As Identified in the Inspections Observation page of the FDA website, in FY 2021, approximately 215 Form 483’s were issued to Drug manufacturers as a result of FDA inspection, resulting in over 1100 identified observations.  The full listing of inspectional observations is downloadable as an excel file.  The top ten observations by frequency of occurrence account for 32% of citations, and the top 10 citations for FY 2021 are:

Reference Number	Short Description	Frequency
21 CFR 211.22(d)	Procedures not  in writing, fully followed	80
21 CFR 211.192	Investigations of discrepancies, failures	49
21 CFR 211.100(a)	Absence of Written Procedures	44
21 CFR 211.160(b)	Scientifically sound laboratory controls	40
21 CFR 211.67(a)	Cleaning / Sanitizing / Maintenance	33
21 CFR 211.68(b)	Computer control of master formula records	30
21 CFR 211.63	Equipment Design, Size and Location	25
21 CFR 211.113(b)	Procedures for sterile drug products	22
21 CFR 211.68(a)	Calibration/Inspection/Checking not done	19
21 CFR 211.25(a)	Training–operations, GMPs, written procedures	18

Note – Tied at number 10 is:

21 CFR 211.110(a)

Control procedures to monitor and validate performance

18

 

FDA Systems Approach for GMP Inspections

FDA uses a Systems based approach for conducting inspections which is defined/described in the Compliance Policy Guide – 7356.002 for Drug Manufacturing Inspections, and additionally 7356.002A for Sterile Drug Manufacturing. These Systems include Quality, Facilities and Equipment, Materials, Production, Packaging and Labeling System, and Laboratory. System descriptions are from 7356.002 and are provided below:

FDA cGMP Systems

Quality System. This system assures overall compliance with cGMPs and internal procedures and specifications. The system includes the quality control unit and all of its review and approval duties (e.g., change control, reprocessing, batch release, annual record review, validation protocols, and reports, etc.). It includes all product defect evaluations and evaluation of returned and salvaged drug products. See the CGMP regulation, 21 CFR 211 Subparts B, E, F, G, I, J, and K.

Facilities and Equipment System. This system includes the measures and activities which provide an appropriate physical environment and resources used in the production of the drugs or drug products. It includes:
a) Buildings and facilities along with maintenance;
b) Equipment qualifications (installation and operation); equipment calibration and preventative maintenance; and cleaning and validation of cleaning processes as appropriate. Process performance qualification will be evaluated as part of the inspection of the overall process validation which is done within the system where the process is employed; and,
c) Utilities that are not intended to be incorporated into the product such as HVAC, compressed gases, steam and water systems.
See the CGMP regulation, 21 CFR 211 Subparts B, C, D, and J.

Materials System. This system includes measures and activities to control finished products, components, including water or gases, that are incorporated into the product, containers and closures. It includes validation of computerized inventory control processes, drug storage, distribution controls, and records. See the CGMP regulation, 21 CFR 211 Subparts B, E, H, and
J.

Production System. This system includes measures and activities to control the manufacture of drugs and drug products including batch compounding, dosage form production, in-process sampling and testing, and process validation. It also includes establishing, following, and documenting performance of approved manufacturing procedures. See the CGMP regulation, 21
CFR 211 Subparts B, F, and J.

Packaging and Labeling System. This system includes measures and activities that control the packaging and labeling of drugs and drug products. It includes written procedures, label examination and usage, label storage and issuance, packaging and labeling operations controls, and validation of these operations. See the CGMP regulation, 21 CFR 211 Subparts B, G, and J.

Laboratory Control System. This system includes measures and activities related to laboratory procedures, testing, analytical methods development and validation or verification, and the stability program. See the CGMP regulation, 21 CFR 211 Subparts B, I, J, and K

As appropriate, each 503B should have these systems implemented and effective, with the applicable cGMPs referenced per the FDA Guidance Current Good Manufacturing Practice – Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act.

Inspection Types

There are three types of FDA Inspection as described in 7356.002.

The Full Inspection Option is a surveillance or compliance inspection which is meant to provide a broad and deep evaluation of the firm’s CGMP. This will be done when little or no information is known about a firm’s CGMP compliance (e.g., for new firms); or for firms where there is doubt about the CGMP compliance in the firm (e.g., a firm whose history has documented short- lived compliance and recidivism); or follow up to previous regulatory actions. The Full Inspection Option will normally include an inspection/audit of at least four of the systems, one of which must be the Quality System (the system which includes the responsibility for the annual product reviews).

The Abbreviated Inspection Option is a surveillance or compliance inspection which is meant to provide an efficient update evaluation of a firm’s CGMP. The abbreviated inspection will provide documentation for continuing a firm in a satisfactory CGMP compliance status. Generally this will be done when a firm has a record of satisfactory CGMP compliance, with no significant recall, or product defect or alert incidents, or with little shift in the manufacturing profiles of the firm within the previous two years. The Abbreviated Inspection Option normally will include an inspection/audit of at least two of the systems, one of which must be the Quality System (the system which includes the responsibility for the annual product reviews).

Compliance Inspections are inspections done to evaluate or verify compliance corrective actions after a regulatory action has been taken, or are conducted For Cause which are done to investigate a specific problem that has come to the attention of some level of the agency. First, the coverage given in compliance inspections must be related to the areas found deficient and subjected to corrective actions.
In addition, coverage must be given to systems because a determination must be made on the overall compliance status of the firm after the corrective actions are taken. Compliance and For Cause inspections follow the The Full Inspection Option and normally include an inspection/audit of at least four of the systems, one of which must be the Quality System (the system which includes the responsibility for the annual product reviews).

 

2022 FDA Form 483’s

The following list is an excerpt of data posted to the FDA website page titled Compounding Inspections, Recalls, and other actions. The below list are the 483’s that were issued to 503Bs in 2022. This includes the firm name, number of observations and a link to the firms 483 on FDA’s website. Please note that there may be other correspondence (warning letter, firm response, Referral Letters to State BOP, DOJ releases etc.) posted to the FDA site.

Ark Pharmacy, PC (DBA Regency Medical Pharmacy – 1 observation, 483 issued Feb 24, 2022

Central Admixture Pharmacy Services – 6 observations, 483 issued Feb 25, 2022

Central Admixture Pharmacy Services – 4 observations, 483 issued May 4, 2022

CFP Acquisitions, Inc – 5 observations, issued 483 Jan 18, 2022

Expert Compounding Pharmacy – 6 observations, 483 issued Mar 4, 2022

Family Pharmacy of Statesville, Inc – 8 observations, 483 issued Mar 11, 2022

Nephron Pharmaceuticals Corporation – 7 observations, 483 issued Apr 20, 2022

The Rite Dose Corporation – 1 observation, 483 issued Mar 18, 2022

The FDA has resumed in-person inspections as of February 2022. This blog post will be updated as FDA posts inspection results. I hope to datamine the posted 483’s and provide additional information on common or frequent observations which may assist other 503Bs from making similar mistakes.

 

FDA Inspection of Compounding Outsourcing Facilities

From FDA CDER Small Business and Industry Assistance – During this 1 hour video FDA presenters Jessica Pressley McAlister, and Lori Cantin PharmD will: Provide an overview of the inspection process for compounding outsourcing facilities. Discuss what to expect during an inspection, from initiation to closeout as well as observations on successes and challenges. Many thanks to the FDA presenters Jessica Pressley McAlister, and Lori Cantin PharmD, for their insight.