Manufacturing sites should prepare now for inspections before the U.S. Food and Drug Administration (FDA) resumes routine on-site inspections.
Since 2020, FDA has delayed many routine inspections due to the pandemic. In December 2021, FDA restated that inspectional activities are being temporarily postponed due to the evolving COVID-19 pandemic and the spread of the Omicron variant. FDA’s published inspection data reflects the significant decrease in the number of inspections. In 2021, FDA inspected about 20% of the number of medical device and drug manufacturing establishments that it had inspected in calendar years preceding the pandemic.
Table 1 presents a summary of observations FDA issued in 2021 at more than 5% of drug manufacturing sites inspected or more than 7% of drug manufacturing sites receiving at least one observation.
Table 1: Drug Manufacturing — Summary of Prevalent 2021 FDA Inspection Observations
| 21 CFR 211.192 |
Failure to investigate unexplained discrepancies thoroughly |
18.8% |
26.1% |
| 21 CFR 211.22(d) |
Procedures not in writing, nor fully followed |
17.0% |
23.6% |
| 21 CFR 211.160(b) |
Lack of scientifically sound laboratory controls |
11.7% |
16.3% |
| 21 CFR 211.25(a) |
Lack of necessary training |
11.3% |
15.8% |
| 21 CFR 211.100(a) |
Lack of written procedures |
8.9% |
12.3% |
| 21 CFR 211.68(b) |
Insufficient computer access controls |
8.5% |
11.8% |
| 21 CFR 211.100(b) |
Failure to follow written procedures |
7.1% |
9.9% |
| 21 CFR 211.166(a) |
Deficient stability program |
6.4% |
8.9% |
| 21 CFR 211.68(a) |
Lack of routine calibrations per written program |
5.7% |
7.9% |
| 21 CFR 211.67(a) |
Failure to clean equipment at appropriate intervals |
5.3% |
7.4% |
| 21 CFR 211.84(d)(2) |
Improper reliance on component supplier’s certificate of analysis (CoA) |
5.3% |
7.4% |
For medical device manufacturing facilities, Table 2 presents a summary of observations FDA issued at more than 3% of inspected sites or at least 8% of sites receiving at least one observation.
Table 2: Medical Device Manufacturing — Summary of Prevalent 2021 FDA Inspection Observations
| 21 CFR 820.100(a) |
Corrective and preventive actions (CAPAs) — lack of or inadequate procedures |
10.4% |
26.3% |
| 21 CFR 820.198(a) |
Complaints — lack of or inadequate procedures |
7.2% |
18.2% |
| 21 CFR 820.75(a) |
Process validation — lack of or inadequate validation |
4.5% |
11.3% |
| 21 CFR 803.17 |
Medical device reports (MDRs) — lack of written procedures |
4.3% |
10.9% |
| 21 CFR 820.50 |
Purchasing controls — lack of or inadequate procedures |
4.0% |
10.2% |
| 21 CFR 820.30(g) |
Design validation — lack of or inadequate procedures |
3.8% |
9.5% |
| 21 CFR 820.184 |
Device history record — not or inadequately maintained |
3.6% |
9.1% |
| 21 CFR 820.90(a) |
Nonconforming product — lack of or inadequate procedures |
3.6% |
9.1% |
| 21 CFR 820.100(b) |
CAPAs — activities and/or results not adequately documented |
3.5% |
8.8% |
| 21 CFR 820.22 |
Quality audits — deficiencies, including lack of or inadequate procedures |
3.3% |
8.4% |
| 21 CFR 820.25(b) |
Training — lack of documentation and/or lack of or inadequate procedures |
3.2% |
8.0% |
The predominant observations listed in Tables 1 and 2 indicate that FDA continues to cite many facilities for noncompliance with fundamental current good manufacturing practice (cGMP). Manufacturers must prepare and follow written procedures, train personnel, document cGMP activities adequately, investigate deviations and inconsistencies thoroughly, and implement appropriate CAPAs. Conducting mock inspections and quality control (QC) audits that focus on these core cGMP principles prior to the next inspection could help sites avoid FDA’s most cited observations.
Pandemic-Affected Issues
Manufacturers should also consider whether the circumstances of the pandemic have introduced similar issues that will attract FDA’s attention. Manufacturers should approve new or revised standard operating procedures (SOPs), conduct training for relevant personnel; and audit periodically to ensure tasks are executed as described in SOPs. The pandemic and related safety measures likely have affected the following types of events and documents:
- Implementation of new or revised manufacturing and QC procedures, and associated documentation that address pandemic concerns.
- Verification during batch production
- Distancing among laboratory personnel
- Sample handling
- Mask or respirator use
- Continuity of cGMP tasks that require personnel presence at the site or a specific location
- Confirm cGMP tasks that typically require in-person or person-to-person contact have been completed.
- Second-person verification activities
- QC presentations to management
- Pest-control inspections
- Internal audits
- Supplier audits
- Ensure calibrations, certifications, qualifications and validations are up-to-date, even if third-party contractors are required.
- Examples include HEPA-filter certification, equipment IQ/OQ/PQ
- If calibrations or certifications expire, QC should evaluate and document written justification for continued manufacturing.
- Ensure reporting obligations are met, especially if they typically required consolidating data from many sources, some of which may be paper-based.
- Consolidate data for annual reports.
- Submit timely field alert reports or MDRs.
- Process returned materials associated with complaints.
- Confirm paper-based systems that cannot be managed remotely are organized and complete.
- Ensure all required initial and periodic trainings are completed.
- Include a review of any changes to the required training for site visitors.
- Hold third-party visitors, including FDA, accountable for all relevant training requirements.
- Evaluate site appearance.
- Check low-traffic areas for leaks and other problems.
- Confirm production area message boards are cleared or current.
- Status of whether the site is noncompliant with FDA Regulations for Product,
- due to reduced production
- due to supply-chain issues
- Readiness of documentation for the next inspection.
- If the Establishment Inspection Report (EIR) from the prior inspection is not in hand, request it now.
- Ensure all prior observations, including comments communicated verbally, have been addressed.
- Compile objective evidence demonstrating the completion of commitments made to FDA.
- Consider whether CAPA effectiveness checks are needed for implemented CAPAs.
