Quality Control Electronic Records for 21 CFR part 11 Compliance

Introduction

The FDA’s 21CFR part 11 guidance1 on the use of electronic records for data retention or submission is clear. With manually implemented Standard Operating Procedures for Quality Control testing and manual transcription of the test results still common practices in the pharmaceutical QC world, the resultant opportunities for human error raises concerns over the integrity of the data in the final electronic record, no matter how safely the final record is stored.

This paper describes how Quality Control instruments can be optimised for pharmaceutical use, helping to improve the integrity of the data in the final electronic record.

Quality Control Manual SOPs

The introduction of the FDA’s Guidance for Industry Part 11, Electronic Records; Electronic Signatures prompted the pharmaceutical industry to take a closer look at how it stored and controlled electronic records. One area however still very much remains a concern: the potential for affecting the integrity of Quality Control (QC) test result data by human error through the use of manual Standard Operating Procedures (SOPs). A manual SOP is where the instrument set-up and configuration is performed manually by the user or where the QC test results are manually transcribed into electronic record format. The electronic record may be kept safely and securely, but the data it contains may not be correct, or may simply be missing!

Electronic SOPs

In an effort to improve data integrity, some manufacturers have optimised their instrumentation specifically for pharmaceutical QC use, building into the instrument design the capability for pre-configured electronic SOPs for:

a) Instrument set-up and configuration b) Automatic pass-fail reports to pharmacopoeial criteria
c) Generation of electronic records straight from the instrument

The user simply selects the electronic SOP that has been pre-configured in the instrument and hits the ‘Go’ button and the instrument configures itself correctly according to the SOP, carries out the correct test and produces and electronic test result record, all automatically.

Final Product QC

Although largely harmonized, the requirements for parenteral drug particulate testing do vary from country to country and from product to product. The volume of the sample to be analysed and the format that the results are reported varies from product to product, e.g. the sampling requirements for small volume biological parenteral product, such as vaccines6, is different for that of a large volume parenteral such as an intravenous drip bag9. Results must be calculated and expressed in the correct format, e.g. counts per container, or counts per mL, depending on the product under test.

Whilst general-purpose liquid particle counting instrumentation can be used for the testing of particles in parenteral products, counters that have been optimized for the application are preferable due to the wide range of complexity in the testing. Particle counters that have been optimized for this testing will have the various compendial tests built-in and will calculate a pass/fail result automatically. As QC teams tend to use their product brand name to describe the product sample under test, optimized particle counters will allow the user to select the required test for each sample by selecting the product by name from a drop-down menu.

Cleanroom Routine Environmental Monitoring Records

Electronic SOPs are of particular benefit in portable air particle counters used in cleanroom routine environmental monitoring. While the FDA’s CGMP5, Europe’s GMP Annex 13, World Health Organisation2 and PICS4 documents specify the maximum concentration of airborne particles in pharmaceutical cleanrooms, it is ISO 14644-110 that specifies the method for cleanroom qualification/classification and routine environmental monitoring plans should be created by each factory based on their own risk assessment. Once SOPs for qualification and routine monitoring are in place they are typically carried out manually, with the instrument operator responsible for configuring the particle counter at each sample location according to the requirements of the SOP. Typically teams of people are dedicated to carrying out routine environmental monitoring on a daily basis and thousands of pieces of data are created each month. The manual SOP typically requires the data to be manually transcribed into an electronic record. Manual instrument configuration and data transcription process can be very error-prone. Counters that are optimised for pharmaceutical cleanroom use allow the whole process to be automated using electronic SOPs that are pre-programmed once into the counter and then simply called up by the operator, who selects the correct SOP by choosing the environmental location name from the counter menu.

