Practical experiences in the transfer and scale-up of freeze-dried products: several key steps should be taken to ensure a successful transfer of a freeze-dried product from a client to a contract manufacturer

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Practical experiences in the transfer and scale-up of freeze-dried products: several key steps should be taken to ensure a successful transfer of a freeze-dried product from a client to a contract manufacturer
February 2004
J. Jeff Schwegman, Lisa M. Hardwick, Donald Crawford, C. Wesley Hines, James Jarman, Brad Korte, Michael J. Akers
Baxter Pharmaceutical Solutions LLC, 927 South Curry Pike, PO Box 3068, Bloomington, IN 47402.
*All correspondence should be addressed to Michael J. Akers, michael_akers@baxter.com, tel. 812.355.7188
Pharmaceutical Technology
Several key steps should be taken to ensure a successful transfer of a freeze-dried product from a client to a contract manufacturer.
As a contract manufacturer of sterile products, including freeze-dried products, our company receives requests for assistance with clients' freeze-dried products at various stages in the pharmaceutical product development process. There are four scenarios in the product development stage in which the product and process may be transferred from a client to the contractor that will require specific activities to take place to obtain a successful transfer. The scenarios occur when a client has
* no formulation or freeze-dry cycle developed.
* some formulation and freeze-dry process information available, but additional development work is required before clinical batches can be prepared.
* a formulation and freeze-dry cycle developed, but it needs further optimization and scale-up work before commercial batches can be prepared.
* a final formulation and freeze-dry cycle developed that requires no additional work except for the process to be transferred at the same scale.
In the first scenario in which a client has no formulation or freeze-dry cycle developed, initial efforts are focused on development batches using a non-GMP freeze dryer. The client must provide as much information as possible about the drug substance (and associated analytical methods) to allow formulation scientists to make rational decisions regarding the formulation.
After product configuration (concentration, route of administration, fill volume, and vial size) and optimal solution conditions (pH, buffer capacity, and tonicity) are established, excipients that are known to produce mechanically strong and elegant cakes with rapid reconstitution rates (typically mannitol or glycine) are added as bulking agents if necessary. The initial solution should have a solute con tent between 5% and 30% with a target of 10-15%. Additional excipients (typically sucrose or trehalose) may be required for protein or peptide drugs to protect against the stresses associated with both freezing and drying. Nonreducing, amorphous excipients that have a high glass-transition temperature ([T.sub.g]') of the maximally freeze-concentrated amorphous phase usually are chosen.
The maximum allowable product temperature permitted during primary drying is determined for the proposed formulations using a combination of techniques. It is critical to characterize the thermal properties of a formulation if a robust, time-optimized freeze-dry cycle is to be developed. The [T.sub.g]' or eutectic melting temperature of a formulation ([T.sub.e]) is routinely measured using either low-temperature differential scanning calorimetry (DSC) or dielectric analysis (DEA). Collapse temperature ([T.sub.c]) also must be determined using a polarized-light freeze dry microscopy system. Results obtained using these two techniques will then be the basis for establishing freeze-dry parameters for use in a small-scale freeze-dry pilot study. The pilot study is critical for establishing the proper balance between the chamber pressure and the shelf temperature, and is required to achieve the desired product temperature and sublimation rate. The maximum allowable temperature permitted during secondary drying is determined by the client or generated in the contract laboratory by monitoring physical integrity and drug stability of the freeze-dried cake as a function of time, temperature, and moisture content.
The appropriate vial size, amount of product fill, and type of rubber closure for a final product (formulation and package system) can then be recommended. These parameters are based on
* the rate of freezing and the need for annealing
* optimal shelf temperature and chamber pressure during primary drying and secondary drying
* whether sealing will be performed under vacuum or nitrogen atmosphere or both
* sublimation rates.
