Clinical Researcher—August 2023 (Volume 37, Issue 4)

CULTIVATING QUALITY

Olena Chervonenko, MS

 

 

Part 1: Data-Driven Decision Making—The Power of Trustworthy Data

In the pharmaceutical sector, data and Data Integrity are subjects of extensive study, research, and publication. Amidst discussions regarding quality control and software, it is crucial to remember the ultimate objective of this effort: the creation of a Registration Dossier ensuring that the data generated during the different stages of the lifecycle of the product are accurate, complete, and reliable.

When purchasing a dossier, one is essentially acquiring a treasure trove of invaluable data. This includes comprehensive information on a pharmaceutical product’s pharmaceutical development, preclinical data, and crucial clinical trials data. Additionally, the dossier contains vital data about the product’s quality—a testament to its efficacy and safety. The assurance of quality lies firmly in the robustness of these data, making it an indispensable asset for any discerning buyer.

The Registration Dossier serves three pivotal purposes, each essential to the success of a pharmaceutical product:

Proving Product Quality: The Registration Dossier acts as a comprehensive testament to the quality of the product. It meticulously documents every aspect of pharmaceutical development, preclinical and clinical data, and quality assurance measures. By presenting a dossier backed by robust data, pharmaceutical companies assert the high quality and efficacy of their products, inspiring trust among stakeholders, regulators, and end-users alike.

Gaining Marketing Authorization: A well-prepared Registration Dossier is a prerequisite for gaining Marketing Authorization from regulatory agencies. By adhering to Data Integrity principles and providing a comprehensive, transparent, and scientifically sound dossier, pharmaceutical companies establish the credibility of their product, the product’s quality, safety and efficacy, and its compliance with regulatory requirements. This paves the way for agencies to grant the necessary permissions, allowing the product to enter the market and benefit patients.

Facilitating Technology Transfer: Beyond regulatory approval, the Registration Dossier serves as a valuable asset for companies that are potentially interested in acquiring the product for further technology transfer. In the complex world of pharmaceuticals, seamless technology transfer relies on the availability of accurate and reliable data. A carefully compiled dossier enables a smooth handover of technology to other pharmaceutical companies, fostering collaborations and expanding the product’s reach.

The creation of a Registration Dossier is not merely a procedural task; it is a strategic endeavor with far-reaching implications. By upholding Data Integrity and providing a robust dossier, pharmaceutical companies unlock new avenues for technology transfer, fostering growth and innovation in the pharmaceutical industry.

Part 2: Understanding Data Integrity and its Relevance

Data Integrity, as defined by ISO/IEC 2382:2015, pertains to maintaining accuracy and consistency regardless of changes made.{1} For pharmaceutical companies, Data Integrity is of utmost importance, driving crucial aspects such as drug development, clinical trials, manufacturing, and regulatory compliance. Uncompromised Data Integrity instills trust in the quality, efficacy, and safety of medicines.

Understanding the “Data Lifecycle” from its origin to the final report is paramount in today’s landscape. The integrity of data, from how they were captured to how they are reported, holds the key to informed decision-making. Data serve as the foundation for critical choices, and data imbued with integrity empower these choices with precision and reliability. Embracing digital data and their governance offers advantages that drive faster and more accurate decisions. Adherence to robust principles such as ALCOA+ and compliance to regulatory requirements such as the U.S. Food and Drug Administration’s (FDA’s) 21 CFR 11 from the Code of Federal Regulations and the European Medicine Agency’s (EMA’s) EudraLex Annex 11, backed by thorough validation, ensure that Data Integrity remains at the core of the entire data lifecycle.

ALCOA+ stands as the gold standard for Data Integrity in the medicinal products realm. Its attributes are hailed as the epitome of data reliability not just within this sector, but also in various other industries. Upholding the principles of ALCOA+ ensures that data remain trustworthy and accurate throughout their lifecycle, instilling confidence in decision-making processes across diverse domains.

