Study on FDA Form 483 observations

An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. For the industry, it’s important to understand the information stated in FDA Form 483. This study report is to perform a case study on an FDA Form 483 through classifying each observation, recreating what kind of information was checked by auditors and proposing CAPA for one of the observations.

Keywords: FDA, Form 483, case study, observation, CAPA

1. Brief summary

An FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that in their judgment may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. For the industry, it’s important to understand the information stated in FDA Form 483.

This article is to perform a case study on an FDA Form 483. During the period of May 4 to May 14, 2009, Stryker Instruments Div. of Stryker Corporation was inspected by four auditors from FDA. There were totally 10 observations listed in the final audit report, FDA Form 483.

This study report is to classify each observation, recreate what kind of information was checked by auditors to identify the deviation and propose CAPA for one of observations.

2. Classification on observations

2.1 Subsystems of pharmaceutical quality system

A modern pharmaceutical quality system has six subsystems, which are Production System, Facilities and Equipment System, Laboratory Controls System, Materials System, Packaging and Labeling System. The observations listed in FDA Form 483 as attachment 1 have impact on one or more of those subsystems, which are summarized in Table 1. From Table 1, it’s found that every observation is linked to quality subsystem. This is because the quality system acts as a subsystem at the center of it all, provides the foundation for other five subsystems and helps them achieve compliance.

2.2 Deviation to GMPs

The observations in the FDA Form 483 were concluded according to cGMP, which is “Part 211-Current Good Manufacturing Practice for Finished Pharmaceuticals”. Observation means a deviation or deficiency to GMPs noted by an inspector during the inspection. The statements of cGMP, as well as GMP regulation of Health Canada corresponding to the observations are summarized in Table 2.

3. Information checked by auditors

During the inspection, documents were checked by auditors to identify the deviation. Table 3 below recreated the possible information checked by auditors. The auditors checked many documents during this inspection, but it seems that they focused on the documentation for validation and compliant.

4. CAPA proposal for observation

As an example, Corrective and Preventive Actions (CAPA) are proposed for observation #1 as below:

Corrective Actions:

• Conduct the revalidation for manufacturing process of the Clover Catheters and Silver Ex-Fen Catheters;
• Conduct the revalidation for the extrusion process of manufacturing the tubing component of the Clover Catheter and Silver Ex-Fen Catheters.

Preventive Actions:

• Review SOP of process revalidation, compare with FDA guidance (Process Validation: General Principles and Practices) to identify gaps and upgrade SOP accordingly;
• Review all the process validation reports according to SOP of process validation, and conduct revalidation when gaps identified.

Table 1: Observations’ impact on pharmaceutical quality system

Table 2: Deviations to cGMP(FDA) and GMP(Health Canada)

Table 2: Deviations to cGMP(FDA) and GMP(Health Canada) (cont.)

Table 3: Information checked by auditors

Table 3: Information checked by auditors (cont.)

References

[1] FDA Form 483 Frequently Asked Questions. https://www.fda.gov/iceci/inspections/ucm256377.htm
[2] Stryker Instruments. Kalamazoo, MI. Form 483 (Inspectional Observations). 5/04/09 – 5/14/09. https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/UCM172096.pdf
[2] Mandatory Reporting Requirements: Manufacturers, Importers and Device User Facilities. http://www.fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/reportingadverseevents/default.htm
[3]The Six Subsystems of a Pharmaceutical Quality System. Maxine K. Fritz. http://www.pharmacompliancemonitor.com/the-six-subsystems-of-a-pharmaceutical-quality-system/4585/
[4] Part 211-Current Good Manufacturing Practice for Finished Pharmaceuticals, CFR-code of Federal Regulations Title 21. FDA. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211
[5] Good Manufacturing Practices (GMP) Guidelines – 2009 Edition, Version 2 (GUI-0001).Health Canada. http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php
[6] Risk Classification of Good Manufacturing Practices (GMP) Observations.GUI-0023.Date issued: 2012-09-11.Health Canada.
[7] Process Validation: General Principles and Practices. FDA. January 2011