Common FDA 483 Observations and Solutions for Quality System Failures

The following FDA 483 observations list highlights common areas of non-compliance identified during inspections at US drug manufacturing facilities conducted between Jan. 1, 2023, to May 31, 2024. This article discusses each observation, provides examples of typical Quality System failures, advises on assessments to identify whether you may have these vulnerabilities, and outlines corrective measures to avoid future occurrences.

1. Responsibilities of the Quality Control Unit

Sec. 211.22 Responsibilities of quality control unit. (d) The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.

Observation Rate: 67.8% Typical Failures: Lack of written procedures for the quality control unit (QCU) or failure to follow existing procedures. Assessment Tips: Review documentation of QCU procedures and verify their implementation across all departments. Also conduct internal audits to ensure all SOPs are being adhered to.

Corrective Measures:

• Develop comprehensive but simple, written standard operating procedures (SOPs) for the QCU. Remember, complexity is the enemy of Quality and Compliance.
• Ensure that all relevant staff comprehensively understand their responsibilities by implementing a training program that transcends the basic "read-and-understand" approach. A truly effective training initiative engages multiple learning modalities: reading, hearing, seeing, and doing. By embracing this holistic approach, we can guarantee that your team not only learns but embodies the skills and knowledge necessary to excel, fostering higher adherence and superior performance.

2. Production Record Review: Deviations

Sec. 211.192 Production record review. All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup.

?Observation Rate: 59.7% Typical Failures: Incomplete reviews of production records, lack of investigations into discrepancies, or investigations conducted are not thorough enough to find true root causes. Assessment Tips: Monitor compliance reports and investigate ongoing discrepancies. Conduct periodic trending and strictly monitor the effectiveness of corrective and preventive actions (CAPAs).

Corrective Measures:

• Implement a robust Deviation investigation process.
• Ensure thorough training on the importance of accurate record-keeping, review, and conducting thorough investigations.

3. Written Procedures; Changes

Sec. 211.100 Written procedures; deviations. (a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

?Observation Rate: 47.6% Typical Failures: Unapproved changes to procedures or lack of documentation regarding deviations to these requirements. Assessment Tips: Examine records for documentation of each procedural revision and ensure appropriate review and approvals occur.

Corrective Measures:

• Establish and follow a formal change control system for approving all procedural changes.
• Provide regular thorough training on handling and documentation of changes to approved documents.

4. General Laboratory Controls

Sec. 211.160 General requirements. (b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.

Observation Rate: 36.5% Typical Failures: Inadequate specifications or testing procedures for laboratory controls that do not have scientific justification. Assessment Tips: Evaluate the appropriateness of existing laboratory methods and standards including the sampling plans. Ensure sampling plans are representative and required testing ensures appropriate materials of adequate quality are used.

Corrective Measures:

• Review and update testing and sampling protocols regularly based on scientific evidence.
• Design a continuous training program for laboratory staff and material samplers on quality controls to ensure material quality.

5. Testing and Approval or Rejection of Components

Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures. (d) Samples shall be examined and tested as follows: (2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.

?Observation Rate: 32.4% Typical Failures: Failure to conduct identity (ID) testing on each receipt of components or inadequate verification of supplier analyses. Assessment Tips: Ensure each receipt of components is minimally ID-tested. Assess the robustness of supplier evaluations and testing protocols.

Corrective Measures:

• Implements robust supplier qualification and monitoring program.
• Conduct at least one ID test per batch of components received.

6. Equipment Design and Location

Sec. 211.63 Equipment design, size, and location. Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.

?Observation Rate: 31.4% Typical Failures: Inadequate facility or equipment layout affecting operations, including cleaning of the equipment. For example, often the equipment design may make it difficult to clean. Assessment Tips: Audit the manufacturing workspace for efficient flow and compliance with design standards and ensure adequate cleaning procedures are in place.

