As a background summary, CGMP represents the Current Good Manufacturing Practice regulations enforced by the US Food and Drug Administration (FDA). CGMP guidelines provide for systems that give assurances of proper design, monitoring, and control of manufacturing processes and facilities in the pharmaceutical industry. Compliance to the CGMP regulations ensures the strength, quality, purity and identity of drug products by making it a requirement that manufacturers are satisfactorily in control of their operations.
To make sure that CGMP guidelines are followed, the FDA conducts audits on pharmaceutical product manufacturers as well as manufacturers of medical devices that are also beneath the same umbrella of the guidelines. In the duration of inspections over many years, the FDA has found an increase in CGMP violations that involve lapses in data integrity. Thus, this guidance was developed to give clarification and explain in detail data integrity problems as in relation to the CGMP requirements in the 21 Code of Federal Regulations part 210, 211, and 212 which tackle manufacturing. It is of keen importance to acknowledge that this guidance document is not a complete compilation of items that must be addressed, but instead are key areas that deal with Data Integrity that have been focal points of issues that must be resolved. It is the responsibility of the manufacturer to enact this guidance in their processes.
The FDA defines Data Integrity within this document 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).
Using this acronym “ALCOA” is something the FDA uses in other guidance documents. Throughout the document, the review of how data is controlled, the method audit trails are managed and how records are maintained are discussed.
Particle Analyzers and their Role in the Pharmaceutical Industry
Particle size specifications are in use in pharmaceutical development as a parameter that can affect the final product. In the majority of cases, solid or suspension delivery or bioavailability of pharmaceuticals are directly related to particle size, given the fact it has control of dissolution characteristics. Dissolution rates are in proportion to the surface area, therefore smaller particles with higher surface areas will promote a quicker dissolution of the pharmaceutical compound.
Aside from particle size, the uniformity of the size distribution is also significant. More narrow particle size distributions enable a more controlled and uniform dissolution rate. On the other hand, pharmaceutical compounds are at times developed with bigger particle distributions to make for a less speedy release of the therapeutic compound.
As particle count, size and shape have been granted a predominant role in controlling the final pharmaceutical products, they have become a standard part of the toolkit in manufacturing and development. Due to this, particle analysis equipment falls under the quality guidelines of each pharmaceutical manufacturer’s quality program and will also draw the attention of the FDA.
What This Means for Users of Particle Sizing Equipment
Granting the fact that the guidance document on Data Integrity has a very similar format to the August 2003 guidance on Part 11 for Electronic records, it is highly probable that putting the Data Integrity guidance document into place will run the same path of enforcement. If you have reached this far into the document, it is clear that you are at least partly informed either in the instrumentation that is in use and / or is in the pharmaceutical sector with particle size analysis equipment.
In either instance, you may have experience of the serious level the FDA takes on 21 CFR 11 and auditing / enforcing of the “guidance” points. It is more probable than not that the FDA will add to their CGMP audits a more penetrating investigation based on the Data Integrity guidance document. Therefore, it is vital for manufacturers to make sure all “computerized systems” are inspected to assess how they comply.
Shown below is an extract of a recent FDA Warning Letter submitted to a Pharmaceutical Company after an audit of their facility. After reading the entire warning letter, Data Integrity deficiency problems were one of the most apparent findings.
As the warning letter demonstrates, the FDA is presently auditing to the Data Integrity guidance document.
Additionally to these points raised in the Data Integrity guidance document, it is just as 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. Satisfactory installation and operational qualifications should be used to show the equipment can perform the assigned task.
What This Means for the Manufacturers of Particle Sizing Equipment
Particle sizing equipment manufacturers have treated 21 CFR 11 as a necessity, not a “guidance”. To compete in the market space, it was the expectation that equipment manufacturers make any required modifications to make sure of compliance. Keep under consideration that the 21 CFR 11, as a guidance document, made it a requisite for the manufacturer to interpret the points within the guidance document and put in place modifications as they saw fit.
However, what was important was not the method of implementation of the guidance points, but how the internal quality auditors and the FDA would interpret how the guidance document was implemented. Therefore, it was evident previously that the instrument manufacturers that best met the points laid out in the guidance document of 21 CFR 11 were those that were working in tandem with pharmaceutical companies and FDA expectations.
It is expected to be the same for the Data Integrity guidance document. It is just a matter of time before every pharmaceutical customer adds to their 21 CFR 11 checklist for purchasing computerized systems’ new checklist items in relation to Data Integrity. Thus it again falls within the instrument manufacturer’s responsibilities to make sure all points and topics are addressed and interpreted with a decent understanding of what the expectations of pharmaceutical customers and the FDA are, and to record how each point is implemented for Data Integrity.
It is also significant that instrument manufacturers have programs implemented to allow the installation and operational qualification of equipment that will record the FDA’s validation requirements.
How Does the Particle Insight Comply with the FDA Guidance Document for Data Integrity
To meet the requirements for installation and operational qualification, the Particle Insight makes use of an IQ, OQ validation package which is recorded in another document. Also, the Particle Insight software is completely compliant to the 21 CFR Part 11, Electronic Records and Signatures requirements put in place by the FDA.
