The EDM 2020 draft of EU GMP Annex 1 has undergone significant changes to incorporate quality management through the introduction of the contamination control strategy (CCS) concept. Environmental monitoring (EM) is the key process measuring the efficiency of the sum of all measures implemented to minimize the contamination risk in the aseptic manufacturing environment. The draft guidance on data integrity and compliance with cGMP (draft guidance 2016) clarifies the role of data integrity in current good manufacturing practice (cGMP) for drugs, as required in 21 CFR parts 210, 211, and 212.
”For the purposes of this guidance, data integrity refers to the completeness, consistency, and accuracy of data. Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA).”
Requirements for achieving data integrity are listed below:
• § 211.68 (requiring that “backup data are exact and complete,” and “secure from alteration, inadvertent erasures, or loss”)
• § 212.110(b) (requiring that data be “stored to prevent deterioration or loss”)
• §§ 211.100 and 211.160 (requiring that certain activities be “documented at the time of performance” and that laboratory controls be “scientifically sound”)
• § 211.180 (requiring that records be retained as “original records,” “true copies,” or other “accurate reproductions of the original records”)
• §§ 211.188, 211.194, and 212.60(g) (requiring “complete information,” “complete data derived from all tests,” “complete record of all data,” and “complete records of all tests performed”)
Authorities, such as the FDA, expect data to be reliable and accurate. Companies or Pharmaceutical companies must implement meaningful and effective strategies to manage their data integrity risk based on their process understanding and knowledge management of technologies used.
For the microbiological path in environmental monitoring, a rough overview of the required steps is indicated in Figure 1. Depending on the available IT infrastructure, these steps can be performed manually using paper-based documentation, using digital tools or a hybrid.
Figure 1.Process steps for Environmental Monitoring (classical microbiological part)
When using air samplers and culture media, it is important to fulfil the requirements for completeness, consistency, and accuracy of data.
The air samplers must be qualified in order to deliver reliable and efficient sampling results. The MAS-100 NT® air sampler provides an accurate flow rate of 100 SLPM ± 2.5%. This is verified on a regular basis by a calibration process. The calibration tool is directly traceable to standards, such as ISO 17025 or NIST. Furthermore, the MAS-100 NT® air sample is validated together with ICR settle plates according to ISO 14698 (now replaced by EN 17141) in European countries for physical and biological efficiency. A d50 of less than 0.8 μm and a biological efficiency of more than 80% is experimentally proven by an external, independent laboratory.
Reducing human error is key to maintaining data integrity. This is achieved by designing an easy to use, with an intuitive interface air sampler.
The MAS-100 NT® microbial air sampler is able to achieve full compliance following one of the two methods listed below:
1. Treat the instrument as a simple probe.
2. Integrate the instrument in a 21 CFR part 11 compliant, fully computerized, EM management system.
In the EM workflow, the operation and documentation of active air sampling should follow the ALCOA+ principles, which are also described by the PIC/S Guidance on Good Practices for Data Integrity in regulated GMP/GDP Environments (Draft 3 Nov 2018):
- Attributable: “It should be possible to identify the individual or computerized system that performed the recorded task. The need to document who performed the task / function, is in part to demonstrate that the function was performed by trained and qualified personnel. This applies to changes made to records as well: corrections, deletions, changes, etc.”
- Legible: “All records must be legible – the information must be readable for it to be of any use. …”
MAS-100 NT® air samplers manufactured by MBV AG, Switzerland. www.mbv.ch
- Contemporaneous: “The evidence of actions, events or decisions should be recorded as they take place. ….”
- Original: “The original record can be described as the first-capture of information, whether recorded on paper (static) or electronically (usually dynamic, depending on the complexity of the system) ….”
- Accurate: “Ensuring results and records are accurate is achieved through many elements of a robust pharmaceutical quality system. This can be comprised of:
• equipment-related factors such as qualification, calibration, maintenance, and computer validation.
• policies and procedures to control actions and behaviors, including data review procedures to verify adherence to procedural requirements.
• deviation management including root cause analysis, impact assessments and CAPA
• trained and qualified personnel who understand the importance of following established procedures and documenting their actions and decisions.”
- Complete: ”All information that would be critical to recreating an event is important when trying to understand the event. …”
- Consistent: “Good Documentation Practices should be applied throughout any process, without exception, including deviations that may occur during the process. This includes capturing all changes made to data.“
- Enduring: “Records … need to remain intact and accessible as an indelible/durable record throughout the record retention period.”
- Available: “Records must be available for review at any time during the required retention period, accessible in a readable format to all applicable personnel who are responsible for their review whether for routine release decisions, investigations, trending, annual reports, audits or inspections”
Environmental monitoring trends are generated by the CFU counts and not the air sampler data. The air sampler, therefore, may act as a simple probe, comparable to a pump, which impacts a defined and precise volume of air on the agar surface. The most important feature for routine use of the air sampler is high accuracy of the flow rate and the precision of the collected volume of air.
In order to avoid any human errors by the operator and to reduce the documentation workload, the MAS-100 NT® air sampler offers the probability to limit the operator action just to a one button-use, meaning loading the plate into the instrument and pressing start for sampling. The sample volume can be fixed in this state. The required configuration to do so is shown in Figure 2. Using this protected mode will ease the process to fulfill the ALCOA+ rules indicated above while following all other rules for good documentation practice.
Figure 2.Protection of the MAS-100 NT® air sampler from changing settings by the operator (see software manual of MAS-100 NT®).
Frequently, software and hardware interfaces are complicated, require too much user interaction, and in the worst case require more time and verification than manual entry. Additionally, when the equipment manufacturer updates drivers or models, the interface must as well be updated. Novatek International (Montreal, Canada) has market leading interfaces that are standard and use the latest technologies.
The partnership and co-development agreement between Novatek and Merck KGaA Darmstadt, Germany helped create the first bidirectional interface, fully compliant to CFR-21 part 11, with the MAS-100 NT® microbial air sampler.
Currently there is a strong trend towards full automation of EM sample planning, data analysis and trending. Automation will reduce time required to collect, report and trend the data while complying to data integrity requirements and eliminating the need for paper-based double checks.
MAS-100 NT® sampler integration with Novatek Environmental Monitoring Software provides a completely compliant solution by removing the manipulations from the device and controlling it from the computerized systems with full traceability, user access controls, user rights and time stamps.
Novatek Environmental Monitoring software uploads the sampling protocols to the MAS-100 NT® instrument via a secure bidirectional integration. The operator follows the instructions on the device and takes the samples as per defined Standard Operating Procedures. Once the sampling is completed, the operator connects the MAS-100 NT® sampler into Novatek EM Software and the system automatically downloads the data (sampling start and stop time, date, volume of air, etc.). The operator must provide a reason for any sample that is not taken.
Compliance to requirements of 21 CFR Part 11 and Data integrity when using MAS-100 NT® air sampler with Novatek EM Software are listed below:
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