Corrective Measures:

• Reassess production layouts and equipment design and make necessary modifications based on workflow, safety, and cleanability.
• Ensure that equipment is suitable for its use and meets maintenance and cleaning requirements.

7 & 8. Equipment Cleaning and Maintenance

Sec. 211.67 Equipment cleaning and maintenance. (a) Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. (b) Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product.

Observation Rate: 31.4% and 27.3% Typical Failures: Insufficient cleaning or maintenance processes or lack of adherence to established cleaning and maintenance procedures. Assessment Tips: Review cleaning logs and maintenance schedules for compliance with the approved procedures. Ensure the approved procedures are both adequate and necessary. Sometimes, the procedures need updating.

Corrective Measures:

• Define cleaning and maintenance cycles based on use and contamination risk.
• Thoroughly train personnel on sanitization requirements and enforce strict adherence to cleaning procedures.

9. Controls for Automated Systems

Sec. 211.68 Automatic, mechanical, and electronic equipment. (b) Appropriate controls shall be exercised over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. Input to and output from the computer or related system of formulas or other records or data shall be checked for accuracy. The degree and frequency of input/output verification shall be based on the complexity and reliability of the computer or related system. 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. In such instances a written record of the program shall be maintained along with appropriate validation data. Hard copy or alternative systems, such as duplicates, tapes, or microfilm, designed to assure that backup data are exact and complete and that it is secure from alteration, inadvertent erasures, or loss shall be maintained.

?Observation Rate: 24.3% Typical Failures: Lack of verification on automated system changes or inadequate backup procedures. Assessment Tips: Check system access logs and validation of changes made to electronic records.

Corrective Measures:

• Implement strict access controls and regular audits of systems and their changes.
• Maintain backup systems and test data recovery processes regularly.

10. Identity Testing of Components

Sec. 211.84 Testing and approval or rejection of components, drug product containers, and closures. (d) Samples shall be examined and tested as follows: (1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.

?Observation Rate: 23.3% Typical Failures: Identity testing not conducted for incoming components and accepting on vendor CoA only. Assessment Tips: Review the testing specifications and adherence to component identity checks upon each receipt.

Corrective Measures:

• Establish mandatory identity confirmation for each component receipt.

11. Stability Testing

Sec. 211.166 Stability testing. (a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates.

?Observation Rate: 20.3% Typical Failures: Absence of stability testing programs, not following the approved stability plan, inadequate follow-up on results, or the results do not support the current expiration dates. Assessment Tips: Check the stability protocols and stability data vs. the expiration dates. Corrective Measures:

• Develop a robust stability testing program with clearly defined timelines and methodologies.
• Analyze stability data in a timely fashion to adjust storage conditions or expiration dates as needed.

12. Personnel Qualifications

Sec. 211.25 Personnel qualifications. (a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.

?Observation Rate: 18.2% Typical Failures: Insufficient training or qualifications for personnel involved in critical manufacturing processes or as trainers. Assessment Tips: Audit employee training curriculums and records, and assess qualifications against job requirements.

Corrective Measures:

• Create and enforce mandatory training programs specific to job functions, including continuous education on current Good Manufacturing Practices (cGMP).
• Create job descriptions by job function.

13. Control of Microbiological Contamination for Sterile Products

Sec. 211.113 Control of microbiological contamination. (b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes.

?Observation Rate: 18.2% Typical Failures: Lapses in aseptic techniques or inadequate sterilization validation. Assessment Tips: Evaluate the effectiveness of contamination control procedures and monitor environmental conditions. Evaluate validation of aseptic and sterilization processes.

Corrective Measures:

• Establish rigorous aseptic techniques training and validate all sterilization processes.
• Perform regular audits of cleanroom practices and environmental monitoring.

14. Sampling and Testing of In-Process Materials & Validation of Processes

Sec. 211.110 Sampling and testing of in-process materials and drug products. (a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.