ALCOA+ is the acronym for Attributable, Legible, Contemporaneous, Original, and Accurate, and encompasses the following quality attributes for data{2,3}:

Attributable: Tracing data to individuals and measurement systems for accountability.

Legible and Permanent: Ensuring data remain readable and accessible throughout their lifecycle.

Contemporaneous: Capturing data in real-time for accurate and timely records.

Original Record or “True Copy”: Preserving the authenticity of data from their sources to subsequent modifications.

Accurate: Defining processes for precise data capture, including source verification and format documentation.

The “+” expands beyond ALCOA to encompass the attributes of Complete, Consistent, Enduring, and Available:

Complete: Ensuring data include relevant metadata for comprehensive documentation.

Consistent: Maintaining the correct chronological order of data to preserve consistency and sequence.

Enduring: Safeguarding the longevity and integrity of data throughout storage and use.

Available: Enabling easy accessibility and verification by authorized personnel.

It is important to note that the ALCOA+ principle applies to electronic data, paper records, and hybrid systems, encompassing various types of data management.{4}

The comprehensive requirements set by regulators for the Pharmaceutical Quality System (PQS) today include the following main documents:

• FDA 21 CFR Part 11
• FDA Guidance for Industry Data Integrity Compliance with Drug current Good Manufacturing Practice (cGMP)
• EMA GMP guidance to ensure Data Integrity
• Medicines and Healthcare products Regulatory Authority (MHRA) GxP Data Integrity Guidance and Definitions{5}
• World Health Organization (WHO) Guideline on Data Integrity, Annex 4{6}
• PIC/S Good Practices for Data Management and Integrity in Regulated GMP/Good Documentation Practice (GDP) Environments{7}
• GAMP Records and Data Integrity Guide—ISPE/GAMP, March 2017{8}
• European Union Good Manufacturing Practice, Volume 4, Annex 11{9}

Part 3: Proving Product Quality

Within the realm of pharmaceutical development, a cornerstone principle to follow, as per the International Council for Harmonization guideline Q8(R2),{10} is Quality by Design (QbD). The objectives of QbD include achieving meaningful product quality specifications, increasing process capabilities and reducing product variability, and increasing product development and manufacturing efficiencies,{11–13} ultimately, designing a manufacturing process that is able to  manufacture a product that consistently meets the set quality requirements. This rigorous approach to pharmaceutical development not only serves as a critical component of the Registration Dossier, it also lays the groundwork for when future changes such as upscaling or transferring a process are planned.

The Registration Dossier is a comprehensive compilation of data, evidence, and scientific understanding that showcases the quality, safety, and efficacy of the product. At its core, the dossier is built upon robust data, carefully documented, and upheld with unwavering belief in the principles of Data Integrity.

Data Integrity is the bedrock on which the Registration Dossier stands tall, providing confidence to stakeholders, regulators, and end-users. A thorough approach to data collection, analysis, and documentation ensures that every facet of the product’s development is transparent, traceable, and credible. As the dossier traverses the regulatory pathway, the assurance of Data Integrity empowers pharmaceutical companies to gain Marketing Authorization and pave the way for future technological advancements.

With Data Integrity at the helm, the Registration Dossier becomes a catalyst for continuous improvement. Data-driven insights gleaned from pharmaceutical development studies and manufacturing experience form the basis for informed decision-making. These insights provide the scientific understanding necessary to support the establishment of the design space, specifications, and manufacturing controls.

Furthermore, as processes evolve and new equipment is introduced, Data Integrity acts as a safeguard against potential pitfalls. It enables companies to assess the impact of changes with confidence, ensuring that the quality, safety, and efficacy of the product remains uncompromised. By building Data Integrity into the fabric of pharmaceutical development, companies create a culture of excellence and accountability that extends far beyond the initial dossier submission.