Electronic Records Direct From QC Instrumentation

There are three methods for electronic record generation direct from QC instrumentation:

1. Export in file format listed in the FDA 21 CFR part 11 guidance via wired Ethernet
2. Export in file format listed in the FDA 21 CFR part 11 guidance via wireless Ethernet
3. Totally separate electronic test results record database on a separate, secure server

QC instrumentation is typically a capital expenditure and this, combined the cost of validation, means that instruments tend to be retained for a very long time, sometimes in excess of 15 years. Customers considering the purchase of QC instrumentation should bear in mind that they may wish to move to full electronic records at some time during the lifetime of the QC instrument and require one of these three electronic record generation methods in any new instrument purchases, even if they intend to remain with manual SOP execution in the shortterm. The availability of wireless Ethernet capability is of particular significance to portable QC instrumentation, such as portable air particle counters used in cleanroom routine environmental monitoring programs. In their guide to 21CFR part 11, the FDA suggests that electronic records may be kept in standard electronic file format and gives PDF, XML and SGML as examples. Many Laboratory Information Management Systems (LIMS) are designed to accept data from QC instrumentation in standard electronic formats including .csv and Excel*.

Conclusion

Pharmaceutical QC testing is complex and at the same time absolutely critical to a successful, compliant batch release. When selecting instrumentation, the QC team leader is well advised to look for instrumentation that has been optimized for pharmaceutical QC use, taking into account automated, pre-configured electronic SOPs, built-in compendial tests and secure electronic file transfer, such as File Transfer Protocol (FTP), for 21CFR part 11 electronic record retention.

References

1. U.S. Department of Health and Human Services Food and Drug Administration Guidance for Industry, Part 11, Electronic Records; Electronic Signatures — Scope and Application August 2003 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center
   for Biologics Evaluation and Research (CBER) Office of Regulatory affairs (ORA) Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 USA
2. World Health Organisation Who Good Manufacturing Practices For Sterile Pharmaceutical Products, 2009 World Health Organization, CH-1211 Geneva 27, Switzerland.
3. European Commission. EudraLex. The Rules Governing Medicinal Products in the European Union. Volume 4. EU Guidelines to Good Manufacturing Practice. Medicinal products for human and veterinary use, Annex 1: Manufacture of Sterile Medicinal Products, 14th February 2008. European Commission Enterprise and Industry Directorate-General, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel – Belgium.
4. Pharmaceutical Inspection Co-operation Scheme, PIC/S Guide To Good Practices for The Preparation Of Medicinal Products In Healthcare Establishments, 1st April 2008, PIC/S Secretariat 14, rue du Roveray CH - 1207 Geneva Switzerland.
5. Food and Drug Administration. Guidance for industry. Sterile drug products produced by aseptic processing – current good manufacturing practice, 2004. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Office of Regulatory affairs (ORA) Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 USA
6. Food and Drug Administration. USP<787> SUBVISIBLE PARTICULATE MATTER IN THERAPEUTIC PROTEIN INJECTIONS, August 1st 2014. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Office of Regulatory affairs (ORA) Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 USA
7. International Society for Pharmaceutical Engineering, The ISPE Good Practice Guide: Ozone Sanitization of Pharmaceutical Water Systems, First edition July 2012 http://www.ispe.org/ispe-good-practice-guides/ozone-sanitization-pharmaceutical-water-systems [14th August 2014]
8. Pharmaceutical and Healthcare Sciences Society, Best Practice for Particle Monitoring in Pharmaceutical Facilities, PHSS Technical Monograph No.16, First Edition 2008, ISBN 978-1-905271-15-3
9. Food and Drug Administration, USP<788> PARTICULATE MATTER IN INJECTIONS, May 1st 2009. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Office of Regulatory affairs (ORA) Division of Drug Information, HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 US
10. International Organization for Standardization, ISO 14644-1:1999(E) Cleanrooms and associated controlled environments — Part 1: Classification of air cleanliness 1st May 1999. International Organization for Standardization Case Postale 56, CH-1211 Genève 20, Switzerland

* Excel is a registered trademark of Microsoft Corporation in the United States and/or other countries.