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

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 Range
Exhaust Air Temperature and End-point
Determination
Drying Curve
Materials 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 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, 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 Deviations
Typical Observations
The Firms Quality Management System - Handling

and Investigating Deviations, Out-of-Specification

Data, and Out-of-Trend Events Is Inadequate. The
firms 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 Firms

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 Firms

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 0.2 Pore
Size But Was Actually Performing at 0.3 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