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 Particle Insight Complies
The Particle Insight has a tough IQ/OQ Qualification Program, which will be performed by qualified Field Service Engineers (FSE) that are specially trained and certified by the factory when the qualification process is executed. To complete the Qualification, a Qualification Kit provides a set of documents and forms, supplies and NIST traceable Standards. In accordance with Standard Operation Procedures (SOPs), maintenance and instrument performance should be routinely monitored.
By making use of the IQ/OQ Qualification program, the end-user is assured of correct installation and proof of operation at the site. The measurements of performance generated by the qualification process are recorded for future reference, audits and tracking. The Particle Insight Qualification verifies the function of the system, the precision and the system performance as measurements are undertaken with devices and standards that are calibrated and traceable to the standards of NIST.
There are three MAIN items involved in the Qualification:
- Service Engineer Manual
- Qualification Kit
- Customer Manual
Added 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 has specific instructions for the Field Service Engineer (FSE) to perform and complete the set of tests and actions in the duration of the execution of the initial instrument qualification and the yearly qualification. The following are the actions in the duration of the annual qualification.
This set of tests have the intention to investigate the performance of the instrument with a specific standard before any preventive maintenance actions taken. The results are saved in the OQ Pre-Test form.
Verification and Cleaning of various sections of the instrument such as optics, fluidics and hardware as well as calibration are actions conducted in the duration of preventive maintenance and the checklist finished.
The Qualification Kit has forms that should be filled out during the execution of the qualification.
- IQ Info Data form – This form is of use in entering all requisite 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 of use in entering 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 when entering the final results during the annual certifications
- Qualification Report – This report has the average readings from OQ Test, Pre-Test and Post forms and the Pass/Fail results
- Post Testing – This set of tests were created to evaluate the performance of the instrument with a specific standard after preventive maintenance actions are conducted. The results are saved in the OQ Post-Test form
- Completion Notification – To report that the Qualification was successfully completed
- Acceptance Notification – To provide confirmation of acceptance
- Out of Specification form – This form should be filled out in the event of the failure of any of the OQ Tests 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 resolve the issue.
- Log form – This form is to keep track of qualifications (initial and annuals)
Data Mirroring is a feature contained the Particle Insight software where the computer software will store data files on a separate directory, hard drive or even a network drive while it is being stored simultaneously on the computer system that operates the instrument.
Optimally, the path for the mirrored files should be a network drive that is already established where there are available Write-Only privileges. By doing this, backup files are generated in real-time that cannot be changed nor can they be deleted by the end-user. This keeps the Data Integrity of the sample analysis.
Key Areas in Section 211.110(b)
This extract of the FDA regulations pointed out by the Data Integrity guidance document emphasizes that data has to be stored to prevent it being lost or deteriorating, and must be easily available for review.
How the Particle Insight Complies
Again, the Data Mirroring feature of the Particle Insight answered this need. Data Mirroring is a feature of the Particle Insight software where the computer software will store data files on a separate directory, hard drive or network drive at the same instance it is being stored on the computer system that operates the instrument.
When the data mirroring is set to store data at the same time on a Write-Only network path, the data is written by the instrument software and cannot be changed or deleted. This makes sure that the data is not lost or cannot be changed, which makes sure 211.110 of the Code of Federal Regulations is complied with.
§§ 211.100 and 211.160 have a requirement that particular 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 necessitate that particular activities be recorded at the time of performance and that the laboratory controls be scientifically sound.
How the Particle Insight Complies
The laboratory control activities conducted generally come under the procedures and quality systems of each lab to make sure CGPM regulations are complied with. 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 help comply with this section, the Particle Insight Instrument Qualification Program, as discussed above, includes NIST traceable standards as well as non-traceable controls that allow the end-user to set up a routine to regularly verify the accuracy of the Particle Insight. Additionally, when the Instrument Qualification is completed, the Particle Insight left with a calibration sticker that not only can serve as objective evidence that the system was installed and calibrated by an authorized engineer but also states the next calibration’s interval.
An instrument certification label example
How the Particle Insight Complies
As mentioned previously, Data Mirroring is a feature contained in the Particle Insight software where the computer software will store the data files on a separate directory, hard drive or even a network drive, while simultaneously being stored on the computer system that operates the instrument.
§§ 211.188, 211.194, and 212.60(g) need complete information, complete data drawn from all tests, complete record of all data, and total records of all performed tests.
How the Particle Insight Complies
21 CFR Part 11 compliance that is built into the Particle Insight incorporates audit trails that capture all activity of all performed tests. Raw data files are stopped from being changed once the sample is completed and saved. Attempts to change data files outside of the Particle Insight software is prevented with Check-Sum verifications on data files.
The Data Mirroring discussed above achieves the assurance that the files are stored where they can only be accessible.
This information has been sourced, reviewed and adapted from materials provided by Vision Analytical Inc.
For more information on this source, please visit Vision Analytical Inc.