4 OARO-Case Studies-04 Feb 2017
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Transcript of 4 OARO-Case Studies-04 Feb 2017
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Pharmaceutical MicrobiologyMultidisciplinary Integrated Approach in Drug Manufacturing
Obaid Ali & Roohi B. ObaidCivil Service Officers, Government of Pakistan
(4/5) Case Studies
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Personnel Practice
Environmental Control
Operational Design
Reference: Richard L. Friedman, FDA, CDER, DMPQ
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Aseptic Processing of a Sterile Active Pharmaceutical Ingredient (API)
Case Study
1
50 Finished product lots recalled
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Background
API shipped Received Assurance of sterility
Sterility failures trend
API lab & Finished good lab
API mfg relied heavily on manual
manipulation
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cGMP Issue
Finished dosage form site compliant for cGMP
Design of process … adequate protection from microbial contamination
Major GMP issue at API site
Manual Opera
Media Fill: Used very high pH medium Growth Promotion Capability not evaluated
Media dried at 85 to 95℃ Representative temp was 20 to 25 ℃ ?
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Quality System
Production system most deficient
Process simulation inadequate
Process simulation insensitive
Loss of media fill basic benefit of
prompt detection
Sound scientific foundation support
was absent
Reliability of daily decisions under
question
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Quality System
Product development & process validation
intended to yield
Important information about product & process
Poorly conceived study and conclusion based on assumption
may lead to
Erroneous process design decision & consequent risk to
product quality
Rational experiment design is required
Continuous learning throughout the life
cycle
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Intensive aseptic activity by personnel considered to be the root of contamination
Ultimately ended up with modification in process to include semi-closed process concept as well as automation
Case Study
1Outcome
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Assuring Container Closure Integrity throughout Manufacturing
Case Study
2
Recall of multiple lots under Class I
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Background
Contamination found
Enterobactercolacae
Other micro-organisms also
found
Xanthomonasmaltophilia
Adverse drug eventsSepticemia
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cGMP Issue
Container closure integrity problem identified
Cleaning of floor with uncontrolled shower of tap water done
Finished product dropped
Sealed vials exposed to tap water ? ? ?
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Quality System
Packaging & labeling system
deficientPoor handling sealed glass
Rough handling
Sub-visible hairline cracks
Contamination confirmed
Same organism found in water
tank
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Quality System
Critical GMP concept required to be reinforced
Every production phase through
packaging must be robust
Assure proper design of
manufacturing operations
Assure proper control of
manufacturing operations
Assure proper maintenance of manufacturing
operations
Continuous learning
throughout the life cycle
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Poor & rough handling
Caused septicemia to several patients
Case Study
2Outcome
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Extensive Aseptic Interventions by Personnel
Case Study
3
Shut down of Manufacturing Facility
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Background
Meda fill-60% units found contaminated
Minor correction to satisfaction 3 media fill runs
2nd media fill with high level of
contamination
Isolate of both failures was common skin borne microbes
(Staph. Cocco)
Sterility failure also occurred in last 6
months
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cGMP Issue
Multiple skilled manual interventions in process
These steps posed significant risk to the product
Significant manual interventions
Inadequate aseptic gowning by personnel ? ? ?
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Quality System
Initial minor corrections
3 consecutive media fill
Personnel performance of
aseptic connections
Personnel performance of
aseptic manipulations
Personnel performance at bulk stage …..
Design flaw in gowning
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Knowledge, Ability & Skills
……equipment connection changed to Sterilized in Place (SIP)
Case Study
3Outcome
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Migration of contamination liberated during Facility Construction
Case Study
4
Manufacturing Operation Suspension
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Background
Major construction in a clean room for
1 month
Next to personnel entry airlock
(gowning area)Media fill failure
Initial investigation concluded source from non-sterile
unit
Corrected the apparent root cause
Again failure of media fill
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cGMP Issue
Did not assess the risk posed by construction activities
Bacillus species
Spore forming bacteria found
Same in both media fills ? ? ?
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Quality System
Production & Quality system was deficient
Change was not carefully evaluated
Migration of contamination is not uncommon
Moving of walls is a common
culprit
Spore formers liberated into
the clean roomPotential impact
not evaluated
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Deviation & Change Control
Implement special precautions and increase monitoring to detect any drift in environmental control
Case Study
4Outcome
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Inadequate System of Environmental Monitoring
Inadequate aseptic processing environment, e.g. No viable air monitoring inside of the Class 100 (ISO 5) filling barrier on the xxx Line (A critical area where drug product and
pre-sterilized components are exposed)
Promed Exports, Aug 2013
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Inadequate System of Environmental Monitoring
Outside of the line xxx filling area, the three air samples taken in the Class 100 (ISO 5) area were not taken under dynamic
conditions. These active samples were instead taken after line set-up and before any filling
Promed Exports, Aug 2013
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Lesson Learned
It is important to collect air samples that adequately
represent filling conditions
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Inappropriate choice of Disinfectant
A sporicidal disinfectant for cleaning inside of the Class 100 (ISO 5) filling areas is not used. XXX alone is used, which is
not effective against spore-forming organisms such as Bacillus spp.
The September 2011 media fill failure investigation for the YYY Line identified the contaminating organism as Bacillus
pumilus.
Promed Exports, Aug 2013
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Inappropriate choice of Disinfectant
Moreover, the XXX disinfectant was not sufficiently evaluated on surfaces inside the Class 100 (ISO 5) area
Promed Exports, Aug 2013
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Lesson Learned
The use of sporicidal disinfectant is essential for cleaning in the
critical areas where drug product & pre-sterilized components are
exposed
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Unreliable Environmental Monitoring Data
The environmental sampling and testing program procedure is inadequate because it fails to adequately identify (e.g., with diagrams) the locations from which the surface samples are
collected.
Hemofarm, Jun 2012
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Unreliable Environmental Monitoring Data
Sufficient active viable air samples and dynamic non-viable particulate air samples from the critical area during
manufacturing are not collected
Hemofarm, Jun 2012
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Lesson Learned
The EM sampling & testing procedure should identify & sufficiently cover the sample
locations for viable & non-viable particles
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Unreliable Environmental Monitoring Data
There is lack of adequate control to assure that the melted agar is sufficiently cool to prevent cell death of viable microorganisms. Specifically, the analyst determines by hand touch, without any instruments, the adequacy of the temperature of the melted agar medium used for the bio-burden testing of the API, XXX and
YYY, before pouring the agar into the plates and mixing it with the samples
Hemofarm, Jun 2012
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Lesson Learned
Inadequate Procedure for Plate Preparation
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sterile preservative-free ibuprofin L-lysine at
17 mg/mL in a single-use glass vial
in premature infants no more than 32 weeks
gestational age
Two batches of this product were
voluntarily recalled by the manufacturer,
Lundbeck
interaction between the product and the Type I borosilicate glass vial
It substitutes for the aluminum oxide
forming an ibuprofen aluminum hydroxide
salt as particulate
Be Alert