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