The consequences of FDA citations can be costly. In this blog article, we discuss the top two FDA citations for pharmaceuticals and how to avoid or prevent them. In the United States of America, pharmaceutical drugs and medical devices are controlled according to The Code of Federal Regulations, Title 21: Food and Drugs (21 CFR). The FDA publicly releases warning letters and citations. Therefore, the cost of addressing citations and warning letters is not limited to production, maintenance, upgrades, or supply chain but also public confidence in your product and company.

Responsibilities of the Quality Control Unit

The Quality Control Unit (QCU) of a company may be referred to as the Quality Assurance Department or a similar name. This division of a pharmaceutical company is responsible for the ultimate quality of the product. The 21 CFR part 211.22, subpart B, details the responsibilities of the quality control unit.

Applying Quality Risk Management (QRM) to C&Q Planning

§ 211.22 Responsibilities of the 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.

(b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.

(c) The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.

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

– Code of Federal Regulations Title 21 Section 211.22

The most frequent FDA citation in pharmaceuticals is 21 CFR part 221.22, subpart B, letter D: “The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.” CFR §211.22(d) accounts for 27% of the observations recorded from 2016 to 2020. This part of the code seems logical, simple, and should be easy to follow. So, why is it the most cited part of the code? Obviously, the procedures are not entirely in writing or wholly followed.

Therefore, having the quality control procedure and the product review documented appropriately is absolutely critical to avoid this citation. We will discuss the second most cited part of 21 CFR before discussing ways to avoid or prevent both citations.

Production Record Review

The next most common citation is regarding production record review, precisely 21 CFR part 211, subpart J, 192. CFR §211.192 accounts for 31% of the observations made by the FDA from 2016 to 2020.

Reviewing documents 101

§ 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.

– Code of Federal Regulations Title 21 Section 211.22

Examples of frequent observations for CFR §211.192:

    • There is a failure to thoroughly review any unexplained discrepancy, whether or not the batch has been already distributed.
    • Investigations of an unexplained discrepancy did not extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy.
    • No written record of investigation
    • The written record of the investigation is incomplete.
    • Quality control unit review of records – Drug product production and control records are not reviewed by the quality control unit to determine compliance with all established and approved written procedures before a batch is released or distributed.

Actions to avoid, prevent or reduce similar observations

a) Create and Implement Quality Systems
b) Create a QCU and establish adequate policies and procedures
c) Follow the six-system inspection model approach for a self-inspection program
d) Monitor the regulatory compliance activities through regular management reviews

a) Create and Implement Quality Systems
    • Quality – product quality
    • Quality by Design – pre-development, development, and launch
    • Quality Risk Management –
    • Corrective And Preventive Action (CAPA)
    • Change Control
    • Quality Unit
    • Six-system based inspection model (quality, production, facilities and equipment, laboratory controls, materials, and packaging and labeling.
b) Create a QCU and establish adequate policies and procedures
    • Procedures need to be clear and describe the responsibilities and authority of the QCU for:
      • approving regulatory and controlled documents,
      • approving or rejecting all components, drug products containers and closures, in-process materials, packaging materials, labeling, and drug products, including those manufactured, processed, packed, or held under control by another company
      • Reviewing batch records to ensure compliance with the requirements etc.
c) Follow the six-system inspection model approach for a self-inspection program
    • Quality, production, facilities and equipment, laboratory controls, materials, and packaging and labeling

Six-System Inspection Model is described according to four major factors:

i) Management responsibilities

ii) Resources

iii) Manufacturing operations

iv) Evaluation of activities

d) Monitor the regulatory compliance activities through regular management reviews on the following examples of Key Performance Indicators
    • Non-conformance and CAPAs
    • Customer Complaints
    • Field Alert Reports (FAR) and Medical Device Reporting under part 803
    • Recalls
    • Internal Audits
    • Training including GMP refresher training 

Summary

To prevent the top two FDA citations, 21 CFR §221.22 and §211.192, create and implement quality systems overseen by a QCU with written policies and procedures, and perform internal inspections and regular reviews. PSC Biotech® has quality professionals to help you evaluate gaps and conduct internal audits and inspections. Contact us today for a free consultation and quote to fit your budget and needs!

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