This white paper discusses how the Insight series of instruments by Vision Analytical complies to the Data Integrity guidance document from the Food and Drug Administration.

The opinions, findings and conclusions expressed in this publication are those of the authors who are responsible for the facts and accuracy of the data presented herein. This report does not constitute a standard, specification or regulation. Authors reserve the right to modify and change this document at any time for the purposes of clarity and corrections.

What is Data Integrity?

In April of 2016, the Food and Drug Administration released a “Draft Guidance” document titled

“Data Integrity and Compliance with CGMP … Guidance for Industry”

Just to serve as some background, CGMP represents the Current Good Manufacturing Practice regulations enforced by the US Food and Drug Administration (FDA).  CGMP guidelines provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities in the pharmaceutical industry. Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers adequately control manufacturing operations.

To ensure that CGMP guidelines are being adhered to, the FDA conducts audits on manufacturers of pharmaceutical products as well as medical device manufacturers that also fall under the same guidelines.  Over many years, during inspections, the FDA has increasingly observed CGMP violations involving data integrity lapses.  Therefore, this guidance was developed to clarify and explain in detail data integrity issues as they relate to the CGMP requirements in the 21 Code of Federal Regulations part 210, 211, and 212 which deal with manufacturing.    It is important to note that this guidance document is not a comprehensive list of items that need to be addressed, but rather are key areas dealing with Data Integrity that have been focal points of problems that need to be addressed. It is up to the manufacturer to apply this guidance do their process.

Within this guidance document, the FDA defines Data Integrity as the following …

Data integrity refers to the completeness, consistency, and accuracy of data.  Complete, consistent, and accurate data should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate (ALCOA).

The use of this acronym “ALCOA” is something the FDA uses in other guidance documents as well.  Throughout the guidance document, the review of how data is controlled, how audit trails are managed and how records are kept are discussed.

Particle Analyzers & their role in the pharmaceutical industry …

Particle size specifications are used in pharmaceutical development as a parameter that can influence the final product.  In most cases, solid or suspension delivery or bioavailability of pharmaceuticals are directly related to particle size given that it controls dissolution characteristics.  Dissolution rates are proportional to surface area, therefore smaller particles with higher surface areas promote a faster dissolution of the pharmaceutical compound.

Besides particle size, the uniformity of the size distribution is also important.  Narrower particle size distributions make for a more uniform and controlled dissolution rate.  Conversely, pharmaceutical compounds are sometimes designed with larger particle distributions to ensure a slower release of the therapeutic compound.

Because particle size, count and shape has taken on a large role in controlling the final pharmaceutical products, they have become a standard tool in development and manufacturing.  Because of this, particle analysis equipment falls under the quality guidelines of each pharmaceutical manufacturer’s quality program and will also be an area of attention for the FDA.

What does this mean for users that own particle sizing equipment …

Given the fact that the guidance document on Data Integrity is formatted very similar to the August 2003 guidance on Part 11 for electronic records, it is highly likely that the implementation of the Data Integrity guidance document will follow the same path of enforcement.  If you have read this far into this document, it is apparent that you have some knowledge either in the instrumentation that is used and / or are in the pharmaceutical sector with particle size analysis equipment.  In either case, you may have experienced the seriousness the FDA takes on 21 CFR 11 and auditing / enforcing of the “guidance” points.  It is more likely than not that the FDA will be adding to their CGMP audits a more in-depth investigation based on the Data Integrity guidance document.  Therefore, it is important, as a manufacturer, to ensure all “computerized systems” are inspected to assess how they comply.

Here we show a section of a recent FDA Warning Letter submitted to a Pharmaceutical Company after an audit of their facility.  After reading the warning letter in its entirety, Data Integrity deficiency issues were one of the most predominant findings.

As this warning letter shows, the FDA is currently auditing the Data Integrity guidance document.

In addition to the points set forth in the Data Integrity guidance document, it is equally important to note that the FDA also references the “ICH Q7 Good Manufacturing Practice of APIs” as a tool for validation protocols for computerized systems.  Adequate installation and operational qualifications should be used to demonstrate the equipment performs the task it was assigned to do.

