FDA 483 Observations in 503A Facilities

In this issue, we will look at specific categories 3 through 6 as presented last week and shown below:.

1. Personnel
2. Facility
3. Equipment
4. Environmental Monitoring
5. Cleaning, Disinfecting, and Deactivating
6. Compounded Product Quality
7. Unapproved Components
8. Insanitary Conditions
9. Complaint Follow-up
10. Administrative and Regulatory

3. Specific Issues - Equipment

• Equipment and utensils not maintained at appropriate intervals to prevent malfunctions that would alter the safety, identity, strength, quality, or purity of the drug product.
• Lack of validation of firms sterilizing autoclaves and ovens to ensure the required internal temperatures are reached and maintained for the required runtime.
• Your firm failed to routinely calibrate, inspect, or check according to a written program designed to assure proper performance of automatic, mechanical, electronic equipment, or other types of equipment, including computers, used in the manufacture, processing, packing, and holding of a drug product.

4. Specific Issues - Environmental Monitoring (EM)

• Media fills were not performed under the most challenging or stressful conditions.
• Only about 4% of the media fill units filled were incubated and inspected for growth, biasing the results.
• Lack of assurance that your firm can aseptically produce drug products within your facility.
• Your firm lacked environmental monitoring procedures and documentation to demonstrate that EM was conducted during sterile processing operations.
• Your firm failed to conduct media fills that closely simulate aseptic production operations incorporating worst-case activities and conditions.
• You firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas.

5. Specific Issues - Cleaning, Disinfecting and Deactivating

• Sporicidal agents were not used in your facility's cleanrooms and/or ISO 5 classified aseptic processing area.
• Your firm uses non-sterile disinfectant for cleaning inside the ISO 5 areas.
• Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions.
• Your cleaning is deficient as hazardous drugs are not adequately deactivated, posing a contamination risk to no-hazardous drug products, as well as other hazardous products.

6. Specific Issues - Compounded Product Quality

• Not all batches of sterile drug products not potency tested prior to release and distribution.
• Releasing product with super-potent results.
• No written testing program designed to assess the stability characteristics of drug products.
• Lack of written procedures for a continuous stability program.
• Does not perform stability testing for sterility or endotoxin on sterile hazardous and non-hazardous drug products.
• Each batch of drug product purporting to be sterile is not laboratory tested to determine conformance.
• There are no written procedures for production and process controls designed to ensure the drug products have the identity, strength, quality, and purity they purport to have.
• There is no written testing program designed to assess the stability characteristics of the drug products compounded. Records related to drug product components, containers, closures, labeling, production, control, and distribution and within the retention period for such records were not readily available for authorized inspection.
• Your firm failed to provide complete documentation, including a Certificate of Analysis, for the receipt and approval from your suppliers.
• Your firm released and distributed several drug products in which the strength exceed the label claim.

More information next week.

The revisions to the USP Compounding General Chapters are available for an extended public comment period until January 31, 2022.

• <795> Pharmaceutical Compounding - Nonsterile Preparations
• <797> Pharmaceutical Compounding - Sterile Preparations

Here is a list of activities and resources that might be helpful, and all are encouraged to share your comments:

• Open Forum sessions to discuss questions with the Expert Committee:

• Open Forum Session <795>: September 8, 2021, 1:00 - 3:00 p.m. ET
• Open Forum Session <797>: September 15, 2021, 10:00 a.m. - 12:00 p.m. ET
• Open Forum Session <795>: January 12, 2022, 10:00 a.m. - 12:00 p.m. ET
• Open Forum Session <797>: January 19, 2022, 2:00 - 4:00 p.m. ET

• Explore informational documents intended to supplement the proposed chapters and explain the CMP EC's rationale behind the revisions. The documents can be downloaded at the above URL.

• BUD Scientific Rationale for the 2021 Proposed Revisions to <795>
• BUD Reference for the 2021 Proposed Revisions to <795>
• Compounding Expert Committee Responses to Stakeholder Engagement Themes for the 2021 Proposed Revisions to <795>
• BUD Scientific Rationale for the 2021 Proposed Revisions to <797>
• BUD Reference for the 2021 Proposed Revisions to <797>
• Compounding Expert Committee Responses to Stakeholder Engagement Themes for the 2021 Proposed Revisions to <797>
• Stability Study Reference Document for the 2021 Proposed Revisions to <795> and <797>