The dossier, fueled by irrefutable data and a commitment to Data Integrity, not only proves the quality and safety of the product but also emboldens the industry to achieve new heights of excellence. As the pharmaceutical landscape continues to evolve, the role of Data Integrity in nurturing robust products and fostering a culture of continuous improvement becomes increasingly vital.

Implementing Data Integrity in pharmaceutical development requires a comprehensive approach that spans various instruments and methods. Here are some key instruments and ways to ensure Data Integrity throughout the pharmaceutical development process:

Data Governance and Standard Operating Procedures (SOPs): Develop clear and robust Data Governance policies and SOPs that outline the principles and procedures for data collection, management, and documentation. These SOPs should encompass all aspects of data handling, from raw data acquisition to data review, approval, and archiving.

Training and Education: Provide regular training and education to all personnel involved in pharmaceutical development on the importance of Data Integrity, best practices, and compliance with relevant guidelines and regulations. Ensure that personnel are aware of their responsibilities in maintaining Data Integrity.

Audit Trails and Data Logging: Implement electronic systems with audit trails that capture all actions taken on data, including data entry, modification, and deletion. Maintain data logs and audit trails and ensure these are readily accessible for audit purposes. A system should be in place describing the periodic review and audit requirements of audit trails and data logs.

Data Backups and Data Recovery: Establish robust data backup and recovery procedures to safeguard against data loss or corruption. Regularly back up data and validate the integrity of backups to ensure data availability and reliability.

Electronic Signatures and Authentication: Use electronic signatures for data entry and approvals, ensuring traceability and accountability. Implement secure user authentication measures to prevent unauthorized access to critical data.{14}

Validation and Qualification of Systems: Validate all computerized systems used in pharmaceutical development to ensure they meet Data Integrity requirements. Regularly assess and requalify systems to ensure their continued reliability.

Risk Assessments: Conduct risk assessments to identify potential vulnerabilities in data management processes and address them proactively. Assess the impact of identified risks on Data Integrity and implement appropriate mitigation measures.

Data Review and Oversight: Implement a robust review process for data to ensure accuracy, completeness, and consistency. Establish a clear oversight mechanism to monitor data-related activities and address any issues promptly.

Vendor Qualification: Perform thorough vendor qualification for outsourced services or software providers to ensure they adhere to Data Integrity principles and regulatory requirements.

Data Encryption and Security: Use encryption and other security measures to protect data during storage, transmission, and sharing. Implement access controls to restrict data access based on the principle of least privilege.

Continuous Improvement: Foster a culture of continuous improvement by regularly reviewing data management processes, identifying areas for enhancement, and implementing corrective actions as needed.

Documentation and Record-Keeping: Maintain comprehensive documentation and records of all data-related activities, including data collection, analysis, and decision-making processes.

Quality Risk Management: Integrate Quality Risk Management (QRM) practices into data-related processes to identify, evaluate, and mitigate risks to Data Integrity effectively.

Periodic Data Integrity Reviews: Conduct periodic Data Integrity reviews and audits to assess compliance with established procedures and identify opportunities for improvement.

By adopting these instruments and methods, pharmaceutical development organizations can establish a strong foundation of Data Integrity, ensuring the credibility, reliability, and compliance of data throughout the entire lifecycle of the pharmaceutical product.

Part 4: Gaining Marketing Authorization

Keeping all primary data and their associated documentation (such as chromatograms, spectra, calculations, validation data, clinical trial data, stability data, and quality control data) together with their backups is a critical aspect of ensuring Data Integrity in the pharmaceutical development and manufacturing process. This comprehensive data preservation is essential for successful GMP inspections. The agency responsible for conducting GMP inspections depends on the region and country where the Marketing Authorization application is submitted.

The GMP inspection is a crucial step in the regulatory approval process. For example, the FDA, TGA (Therapeutic Goods Administration of Australia), MHRA of the United Kingdom, Health Canada, and PMDA (Pharmaceuticals and Medical Devices Agency of Japan) conduct pre-authorization GMP inspections to ensure compliance with GMP regulations before issuing Marketing Authorization for medicinal products.

