CHARLES I. AHN, USFDA

ASSISTANT COUNTRY DIRECTOR, CHINASHANGHAI OFFICE

Trending GMP Issues In API Manufacturing

Operations

Trending GMP IssuesAPI Mfg. Operations

Quality System Infra-structure Still Being Implemented Double Standards Quality System Concept Not Deep-rooted

Process ValidationUser/Process Requirement Assessment

New Systems, New Equipment-Not Enough SupportMonitoring, Recording ActivitiesHandling & Investigation of Deviations and

OOS

Process Validation

Protocol Define Process Identify &Qualify Controlled Parameters Identify & Qualify Monitored Parameters Describe Evaluation Criteria Establish Metrics

No More Three Passing BatchesOn-going Effort, Continuous Assessment of

Variables

Case StudyAPI Final Drying Process

Drying Process Vacuum > 0.08MPa Drying Temp: 70~90oC Dryng Time: 7~8 Hours

Historical Range Narrower 75~78oC and 7 Hours Fixed Time Based on R&D

Validation Data Firm Considers the

Process Validated

Validation Issues

Blender/Dryer Jacketed with Coil Circulating Heated Water

Source of Heat: Water Coil Heat-exchange in “Steam Box” with Manual Valve to Steam Generator

No Correlation Established between Jacket Temp. and Steam Box Temp.

The Firm Uses Both Jacket and Steam Box Temperature Readings as Process Control Parameters

Excessively Wide Temperature and Drying Time Ranges Specified

Validation Consideration

Need to Correlate Jacket Temperature and Heat Source Temperature

One Can Only “Control” Source Temperature; and Jacket Temperature is Dependent on the Source

Drying Temp. Should Be A Narrow Target RangeExhaust Air Temperature and End-point

DeterminationDrying CurveMaterial’s Initial Wetness, Potential Variable(?)Assumption of Efficient Vacuum

Deviation Investigation: November, 2008

A Drying Failure

Deviation Was Noted During Final Drying Process Temperature Fell Below Limit For A Short-while Did Not Indicate How Long, What Caused

DeviationLOD Testing Confirmed Drying FailureRe-drying and Re-milling per Modified

InstructionNo Investigation Into Cause of Temperature

Fluctuation – Only Operator Error (?)No Stability Profile

Deviation Investigation: November, 2008

F/U Action to Deviation: November, 2008

Deviation Report, March, 2009Another Drying Failure

Loss on Drying Test Result 1.12% (Limit 0.5%)Operator Error- Drying Time 6.5 Hrs. (>7

Hrs) Operator Re-trained Drying Process (and Milling) Repeated 3.5 Hrs.

API Released upon Retesting No Concern for Other Quality attributes No Concern for Adequacy of Controls, or Process Reprocessing Procedure(?), Stability No Look-back of November Deviation Event

OOS Report, March, 2009

Deviation Investigation Upon OOS Confirm

F/U Action: March, 2009

QS Feedback And Process Consideration

The Drying Process Might Not Be Robust Brief Fluctuation of Temperature and Shortened Drying

Time Resulted in Drying Failure Drying Time and Drying Temperature Critical

ParametersCapturing Relevant Production Data, Out-of-

Trend Events Useful and Necessary to Evaluate Process

Data Should Not Be Filed Away, But Collected in Systematic Way to Allow Trending and Quality Assessment

Quality Management System Discrepancy

Case Study- Water System Validation

Water SystemAppearance May Deceive Your Eyes

Sand Bed, Carbon Bed, 10 Filter, 1st RO, Intermediate Storage, 2nd RO, Purified Water, UV

Conductivity Reading Monitored At Pre-treatment, 1st RO, and 2nd RO.

Reading at the 1st RO Invariably Spikes Up When the System Starts Up on Demand; Water Discharged Until Reading Back to Normal

Has the Water Purification System Been Validated?

Handling of DeviationsTypical Observations

The Firm’s Quality Management System - Handling and Investigating Deviations, Out-of-Specification Data, and Out-of-Trend Events Is Inadequate. The firm’s Identification and Documentation of Events, Investigation Activities, Conclusions, and F/U Actions Are Incomplete and Not Supported by Factual Findings.

Actions Retrospective, Not Prospective.

Example of Deviation Handling

A Seed Culture Lot XXXXX for Neomycin Sulfate Was Contaminated and Discarded. The Firm’s Investigation and Disposition of the Deviation Event Concluded the Cause of Contamination Was Likely Due to Cracked Viewing Glass and Microbial Ingression During the Seed Culture Growth Step

However, There Is No Documentation of Sequence of Event Supporting Such Conclusion.

Time of Breakage, Identity of Contamination, Look-back

Example of Deviation Handling

Final API Fermentation Lot YYY, Streptomycin, Was Contaminated and Discarded. The Firm’s Investigation Concluded That the Cooling Water Coil Running Through the Fermentation Vessel Was Discovered Cracked Along the Welded Connection While Cleaning the Vessel After the Operation.

No Further Investigation for Other Potential Root Causes or Look-back of Previous Batches Were Noted to Have Been Conducted.

Example of Deviation Handling

Deviation Report ZZZ Addressed a Yield of Erythromycin Lot xxx Calculated to be 85%, Outside the Established Range of 88-97%.

It Was Observed During Drying of Crystallized Material, Part of It Was Adhering to the Surface of Dryer.

Recovered the Material Amounting to 35kgs, Tested for Specifications, Determined to Be Acceptable, Re-dried to 29kgs, and Used in the Subsequent Step.

Example of Deviation HandlingSupply Chain Issue

Sterile Filtration Failure. Attributed to Failure of Membrane Pre-filter.

Sample Membrane Filter Units Sent to the Vendor for Evaluation.

Bubble Point Testing Performed by Vendor Confirmed That Filter Units Were Indeed Not Rated for 0.2μ Pore Size But Was Actually Performing at 0.3μ Range.

Vendor Explained It Was Unable to Test The Filter Lot at The Time of Shipping Due to Temporary Unavailability of Testing Apparatus.

Processing Steps Temporary Storage

Typical API Manufacturing Process Is Broken Down Into a Number of Discrete Steps, Requiring Temporary Storage of Processed Materials Prior to Start of the Subsequent Step.

Not (Necessarily) a Stability IssueBut Must Establish a Procedure to Minimize

Contamination or to Maintain Suitability to Continue

Other Common Issues

Stability Indicating Analytical MethodsUse of In-House (Working) Reference

Standard Qualification of Working Standard

Loose Analyst Work-sheets and Accountability