Transcript Stability Program 21 CFR 211.67

FIELD COMPLIANCE UPDATE
CDR Thomas R. Berry, RPh
FDA, Investigator
RAL-RP / ATL-DO
Information Disclaimer:
The information provided is only intended to
be general summary information. It is not
intended to take the place of either the
written law or regulations.
Opinion Disclaimer:
The comments and opinions expressed are
those solely of the presenter. They are not
intended to take the place of either the
written law or regulations
CRISSP Score
 CDER/ORA Risk-based Inspection Site
Selection Prioritization
 Larger the score – higher priority
 “High” priority = “Tier 1” establishments
 Developed by the Division of Manufacturing
and Product Quality, OC/CDER
CRISSP Score
 Derived from three categories of risk:
 Product
 Process
 Facility
FY 06
 Approximately 500 establishments identified by CDER
as high-risk sites
 Includes the following programs:
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56002 – Drug Process Inspections (DPI)
56002a – DPI / Small Volume Parenterals
56002b – DPI / Drug Repackers and Relabelers
56002c – DPI / Radioactive Drugs
56002f – API Process Inspections
56002m – DPI / Therapeutic Biological Product Inspections
CRISSP Score Exclusions
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Medical Gas Establishments
PADE Inspections
Therapeutic biological-only sites
Pharmacies
Positron-Emission Tomography
FY 06 – ATL-DO Drug Cadre
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Tier 1 = 44 inspections
Tier 2 = 133 inspections
Pre-Approval Inspections
Directed Inspections
Complaint Investigations
FY 06 – ATL-DO Drug Cadre
 Drug Surveillance Samples = 29
 Collected during GMP Inspections
 Surveillance vs Compliance
FACTS
 Field Accomplishments and
Compliance Tracking System
 Creates the assignments for the
investigator
 Provides firm status and historical
investigatory information
Investigator Example
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High Risk GMP Inspections = 8
Downgraded High Risk Inspections = 1
PADE Inspections = 2
District Investigations = 4
Drug Surveillance Samples = 15
Other Assignments
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OCI Investigations = 1
Pharmacy = 1
Seizure = 1
Destruction = 2
Katrina (MS + LA) x 1 month
Training x 1 month
Turbo EIR
 Provides more consistency between
inspections and investigators
 Provides specific citations and examples
of violations
 Provides information for statistical analysis
and identifies potential investigator / FDA /
industry trends
Top 10 Drug Observations Used in Turbo EIR CY 05
CY 05 & CY 04
140
120
Count
100
80
60
40
20
0
1105 3585 1358 2027 1361 3603 1112 1883 4391 2009
Turbo Cite ID
FDA Top 10 (CY 05)
1. 21 CFR 211.22 (d) – Quality Control Unit
Responsibilities and Procedures
2. 21 CFR 211.110 (a) – Process Validation
3. 21 CFR 211.100 (b) – Written Production &
Process Controls
4. 21 CFR 211.192 – CAPA
5. 21 CFR 211.100 (a) – SOPs / Process
Validation
FDA Top 10 (CY 05)
6. 21 CFR 211.160(b) – Laboratory controls
7. 21 CFR 211.25(a) – Employee Training
8. 21 CFR 211.165(a) – Laboratory Testing &
Release
9. 21 CFR 211.180(e)(2) – APRs
10. 21 CFR 211.188 – Batch Production &
Control Records
Investigator’s Top Ten
21 CFR 211.192 (4) – CAPA
21 CFR 314.80 – PADE Program
21 CFR 211.160 (6) – Laboratory Controls
21 CFR 211.100 (3) – Written production and
process controls
5. 21 CFR 211.25 (7) – Employee Training
1.
2.
3.
4.
Investigator’s Top Ten
6. 21 CFR 211.166 – Stability Program
7. 21 CFR 211.67 – Written Procedures Not
Followed for Cleaning & Maintenance of
Equipment
8. 21 CFR 211.188 (10) – Batch Production &
Control Records
9. 21 CFR 211.22 (1) - Quality Control Unit
Responsibilities and Procedures
10. 21 CFR 211.110 (2 +5) – Process Validation
FDA 483 Disclaimer
This document lists observations made by the FDA
representative(s) during the inspection of your facility. They are
inspectional observations, and do not represent a final Agency
determination regarding your compliance. If you have an
objection regarding an observation, or have implemented, or plan
to implement, corrective action in response to an observation,
you may discuss the objection or action with the FDA
representative(s) during the inspection or submit this information
to FDA at the address above. If you have any questions, please
contact the FDA at the phone number and address listed above.
Investigator’s Significant Issues
#5 - 21 CFR 211.22(a) - There is no quality
control unit.
Must be independent of production.
Must prevent innovative “Marketing Strategies”
Investigator’s Significant Issues
#4 - 21 CFR 211.110 Control procedures are not
established which validate the performance of those
manufacturing processes that may be responsible for
causing variability in the characteristics of inprocess material and the drug product.
The manufacturing and cleaning processes should be
validated to assure that each batch of drug product
produced meets pre-defined written specifications for
identity and strength.
Investigator’s Significant Issues
#3 - 21 CFR 211.166 Results of stability testing
are not used in determining expiration dates.
Must provide data that supports expiration dates.
Must provide data to continuously support the
expiration date included in the Application.
Investigator’s Significant Issues
#2 -21 CFR 211.160(b) Laboratory controls do not
include the establishment of scientifically sound
and appropriate specifications, standards,
sampling plans, and test procedures designed to
assure that drug products conform to appropriate
standards of identity, strength, quality and purity.
Test incoming materials and test finished product
with scientifically sound methods.
Investigator’s Significant Issues
#1 - 21 CFR 211.165(f) - Drug products failing to
meet established standards, specifications, and
quality control criteria are not rejected.
If your active ingredient has not arrived and you
receive an immediate order for a product containing
that active ingredient, FDA still expects you to wait
for the active ingredient to arrive from the supplier
and put it in the product.
Investigator’s Concerns
1. Sterilization –
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Pyrogenic reaction case
2. Position Papers –
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Explanation of why specific regulation does not
apply to the firm
Explanation of why the firm has elected not to
follow a specific regulation
Investigator’s Concerns
3. Corrective Actions / Preventative Actions –
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Implementations of CAPA
Review of the potential impacts the event may have
on other products / lots.
Retraining
4. Cleaning & Maintenance of Equipment –
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Log Documentation
Hold times
5. 100 % Visual Inspection of Sterile Products
Investigator’s Limited Vision
1. High Priority Large Firms – Inspections
annually of different product classes.
2. More Cascade Assignments – Inspections
resulting from findings at another firm.
3. Compounding Pharmacies – Manufacturing
and/or evaluation of how the pharmacy is
ensuring the safe and effective use of the
compounded product
Investigator’s Limited Vision
Corporation Responsibility – Holding
corporate officers responsible for making sure
problems at one facility are not occurring at
any of the firm’s other facilities.
Field Compliance Update
Questions ???