What does this mean for the manufacturers of particle sizing equipment …

Manufacturers of particle sizing equipment reacted to 21 CFR 11 as a requirement, not a “guidance”.  To compete in the market space, it was expected that manufacturers of equipment make any needed changes to ensure compliance.  Keep in mind that the 21 CFR 11, being a guidance document, required the manufacturer to interpret the points within the guidance document and implement changes that they saw fit.  However, what mattered was not how they implemented the guidance points, but rather how the internal quality auditors and the FDA would interpret the implementation of the guidance document.  Therefore, it was evident back then that the instrument manufacturers that best satisfied the points set forth in the guidance document of 21 CFR 11 were those that were well synchronized with pharmaceutical companies and the expectations of the FDA.

For the Data Integrity guidance document, it is expected to be the same.   It is only a matter of time before all pharmaceutical customers add to their 21 CFR 11 checklist for purchasing computerized systems new checklist items related to Data Integrity.  Therefore, it falls, again, under the responsibility of the instrument manufacturer to ensure all points and topics are addressed, interpreted with a good understanding of what a pharmaceutical customer and the FDA expectation is, and to document how each point is implemented for Data Integrity.  It is also important that instrument manufacturers have programs in place to facilitate the installation and operational qualification of equipment that will document the validation requirements of the FDA.

How do the Insight series of products from Vision Analytical comply to the FDA guidance document for Data Integrity …

To satisfy the installation and operational qualification requirements, the Insight series of products uses an IQ, OQ validation package which is documented separately from this document.  In addition, the Vision Analytical Insight series of products software is fully compliant to the 21 CFR Part 11, Electronic Records and Signatures requirements set forth by the FDA.  More information on this is available in the instrument manual.

Key areas in section 211.68 …

… If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.

… A backup file of data entered into the computer or related system shall be maintained except where certain data, such as calculations performed in connection with laboratory analysis, are eliminated by computerization or other automated processes.

How the Vision Analytical Insight series of products comply to this …

The Vision Analytical Insight series of products has a robust IQ/OQ Qualification Program which is to be performed by qualified Field Service Engineers (FSE) specially trained and certified by the factory in the execution of the qualification process.  A Qualification Kit provides a set of documents and forms, supplies and NIST traceable Standards to complete the Qualification.  Maintenance and instrument performance should be monitored on a routine basis in accordance with Standard Operation Procedures (SOPs).

By using the IQ/OQ Qualification program, the end user is ensured of a proper installation and proof of operation at the site.  The performance measurements produced by the Qualification process are documented for future reference, audits and tracking.  The Vision Analytical Insight series of products Qualification program verifies the system functionality, the accuracy and performance of the system as measurements are made with devices and standards that are calibrated and traceable to NIST standards.

There are three MAIN items involved in the Qualification:

• Service Engineer Manual.
• Qualification Kit.
• Customer Manual.

Additional SUPPORTING documents:

• Qualifying Engineer Certificate of Qualification.
• Certificate of Analysis / Assay Sheet of Whitehouse Scientific NIST traceable standard.
• Local Field Service Report.

The Service Engineer manual contains the specific instructions for the Field Service Engineer (FSE) to complete and perform the set of tests and actions during the execution of the initial instrument Qualification and the annual qualification. The following are the actions during the annual qualification.

• Pre-Testing

This set of tests is intended to evaluate the performance of the instrument with a specific Standard before any preventive maintenance actions are taken. The results are saved in the OQ Pre-Test form.

• Preventive Maintenance

Verification and Cleaning of different sections of the instrument such as Optics, Fluidics and Hardware as well as Calibration are actions taken during Preventive Maintenance and the Checklist completed.

The Qualification Kit contains the forms that should be filled out during the execution of the Qualification.

