lyophilization validation: a regulatory perspective · qualification, and process validation ......
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Lyophilization Validation: A Regulatory Perspective
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Ellen HuangCBER/OCBQ/DMPQ
CASSS CMC Strategy ForumJuly 19, 2016
Overview• Objective• Definition of lyophilization• Observations and challenges• Lyophilization process validation• Aseptic processing• Cleaning and sterilization• Orphan products• Alternative containers
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Objective• The objective of this presentation is to
present an overview of FDA’s expectations for validating the lyophilization process
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What is Lyophilization• A process in which water is removed from
a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase.
• The process consists of three separate, unique, and interdependent processes; freezing, primary drying (sublimation), and secondary drying (desorption).
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Annealing• Optional step(s), that typically follows the
freeze step where the product is warmed up to allow crystals to grow
• Performed because crystalline component may not be completely crystallized– Provides necessary cake structure or more
stability to the protein • Facilitates faster sublimation, thus
optimizing the process5
Lyophilization• In general, lyophilization is used for drug
products to provide for greater stability and increase the product’s shelf life.
• Prior to use, the product is reconstituted with the appropriate diluent.
• Lyophilization is sometimes used on drug substance, especially for long-term storage, e.g., multiple conjugates
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Observations and Challenges• Establishing a commercial lyophilization
process can be challenging• Successful validation requires robust
development studies, equipment qualification, and process validation
• Not enough focus on developing the freezing phase, the most important phase of the cycle
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Observations and Challenges• Inappropriate bracketing strategies (e.g., load
size or number of lyophilizers)• Inadequate empty chamber shelf temperature
and product temperature mapping• Insufficient sampling for quality and uniformity
– Sample locations unknown• Worst-case load not repeated• Scale-up or technical transfer issues• Vial/container imperfections 8
Equipment Qualification• Empty chamber temperature mapping
– Thermocouples (TC) are typically placed in the four corners and center of each shelf
– Identify cold and hot spots– Expect limited variability on each shelf and
between shelves (usually about 1-2°C)– Temperature range should exceed actual
lyophilization temperatures• Leak rate test• Condenser capacity 9
The Process Validation Continuum
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Stage 1: Process Design through iterative risk assessment, quality characterization and process characterization cycles, with the objective of establishing a commercial process with sufficient control to consistently produce drug substance and drug product meeting defined specification manufacturing phases linked through comparability
Stage 2: Process Qualification that is sufficiently comprehensive and robust to provide conclusive evidence that the commercial process as designed consistently achieves specified product quality in the commercial production environment
Stage 3: Continued Process Verification Continuous
process and product monitoring Trending and
annual product reviews Deviation
management Change control Validated process
improvements State of control
INDPre-IND Phase I Phase IIb BLAPhase III Post-marketingPhase II
Stage 1: Process DesignProcess Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities• Understand the product and critical properties of
the formulation – Thermal characterization (collapse temperature,
eutectic temperature, and/or glass transition temperature)
– Stability of the product– Properties of the excipients used
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Development Studies• Laboratory, pilot, and at-scale scale
studies to support commercial cycle • Design of experiment studies to
understand impact of parameters (e.g., shelf temperature, pressure, time, and ramp rate) and design space for the product
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Stage 2: Process QualificationAt this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
– Combines qualified facility, equipment, utilities, and trained personnel with the Process Performance Qualification (PPQ) (may include at-scale engineering runs)
• To demonstrate product uniformity and the ability to repeat and consistently manufacture product.
• Product uniformity is demonstrated through product temperature mapping and extended sampling/testing of reconstituted product. 13
Product Temperature Mapping• TC are typically placed in the product in the four
corners and center of each shelf– Can use “seeded” runs– Use of an appropriate surrogate
• Temperature profile diagrams useful in determining when primary and secondary drying have completed– Need to add additional time to primary drying since
containers with TC nucleate at higher temperature• Usually performed as engineering runs since
using TC throughout the load is not aseptic14
Temperature Profile Diagram
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Freezing Primary Drying Secondary Drying
Trappler, E. H. (2007). Validation of Lyophilization. In F. J. James P. Agalloco, Validation of Pharmaceutical Processes (p. 388). CRC Press.
