Low-Risk Lyophilization

Developing a successful lyophilization program requires equal parts design, technology, and expertise.

By Brian Bucur, Associate Director, Lyophilization & Sterilization and Timothy Smith, Director, Product & Process Development - Ben Venue Laboratories, Inc.

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Freeze-drying (lyophilization) of pharmaceuticals has been used successfully for many years to provide stable, sterile injectable dosage forms.  However, as with any technology, lyophilization continues to evolve. Advances in analytical and process sciences allow pharmaceutical manufacturers to further exploit both chemical and physical phenomena that occur during lyophilization. At the same time, energy conservation, safety and complexity of pharmaceutical formulation chemistry continue to push the science of lyophilization well beyond the limits of basic cryogenic and sublimation equipment. This article presents suggested practices for developing a lyophilization program based upon Ben Venue Laboratories' years of experience and technical expertise.  Key points include cycle development for new products, container/closure systems, equipment issues, and risk mitigation. BVL monitors new technologies and strives to remain current with industry and regulatory expectations for optimized development practices based upon Quality by Design (QbD).

BVL continues to be a leader in contract lyophilization of investigational and commercial parenteral pharmaceuticals. We have new and  long term relationships with many domestic and international clients, a longstanding relationship with the National Cancer Institute and a successful generic division,  Bedford Laboratories.  Many of the products we manufacture (which include cytotoxins, genotoxins, biologics and diagnostics) require unusually complex production processes.

The exterior of Ben Venue's
385-square-foot lyo
chamber, its largest.

 BVL operates twenty-nine production lyophilizers and five development lyophilizers (one of which is a production-scale unit). BVL is currently validating a new cytotoxic/genotoxic facility which houses nine of the twenty-nine production lyophilizers.

These will be loaded through the use of laminar flow carts and unloaded into special isolators used to transfer vials to capping equipment. Production chambers range in shelf capacity from 96 square feet to 380 square feet for a total of 7692 square feet. This represents approximately 2.5 million 3cc or approximately 1.25 million 10cc standard tubing vials. BVL presently operates eight vial filling lines, six of which dispense liquid and lyophilized products and two that dispense liquid products only.

The new cytotoxic/genotoxic complex houses three additional filling lines, all of which will dispense both liquid and lyophilized products. Vial size processing capability ranges from 2cc/13mm to 200cc/28mm.

Given our substantial capacity, lyophilization equipment scheduling is logistically complex. For example, as a result of varying cycle lengths from product to product, rescheduling one lot may leave an opening that is either too short or too long for pending products to be scheduled into that slot.  Well developed and defined manufacturing procedures and lyophilization cycles are critical to maintaining a stable schedule.

The interior of the
385-square-foot
chamber, with one
shelf loaded
with 2cc vials.

Infrastructure planning for new equipment and upgrades now, more than ever, necessarily involves early interaction between internal departments, outside vendors, regulatory agencies, utility companies and local communities. Development project planning is equally complex.

Presuming that a product’s therapeutic potential has been clearly established, the steps required for further assessment, dosage form development,  and lyophilization cycle development must be carefully mapped and coordinated.

These include scale-up studies to identify resources necessary not only to ensure technical success but also to make certain that safety, regulatory, environmental, cost, and risk guidelines are met.

Development Activities Leading to a Lyophilization Cycle

Beginning with an established target dose, additional information needs to be collected to successfully develop a formulation and suitable lyophilization cycle. This includes:

  • optimum pH
  • solubility - are special excipients indicated? (e.g. ethanol, t-butanol, DMSO, cyclodextrins)
  • stability characteristics - room temperature, refrigerated, freezing (is a cryoprotectant indicated?), light sensitivity
  • headspace lability - does oxygen need to be excluded?
  • administration route - intramuscular, intrathecal, intravenous, (bolus, infusion pump?), instillation?
  • constitution volume - what concentration will be administered (if administered undiluted or diluted into intravenous fluid?
  • constitution diluent/vehicle - is a buffer or special solvent indicated?

A thoroughly-considered development plan is established based on dosage form expectations, pre-clinical data and literature/search information, arriving at one or more formulae for evaluation.  Solutions from small lab batches are examined before and after filtration for their pH, color, clarity, assay, impurity levels and stability.  If no issues are identified, analysis of the liquid using lyophilization development tools can proceed. These include differential scanning calorimetry, moisture measurement methods and freezing-stage microscopy, all of which provide information regarding thermal events and conditions that will ultimately impact lyophilization.  At this point, pilot-scale lyophilization batches are prepared.

In most cases, multiple lyophilization experiments are required to achieve a successful cycle, particularly where unusual or non-optimal product formulae are involved. Lyophilization difficulties may, unfortunately, dictate a return to the formulation “drawing board” with, at minimum, revisions to excipients, concentrations, volumes or other variables.  We recommend that unusual or non-optimal conditions be carefully taken into consideration at the outset of development.  By the time a formula gets to the pilot lyophilizer, there should be a limited number of unknowns.

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