FIELD COMPLIANCE UPDATE

CDR Thomas R. Berry, RPhFDA, 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:

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

Medical Gas Establishments PADE Inspections Therapeutic biological-only sites Pharmacies Positron-Emission Tomography

FY 06 – ATL-DO Drug Cadre

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

High Risk GMP Inspections = 8 Downgraded High Risk Inspections = 1 PADE Inspections = 2 District Investigations = 4 Drug Surveillance Samples = 15

Other Assignments

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

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20

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60

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100

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1105 3585 1358 2027 1361 3603 1112 1883 4391 2009

Top 10 Drug Observations Used in Turbo EIR CY 05CY 05 & CY 04

Turbo Cite ID

Cou

nt

FDA Top 10 (CY 05)

1. 21 CFR 211.22 (d) – Quality Control Unit Responsibilities and Procedures

2. 21 CFR 211.110 (a) – Process Validation3. 21 CFR 211.100 (b) – Written Production &

Process Controls4. 21 CFR 211.192 – CAPA5. 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

1. 21 CFR 211.192 (4) – CAPA

2. 21 CFR 314.80 – PADE Program

3. 21 CFR 211.160 (6) – Laboratory Controls

4. 21 CFR 211.100 (3) – Written production and process controls

5. 21 CFR 211.25 (7) – Employee Training

Investigator’s Top Ten

6. 21 CFR 211.166 – Stability Program7. 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 in-process 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 – – Pyrogenic reaction case

2. Position Papers –– 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 – – Implementations of CAPA

– Review of the potential impacts the event may have on other products / lots.

– Retraining

4. Cleaning & Maintenance of Equipment –– 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 ???