation reports. Deviation reports usually include the site of the excursion, its result(s), microbial ID results, manufacturing department’s response (cleaning activities of the room for example), and the next consecutive sample’s result.
EM excursions higher than or equal to action levels are first documented in deviation reports and are usually escalated to investigations. Investigation reports include the same information mentioned in previous paragraph plus any CAPAs issued and implemented, previous results trends from the same site, and if the deviation had any adverse impact on the product. Three consecutive alert level excursions of a site warrant an escalated investigation.
Three action level excursions will have a major investigation. Recovery of objectionable microorganisms, regardless of the count, will result in action level major investigation. During the time of a major investigation, production may be halted until quality assurance, QC, and manufacturing group can work out CAPAs to the problem. The alert or action level status of a site is resolved if the next consecutive sample’s result are below the alert level. Deviation and investigation reports are usually due 30 business days after they were initiated.
TrackWise Event Tracking System® (SPARTA Systems; Holmdel, NJ) and SAP Quality Notification System® (SAP; Walldorf, Germany) are two commercially available software to document deviation reports, escalating the reports to investigations, and issuing Corrective Action/Preventative Actions. These systems block any batches of products with open deviation or investigations reports to be released to packaging or distribution centers.
Corrective Action/ Preventative Action (CAPA)
CAPAs are assigned to various department heads to be implemented. CAPAs have deadlines in which their owners have to complete the action items. Examples of CAPAs include sanitizing affected sites with secondary sporocidal disinfectant after recovery of objectionable microorganisms by manufacturing department, installing additional High Efficiency Particulate Air (HEPA) filters in a classified room with consistently high level non-viable particulate air counts by maintenance department, and retraining on proper aseptic and gowning techniques to manufacturing operators who consistently fail gowning samples by QC personnel.
Wednesday, May 4, 2011
Tuesday, May 3, 2011
Environmental Monitoring Alert/Action levels.
Personnel Monitoring
In my last blog, I talked about viable surface, viable air, and non-viable particulate air environmental monitoring (EM) and the equipment used in these EM activities. However I didn’t talk about personnel monitoring. Manufacturing operators, who work in aseptic filling areas have to be sampled for microorganisms because most microbial contamination of product come from humans. Most of the time, operators’ gloved fingers and clean room garment on the chest area are touched with TSA plates and the plates are incubated and then checked for microbial growth. Personnel EM program is designed to monitor cleanliness of the operators who perform manufacturing activities in aseptic processing areas, such as the drug fill room. Personnel monitoring is usually done at the end of operators’ shifts inside the clean rooms to determine if operators’ gloves and clean room garment were contaminated during manufacturing operations.
Alert and Action levels
Out of specification EM results are classified either as alert level or action levels. According to University of Florida’s Center of Excellence for Regenerative Health and Biotechnology, alert levels are “quality levels that, when exceeded, signal a possible deviation from normal operating conditions and may not require action, but may need to be monitored more closely” and action levels are “quality levels that, when exceeded, signal an apparent deviation from normal operating conditions and require immediate action”.
Every type of EM program; viable air, viable surface, non-viable particulate air, and personnel gown monitoring all have alert and action levels. Alert and action levels are set depending on the clean rooms in which samples are collected. Until recently, Pharmaceutical manufacturing clean rooms are generally classified as per the US Fed Std 209E as class 100, class 1000, class 10,000, and class 100,000 depending on the level of cleanliness of the rooms and type of manufacturing activities take place. For example, in class 100 room, the action level limit is 99 particles greater than or equal to 0.5 um / ft3. Although the US Fed Std 209E was officially replaced by ISO 14644-1, its terminology is still widely used in most of US pharmaceutical plants. ISO 14644-1 classifies clean rooms as ISO class 5, 6, 7, and 8. If a plant manufactures drugs to export to the European Union, then its clean rooms must be classified according to EU Annex I regulations. EU Annex I classifies clean rooms as classes A, B, C, and D. Since Class 1000/ISO 6/EU Class B rooms are not widely used in the pharmaceutical manufacturing, I will not mention the Alert and Action levels for this class. The four tables below present typical alert and action levels for non-viable particulate air, viable air, and viable surface EM. Every firm has alert/action levels not so different from these values below.
Action Level Alert Level
US Fed Std 209E EU Grade ISO 14644-1 ≥ 0.5 µm particles/ft3 ≥ 0.5 µm particles/m3 ≥ 0.5 µm particles/ft3 ≥ 0.5 µm particles/m3
Class 100 A Class 5 100 3,500 80 2800
Class 10,000 C Class 7 10,000 350,000 7000 245,000
Class 100,000 D Class 8 100,000 3,500,000 40,000 1,400,000
Table 1: Non viable particulate air Alert/Action levels
US Fed Std 209E EU Grade ISO 14644-1 Viable air Alert level (CFU/test)
Viable air Action level
(CFU/test)
Class 100 A Class 5 1 5
Class 10,000 C Class 7 13 15
Class 100,000 D Class 8 113 125
Table 2: Viable Air Alert/Action Levels
CFU/test means colony forming units recovered during a 50 minutes sampling period.
US Fed Std 209E EU Grade ISO 14644-1 Viable Surface Alert Viable Surface Action
Class 100 A Class 5 1 2
Class 10,000 C Class 7 2 // 5* 4 // 8*
Class 100,000 D Class 8 2 // 10* 4 // 13*
Table 3: Viable Surface Alert/Action Levels; walls & work surfaces//floors*
In classes 10,000 and 100,000, alert/action levels are different for walls and work surfaces and floors. Alert/action levels on the walls and work surfaces are lower than that of the floors. Recovery of objectionable microorganisms will prompt an action level deviation. An objectionable microorganism is a bacteria or mold that adversely impacts product quality, stability, and patient safety. Some examples of objectionable microorganisms are gram-negative bacterium such as Escherichia coli, gram-positive bacterium such as Staphylococcus aureus, and mold such as Aspergillus niger.
