Traditional semi-solid pharmaceutical and cosmetic manufacturing processes utilize large, stirred kettles to
combine the various components into the bulk product. When used to manufacture liposomal liquids and semi-solids, the lipid phase
components are added to the aqueous phase in the kettle. As the first drop of lipid comes into contact with the pure aqueous phase, a
concentration gradient occurs. As additional lipid contacts the aqueous phase, liposomes are inconsistently formed due the undesirable
changes in the concentration gradient. It is extremely difficult to accurately control liposome formation with this traditional process.
In addition, product yields are fairly low at large production batch sizes due to the amount of material that is held up on the large
surface area of the kettle and material that is lost during transfer processes.
Systemic parenteral liposome manufacturing employs batch processes involving numerous unit operations that do not easily scale to
commercial production levels The thin film lipid manufacturing processes is adequate for laboratory testing and for very small batches.
However, as these processes are scaled up to commercial sizes, two disadvantages become apparent; 1) very large quantities of volatile
solvents are required to create the thin lipid film that is then hydrated with the aqueous/active solution to form liposomes under
constant agitation, and 2) process yields are typically very low. The use of large quantities of volatile solvents makes this process
quite expensive. When the solvent is evaporated to form the thin lipid film, it must be collected and recovered or burned off. Solvent
abatement systems require significant capital expenditures to install and are very expensive to operate and maintain. Low yields are a
result of the filtration step that is required to produce the liposomal liquid prior to packaging. Filtration removes all but the
smallest liposomes. This is the "sizing" method that is used to gain consistent liposomes in the final product. Again, the cost for this
consistency is a result of the very large proportion of material that is discarded during the filtration step. For systemic parenteral
liposomal products, this very low yield is currently accepted due to the low price sensitivity that exists for the parenteral
market.
LIPPOMIX's OPTIMIXTM Process
LIPPOMIX's products are produced using the Company's proprietary OPTIMIXTM (patented) manufacturing technology. Over six
patents have issued (three in the United States, three foreign, others pending) This continuous-operation manufacturing process allows for the production
of consistent and reproducible liposome-encapsulated drug products. The process and equipment have been developed to address the barriers associated
with the large-scale production of liposomal drug products.
The OPTIMIXTM technology involves a process that continuously mixes multiple streams of raw materials. Since liposomes are formed continuously in a
relatively small chamber of optimal geometry and under closely controlled conditions, the process does not require the use of dangerous and costly
volatile solvents or large surface areas to produce liposomal products.
OPTIMIXTM technology can also be integrated with downstream packaging equipment to minimize the number of unit operations
required in the process.
Utilizing the OPTIMIXTM technology, the dispersion of the lipid phase into the water phase is precisely metered using computer-controlled pumps under
computer-controlled temperature conditions. Liposome formation occurs within a proprietary custom designed mixing assembly. The result is a homogeneous
drug product with structurally consistent liposomes (intra-batch uniformity), as well as batch-to-batch (inter-batch) reproducibility.
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Advantages of OPTIMIXTM over Alternative Processes
The OPTIMIXTM process provides significant performance improvements over competing processes in several critical categories:
| The OPTIMIXTM Process In Comparison |
| OPTIMIXTM |
Stirred Kettle |
Thin Film Lipid |
| Liposomal and non-Liposomal liquids and semi-solids |
Non-Liposomal liquids and semi-solids |
Liquid Liposomal Parenterals |
| Greater than 95% |
80% - 90% |
Typically less than 10% |
| Infinitely scalable due to the continuous nature of the equipment |
Incrementally scalable. Standard mixing kettles are available in any size, and cannot be modified if the batch size must change |
Incrementally Scalable |
| $500K - $750K for complete, validated compounding and packaging line |
$750K – $1,000K for complete drug compounding and packaging line. |
$1,000K - $2,500K with associated solvent abatement equipment |
| $1.00 - $2.00 per unit COGS |
$3.00 or more per unit COGS due to low yield/high hold up on tank walls and anchor blades |
High due to low yield, but supported by high product price point |
| Very low with respect to raw materials, particularly lipid and drug actives |
Very low with respect to raw materials, particularly lipid and drug actives |
High due to required specialized equipment |
Very safe due to minimal volatile solvent use |
Very safe due to minimal volatile
solvent use
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Safe only with proper solvent
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Very high inter- and intra-batch consistency due to inherent control of flow rates and temperature |
Inadequate for LIPPOMIX's products |
Adequate but inefficient for liposome encapsulated products |
Due to the higher yields and lower capital and material costs associated with the OPTIMIXä, LIPPOMIX can compete effectively in a wide variety of
markets, including the price-sensitive OTC market. LIPPOMIX's lower manufacturing cost also provides an effective barrier against competitive
imitation of LIPPOMIX's product line.
Operational Status of OPTIMIXTM
cGMP and FDA Approved Manufacturing Equipment
To date, OPTIMIXTM Manufacturing Equipment has been sold or licensed to third
parties. Having endured a series of rigorous qualification exercises in order to be approved for use in the manufacturing of pharmaceutical products for human use, LIPPOMIX's OPTIMIXTM Manufacturing Equipment has been placed in FDA approved cGMP contract manufacturing facilities.
Many cGMP regulated batches resulting in finished units have been produced at the facility of a contract manufacturer. The quality testing results
after the production of these batches has confirmed the ability of the technology to produce consistent and reproducible liposome-encapsulated drug
products. The process produced product at the expected rate of approximately one liter per minute (1 L/min) consistently throughout all of the
manufacturing campaigns. Yields for these batches ranged from 96% to 98%. This is extremely efficient at the pilot scale and is expected to improve
as batch sizes increase.
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OptiMixTM Mixer |
Copyright © Lippomix, Incorporated 2007
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