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  • Lyophilization Validation: A Regulatory Perspective


    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


  • Objective The objective of this presentation is to

    present an overview of FDAs expectations for validating the lyophilization process


  • 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).


  • 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 products 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


  • 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


  • 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 1-2C) Temperature range should exceed actual

    lyophilization temperatures Leak rate test Condenser capacity 9

  • The Process Validation Continuum


    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


  • 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


  • 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


    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 -


    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


  • 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


  • 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


  • 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


  • 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 l