Spreadsheet Validation: A Detailed Review

Quality Assurance

Quality Assurance (QA) encompasses a set of predetermined actions undertaken to ensure adequate confidence in the adherence of goods or services to established standards of quality and suitability. It represents the culmination of all endeavors aimed at meeting the required criteria [5].

Elements of Quality Assurance: • Establishing the system • The Quality Manual • Training • Standard Operating Procedure • The Quality Assurance manager • Auditing and ensuring compliance • Sustaining Quality Assurance

Quality Assurance Framework

Quality holds a significant place in the identity of the Institute and is one of the foundational elements of UNITAR’s Six-Point Vision, which will guide its programming in the future. In 2012, UNITAR established the Quality Assurance Framework (QAF) for learning events in response to the increasing focus on learning outcomes and the strategic objective of enhancing the quality of training products and services, as outlined in the 2010-2012 Strategic Framework. Since 2010, there has been a significant rise in the number and proportion of beneficiaries associated with learning events and broader capacity development initiatives. In 2016 alone, UNITAR conducted over 300 learning-related events, including briefings, courses, workshops, seminars, and fellowship programs, reaching out to more than 32,000 individuals, marking the highest level of engagement in the Institute’s history [5].

The QAF serves two purposes: (a) validating the quality of UNITAR’s training through relevant certification and/ or accreditation schemes, and (b) providing a platform for sharing experiences and learning related to quality. It consists of three key components:

• The Quality Assurance Committee (QAC) • A set of quality assurance standards and guidelines • A self-assessment and peer review process By incorporating these elements, the QAF ensures that the quality of UNITAR’s training is upheld and provides a mechanism for continuous improvement and knowledge exchange in relation to quality matters.

The Quality Assurance Committee (QAC), quality standards and guidelines, and self-assessment and review processes not only contribute to enhancing the quality of products and services offered by the Institute but also offer valuable opportunities for improvement. Additionally, they serve as a point of reference for external quality certification schemes and help facilitate the Institute’s journey towards accreditation. By implementing these measures, UNITAR can ensure continuous enhancement of its offerings and align them with recognized quality benchmarks, both internally and externally. The framework in brief is shown in Figure 1 [5].

Click to enlarge

Functions of Quality Assurance

• Ensures validation and qualification of designated formulations. • Qualifies batches for scaling up to production batches. • Assists in the design of validation protocols. • Establishes clinical programs for manufacturing bio batches, aiming for FDA pre-approval clearance. • Ensures the delivery of safe, effective, and high-quality medicines to patients. • Encompasses technical and managerial activities necessary to fulfill all quality functions. • Includes documentation, review of quality control laboratory tests, and product performance [6, 7].

Data Validation

Data validation plays a crucial role in upholding the integrity and reliability of data used in any programs and research. While current guidance primarily emphasizes data validation at the industrial level, extending validation efforts to a broader level such as companies, laboratories or industries can provide valuable insights and serve as a useful tool.

Expanding the scope of data validation beyond individual firm allows for a more comprehensive assessment of data accuracy, completeness, and consistency across a larger works or projects. This broader perspective enables the identification of trends, patterns, and potential discrepancies that may not be evident when focusing solely on individual centers. It facilitates the detection of systemic issues or variations in data quality, providing opportunities for improvement at a higher level.

By implementing data validation processes at regional or state levels, stakeholders can gain a more comprehensive understanding of the overall quality of the data collected. This approach enhances the reliability and usability of the data, ensuring that it meets the necessary standards for many programs and research. It also promotes consistency and harmonization of data across different entities, facilitating collaboration and enabling more robust analyses and evidence-based decision-making in the field of trauma care [8].

Maintenance of Data Collection Quality

Data management refers to the comprehensive framework employed to acquire, maintain, organize, track, assess, and present identifiable data, while determining its relevance for achieving the objectives of the registry. Conversely, quality assurance guarantees that the information was indeed collected in accordance with guidelines, and that the data recorded in the registry system fulfills the necessary quality standards typically established based on the intended purposes.

Click to enlarge

Furthermore, specific users of data may require adherence to certain rules or specifications during the data gathering and verification process. For instance, a database collecting data intended for use by the United States Food and Drug Administration (FDA) must comply with the authentication standards of the system and the final recipient’s requirements, such as Title 21 of the Code of Federal Regulations Part 11 (21 CFR Part 11). The quality assurance framework for data management is depicted in Figure 2 [9].

