2. 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
3. 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
4. Case Study
API Final Drying Process
Drying Process
Vacuum > 0.08MPa
Drying Temp: 70~90o
C
Dryng Time: 7~8 Hours
Historical Range Narrower
75~78o
C and 7 Hours
Fixed Time Based on R&D
Validation Data
Firm Considers the
Process Validated
5. 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
6. 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 Range
Exhaust Air Temperature and End-point
Determination
Drying Curve
Material’s Initial Wetness, Potential Variable(?)
Assumption of Efficient Vacuum
7. 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 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
10. 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
14. 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
17. Water System
Appearance May Deceive Your Eyes
Sand Bed, Carbon Bed, 10µ 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?
18. 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.
19. 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
20. 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.
21. 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.
22. 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.
23. 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
24. Other Common Issues
Stability Indicating Analytical Methods
Use of In-House (Working) Reference Standard
Qualification of Working Standard
Loose Analyst Work-sheets and Accountability