FDA 21 CFR Part 211 and Understanding its Requirements

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What is FDA 21 CFR Part 211 ?

Introduction: 21 CFR 211 compliance is your organization’s stepping stone to meeting the FDA’s definition of current good manufacturing practice (cGMP). Complying with 21 CFR 211 proves that your business has a safe, effective, consistent and quality-managed drug manufacturing operation in place.

FDA 21 CFR Part 211, also known as the Current Good Manufacturing Practice (CGMP) for Finished Pharmaceuticals, is a set of regulations established by the U.S. Food and Drug Administration (FDA). It outlines the requirements for the manufacturing, processing, packing, and storing of drug products to ensure their safety, identity, strength, quality, and purity. It is the gold standard for pharmaceutical manufacturing practices in the United States. Compliance with these regulations is required for pharmaceutical companies to obtain and maintain FDA approval for their products.

Complying with 21 CFR Part 211 and its controls over computerized system ensures compliance with U.S. regulations and facilitates international market access and acceptance.

An FDA data integrity inspection of a drug manufacturing facility focuses on computer systems validations, computer generated, time-stamped audit trails, ability for FDA to inspect, review, and copy records and proper records retention based on “a justified and documented risk assessment and a determination of the value of the records over time.”

How 21 CFR Part 211 controls over Computerized Systems ?

21 CFR Part 211.68 mandates rigorous controls over computerized systems in pharmaceutical manufacturing to ensure the integrity and security of production and control records. This regulation is crucial for maintaining the quality and safety of pharmaceutical products.

21 CFR Part 211.68 revolves around ensuring the integrity and security of data within computerized systems used in the manufacturing and control of pharmaceutical products. It mandates strict controls over these systems to ensure that only authorized personnel can make changes to critical records, such as master production and control records. The regulation emphasizes the importance of verifying the accuracy of data entered into and outputted from these systems, with the extent and frequency of these verifications being tailored to the system’s complexity and reliability.

Furthermore, it requires the maintenance of backup files for data inputted into these systems to safeguard against data loss, except in cases where data, like certain calculations related to laboratory analyses, are rendered unnecessary by the computerization process. In such scenarios, it’s important to keep a written record of the computer program alongside relevant validation data to demonstrate its accuracy and reliability. To ensure the integrity of the backup data, the regulation specifies that hard copies or alternative storage methods (e.g., duplicates, tapes, microfilm) must be used. These should be designed to guarantee that the backup is exact, complete, and protected against unauthorized alterations, accidental erasures, or loss.

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How 211.68 works with Vial Filling M/C Production Data and Records?

Imagine a vial filling machine used in a pharmaceutical, responsible for accurately dispensing a liquid drug into vials. This machine is controlled by a computer system that manages the operation parameters, records production data (like batch numbers, fill volumes, and production dates), and ensures that the product meets quality standards.

Compliance with these below requirements ensures that the vial filling process is reliable, consistent, and up to the standards expected by regulatory authorities, ultimately safeguarding patient safety.

1. Only individuals with authorized access can make operational changes to the machine, preventing unauthorized modifications.
2. Regular verification of the accuracy of both input (like fill volume) and output data (such as production data) to ensure product quality.
3. The need for these verifications depends on the system’s complexity and reliability, with critical parameters requiring stringent oversight.
4. Keeping backups of all production data to prevent data loss, including detailed batch records.
5. Ensuring backups are exact, complete, and secure against alterations or loss.
6. Maintaining documentation for any data not stored due to direct management by the computerized system, including validation of the computer program.

What is ALCOA and ALCOA+ Principles?

ALCOA stands for the original five principles which ensure data integrity in the life sciences sector. It has been introduced by USFDA- Its significance spans a broad spectrum of activities, notably in pharmaceutical research, production, testing, and logistics.

It talks about data. Whereas data is facts, figures, and statistics generated / collected during the GXP activity. Data includes all original records, true copies, source data, metadata, reports which are record during the GXP activity.

• ALCOA stands for Attributable, Legible, Contemporaneous, Original, And Accurate. But now, ALCOA is old and ALCOA+ is the updated concept.
• This “+” includes  Complete, Consistent,Available and Enduring,
• Many of Pharma industry and regulatory bodies like FDA, WHO follow this concept.

The ALCOA framework is essential for ensuring the data integrity of different GMP records

• Electronically recorded data captured via equipment ranging from straightforward machinery to intricate, highly customizable computerized systems.
• Paper-Based records involves the manual jotting down of observations or activities on paper.
• Hybrid Records is a combination of paper-based and electronic records that together form the original record.
• Other Formats extends to photographs, images, chromatography plates, and beyond, covering a diverse array of data recording methods.ludes

ALCOA+ Principles:

21CFR Part 11 focuses specifically on electronic records and signatures, in practice it is part of the good manufacturing practices (GMP) explained in 21 CFR Part 211. For example, in their data integrity criteria Part 11 and Part 211 links to ALCOA: attributable, legible, contemporaneously recorded, original, and accurate.  Lets understand ALCOA + Principle in detail.

Attributable (Who, when, what and why?)

Legible (Readable and permanent?)

Contemporaneous (At the right time?)

Original (Unaltered state and ‘true copy’?)

Accurate: (Is it the right value/action?)

Complete (Is all information available?)

Consistent (Is the sequence correct?)

Enduring (is it securely stored for long term use?)

Available (Is the data accessible immediately

What are the requirements of 21 CFR Part 211?

21 CFR 211 compliance is your organization’s stepping stone to meeting the FDA’s definition of current good manufacturing practice (cGMP). Complying with 21 CFR 211 proves that your business has a safe, effective, consistent and quality-managed drug manufacturing operation in place

FDA 21 CFR Part 211 establishes several requirements for pharmaceutical manufacturers to ensure the quality, safety, and effectiveness of drug products.

1. General provision

2. Organization and Personnel

3. Buildings and Facilities

4. Equipment

5. Control of Components and Drug Product Containers and Closures

6. Production and Process Controls

7. Packaging and Labeling Control

8. Holding and Distribution

9. Laboratory Controls

10. Records and Reports

11. Returned and Salvaged Drug Products

Conclusion

Maintaining compliance with FDA 21 CFR Part 211 can be complex and rigorous, requiring careful attention to detail, robust quality systems, and effective processes. However, the benefits of compliance far outweigh the challenges. Compliance helps protect patients’ health and safety, builds trust with regulatory authorities, enhances product quality, and mitigates the risk of regulatory noncompliance.

As we understand that data integrity is essential to all validation processes in pharmaceutical and medical device manufacturing facilities. Understanding and following the ALCOA+ principles will help you ensure data integrity, selecting data solutions and implementing data recording and protocols. As well as following the ALCOA+ principles should be a high priority for all life sciences sector manufacturers.

Useful Links

• https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211

• https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-11

• https://www.fda.gov/files/drugs/published/Data-Integrity-and-Compliance-With-Current-Good-Manufacturing-Practice-Guidance-for-Industry.pdf