Data Integrity

• The extent to which data are comprehensive, logical, precise, dependable, and accurate and that these data attributes remain intact across the data life cycle. • It is done to avoid intentional, accidental falsification or deletion of data to withstand data quality during regulatory inspections • Data integrity and security infractions are not only 21 (CFR) Part 11 issues, but also severe cGMP violations. • This need disciplined quality systems, quality principles, GDP and trained individuals [10]. • It plays a very crucial role in USFDA auditing functions. It is critical for backing up the data, which includes legitimate information from the entire department [1].

On the basis of mechanism and data integrity stream integrity can be divided as shown in the Figure 3.

Click to enlarge

ALCOA Concept

The FDA guidelines define ALCOA as shown in Figure 4 [11].

Click to enlarge

Attributable: The necessity of preserving records to determine identification marks, personalizes, or expected personalities of people who finish broadsheets. It is recommended that you use permanent ink after the document is done. When editing an entry, unique verdict is constantly designated above the primary record. The approach confirms readability of the records. All the mentioned data should be consistent and clear under all situations [12]. Legible: The data of records involved in maintaining the data integrity must have appropriate accessibility during the entire duration of action [12]. Contemporaneous: All the data are documented during the entire course of action. It generally determines the accumulation of the all the data, records and important information from several sources into the suitable operational documents in sequential runs [11]. Original: The genuine or accurate copy of the raw data must be given. Example: The original data becomes lost during the processing of a series of raw data into usable binary number formats, tables, columns, etc [13]. Accurate: Data must include complete meaning. Use an observation check for the purpose of basic record collecting to confirm the correctness of the information. Take into account electronic techniques for data collection and verification. Include accuracy checks in every aspect of the design of the electrical framework. For instance, verify the manual information flow; temperature data must be reported within the predefined range of 0-100°C [14].

Alcoa Plus

To further clarify the characteristics of legitimate contemporaneous attributable original accurate excellent documentation practice, more terms were added. As follows: Simple to get, practical to utilise, already existent, or ready usage Accessible: Reachability, sorted, used, or acquired. Complete: Nothing is lacking, Consistent: Doing or acting in the same way again. Credible: Capable of convincing someone or doing something. Corroborated: To support the evidence with further data or information [15].

Global Data Integrity Regulation Guidelines

USFDA: 21-CFR: The Code of Federal Regulation (CFR) is a collation of the overall and lasting rules that the supervisory sectors and interventions of the civic regime have issued in the Federal Register. Title 21 of the Code of Federal rules contains the rules of the Food and Drug Administration. For every title/volume, the CFR is updated once a year on or around April 1st [16]. MHRA: The MHRA’s GMP data integrity criteria for the industrial direction are envisioned to heighten the EU’s current GMP standards for dosage. The pharmaceutical quality system, which guarantees that medications are of the requisite quality, is fundamentally dependent on data integrity [16].

TGA: The Therapeutic Goods Administration (TGA), an Australian regulatory organization, specifies the need for data integrity as a deficit. A flaw in a procedure that has resulted in or might lead to a considerable risk of creating a user-harmful product. Also, it happens when it is discovered that the producer has cheated, lied about, or fabricated items or data [16]. WHO: Vital drugs and medical supplies, WHO releases data integrity recommendations to safeguard patients worldwide. In order to lessen instances of manufacturers providing inadequate data or purposeful data fabrication, has WHO produced a guideline on worldwide best practices for regulatory bodies and inspectors while we are creating a medication and marketing it. Several people and things are involved, and the reliability and quality of the information manufacturers provide to national regulatory agencies is important at every stage. To guarantee the caliber of research supplying requests for medications to be placed on the market, that data must be extensive, thorough, exact, and truthful. Moreover, it must adhere to a variety of requirements, including: excellent manufacturing procedures (GMP), good clinical practice (GCP) and good laboratory practices (GLP) [16]. EME: To ensure the generated data integrity at the time of testing, manufacturing, packaging, distribution, and monitoring of medicines, the European Medicines Agency (EMA) has published new Good Manufacturing Practice (GMP) guidelines. These data are used by regulators to assess the effectiveness, safety, and quality of medications as well as to track the benefit-risk profile of such medications over their entire life cycle. Effective data record management enables regulatory agencies and pharmaceutical producers to make informed decisions by ensuring that the data produced are correct and consistent.

