Trending GMP Issues In
API Manufacturing Operations
CHARLES I. AHN,
USFDA
ASSISTANT COUNTRY DIRECTOR, CHINA
SHANGHAI OFFICE
Trending GMP Issues
API Mfg. Operations
 Quality System Infra-structure
 Still Being Implemented
 Double Standards
 Quality System Concept Not Deep-rooted
 Process Validation
 User/Process Requirement Assessment
 New Systems, New Equipment-Not Enough Support
 Monitoring, Recording Activities
 Handling & 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 Batches
 On-going Effort, Continuous Assessment of
Variables
Case Study
API Final Drying Process
 Drying Process
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Vacuum > 0.08MPa
Drying Temp: 70~90oC
Dryng Time: 7~8 Hours
 Historical Range Narrower
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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
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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
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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
Drying Curve
Material’s Initial Wetness, Potential Variable(?)
Assumption of Efficient Vacuum
Deviation Investigation: November, 2008
A Drying Failure
 Deviation Was Noted During Final Drying Process
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Temperature Fell Below Limit For A Short-while
Did Not Indicate How Long, What Caused Deviation
 LOD Testing Confirmed Drying Failure
 Re-drying and Re-milling per Modified Instruction
 No 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, 2009
Another 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 Parameters
 Capturing 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 System
Appearance May Deceive Your Eyes
 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?
Handling of Deviations
Typical 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, Lookback
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, Redried to 29kgs, and Used in the Subsequent Step.
Example of Deviation Handling
Supply 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 Issue
 But Must Establish a Procedure to Minimize
Contamination or to Maintain Suitability to
Continue
Other Common Issues
 Stability Indicating Analytical Methods
 Use of In-House (Working) Reference Standard
 Qualification of Working Standard
 Loose Analyst Work-sheets and Accountability