Regulatory inspectors will review the PQS during the inspection, together with all data generated during the development, manufacturing, and testing of the pharmaceutical product, to ensure data have been appropriately recorded, stored, and maintained.

The key aspects that regulatory inspectors will focus on during the GMP inspection regarding Data Integrity include:

Data Integrity Controls: The regulatory inspectors will examine the PQS to ensure that robust controls are in place to prevent data manipulation, loss, or unauthorized access. This includes implementing ALCOA+ principles for Data Integrity.

Data Management and Storage: The inspection will verify whether the PQS has the required procedures for data management and storage. This includes secure data storage, appropriate access controls, and regular backups to prevent data loss.

Audit Trail and Version Control: The regulatory inspectors will assess if there is a comprehensive audit trail system in place that records all changes to data and provides details on who made the changes, when the changes were made, and why these changes were made. Version control for documents and data is essential to ensure traceability and prevent unauthorized alterations.

Data Accessibility: During the inspection, it is expected that data are easily accessible for review and verification. This includes having organized and well-maintained records that can be readily presented to the inspectors.

Training and Personnel Competency: The regulatory inspectors will assess the training, competency, and understanding of the importance of Data Integrity of personnel who are involved with data generation, recording, and management. Adequately trained personnel, with a good understanding of the principles of Data Integrity, are more likely to adhere to Data Integrity practices.

Validation and Documentation: The inspection will verify that all analytical methods, equipment, and processes used to generate data are properly validated or qualified and documented.

Data Review and Approval: The PQS should outline a clear process for data review and approval with definitions of roles and responsibilities, ensuring that data are thoroughly reviewed and approved by authorized personnel before their inclusion in the Registration Dossier.

The consequences of Data Integrity issues identified during a GMP inspection can be severe, putting the company under significant financial and reputational risk. A Warning Letter from regulatory authorities such as the FDA or a Non-Compliance Report from European regulatory bodies not only highlights potential shortcomings in Data Integrity practices, but also reflects on the overall quality and compliance of the company’s operations.

Notably, between 2017 and 2022, the FDA issued more than 160 Warning Letters citing Data Integrity deficiencies, with 13 Warning Letters issued in 2022 alone.{15}

Approximately half (42, 49%) of the total 85 GMP Warning Letters issued by the FDA in 2018, for example, included a Data Integrity component.{16}

Such regulatory actions can lead to costly remediation efforts, possible product recalls, delays in product approvals, and even the suspension of manufacturing activities. Moreover, the damage to the company’s reputation can erode trust among stakeholders, customers, and the public, impacting future business opportunities and market standing. Therefore, ensuring robust Data Integrity measures is paramount for safeguarding the company’s financial stability and preserving its reputation within the pharmaceutical industry and regulatory bodies.

Part 5: The Final Milestone—Ensuring Success After Receiving Marketing Authorization

Receiving Marketing Authorization is a momentous achievement for any pharmaceutical company, marking the green light for commercialization. At this juncture, companies are presented with two pivotal paths: embarking on commercial manufacturing independently or exploring the possibility of selling the authorization and executing a site transfer to another manufacturer. The success of the first option rests entirely on the company’s capabilities, while the latter demands a rigorous evaluation of Data Integrity through a thorough due diligence process.

During due diligence, potential buyers or partners thoroughly examine the data presented in the Registration Dossier to gain an in-depth understanding of the product’s scientific foundation and technological intricacies. Key elements, such as the Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), clinical/non-clinical data, risk assessments, design space, control strategy, and product lifecycle management, undergo rigorous scrutiny. The integrity and reliability of data become the focal points, serving as the bedrock of assessing the product’s quality, safety, and efficacy, and the robustness of associated processes and potential risks.