Spreadsheets

The spreadsheets are the type of collective computer application used for the analysis and data storage in the form of tables to make it valid for other organizations. The paper-based documentation was replaced by such sheets throughout the business world. In early days they were used for keeping accounts, books while today multiple data is stored, shared and sorted in the form of tables and lists.

A spreadsheet, also known as a worksheet, is a structured arrangement of rows and columns. Rows run horizontally, while columns run vertically. It serves as a tool for recording, calculating, and comparing numerical or financial data. In a spreadsheet, each cell can contain either an independent value or a value derived from other variables. Derived values are typically the result of arithmetic expressions or functions, represented by formulas.

A spreadsheet application, often referred to simply as a spreadsheet, is a computer program that enables users to input and manipulate data. One well-known example is Microsoft Excel, which is part of the Microsoft Office Suite of software. Excel provides a user-friendly interface for creating and working with spreadsheets, offering a wide range of functions and features to perform calculations, analyze data and present information visually [17].

Spreadsheet’s Historical Importance

• The original version, Dan Bricklin Visi Calc for the Apple II, was created by a Harvard student in the late 1970s, and the most well-known version was Lotus 1-2-3. • In charge of the corporate world’s adoption of the PC. • Decision-makers who approve computer acquisitions have profited from: Faster and easier operations. Original invention of new or utilised. At a period when PCs were mostly utilised by enthusiasts, spreadsheet software was exclusively available on PCs. • In contrast, word processing was evolutionary. • Mostly administrative workers are benefited. • By comparison, productivity increases were minimal [18].

Overview of Excel Spreadsheet

Spreadsheet software of today can contain numerous interconnected sheets, execute basic mathematical and arithmetic operations, and display data either graphically or as text and numbers. For typical economical and scientific activities, it offers integrated functions. In contrast, a spreadsheet manipulates numerical data, text and the formula The Excel Screen:

or the information. Spreadsheet can be useful in creating budgets, data analysis, financial planning, and to perform the critical numerical operations. These sheets have tendency of automatic recalculation, self feeded formulas by the user, or by default included math functions, along with this changes in already given command or formulas could also be seen enhances the monitoring and error findings [19].

How to Start Excel

• Go to START OPTION on the windows taskbar • It can be find in the search bar as well • Click on MS- Excel option, the window appears as shown in Figures 5 & 6

Click to enlarge

Click to enlarge

The large window, labeled “Microsoft Excel” may take up the entire screen. This is referred to as the Application Window. The top line is called the Title Bar and has three buttons (Minimize, Restore, and Close) to the right. These buttons are used to size the window and close it. This title bar is standard in all Windows programs [20].

The second line is called the Menu Bar. Notice that one character of each selection is highlighted or underlined. This menu bar is also standard in all Windows programs. The next two lines contain buttons with text or images and are referred to as the Standard and Formatting Toolbars. If you have a mouse, these toolbars allow you to enhance your worksheet without accessing the menu. Keep in mind that these may not be in the exact same place as on the illustration above. All toolbars can be customized to display any buttons you desire.

The next line is the Formula Bar and displays the current cell address and contents. As you move from cell to cell, Excel will keep track of the current cell address for you. The Formula Bar can also be used to edit the text (contents) or formulas contained in the cell [21].

Creation of Spreadsheets

The spreadsheet’s design should be: • Organized and structured • Data entry should be done either automatically or manually by the user • Able to summarize a clear description of its goals and objectives • Able to include clearly defined procedures (such as limit checks, data transmission to other spreadsheets, online creation, and usage of macros), computations • Able to provide results that are simple to track for each unique product [22].

Objective of Spreadsheets

• The spreadsheets are simple to utilize for different goods • The spreadsheet must be adaptable to produce results even if values alter. • The data that is utilised to calculate results should be readily visible in the spreadsheet. • It should be simple to validate and revalidate the spreadsheet. • To prevent modifications or manipulation, the spreadsheet cells holding important data should be secured [22].

Need of Spreadsheet Validation

During an FDA inspection of a QC analytical laboratory in a pharmaceutical firm, several spreadsheet problems were identified. These problems indicate a failure to adhere to current good manufacturing practice (cGMP) and good laboratory practice (GLP) regulations. Furthermore, the laboratory lacked proper multi-user spreadsheet design, validation, and documentation practices. Some specific problems observed in the laboratory include as described in Figure 7 [23].

