Lyophilization Validation: A Regulatory Perspective. Ellen Huang CBER/OCBQ/DMPQ CASSS CMC Strategy Forum July 19, 2016

Transcription

1 Lyophilization Validation: A Regulatory Perspective Ellen Huang CBER/OCBQ/DMPQ CASSS CMC Strategy Forum July 19,

2 Overview Objective Definition of lyophilization Observations and challenges Lyophilization process validation Aseptic processing Cleaning and sterilization Orphan products Alternative containers 2

3 Objective The objective of this presentation is to present an overview of FDA s expectations for validating the lyophilization process 3

4 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). 4

5 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 process 5

6 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 6

7 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 7

8 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

9 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

10 The Process Validation Continuum Pre-IND IND Phase I Phase II Phase IIb Phase III BLA Post-marketing 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 10

11 Stage 1: Process Design Process 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 11

12 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 12

13 Stage 2: Process Qualification At 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 13 sampling/testing of reconstituted product.

14 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 aseptic 14

15 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. 15

16 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

17 Cake Appearance Discernible Effects - Syringes Discernible Effects - Vials PDA Course No. 282, Validation of Lyophilization (May 2015) 17

18 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 18

19 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 19

20 Bracketing Strategy Load size (maximum and minimum) Multiple lyophilizers Demonstrate equivalence between the units Typically Multiple dosage strengths Consider thermal characteristics between dosage strength Fill volume Different vials size or manufacturers 20

21 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

22 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 22 of lyophilization cycle

23 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

24 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 SIP 24

25 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 25

26 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 26

27 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 vial 27

28 Acknowledgements Nicole Trudel Randa Melhem, PhD Qiao Bobo, PhD Tony Lorenzo Debbie Trout Jay Eltermann Laurie Norwood Mary Malarkey 28

29 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

30 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. 30