In today’s competitive environment it is the objective of all life science manufacturing companies to minimize the risks of compliance non-conformance and the significant associated post-event costs. These costs are seen in human resource non-production time allocations, production delays or halts, and ultimately shut downs and product recalls with potential fines or consent decrees. The ultimate costs will be seen in the potential impacts to patients. These costs can mount into the hundreds of millions of dollars and, as such, should be at the forefront of boardroom discussions.

PROCEDURE MANAGEMENT SOLUTIONSIGNIFICANTLY REDUCES COMPLIANCE RISKWhitepaper

INTRODUCTIONThe total number of Form 483s issued using FDA tools for Drug Inspections in increased again in 2019, reaching 779 for the year. The most frequent inspection observation citation was §211.22(d) “Procedures applicable to the quality unit shall be in writing and shall be followed”. Another observation that increased in a number of citations and that is also related to the laboratory was §211.160(b) “Lab controls should include sci-entifically sound specifications”. Organizations can avoid these observations for the laboratory with systems that include the procedures for QC lab testing with the according specifications, and that can enforce their execution. With such a procedure exe-cution solution in place organizations can significantly decrease compliance risks.

Today, technology advances can provide an assured procedural compliance “execution” process that can be applied to any defined workflow. This procedure management system is cur-rently implemented in dozens of operations on a global basis and has demonstrated significant deviation reductions for compliance operations.

REGULATORY PERSPECTIVE AND PROCEDURE EXECUTIONRegulatory agencies on a global basis have done an excellent job of documenting the guidelines for drug manufacturers to produce and deliver safe and effective medicines. In fact, today the major agencies (US, Europe, Asia) are working to harmonize the regulations for global operations. Their goal is to modify the regulations to modernize and provide further clarification of the requirements for international cGMP standards. A key focus of the efforts centers on the FDA’s regulations outlined in 21 CFR Parts 210 and 211 (Current Good Manufacturing Practice (cGMP) Regulations for Finished Pharmaceuticals). A pervasive element of all the regulatory commentary is the requirement for manufacturers to a) document what they are going to do, b) follow the document while they are doing it, and then c) docu-ment what they did. So it is necessary to create the procedure/Standard Operating Procedure (SOP) that you want your per-sonnel to follow and provide assurances that the procedure was comprehensively executed. In fact, when you read the regulation you see comments such as the following:

• Subpart I — Laboratory Controls, 211.165 — …Testing and release for distribution described in written procedures … such written procedure shall be followed…

• Subpart F — Production and Process Controls, 211.110 … to assure batch uniformity and integrity of drug products, written procedures shall be established and followed…

Procedures “shall be established and followed.” This is the central human “control” process for routine operations in the manu-facture of drug products. To improve compliance-risk control, an automated electronic “procedure/SOP execution” system is warranted.

PROCEDURE EXECUTION AND DOCUMENTATION — PAPER VS. ELECTRONICOne major cGMP 483 citation states “…the responsibilities and procedures applicable to the quality control unit are not [in writ-ing] fully followed.” This situation is pervasive throughout the industry. Many IT/IS systems (LIMS, ERP, MES, etc.) that were intended to automate and provide electronic records of pro-cess activities are lacking automated controls for the real-time execution of the procedures. These systems are mostly “results-oriented” and not workflow-process oriented. In fact, with many of the systems, process or analytical results are captured manu-ally and on paper, and then keyed into the system with little evidence of compliance with the procedure/SOP. With the addi-tion of a true “process management and compliance system,” all data and most importantly, the metadata surrounding the result, is captured and cataloged in real-time, thus assuring compliant workflow for each procedure or SOP followed.

Equally important to the procedure final result is the compliance metadata that supports the result. This includes items such as the compliance state (i.e., calibration status) of the equipment used, personnel eligibility to execute the procedure, expiration dates of reagents used in the process of analyzing materials, tracking and tracing of consumables used in the workflow process, and a host of other “metadata” components. A comprehensive process management and compliance system must capture and catalog these metadata elements in real-time as the written procedure is followed. This is the “control” required for assured compliance with written procedures in cGMP operations.

Another key opportunity for electronic systems (vs. paper) in quality operations is the ability to set thresholds for each step in the procedure or SOP and have the system “watch” in real-time as values are documented. Since production processes should yield virtually identical process step values, the electronic system can compare the actual values to the required specifications at each step in the procedure. Should a value fall outside of the expected norm, the operator/analyst is immediately warned before moving forward. This provides “right first time” opportu-nities and reduces deviation/compliance risks and subsequent investigation costs.

The eight critical functional requirements for a procedure man-agement system are outlined in Table 1.

procedure MANAGEMENT FUNCTIONALITY

COMMENT

User Interface-guided procedures Regulatory requirements specify the actual viewing of the current procedure during workflow execution. Each procedure paragraph/step spawns the appropriate data and metadata capture needs for the procedure step, instruments used, and documenta-tion input.

Step-by-step control of the workflow execution by analyst/operator

This control element enforces required data and documentation with electronic veri-fication of desired thresholds with compliance flags on any out-of-specification (OOS) situation. All instruments are checked for calibration state prior to taking readings.

Data capture LINKED to procedure and can ACTIVATE other procedures in real time based on captured data entry

Ensures data and metadata are contextually linked to the actual approved procedure step. Data is captured direct to database for compliant recording (patented process). Procedures can be linked to create situational workflows (i.e., calibrate balance before use). Quality data elements are parsed from the entire instrument report at the same time as the cataloging of the entire instrument report output.

