4. Design, Trust & Control of Sterile Manufacturing (Observations)
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Transcript of 4. Design, Trust & Control of Sterile Manufacturing (Observations)
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Design, Trust & Control of Sterile Manufacturing
Obaid Ali & Roohi B. ObaidCivil Services Officers, Government of Pakistan
12th March 2016, Saturday, Karachi
08th
Technical Meeting / Forum
Sterile Manufacturing
Part II 4
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Sensitivity Instability Aseptic processing
But no packaging
component
Terminal Sterilization vs. Aseptic Processing
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Terminal Sterilization vs. Aseptic Processing
It is a well accepted principle that sterile drugs should be manufactured by aseptic
processing ONLY when terminal sterilization is NOT feasible
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Design, Trust & Control of Sterile Manufacturing
Regulatory Observations and Comments
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Case Study (1)
From US-FDA for Sun Pharma Dec 2015
Smoke Studies
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Unidirectional Air Flow studies under Dynamic Conditions to determine how MOVEMENT of Personnel & Air pose risk to STERILITY of product
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Significant airflow turbulence
Lack of dynamic simulation of
critical intervention
No studies during manual aseptic
transfer
Inadequate evaluation of
pattern in stopper area
Turbulence around stopper
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Without smoke studies to demonstrate unidirectional airflow over all aseptic operation & processing steps, one cannot prove that the process is designed to prevent microbiological contamination or provides adequate assurance of product sterility
Take home message
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Case Study (2)
From US-FDA for Mylan Labs Aug 2015
Gowning in Aseptic Area
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Aseptic garments worn in the filling area were non-integral. The inspector observed 7 of the sterile gowns with tear or holes, and 8 of the gowns with loose threads. 8 Sterile booties were also observed with tear or holes and 11 had loose threads. 2 sterile hoods with tears or holes, and 12 with loose threads were also observed.
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Non-integral aseptic garments
Procedure requiring production personnel to examine garments for tears, holes etc. was
available
Inspector found that these checks as per procedure were not
performed
No assurance that gowns are suitable for aseptic
manufacturing
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Failure to follow the procedures leads to lack of assurance that manufacturing environment is maintained in a state of control suitable for aseptic processing.
Take home message
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Case Study (3)
From US-FDA for Agila Specialities Aug 2015
Inappropriate Sampling Plan for
Environmental Monitoring
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A robust sampling plan was not in place as part of environmental monitoring plan. No representative non-viable particle (NVP) monitoring data supports firm’s current (ISO5) classification for the product path from X to Y, which transfers product during aseptic processing.
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NVP probes were placed on X surface instead of near the working area
Placing probes away from working area
means inability to detect NVPs where sterile
drugs are exposed during aseptic processing
Furthermore, inspector found that transferring vials from the filling
suite to the X can take up to Y time.
This extended exposure time may increase
contamination hazards
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It is essential that the sampling plan include areas where product is exposed to the environment, and is at greater risk of contamination.
Take home message
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Case Study (4)
From US-FDA for Agila Specialities Aug 2015
Failure to identify Source of Microbial
Contamination
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The source of gram-negative contamination in your ISO 7 area was not identified and appropriate corrective actions and preventive actions were not implemented
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In the ISO-7 Suite, Pseudomonas, sp. during passive
air sampling collected from firm’s passage way, in X rooms
Y and Z was identified
The potential routes of contamination were not
evaluated.
The evaluation of environmental microbial data should not be narrowly limited to specific lots or events
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Trend analysis, identifying sources of contamination, and risk assessment are essential to maintain adequate microbiological control
Take home message
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Case Study (5)
From US-FDA for Promed Exports Aug 2013
Inadequate system for cleaning &
disinfecting aseptic processing areas
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A sporicidal disinfectant for cleaning inside of the Class 100 (ISO 5) filling areas is not used.
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The inspection documented that the firm uses XXX alone, which
is not effective against spore-forming organisms such
as Bacillus spp.
The September 2011 media fill failure investigation for
the X Line Y identified the contaminating organism
as Bacillus pumilus.
Additionally, the disinfectant X on surfaces inside the Class 100 (ISO 5) area including Y was not sufficiently
evaluate
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It is essential that the sporicidal agent be used regularly to ensure a suitable ISO 5 (Class 100) environment
Take home message
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Case Study (6)
From US-FDA for Wintac Feb 2012
Poor aseptic practices by
Personnel in aseptic processing areas
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Poor aseptic practices during the filling of sterile X products were demonstrated by operators such as
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An operator performing critical aseptic operations with exposed skin at the forehead, posing an
unreasonable risk of the product becoming contaminated
Operators moving very quickly in the aseptic area, which may create
unacceptable turbulence in the area, and disrupt the unidirectional airflow
Operators leaning halfway in and out of the class 100 area
while performing interventions over opened
bottles
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Operators must be trained for the particular function/operation and the effectiveness of training be monitored at regular intervals
Take home message
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Case Study (7)
From US-FDA for Hemofarm Jun 2012
Unreliable Environmental
Monitoring Data
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Environmental monitoring (EM) data is not reliable. This is a serious deviation, as the ability to detect microbial contamination in the manufacturing environment during aseptic processing is fundamentally compromised
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The firm used dried/desiccated media agar plates for
environmental monitoring testing used to support the release of
batches.
