According to the FDA (“Data Integrity and Compliance with CGMP Guidance for Industry”), data integrity refers to the completeness, consistency, and accuracy of data. Data should be attributable, legible, contemporaneously recorded, either original or true copy, and accurate (ALCOA+). These requirements are based on existing regulations such as the FDA 21 CFR Part 11, 210 et seqq., and EU EudraLex Chapter 4 and Annex 11.
Increase in data integrity violations
In the last years, the FDA has seen an increase in data integrity violations. The number of Data Integrity warning letters has increased from 4 in 2011 to 55 in 2017. Why? Andrew Hopkins, MHRA, explained to me that they “are now watching closely what the industry is supposed to do”. Interestingly, the requirements have not changed. For example, record retention and review do not differ by data format: As Paula Katz, FDA, stated, “paper-based and electronic data record keeping systems are subject to the same requirements”.
Reasons for data integrity violations
US regulators, for example, are enforcing the availability of drugs on the market due to current drug shortages and lack of quality. Lawrence Yu, FDA, says that “the fundamental problem we identify is the inability of the market to observe and reward quality. This lack of reward for quality can reinforce price competition and encourage manufacturers to keep costs down by minimizing quality investments.” He requests the industry to invest and use state-of-the-art technologies like manufacturing IT systems to improve the quality and to operate a “Process Performance & Product Quality Monitoring System”, asstated in ICH Q10.
How MES enforce data integrity: examples
Karen Takahashi, FDA, has analyzed the data integrity warning letters statistically. Manufacturing Execution Systems (MES) like Werum’s PAS-X can prevent these issues with their incorporated ALCOA+-based functionalities.
Three examples: The 7th most frequent quotation was: “Your firm failed to document production and process control functions at the time of performance (21 CFR 211.100(b)).” Having an operator execution dialog, a timely data entry and capture is enforced. If the PAS-X MSI Plug & Produce interface is in place, data will even be captured automatically.
4th most frequent quotation was: “Your firm failed to maintain complete information relating to the production and control of each batch (21 CFR 211.188).” In MES, this is typically controlled by an integrated order data management with ERP, LIMS, CAPA and other interfaced IT systems involved in the batch record execution. Review by Exception features, for example, enforces the audit trail review regarding the CPPs and CQAs.
The 2nd most frequent quotation was: “Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in the master production and control records, or other records (21 CFR 211.68 (b)).” MES enforce the formal user administration and workflows related to the access and the record change management. They also support features related to the use of RFID card readers or biometric equipment, thus enforcing data integrity by streamlining the identification and user access procedures.
Basic principles to avoid data integrity issues by implementing MES
The number-one best practice for implementing an MES is to follow a data-integrity-by-design approach. For the implementation, it is essential to have a clear description and understanding of the business and pharmaceutical processes. The number-two enabler is a risk-management-based implementation approach as requested in ICH Q10. Predefined content libraries are very important elements to streamline, harmonize and standardize manufacturing processes as they are based on best practices agglomerated in many MES projects. This ensures that the same tableting process is running the same procedures and electronic signature rules in all production areas and the central MES libraries enable the enforcement of data integrity rules across the whole pharmaceutical organization.
Role of MES in ICH control strategy
The ICH control strategy ensures that the Quality Target Product Profile (QTPP) is met by the control of the CPPs and CQAs. The initial control strategy needs to be enhanced to a manufacturing control strategy by the production, facilities and GMP control strategy elements while it is applied to commercial manufacturing in the tech-transfer and scale-up phases. This strategy is calleda Holistic Control Strategy. All manufacturing execution elements are controlled and documented in the MES.
With this key role, using an MES will boost your data integrity compliance and your process understanding, since your processes will be well structured, executed, maintained and documented across the pharmaceutical product life cycle.