Conducting due diligence is a comprehensive undertaking, involving a precise evaluation of all aspects of the product, including the data captured in the dossier. The comprehensiveness of the data is crucial, as potential buyers or partners, who might not be intimately familiar with the pharmaceutical product, seek transparency and clarity. This is particularly significant when contemplating technology transfer or divesting the Marketing Authorization to another manufacturer.

In addition, the due diligence process assesses the feasibility and practicality of the technology involved in the pharmaceutical product’s manufacturing process. This entails evaluating the compatibility of the manufacturing equipment and facilities with the processes and specifications detailed in the dossier. The ability of the technology to scale up and adapt to the new manufacturing site becomes a pivotal consideration, and only concrete data can instill confidence in interested buyers.

Indeed, the due diligence process holds immense importance as it directly influences the chances of success of the chosen path. Thoroughly assessing Data Integrity and technological workability lays the groundwork for seamless technology transfer or fruitful collaborations with new partners. This rigorous evaluation ensures that the Marketing Authorization, accompanied by the reliable data and scientific understanding within the dossier, opens doors to a successful journey in the pharmaceutical market.

Part 6: To Sum Up

The unwavering commitment to Data Integrity, adhering to current requirements and expectations, stands at the core of the pharmaceutical industry. This foundational principle empowers every stage of a pharmaceutical product’s development, from inception to the market’s fruition. By upholding Data Integrity, pharmaceutical companies establish a strong reputation for excellence, inspiring confidence among stakeholders and regulatory bodies and fostering a culture of trust. Furthermore, this dedication to Data Integrity paves the way for transformative innovations that ultimately benefit patients and society as a whole. The significance of Data Integrity cannot be overstated, as it not only ensures compliance with regulations, but also elevates the pharmaceutical industry to new heights of integrity and reliability.

References

1. ISO/IEC 2382:2015 – Information technology — Vocabulary
2. ALCOA+ – what does it mean? – ECA Academy (gmp-compliance.org)
3. Data Integrity: History, Issues, and Remediation of Issues | PDA Journal of Pharmaceutical Science and Technology
4. Guidance on good data and record management practices; World Health Organization, WHO Technical Report Series, No.996, Annex 5; 2016. http://apps.who.int/medicinedocs/en/m/abstract/Js22402en/
5. GMP Data Integrity Definitions and Guidance for Industry letter (publishing.service.gov.uk)
6. TRS 1033 – Annex 4: WHO Guideline on data integrity
7. PIC/S. https://picscheme.org/docview/4234
8. GAMP Guide: Records & Data Integrity | ISPE | International Society for Pharmaceutical Engineering
9. EudraLex – Volume 4 (europa.eu)
10. ICH Q8(R2)—Pharmaceutical Development, November 2005, Step 4.
11. FDA Guidance for Industry: Quality by Design (QbD) for ANDAs, November 2021.
12. AAPS PharmSciTech, Volume 20, Issue 2, March 2019—“Quality by Design Approach: Regulatory Perspective.”
13. Pharmaceutical Research, Volume 37, Issue 7, July 2020—“Quality by Design: An Overview.”
14. Part 11, Electronic Records; Electronic Signatures – Scope and Application | FDA
15. Data integrity issues in pharmaceutical industry: Common observations, challenges and mitigations strategies – ScienceDirect
16. European Industrial Pharmacists Group (EIPG) The new PIC/S guideline on data integrity

Olena Chervonenko, MS, (Olena.Chervonenko@pharmalex.com) is Associate Director of Quality Management and Compliance for PharmaLex. Hailing from the Odesa region of Ukraine, she is an accomplished professional with a strong background in pharmaceutical chemistry and quality management, including work at Arterium Pharmaceutical Corporation, first as a Chemist-Analyst in the R&D Department and then as Leading Specialist in the Quality of the Pharmaceutical Development Department. She later served as the Head of the QA and CMC RA Departments at LLC Organosyn LTD.