CHARLES I. AHN, USFDA ASSISTANT COUNTRY DIRECTOR, CHINA SHANGHAI OFFICE. Trending GMP Issues In API Manufacturing Operations. Trending GMP Issues API Mfg. Operations. Quality System Infra-structure Still Being Implemented Double Standards Quality System Concept Not Deep-rooted
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ASSISTANT COUNTRY DIRECTOR, CHINA
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
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 Range
Exhaust Air Temperature and End-point Determination
Material’s Initial Wetness, Potential Variable(?)
Assumption of Efficient Vacuum
Sand Bed, Carbon Bed, 10m 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?
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.
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
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.
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.
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.
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 Issue
But Must Establish a Procedure to Minimize Contamination or to Maintain Suitability to Continue