Understanding Regulatory Expectations and Review of USFDA 483s
for Freeze Dried Product
Dhavalkumar Surti
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Guidance
• Guide to Inspection of Lyophilization of Parenterals (7/93)
• Inspection Technical Guide: Lyophilization of Parenterals (4/8/86)
• FDA compliance program guidance manual 7356.002A
• Guidance for industry: Sterile Drug Products Produced by Aseptic
Processing – Current Good Manufacturing Practice
• Guidance for industry: Content & format of Chemistry,
Manufacturing & controls & Controls Information & Establishment
Description Information for a Vaccine or Related Product (1/99)
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Guidance
• FDA compliance program guidance manual 7356.002A
• If lyophilization performed inhouse, following needs to be reported to agency:
Manufacturer of lyophilizer
Percentage of firm’s product which are lyophilized
Describe the heating and cooling system used in the lyophilizer, the vacuum
system, what gas is used to break the vacuum and whether it is sterile, and the
temperature controlling system.
Briefly describe preparation of the sterile product for drying, including procedures
for protecting the product from contamination while loading into the lyophilizer.
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Guidance
• How is stopper seating is of vials is performed?
• If performed automatically, is it under vacuum, of if not under
vacuum, what gas is used and how is it sterilized?
• Review at least three lyophilization production records for the
product referenced above; are the cycle parameters and observed
results within validated cycles?
• What are firm’s criteria for acceptable vs. unacceptable runs,
including general appearance, moisture etc.
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Guidance
• How is stopper seating is of vials is performed?
• If performed automatically, is it under vacuum, of if not under
vacuum, what gas is used and how is it sterilized?
• Review at least three lyophilization production records for the
product referenced above; are the cycle parameters and observed
results within validated cycles?
• What are firm’s criteria for acceptable vs. unacceptable runs,
including general appearance, moisture etc.
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Why inspection can trigger?
• Inadequate understanding of product characteristics (thermal properties of formulation,
appearance)
• Inadequate understanding of the process & equipment
• Inconsistencies in process parameters delivered
• Inadequate validation performed, not documented, or not available (utilize range testing)
• Legacy cycles utilized for new/re-formulated products
• Non-sterilizable lyophilizers
• Minimal (or non-existent) routine maintenance on lyophilzer and support components
• Different lyophilizer models with identical cycles for different fill volumes/products – a one
cycle fits all- approach
• Excessively long lyophilization cycles
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Why inspection can trigger?
• Cycle controlled by only one thermocouple (TC)
• Use of non-validated containers (no stability data available to suitability of alternate
containers)
• Maximum allowable reconstitution limits not based on historical data
• Locations of final product sampling not specified, or no rationale for choice of location
• Small number of sample size tested (particularly during validation)
• Variability in container closure (C/C) integrity test results
• Evidence of broken, damaged or unstoppered vials during lyophilization or unloading
• Stopper sticking to shelf bottom
• Unseated or popping stoppers
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FDA Observations regarding lyo products
• There are no data available for moisture mapping studies performed on actual full scale production
runs
• Process validation study samples were not collected for shelves 8 through 10, which have been
used during production
• There are no data available to support the acceptability of the lyophilization cycle that was
transferred directly from the previous lyophilizer to the new lyophilizer.
• Studies have not been performed to evaluate the physico-chemical properties of the formulation
(i.e. freezing and collapse temperature)
• Media fill procedures do not include a challenge of the entire process in that there are no
provisions for fill set-up, fill volume adjustments, removal of mis-stoppered vials, personnel
interventions/interruptions, and cumulative tray loading activities.
• No instructions available for transporting vials from the class 100 filling room to the lyophilizer.
Trayed product must pass through a class 10,000 area during transport to the lyophilizer.
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FDA Observations regarding lyo products
• Lyophilzer door extends outside the class 100 area during chamber loading operations.
• Nitrogen gas used to backfill lyophilizer chamber during media fill studies.
• Portions of the media fill are frozen in the lyophilizers in order to simulate the actual cycle.
• There are no sterilizing grade vent filters on the lyophilzer chamber.
• Integrity testing of the sterilizing grade vent filter for the condenser has not been performed.
• There are no data available to support the acceptability of the six-day hold time during the freezing
stage in the lyophilizer.
• No specified maximum allowable hold time for filled, partially stoppered vials, prior to loading and
freezing in lyophilizer.
• Four thermocouples were used in each qualification run. Only four shelves out of ten were ever
monitored during the qualification to demonstrate shelf temperature uniformity.
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FDA Observations regarding lyo products
• Thermal mapping representative of each shelf has not been performed.
• Lyophilizers incapable of meeting predetermined criteria for leak rate in current condition due to
excessive leak rates exceeding the maximum allowable level.
• Maximum load configuration employed during validation does not reflect maximum capacity of the
equipment. In addition, there are no specifications in the batch records limiting use to only the
load configurations that had been validated.
• Lyophilizer cycle changes made for xx ml vial size has not been validated. Cycle changes were
implemented for the vacuum set points and secondary drying time to correct melt back and
foaming problems.
• Insufficient data to support process qualification in that two vials/shelf were tested for residual
moisture, one vial/shelf was tested for potency and three vials/lot tested for pH, reconstitution and
osmolarity. Sampling locations within the unit were not defined, with lot sizes ranging from 7600 to
10,000 vials.
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FDA Observations regarding lyo products
• Retrospective validation data was used to qualify the lyophilization process.
Testing data did not demonstrate uniformity or reproducibility of the process.
• Cleaning validation studies did not incorporate surface sampling and testing.
Interior surfaces are visually inspected for cleanliness.
• Chamber and surfaces are not periodically monitored for the presence of
residual oil or thermal transfer fluid.
• Periodic monitoring for the presence of thermal transfer fluids in the lyophilizer
chamber is not performed post-use.
• There are no data available to support the acceptability of the residual
moisture specifications established for final lyophilized product.
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Points to remember
Product and shelf temperature differ. Keep data available demonstrating that you know exactly what
these temperature differences could be.
• Assure that uniform freezing conditions are provided to all vials in load.
• Map all shelves in your system to demonstrate temperature uniformity.
• Requalify lyophilizer at appropriately defined time intervals (not more than one year is expected)
• Institute and document the preventive maintenance program for lyophilizers so that they can
continue to meet performance criteria.
• Validate any cycle changes implemented.
• Have sufficient final product testing data available to support validations. Document locations of
samples tested. Do not rely exclusively on release criteria.
• Demonstrate uniformity and reproducibility of lyophilization process through sufficient final
product testing.
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Points to remember
• Product and shelf temperature differ. Keep data available demonstrating that you know exactly what these
temperature differences could be.
• Assure that uniform freezing conditions are provided to all vials in load.
• Map all shelves in your system to demonstrate temperature uniformity.
• Requalify lyophilizer at appropriately defined time intervals (not more than one year is expected)
• Institute and document the preventive maintenance program for lyophilizers so that they can continue to
meet performance criteria.
• Validate any cycle changes implemented.
• Have sufficient final product testing data available to support validations. Document locations of samples
tested. Do not rely exclusively on release criteria.
• Demonstrate uniformity and reproducibility of lyophilization process through sufficient final product testing.
• Monitor chamber for residual oils and heat transfer fluids using qualified methods.
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Thank You
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