Data Integrity In pharma’s rush to end the pandemic

As per the FDA Warning Letter of 2018, the regulations most frequently cited are:

21 CFR reference Title of CFR Section

211.194

211.188 Laboratory Records, Review of All Data

Batch Production and Control Record

211.192

211.68 Production Record Review, Deviations and Investigations

Automatic, Mechanical and electronic Equipment

211.165(a and b) Testing and Release for Distribution

may include procedural controls, organizational controls and functional controls.” (WHO)

Data integrity enforcement action

Poor data integrity practices in the manufacturing and testing of pharmaceuticals products have resulted in a steady rise in the number of enforcement actions, such as warning letters, import alerts and consent decrees. Criticality of data integrity is substantiated by a global report that states that roughly 50 per cent of all Center for Drug Evaluation and Research (CDER) inspection observations (form 483) issued between 2014 and 2018 cite data integrity violations. These violations are even more prevalent in warning letters, with 79 per cent of global drug warning letters during this period citing data integrity issues.

Further, the underlying similarity in the recent warning letters issued by the FDA is to engage a consultant to audit a company’s operations and assist in meeting FDA requirements for the data integrity remediation activity.

Examples from warning letters include:

“Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture… We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following…A comprehensive investigation into the extent of the inaccuracies in data records and reporting.”

“We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. We strongly recommend that you retain a qualified consultant to assist in your remediation…An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses…A comprehensive retrospective evaluation of the nature of the manufacturing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses. ”

Conclusion

With the increase in the issuance of warning letters and forms 483 over the years, pharmaceutical companies have become increasingly cognisant of the importance of data integrity to ensure the safety, efficacy and quality of their products. Under the pressures of the COVID-19 pandemic in particular, company leadership should focus on taking proactive measures to manage data integrity risk and ensure compliance with the CGMP regulations before the next FDA inspection happens. These efforts may include review and assessment of procedures as per the guidance of CGMP for responding to COVID-19 infection in employees, to prevent or mitigate potential adverse effects on the safety and quality of drugs from an infected or potentially infected employee engaged in drug manufacturing. Companies should also utilise advanced digital tools and technologies that can proactively identify data integrity lapses in electronic data of certain equipment (e.g. Chromatography Data Systems (CDS), NON-CDS, LIMS, etc.) and highlight on a real-time basis, so management can enable the company to take necessary actions.

Companies that have already received a form 483 and warning letter should consider implementing a remediation plan for the violations identified. This would involve a comprehensive investigation that includes identification of the causes of the lapse, ongoing monitoring and preventive steps for potential recurrence. Since data integrity is a critical component of the basis for maintaining quality and the confidence of regulators, pharmaceutical companies should seek the expertise of a third-party expert to audit company operations and assist in meeting FDA requirements. References are available at www.pharmafocusasia.com

AUTHOR BIO

Ankush Lamba is a Managing Director in FTI Consulting’s Technology segment in Mumbai. He brings more than 12 years of experience in fraud data analytics and digital forensics. He has worked on high profile data integrity investigations for pharma companies involving regulators including the USFDA.

Research Insights

The Evaluation of Drug Delivery Nanocarrier Development and Pharmacological Briefing for MetabolicAssociated Fatty Liver Disease (MAFLD): An Update

Reem Abou Assi, Discipline of Pharmaceutical Technology, College of Pharmacy, Al-Kitab University Ibrahim M Abdulbaqi, Academic Staff Member, College of Pharmacy, Al-Kitab University Chan Siok Yee*, Academic Staff Member, School of Pharmaceutical Sciences, USM *Author to whom correspondence should be addressed. Dedicated to the memory of my father and the physician in the field who has passed recently, Ahmad Abou Assi. Academic Editor: Dimitris Tsiourvas Pharmaceuticals 2021, 14(3), 215; https://doi.org/10.3390/ph14030215 Received: 22 December 2020 / Revised: 22 January 2021 / Accepted: 27 January 2021 / Published: 4 March 2021 (This article belongs to the Section Pharmaceutical Technology) Keywords: non-alcoholic fatty liver disease (NAFLD); metabolic fatty liver disease (MAFLD); insulin resistance; obesity; nanoformulations; nanotechnology; nanocarrier; nanosystem

Abstract: Current research indicates that the next silent epidemic will be linked to chronic liver diseases, specifically non-alcoholic fatty liver disease (NAFLD), which was renamed as metabolic-associated fatty liver disease (MAFLD) in 2020. Globally, MAFLD mortality is on the rise. The etiology of MAFLD is multifactorial and still incompletely understood, but includes the accumulation of intrahepatic lipids, alterations in energy metabolism, insulin resistance, and inflammatory processes. The available MAFLD treatment, therefore, relies on improving the patient’s lifestyle and multidisciplinary pharmacotherapeutic options, whereas the option of surgery is useless without managing the comorbidities of the MAFLD. Nanotechnology is an emerging approach addressing MAFLD, where nanoformulations are suggested to improve the safety and physicochemical properties of conventional drugs/ herbal medicines, physical, chemical, and physiological stability, and liver-targeting properties. A wide variety of liver nanosystems were constructed and delivered to the liver, only those that addressed the MAFLD were discussed in this review in terms of the nanocarrier classes, particle size, shape, zeta potential and offered dissolution rate(s), the suitable preparation method(s), excipients (with synergistic effects), and the suitable drug/compound for loading. The advantages and challenges of each nanocarrier and the focus on potential promising perspectives in the production of MAFLD nanomedicine were also highlighted.

1. From NAFLD to MAFLD—What Is Going on?

Non-alcoholic fatty liver disease (NAFLD) is defined by the presence of excessive fat in the liver, which is identified either by imaging or liver biopsy. It is the term used to describe various histologic anomalies, ranging from benign steatosis to non-alcoholic steatohepatitis, in people who consume little to no alcohol. NAFLD has a substantial potential to progress to cirrhosis, hepatocellular carcinoma, end-stage liver disease, liver-related death, and recurrence after transplantation. In 2013, scientists released an alarm about the future of liver diseases in which NAFLD is turning to become an epidemic. Given the drastic and growing prevalence of NAFLDs, which affect more than one-quarter of the world’s population, the severe hepatic and extra-hepatic sequelae, and the inadequacy of treatment options, thus, re-naming and re-defining the disease are welcome. The term “fatty liver” was first described in 1836, while the name “NAFLD” was first used in 1980 and for 40 years until 2020 when it was re-evaluated for a more precise nomenclature indicating the existence of metabolic dysfunction, rather than the absence of other conditions, such as alcohol intake, as a safe limit of alcohol consumption could not be set. As a result, the well-known NAFLD nomenclature was replaced by metabolic-associated fatty liver disease (MAFLD), to open the door to the development and implementation of a set of “positive” criteria for defining the condition rather than depending on a “non” or “negative” definition.