Click to enlarge

There are some more problems as follows: • One specific problem identified in the QC analytical laboratory was the presence of rounding-off errors in nearly all the spreadsheets. Rounding-off errors can occur when numerical values are truncated or approximated without considering the appropriate rounding rules. • Proper excel equations are not followed to put formulas into the sheets. • No expressions of conversion factors in the sheets.

• Unmatched formulas used for manual calculations and excel calculations. • The standard limits were not mentioned in the spreadsheets. • No clear documentation of spreadsheets.

For example, No clear indication of product statement replacing it by number in a cell. • No labels such as mg/g, mg/ml is provided for unit expressions. • No provision to maintain data integrity and security. • Sheets are not protected from unauthorized changes and access.

Unique designing of these analytical spreadsheets by the user itself can remove these errors. A modest confirmation document must have following points: • Properly describe the programme, its use and working. • Entries of data should be color coded. • Properly described calculation formulas. • Appropriate relationship between excel equations and formulas. • Macro functions must be listed. • Investigation sheets with projected and authentic outcomes, contracted and studied, that have been confirmed by physical calculations. • Properly secured and password protected. • Installation date, version no. and system type [24].

Approach to Specific Part 11 Requirements

Title 21 of the Code of Federal Regulations Part 11 (21 CFR Part 11) is a set of regulations established by the U.S. Food and Drug Administration (FDA) that specifically governs electronic records and electronic signatures in the context of pharmaceutical, biotechnology, and medical device industries. These regulations outline the requirements for the use of electronic systems in capturing, storing, and managing data that is subject to FDA regulations.

21 CFR Part 11 sets forth criteria for electronic records and signatures to be considered dependable, reliable, and legally binding, equivalent to traditional paper records and handwritten signatures. It covers aspects such as the security of electronic records, validation of computer systems, audit trails, electronic signatures, and documentation practices as described in Figure 8.

Compliance with 21 CFR Part 11 is crucial for companies operating in FDA-regulated industries to ensure the integrity, confidentiality, and authenticity of electronic data and to maintain regulatory compliance. Organizations must implement appropriate technical and procedural controls to meet the requirements outlined in 21 CFR Part 11 when using electronic systems for data collection, storage, and management [25].

Click to enlarge

Spreadsheet Designing

The framework of an Excel spreadsheet is almost identical to that of an electronic programme. Spreadsheet formulas are essentially a type of computer code. Alternative to generating the template file and then verifying for mistakes, check for problems throughout the different phases of the creation process. A spreadsheet model is a collection of spreadsheets and custom sheets that are used to analyse and organize data or to solve a specific issue. This designing in appropriate format is shown in Table 1 [26].

Steps in Performing Validation

The steps followed while performing the validation are as follows: Validation Planning: A comprehensive document consisting of actions done, approaches, schedule and validation activities. Validation procedure: The validation procedure should include detailed steps on how to conduct the validation. It should describe the computer system configuration, as well as test methods and objective acceptance criteria, including expected outcomes. The procedures should be reviewed and approved by designated management. The validation procedure should be divided into an Installation Qualification (IQ) and Performance Qualification (PQ) [23]. Installation Qualification: It consists of the points to establish the confidence that the results are in compliance with the regulations. Performance Qualification: PQ will systematically, strictly and constantly test the software by testing all involved and resultant values, records, procedure, and control flow logic [24].

Validation report: The verification report should include complete validated results, particularly the outcomes of the tests. When feasible, evaluations should be reported quantitatively rather than as “pass/fail.” Qualified authority must assess and consent to the report. Validation Lifecycle: It consists of preservation, controlling and maintenance of the validated sheets. These controls include computerized systems and it compliance with the regulations. Some controls to support the system includes • Preventive Maintenance • Environment Control • Monitoring of performance • Retention • Recovery • Training to users, developers and administrators Validation Documentation: The following points should be considered while validating an excel sheet as described in Figure 9. Every worksheet taken into process must be fully documented consisting of all formulas, macros, and user interface elements along with their copies in the validation documentation [25].

Click to enlarge

Operational Change Control: Changes to spreadsheet apps must be managed while in use. This modification management must be established from the stage in the creation life cycle where an individual begins to use the programme and will continue throughout the application’s existence [26].