Action Level Alert Level
US Fed Std 209E EU Grade ISO 14644-1 Personnel Monitoring Gloved Finger tips Personnel Monitoring Cleanroom garment Personnel Monitoring Gloved Finger tips Personnel Monitoring Cleanroom garment
Class 100 A Class 5 1 3 N/A 1
Class 10,000 C Class 7 N/A N/A N/A N/A
Class 100,000 D Class 8 N/A N/A N/A N/A
Table 4: Personnel Gown Monitoring Alert/Action levels
Operators, quality control, and maintenance personnel who enter Class 100 aseptic processing or filling rooms have to be sampled for microorganisms at the end of their shifts before they exit the aseptic areas. Finger-tips and clean room garment on wrist and chest areas are usually sampled on a routine production day.
In my last blog, I talked about viable surface, viable air, and non-viable particulate air environmental monitoring (EM) and the equipment used in these EM activities. However I didn’t talk about personnel monitoring. Manufacturing operators, who work in aseptic filling areas have to be sampled for microorganisms because most microbial contamination of product come from humans. Most of the time, operators’ gloved fingers and clean room garment on the chest area are touched with TSA plates and the plates are incubated and then checked for microbial growth. Personnel EM program is designed to monitor cleanliness of the operators who perform manufacturing activities in aseptic processing areas, such as the drug fill room. Personnel monitoring is usually done at the end of operators’ shifts inside the clean rooms to determine if operators’ gloves and clean room garment were contaminated during manufacturing operations.
Alert and Action levels
Out of specification EM results are classified either as alert level or action levels. According to University of Florida’s Center of Excellence for Regenerative Health and Biotechnology, alert levels are “quality levels that, when exceeded, signal a possible deviation from normal operating conditions and may not require action, but may need to be monitored more closely” and action levels are “quality levels that, when exceeded, signal an apparent deviation from normal operating conditions and require immediate action”.
Every type of EM program; viable air, viable surface, non-viable particulate air, and personnel gown monitoring all have alert and action levels. Alert and action levels are set depending on the clean rooms in which samples are collected. Until recently, Pharmaceutical manufacturing clean rooms are generally classified as per the US Fed Std 209E as class 100, class 1000, class 10,000, and class 100,000 depending on the level of cleanliness of the rooms and type of manufacturing activities take place. For example, in class 100 room, the action level limit is 99 particles greater than or equal to 0.5 um / ft3. Although the US Fed Std 209E was officially replaced by ISO 14644-1, its terminology is still widely used in most of US pharmaceutical plants. ISO 14644-1 classifies clean rooms as ISO class 5, 6, 7, and 8. If a plant manufactures drugs to export to the European Union, then its clean rooms must be classified according to EU Annex I regulations. EU Annex I classifies clean rooms as classes A, B, C, and D. Since Class 1000/ISO 6/EU Class B rooms are not widely used in the pharmaceutical manufacturing, I will not mention the Alert and Action levels for this class. The four tables below present typical alert and action levels for non-viable particulate air, viable air, and viable surface EM. Every firm has alert/action levels not so different from these values below.
Action Level Alert Level
US Fed Std 209E EU Grade ISO 14644-1 ≥ 0.5 µm particles/ft3 ≥ 0.5 µm particles/m3 ≥ 0.5 µm particles/ft3 ≥ 0.5 µm particles/m3
Class 100 A Class 5 100 3,500 80 2800
Class 10,000 C Class 7 10,000 350,000 7000 245,000
Class 100,000 D Class 8 100,000 3,500,000 40,000 1,400,000
Table 1: Non viable particulate air Alert/Action levels
US Fed Std 209E EU Grade ISO 14644-1 Viable air Alert level (CFU/test)
Viable air Action level
(CFU/test)
Class 100 A Class 5 1 5
Class 10,000 C Class 7 13 15
Class 100,000 D Class 8 113 125
Table 2: Viable Air Alert/Action Levels
CFU/test means colony forming units recovered during a 50 minutes sampling period.
US Fed Std 209E EU Grade ISO 14644-1 Viable Surface Alert Viable Surface Action
Class 100 A Class 5 1 2
Class 10,000 C Class 7 2 // 5* 4 // 8*
Class 100,000 D Class 8 2 // 10* 4 // 13*
Table 3: Viable Surface Alert/Action Levels; walls & work surfaces//floors*
In classes 10,000 and 100,000, alert/action levels are different for walls and work surfaces and floors. Alert/action levels on the walls and work surfaces are lower than that of the floors. Recovery of objectionable microorganisms will prompt an action level deviation. An objectionable microorganism is a bacteria or mold that adversely impacts product quality, stability, and patient safety. Some examples of objectionable microorganisms are gram-negative bacterium such as Escherichia coli, gram-positive bacterium such as Staphylococcus aureus, and mold such as Aspergillus niger.
Action Level Alert Level
US Fed Std 209E EU Grade ISO 14644-1 Personnel Monitoring Gloved Finger tips Personnel Monitoring Cleanroom garment Personnel Monitoring Gloved Finger tips Personnel Monitoring Cleanroom garment
Class 100 A Class 5 1 3 N/A 1
Class 10,000 C Class 7 N/A N/A N/A N/A
Class 100,000 D Class 8 N/A N/A N/A N/A
Table 4: Personnel Gown Monitoring Alert/Action levels
Operators, quality control, and maintenance personnel who enter Class 100 aseptic processing or filling rooms have to be sampled for microorganisms at the end of their shifts before they exit the aseptic areas. Finger-tips and clean room garment on wrist and chest areas are usually sampled on a routine production day.
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