Strategies in Development of Lyophilized Parenteral - Lyophilization Articles & Reports

Strategies in Development of Lyophilized Parenterals
Edward Trappler, Lyophilization Technology, Inc.
For lyophilized parenteral preparations, as with any dosage form, product design parameters and objectives define the focus and direct the efforts in product development. Design parameters need to consider pharmacological, clinical and physio-chemical aspects of the active ingredient. These encompass the therapeutic response, administration, and stability requirements.
The therapeutic response entails the therapeutic regime and route administration. A regime may range from a single injection to multiple routine administrations. Single administration may be for an acute condition or vaccination. Short-term administration of oncology preparations for chemotherapy is often intermittent. IV therapy of antibiotics is used as a post-operative prophylactic. Long-term therapy may require relatively frequent administration, as in anti-hemophilia therapy.
Routes of administration also vary. The three most common routes are intravenous, intramuscular, and subcutaneous. Some less common routes are intraocular, intrathecal, intra-arterial, and intra-articular (1). Volumes of an injection, influenced by solubility of the active ingredient, need to take into account the preferred route of administration. A therapy may require a bolus injection of 10 ml in 10 minutes, an intermittent infusion of 50 or 100 ml using a ?piggyback? i.v. administration system, or a continuous infusion over several hours or days (2). Intramuscular injections of 2 ml are not uncommon. Smaller volumes of 0.5 to 1.5 ml are appropriate for subcutaneous injection (3).
Factors necessary in achieving adequate finished product characteristics include physio-chemical, microbiological, therapeutic and toxicological aspects. Lyophilization is principally a method of preservation for products that degrade in solution due to reactions with water. Products may also be light and oxygen sensitive. Providing adequate stability is a major product and process design objective for a lyophilized therapeutic. Sufficient stability is necessary to allow for preparation and processing during manufacturing that includes bulk solution preparation, sterile filtration, filling, and loading into the lyophilizer. Stability of the constituted solution is also important for convenient clinical use. The product design, focusing on the product formulation, also needs to provide sufficient stability in the dried state to accommodate adequate time for distribution and storage until final use.
Loss of potency may be attributable to direct chemical degradation or structural alteration. Chemical reactions readily occur in solution and can also occur in the dried state. These reactions include hydrolysis, oxidation, isomerization, and deamidation. Structural alteration of peptides and proteins is mostly but not exclusively associated with biopharmaceuticals. These alterations may manifest as precipitation, adsorption onto the glass vial, reversible and irreversible denaturation, polymerization and aggregation (4).
The objective for any lyophilized preparation is stability through the expiry date to provide sufficient chemical/biochemical recovery upon reconstitution in order to achieve the desired therapeutic effect. This also assumes the absence of any significant amount of degradation products. Parenteral products, regardless of the administration routes must meet all the criteria for an injection defined in the USP (5). They need to be no less clear than the diluent, be completely in solution, with no visible residue of undissolved material, and essentially free of visible particulate matter. These preparations must also be sterile and with a sufficiently low level of endotoxin.
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