To evaluate moisture levels on the basis of product quality attributes, various studies should be conducted. The product must be exposed to various humidity conditions, and changes in the solid-state glass transition temperature and drug stability must be monitored. Characterization of the final dried solid should be evaluated once the final formulation and the freeze-dry cycle have been developed. Accelerated stability studies also may be conducted at the client's request to determine polymorph changes of crystalline excipients or the crystallization of added amorphous components.
Once a final formulation, lyophilization cycle, and acceptable residual moisture level have been established, the freeze-dried solids must be characterized to determine the acceptable physical characteristics. This baseline information could prove invaluable if the chemical or physical integrity of the product changes in time. X-ray powder diffraction patterns should be collected for the dried material. In time, comparing changes in these patterns with the original patterns may be useful for identifying and quantifying amorphous-to-crystalline relaxation or polymorph changes in the crystalline material. Isothermal microcalorimetric techniques may also be used. The glass-transition temperature of the dried solids also should be measured if amorphous excipients are included in the formulation. A decrease in glasstransition temperature could indicate that moisture is being extracted from the container-closure system or the outside environment, or it could indicate the crystalline relaxation of some or all of the amorphous components.
In the scenario in which a client has some formulation and process information available but additional development work is required before clinical batches can be prepared, all data about the product must be reviewed with the client to determine whether additional data must be developed. Any needed changes in formulation, package, or process should be assessed. The following activities and studies may OCCUr:
* confirm [T.sub.e], [T.sub.g]', and [T.sub.c] of proposed formulation
* propose changes, if any, in the freeze-dry cycle
* conduct preliminary freeze drying experiments (2-4 batches)
* propose final formulation, package, and process
* verify the cycle on proposed final product in a laboratory dryer
* run a practice cycle (demonstration batch) in a GMP clinical dryer.
All data must be reviewed and approved by the client. Further work might be necessary to improve the formulation and the process. One or more laboratory or demonstration batches will need to be prepared before the preparation of clinical batches.
In the scenario in which a client has a formulation and freeze-dry cycle developed but needs further optimization and scale-up work be fore commercial batches are prepared, it is assumed that the formulation is adequate, on the basis of stability and other performance data, but that the cycle could be optimized before scale-up operations occur The [T.sub.e] or [T.sub.g] of the proposed formulation should be confirmed and, if not already available, [T.sub.c] should be determined. From the client's data and any new data generated, changes in cycle parameters based on the formulation and the thermal behavior of the formulation must be proposed.
The proposed optimization cycle should be evaluated first in a laboratory freeze dryer (2-4 batches), where stability and performance data are gathered to verify that the cycle optimization is successful at small scale. Further studies in a laboratory dryer should be conducted to determine the proven acceptable ranges of the cycle's parameters. Other critical variables should be tested in a similar manner. The finished product must be evaluated for appearance, potency, moisture, and other acceptance criteria. Stability studies also may be conducted, depending on a client's preference.
Subsequently, the scale-up cycle based on laboratory-dryer data can be estimated. One demonstration batch should be manufactured at full-scale in a production dryer. The final product from the production batch should be evaluated for all quality parameters. One scale-up problem frequently encountered is having rubber closures stick to the shelves during the automated stoppering process. Closure design, closure preparation, and shelf temperature all affect closure sticking.
Decisions must be made to determine whether any changes are necessary in the cycle. Although it is expected that the first demonstration batch will be successful, changes may necessitate one or two additional demonstration batches. Subsequently, three GMP process-validation batches should be produced.
Finally, in the scenario in which a client has a final formulation and freeze-dry cycle developed, including robustness studies (data using ranges in temperature and pressure), and no additional work is required except for the process to be transferred at the same scale, at least one practice run in a laboratory dryer should be conducted (unless the client already has a cycle developed using a commercial dryer with no thermocouples). R&D scientists and technical services representatives (engineering and validation included) must review the client's data. If necessary, a demonstration or experimental large-scale batch should run in a production dryer.
A discussion with the client can determine the need to conduct further robustness studies. One possibl