?Observation Rate: 18.2% Typical Failures: Inadequate in-process control measures, lack of descriptive testing procedures for batches, or most commonly lack of validation supporting those processes. Assessment Tips: Review procedures for in-process testing and compare them to actual practices. Ensure processes are appropriately validated.

Corrective Measures:

• Define clear in-process control measures and update testing documentation accordingly.
• Train personnel on in-process sampling techniques, ensuring procedures are followed correctly.
• Ensure processes are appropriately validated for the stage of the product lifecycle.

15. Authority of the Quality Control Unit

Sec. 211.22 Responsibilities of quality control unit. (a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.

?Observation Rate: 17.2% Typical Failures: Quality control unit lacking authority, failing to fully review production processes adequately, or failing to reject components or products that do not meet specifications. Assessment Tips: Assess the release/reject decisions made by the quality control unit and ensure they are justified.

Corrective Measures:

• Clearly delineate the authority and responsibilities of the quality control unit through documented procedures.
• Ensure that the QCU is independent and adequately staffed to fulfill its responsibilities.

16. Testing and Release of Drug Products for Distribution

Sec. 211.165 Testing and release for distribution. (a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on specific batches of shortlived radiopharmaceuticals, such batches may be released prior to completion of sterility and/or pyrogen testing, provided such testing is completed as soon as possible.

?Observation Rate: 15.2% Typical Failures: Incomplete laboratory determinations prior to release or failure to document testing results. Assessment Tips: Investigate and ensure compliance with testing completion before product distribution.

Corrective Measures:

• Institute a strict release policy that requires all testing to be concluded before products leave the facility.
• Document and maintain records on all testing outcomes for accountability.

17. Complaint and Adverse Event Handling

Sec. 211.198 Complaint files. (a) Written procedures describing the handling of all written and oral complaints regarding a drug product shall be established and followed. Such procedures shall include provisions for review by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with § 211.192. Such procedures shall include provisions for review to determine whether the complaint represents a serious and unexpected adverse drug experience which is required to be reported to the Food and Drug Administration in accordance with §§ 310.305 and 514.80 of this chapter.

?Observation Rate: 12.2% Typical Failures: Ineffective handling of complaints regarding product specifications or lack of thorough investigation. Failure to identify and report adverse drug experiences. Assessment Tips: Review the processes for tracking and responding to customer complaints and ensure appropriate investigations occur and adverse events are appropriately handled.

Corrective Measures:

• Establish a formal complaint management system that includes detailed investigation procedures.
• Incorporate feedback mechanisms that lead to corrective actions based on customer complaints.
• Coordinate adverse drug experience handling process with Complaint handling process.

18. General Laboratory Control Requirements

Sec. 211.160 General requirements. (b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include: (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.

?Observation Rate: 12.2% Typical Failures: Failure to calibrate instruments regularly or risk of using faulty equipment. Assessment Tips: Audit calibration history and ensure compliance with established procedures.

Corrective Measures:

• Develop a calibration schedule and ensure all instruments are calibrated according to specified intervals.
• Train staff on the importance of ensuring equipment accuracy (calibration) prior to use.

Conclusion

Ensuring compliance with FDA regulations is vital for maintaining product quality and organizational integrity in drug manufacturing. By understanding common FDA 483 observations, assessing existing quality systems, implementing corrective measures, and fostering a culture of quality compliance, drug companies can minimize vulnerabilities and enhance overall operational efficiency. Regular audits, employee training, and procedural updates are critical commitments in this ongoing effort.

?

To genuinely address and prevent the recurrence of the identified deficiencies within these 483 observations, it's crucial not only to identify employee training as a corrective measure but to transform our approach. Simply repeating previous training methods will likely not yield better results. Instead, we should critically evaluate and enhance our training programs specific to each deficiency. By tailoring these programs, we ensure they are comprehensive and cater to diverse learning styles—reading, hearing, watching, and doing. This strategic enhancement will foster a deeper understanding and mastery of necessary skills, driving performance improvements and securing a more resilient and capable workforce.