Extended Sampling• Sample vials typically from four corners
and center of each shelf• Sample locations should be known• Testing often includes residual moisture,
reconstitution time, cake appearance (no collapsed cake or melt back), and reconstitution appearance,
• Can be performed as part of PPQ / conformance runs 16
Cake AppearanceDiscernible Effects -
SyringesDiscernible Effects -
Vials
PDA Course No. 282, Validation of Lyophilization (May 2015)17
Boundary Studies• Studies where shelf temperature and
chamber pressure were offset from commercial set-points– High and low shelf temperature– High and low chamber pressure
• Sometimes time is also varied during these studies
• Not required for fixed cycles but provides confidence in lyophilization process
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How many runs?• It depends
– Typically three runs are performed on the maximum load and one run is performed on the minimum load
– How much supportive development work– How many factors there are (e.g., number of
lyophilizers, dosage strength, etc.) and how study is bracketed
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Bracketing Strategy• Load size (maximum and minimum)• Multiple lyophilizers
– Demonstrate equivalence between the units– Typically 3+1+1
• Multiple dosage strengths– Consider thermal characteristics between
dosage strength• Fill volume• Different vials size or manufacturers 20
Stage 3: Continuous Process Verification (CPV)
CPV: Ongoing assurance is gained during routine production that the process remains in a state of control.• Continued monitoring and sampling of process
parameter and quality attributes– Analyze and trend the data– Once sufficient data has been gathered, can reduce
monitoring with justification– Monitor changes in process inputs, including materials
and container/closure components• Imperfections in the vial can have negative impact on crystal
formation during freezing. 21
Aseptic Processing• Transportation of vials from the filling line to
the lyophilizer should be done aseptically since vials are partially stoppered
• Media challenges should include transportation, loading, holding, partial vacuum, stoppering, and unloading the lyophilizer, however:– Media should not be frozen as this may kill
organisms– Hold time does not need to be the actual duration
of lyophilization cycle22
Cleaning• Perform between each run• Clean-In-Place (CIP) or manual cleaning
– CIP cycle: initial rinse, recirculation, final rinse, drying
– CIP CV should demonstrate total chamber coverage (riboflavin)
• WFI is preferred– If cleaning agent is used, must demonstrate
removal from the chamber• Cleaning process should be validated
– Use worst-case soil– Procedure for potential spills 23
Sterilization• Lyophilizer should be sterilized after
cleaning • Typically observe steam sterilization (SIP)
(overkill approach)• Sterilization process should be validated
– Heat distribution and biological indicators– Demonstrate Sterility Assurance Level of 10-6
• Chamber should be dry after SIP24
Orphan Products• Use of an appropriate surrogate or
perform with seeded runs• Less PPQ runs may be submitted in
submission since product is manufactured infrequently– Perform additional runs in the future to
support the PPQ• No exemption from CGMP compliance
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Alternative Containers: Trays• Membrane Trays (e.g., LYOGUARD®)
– Tray with a PTFE membrane– Usually has low fill depth -> Larger shelf
contact area– Temperature mapping requires more than one
TC per container– Typically seen used for drug substance
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Alternative Containers: Syringes• Pre-Filled Syringes and Dual Chamber
Syringes• Syringe has less/no contact with the shelf, so
heat transfer will be different than a vial. Therefore, syringes respond more slowly to shelf temperature changes.
• Consider type of syringe holder and loading configuration
• Validation expectation same as vial27
Acknowledgements• Nicole Trudel• Randa Melhem, PhD• Qiao Bobo, PhD• Tony Lorenzo• Debbie Trout• Jay Eltermann• Laurie Norwood• Mary Malarkey 28
Definitions• Collapse Temperature (Tc) – The temperature
above which the frozen formulation undergoing lyophilization loses macroscopic structure and collapses; below this temperature, the solute/solvent mixture is able to retain its structure, even when it is not supported by surrounding ice, which is removed via sublimation during primary drying.
• Eutectic Temperature (Te) – The point at which the product only exists in the solid phase, representing the minimum melting temperature. Not applicable to amorphous material. 29
Definitions• Glass Transition Temperature (Tg or Tg’) – the
temperature above which the formulation undergoing lyophilization
• Metastable – pertaining to a body or system existing at an energy level above that of a more stable state and requiring the addition of a small amount of energy to induce a transition to the more stable state.
• Sublimation – The transition of a substance (such as ice) from a solid state directly to the vapor state (such as water vapor) without first passing through an intermediate liquid phase.
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