Data review dashboard view with compliance flags for streamlined “review by exception”

Automates the aggregation of ALL data, metadata, supporting data (instrument reports etc.) with any OOS situation flagged for review. As a validated system, this provides reviewers with visual indication of what needs review vs. the need to review everything.

Procedure Authoring tool to automate existing documented procedures/SOPs

Drag-and-drop technology to enforce best-practice procedure steps within existing docu-ment and automatically create validation script and workflow diagram for compliance documentation. These validated electronic workflows are captured in a method library for additional uses, thus harmonizing ongoing lab and process workflows.

Procedure-driven data exchange to other IT/IS systems

Regulatory requirements specify the actual viewing of the current procedure during workflow execution. Each procedure paragraph/step spawns the appropriate data and metadata capture needs for the procedure step, instruments used, and documentation input.

Custom Off-the-Shelf solution Off-the-shelf product vs. custom-coded project enables fast installation and validation. Method Builder scales up the methods enabling compliant automation of process busi-ness workflows.

Procedure-based operational excellence

Comprehensive set of rich data, metadata, and compliance flag info available for analysis/trending and process optimization from lab to plant.

Table 1: Key capabilities for procedure execution in cGxP

All lab or at-line instruments are integrated into the system with their compliance states checked prior to capturing data. Audit trails are maintained automatically and final review and approvals areconducted with a dashboard view of all data and metadata. Data elements are electronically checked by the software, and should any data fall outside of the expected threshold, a compliance flag will appear to call attention to the reviewer (see Figure 2). Organizations automating these capabilities have published 50 percent to 75 percent cycle time savings for data review and approvals advancing the operational excellence goals of the operation (see Table 2). A standards-based approach to procedure authoring enables the right content to be input into processes from the beginning and enables carrying out production in similar ways globally.

The standards put in place will give the production system a common language and a shared way of working supporting com-pliance across the organization (see Figure 3)

Procedure or

SOP

Procedure Step Data Captured

A PROCEDURE MANAGEMENT SYSTEM — REAL-TIME VIEWING, DATA CAPTURE, CHECKING, REVIEW AND DOCUMENTATIONThe electronic procedure management system illustrated in Figure 1 displays the approved cGxP procedure with a short work list view and data capture fields. Each step must be completed to close out the session and all data is captured directly to the database for compliant data management.

Figure 1: BIOVIA provides step-by-step viewing of the cGxP procedure with a dynamic web-based user experience for data recoding with desktop, laptop and mobile devices

Figure 2: BIOVIA Capture provides real time audit trail with compliance flag warnings of Out of Limit (OOL) and Out of Specification (OOS) values allowing for Review-by-Exception to assure compliant adherence to regulatory requirements.

Figure3: BIOVIA Compose provides easy creation and automation of workflows according to SOPs based on drag-and-drop from customer and site specific operation libraries for standardization of recipes and methods.

Table 2: Cycle-time reductions for QC lab test results using an automated process management and compliance system. (Source: Bristol-Meyers Squibb, IMACS User Conference)

TaskAverage

# Samples per Test

Test

Time

Paper Based BIOVIA % Resource Savings

Write Up Results

5 Hardness 13 Minutes 3 Minutes 77%

2 Appearance 9 Minutes 3 Minutes 67%

6 Dissolution 7 Hours, 40 Min. 2 Hours, 50 Min. 63%

15 Potency & Impurities 12 Hours, 40 Min. 6 Hours, 30 Min. 49%

Review & Approve

6 Dissolution 2 Hours 1 Hour 50%

15 Potency & Impurities 2 Hours 1 Hour 50%

DOING NOTHING IS NOT AN OPTION

To thrive in today’s economic and competitive marketplace, life science companies must drive operational excellence into all lab and production processes. An often overlooked critical risk is controlling the compliance-based documentation of procedures/SOPs that drive everyday human resource tasks. Not automating the step-by-step human processes in operations can result in significant potential costs to companies. We have seen product recalls, plant shut-downs, consent decrees and operational reme-diation costs mounting into the hundreds of millions of dollars. In addition, public company valuations have plummeted as a result of these multi-year remedies. At the senior management level, doing nothing is not an option. Automating process management and procedure execution is the answer to minimizing compliance risks in cGxP environments.

CONCLUSION

To comply with the guidelines outlined by current GxP regula-tions, companies must ensure that human resources view, follow, and document written procedures. The top regulatory citation in 2019 includes non-compliance because of operators/analysts fail to follow written procedures. Today, this is mostly a paper-based pro-cess with manual entry of results into an electronic system (LIMS, ERP, etc.). By utilizing an automated procedure management system, the resulting paperless environment assures that step-by-step compliance with written procedures is followed, all data and metadata are captured and cataloged, and review and approvals are streamlined. Significant benefits improving operational excellence include 50 percent to 75 percent cycle-time reductions, reduced compliance risk and harmonization of procedure/method/SOP best practices across the enterprise.

Our 3DEXPERIENCE® platform powers our brand applications, serving 12 industries, and provides a rich portfolio of industry solution experiences. Dassault Systèmes, the 3DEXPERIENCE® Company, provides business and people with virtual universes to imagine sustainable innovations. Its world-leading solutions transform the way products are designed, produced, and supported. Dassault Systèmes’ collaborative solutions foster social innovation, expanding possibilities for the virtual world to improve the real world. The group brings value to over 220,000 customers of all sizes in all industries in more than 140 countries. For more information, visit www.3ds.com.

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