Understanding data integrity in GMP, GLP environments

Maintaining data quality in GLP (Good Laboratory Practices) studies is as important as maintaining data integrity.  In both GLP and GMP (Good Manufacturing Practices), data quality means the data produced are generated in compliance with applicable standards and can be used for its intended purpose. Throughout this article, GLP refers to OECD GLP. If the data generated can be trusted, then it can be said that the data has integrity. To have quality data, the prime requirement is the person who generates data in both GLP and GMP environments should have adequate qualification and experience.

Quality Control (QC) in GLP, GMP environments
A quality control department of a pharma industry carries out sampling (raw materials, finished products, etc) following established procedures and analyzes it in the QC laboratory. In the earlier GLP documents, the terminology QC never existed. But in the recent OECD document No. 22 (2021) the role of QC is emphasized. As per this document, QC comprises routine independent checking, measuring, and testing procedures to ensure the accuracy of data. These QC activities ensure a product meets predefined requirements. ISO 9001 defines quality as “the degree to which a set of inherent characteristics fulfills requirement”. A characteristic is defined by ISO as a distinguished feature. Quality is a set of attributes of a product. In pharma industries, the quality of a product, for example, tablets relates to its active ingredient, weight, color, shape, etc. The characteristics that a tablet is required to possess have already been defined and if the tablet meets the requirements of these characteristics, the tablet will have quality. Concerning GLP, a product can be, a study plan, study report, analytical results, test item receipt records, dosing records, etc. These products will have quality if they are generated and managed as per GLP principles.

Data quality issue
Bisphenol-A (BPA) is a chemical present in plastics and a small amount of it reaches man through food, water, etc. Since this amount is too small, according to the US FDA, it will not adversely affect the health of man. Continuous exposure to BPA  in higher quantities causes adverse effects on the prostate gland of fetuses, infants, and children. US FDA concluded that BPA has no effect at low doses based on a safety evaluation study conducted under GLP in mice. However, more than 200 studies in experimental animals have reported significant effects of BPA at low doses that are relevant to human and ecologic exposures. The study report on the safety evaluation study conducted under GLP on mice showed a higher weight of prostate glands in control animals, whereas the data on the weight of prostate glands in control animals in other studies conducted with BPA showed much lower weights.  In an article titled. ‘Good laboratory practices are not synonymous with good scientific practices, accurate reporting, or valid data’, published in Environment Health and Perspectives in 2010, the authors suggested the reason for showing higher prostate weights in control mice in the GLP study that US FDA considered for safety assessment might be due to improper dissection, exposure of control mice o a contaminating estrogen, or diseased prostates. This issue seems to be more related to data quality than data integrity.

Data integrity issue
Glyphosate a widely used herbicide was introduced in 1974. The International Agency for Research on Cancer (IARC) concluded in March 2015 that it is probably carcinogenic. Using additional evidence, the IARC conclusion was not confirmed by the European Union (EU) assessment or the recent joint FAO/ WHO (Food and Agricultural Organization/World Health Organization) evaluation. IARC assessments do not include recommendations regarding regulatory or legislative decisions. In 2016 the Joint FAO/WHO Meeting on Pesticide Residues concluded that glyphosate is not carcinogenic in rats but could be carcinogenic in mice at high doses. In the JMPR  (Joint Meeting on Pesticide Residues) document published in 2016, these study findings in rats and mice were used in the risk assessment concluding that glyphosate is unlikely to pose a carcinogenic risk to humans from exposure through the diet.

In the risk assessment of a chemical (a drug or a pesticide), genotoxicity studies play an important role. The EU considers in vitro genotoxicity tests and in vivo studies performed in mammals to be more relevant for the assessment of the risk of cancer in humans.

In an article, entitled ’Dangerous confidence in ‘Good Laboratory Practice’ published by Dr. Helmut Burtscher Schaden and two other authors stated that out of 47 GLP studies of the manufacturer's report, 46 GLP studies showed that glyphosate does not cause genotoxicity, while most of the independent studies showed glyphosate is mutagenic. The majority of the GLP mutagenicity studies with glyphosate were conducted by a German GLP-certified facility, and the integrity of these studies was questioned by the scientific community. This prompts me to quote the famous Senator Kennedy hearing in 1976 on Preclinical and Clinical Testing by the Pharmaceutical Industry. Senator Kennedy stated, ‘Inaccurate science, sloppy science, fraudulent science are the greatest threats to the health and safety of the American people. Whether the science is wrong because of clerical errors, or because of poor techniques, or because of incompetence, or because of criminal negligence is less important than the fact that it is wrong’.

Ensuring data integrity through ALCOA++
For ensuring data integrity, in OECD Document No. 22 (2021) great emphasis has been given to the acronym ALCOA (Attributable, Legible, Contemporaneous, Original, Accurate).  Though ALCOA is new to GLP, it was not new to GMP pharma industries. The ALCOA was introduced by Stan W. Woollen in the early 1990s. Later, US FDA introduced ALCOA in the pharmaceutical manufacturing industry. The European Medicines Agency added another four quality parameters to ALCOA: Complete, Consistent, Enduring, and Available. Both GLP and GMP require contemporaneous recording of the data when the activity is performed. It is considered a serious observation of FDA auditors when data recording is not done when the activity is performed. In GMP pharma industries the data are checked on 2-3 levels, hence contemporaneous recording of data is always never overlooked. The author of this article has seen ALCOA principles displayed prominently in various places on the premises of several pharma industries. Compromising data integrity is considered a serious observation in GMP audits. Based on audit findings, USFDA issues warning letters to the audited company. Such warning letters are available on the FDA website for the public to read. The warning letters relating to serious issues will affect the reputation of the company and its share market value may plunge. Hence pharma companies always pay special attention to maintaining the integrity of data. The number of data integrity issues cited in warning letters of USFDA was 3 each in the year 2017-2020, and none in 2021.  GLP does not publish warning letters on its website.

Unfortunately, data integrity has become a serious observation in the inspections conducted by the National Good Laboratory Practice Compliance Monitoring Authority (NGCMA) of India at several GLP-certified facilities. To overcome this serious issue, NGCMA has imparted a few trainings on data integrity for the benefit of personnel working in GLP test facilities in our country. Let us try to understand the word, ‘integrity’ literally and philosophically.  According to Webster's dictionary, integrity is defined as “moral soundness; honesty; freedom from corrupting influence or motive”. A person with integrity will be honest and have strong moral principles. An honest person is incorruptible, does not tell lies, and is always uncompromising in moral values. Morality implies being good at one’s profession and enjoying freedom while executing his/her professional duties. According to George Orwell ‘freedom is the freedom to say that two plus two equals four, If that is granted, all else follows’. The data that we capture from the studies have integrity; the data loses its integrity when it is handled by a person who does not have integrity. Personnel working in a GLP-certified facility must always bear in mind that the regulatory agency is relying on their data to assess the safety of the test item (drug, pesticide, etc.). This means the personnel has an additional responsibility to mankind and society. At the beginning of this article, the author of this article stated that personnel working in GLP facilities should have adequate qualifications and experience. Maybe this requirement can be expanded, personnel working in GLP facilities should have adequate qualifications, experience, honesty, and morality. Whatever system we implement to ensure data integrity, if the personnel who is conducting the study does not have honesty or morality, misconduct of studies/research may occur. The US Federal Policy on Research Misconduct defines misconduct as fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results.