• IQ Info Data form – This form is used to enter all required information at installation time.
• OQ Test and OQ Pre-Test forms
• OQ Test form – OQ Test form is used to enter the initial results.
• OQ Pre-Test form is used to enter the preliminary results during the annual certifications.
• Maintenance/Checklist form – This form contains the results of preventive Maintenance / Checklist.
• OQ Post-Test form – This form is used to enter the final results during the annual certifications.
• Qualification Report – This report contains the average readings from OQ Test, Pre-Test and Post forms as well as the Pass/Fail results.
• Post Testing – This set of tests are intended to evaluate the performance of the instrument with a specific Standard after preventive maintenance actions have been taken.  The results are saved in the OQ Post-Test form.
• Completion Notification – To report that the Qualification was successfully completed
• Acceptance Notification – To confirm acceptance.
• Out of Specification form – This form should be filled out if any of the OQ Test or Pre-Test
• Corrective Actions form – This form should be filled out if Out of Specification notification was completed.  Name of the Test that failed should be entered and details on the corrective action taken to fix the problem.
• Log form – This form is to keep track of qualifications (initial and annuals).

Data Mirroring …

• Data Mirroring is a feature within the Vision Analytical Insight series of products software where the computer software will store the data files on a separate directory or hard drive or even a network drive at the same time it is being stored on the computer system operating the instrument.

• Ideally, the path for the mirrored files should be an established network drive were Write-Only privileges are available. In doing so, backup files are created in real-time that cannot be modified nor can they be erased by the end user.  This retains the Data Integrity of the sample analysis.

Key areas in section 211.110(b) …

This section of the FDA regulations pointed out by the Data Integrity guidance document stresses that data must be stored to prevent deterioration or loss and must be readily available for review.

How the Vision Analytical Insight series of products complies …

Again, the Data Mirroring feature of the Vision Analytical Insight series of products satisfied this requirement.  Data Mirroring is a feature within the Vision Analytical Insight series of products software where the computer software will store the data files on a separate directory or hard drive or even a network drive at the same time it is being stored on the computer system operating the instrument.

By having the data mirroring set up to store data simultaneously on a Write-Only network path, the data is written by the instrument software and cannot be erased or modified.  This ensures that the data is not lost or cannot be modified, which ensures compliance with 211.110 of the Code of Federal Regulations.

• §§ 211.100 and 211.160 require that certain activities be documented at the time of performance and that laboratory controls be scientifically sound

Key areas in sections 211.100 and 211.160 …

These sections of the FDA regulations pointed out by the Data Integrity guidance document require that certain activities be documented at the time of performance and that the laboratory controls be scientifically sound.

How the Vision Analytical Insight series of products complies …

The laboratory control activities carried out generally fall under the procedures and quality systems of each lab to ensure compliance to CGPM regulations.   However, in section 211.160(4), the regulation states the following …

4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.

To assist with this compliance to this section, the Vision Analytical Insight series of products Instrument Qualification Program, discussed above, does include NIST traceable standards as well as non-traceable controls that enable the end user to establish a routine to verify accuracy of the Vision Analytical Insight series of products at regular intervals.  Also, upon completion of the Instrument Qualification, the Vision Analytical Insight series of products left with a calibration sticker that not only serves as objective evidence that the system was installed and calibrated by an authorized and trained engineer but also sates the interval of the next calibration.

Example of an instrument certification label …

• 211.180 requires true copies or other accurate reproductions of the original records.

How the Vision Analytical Insight series of products complies …

Data Mirroring …

As mentioned above, Data Mirroring is a feature within the Insight software where the computer software will store the data files on a separate directory or hard drive or even a network drive at the same time it is being stored on the computer system operating the instrument.

• § 211.188, 211.194, and 212.60(g) require complete information, complete data derived from all tests, complete record of all data, and complete records of all tests performed.

How the Vision Analytical Insight series of products complies …

21 CFR Part 11 compliance that is embedded into the  Vision Analytical Insight series of products  incorporates Audit Trails capturing all activities of all tests performed.  Data files with raw data are prevented from modification once the sample is completed and saved. Any attempt to modify data files outside of the Vision Analytical Insight series of products software is prevented with Check-Sum verifications on data files.

Assurance that the files are stored where they can only be accessible is achieved with the Data Mirroring featured discussed above.

• Gov Website
• Current Expectations and Guidance, including Data Integrity and Compliance With CGMP, Sarah Barkow, PhD
• Particle size analysis, Apr 01, 2009, By Paul Kippax, Pharmaceutical Technology Europe PTE, Volume 21, Issue 4
• ICH Topic Q6A — Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, December 2000. http://www.ich.org/