On November 15, 2011, it was documented that 155 of a total of 247 media plates evaluated (more
than 50%) were dried.
The use of dried agar plates, which do not reliably support microbial growth, to recover microbial contamination is
inadequate.
1
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On November 14, 2011, the FDA investigator observed desiccated environmental monitoring plates in the
incubators
However, the analysts only recorded the results as dried
media but not the counts from the plates (if any)
On this same day, the FDA investigator observed plate “X” sampled on November 9, 2011, to have growth of 1 Colony Forming Unit (CFU)
However, the firm documented the result of this plate’s reading as
"SAUSEN MEDIUM", dry medium, and failed to report the
microbial growth.
2
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Environmental monitoring data for January 2009 through October 2011 contains documentation of only two action limit excursions in the Grade A
manufacturing areas.
In apparent contradiction, during an FDA visit to the microbiology laboratory on November 14, 2011, nine plates, collected as part of the
environmental monitoring program from the Grade A manufacturing area were found inside an incubator in the microbiology laboratory with
visible growth of microorganisms.
3
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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
In addition, the firm do not collect sufficient active viable air samples and dynamic non-viable particulate air samples
from the critical area during manufacturing
4
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The agar level on surface contact plates (used for surface environmental and personnel monitoring sample testing) was below the rim of the plates creating the
possibility that the agar would not have contact with the surface intended to be sampled
5
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The bioburden testing of the X components is inadequate. It lacks adequate controls 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 bioburden testing of the API, X and Y before pouring the agar
into the plates and mixing it with the samples
The firm’s response indicated that a study was completed to determine the time required for
the agar media to cool to the temperature of the water bath (X°C) prior to use of that media in
pouring microbiological plates
The response is inadequate because it did not describe the
study method, laboratory controls used for temperature monitoring, and time controls
during the study
6
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EM data is critical to monitor the acceptability of the environment that the sterile drug and its container-closure components are exposed to during processing, and assure that these conditions consistently safeguard product sterility
Take home message
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Case Study (8)
From US-FDA for Mc Guff Pharmaceuticals, Dec 2010
Inappropriate Autoclave
Qualification
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Qualifications of the AA autoclave and the BB oven are inadequate in that the equipment have not qualified with representative loads
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The firm’s practice is to qualify the equipment using minimum loads as opposed to actual loads during routine operation (e.g., BB oven was qualified to depyrogenate glass vials using X tray when the actual load is a
maximum of Z trays)
In addition, the use of biological indicators and penetration
thermocouples in the qualification studies are inadequate
Any penetration thermocouples were not used during the qualification of GetingeAA autoclave since February X, nor the
use of biological indicators was incorporated
During the maximum load configuration study, only a X penetration thermocouple were used and the firm failed to use any
biological indicators
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Without appropriate qualification of the equipment, there is no assurance of the consistent quality of product being manufactured
Take home message
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Case Study (9)
From US-FDA for Genzyme, Feb 2009
Inappropriate HVAC Qualification
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Air flow pattern testing studies, executed in August of 2007 during the operational qualification of the HVAC system for fill suite XXX, do not fully demonstrate air flow movement away from work surfaces during representative personnel activities and manual simulations of the aseptic filling processes
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Operations & practices not preformed during air flow pattern testing studies
include: Critical aseptic connections
Routine functions of aseptic core operators, for example: Manually placing stoppers or
reorienting stoppers using forceps for filled vials
Withdrawing unfilled vials from the filling line for weight checks
Redirecting filled vials typically with stoppers on the exit feed
wheel
Cont’d
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Unidirectional air flow over the rotary in-feed table
Opening the lyophilizer door or the automated double doors
into the aseptic preparation area
Active viable air sampling
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Without appropriate qualification of the HVAC, prevention of microbiological contamination of the product cannot be assured
Take home message
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Case Study (10)
From US-FDA for Sanofi, Germany Feb 2011
Inappropriate HVAC Qualification
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Separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing have not been established
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e.g. the airflow velocity inside critical areas of the aseptic processing operations
of Line X was found unacceptable
The documentary evidence of in-situ air pattern analysis (e.g.,
smoke studies) reviewed during the inspection
confirmed this condition.
The firm should be able to demonstrate unidirectional airflow and sweeping action
over and away from the product under dynamic conditions
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Proper design and control prevents turbulence and stagnant air in the critical areas. It is crucial that airflow patterns are evaluated for turbulence that can act as a channel for contamination, and that any deficient conditions are addressed.
Take home message
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Design, Trust & Control of Sterile Manufacturing
Questions and Answers