In my three previous essays on the use of single use systems in biopharmaceutical drug manufacturing, I provided my assessment of the value that these systems will bring in the production of bulk drug substance (DS) or active pharmaceutical ingredient (API). The first essay dealt with environmental consideration, the second with fermentation of drug substance, and the third with purification and recovery of drug substance. This fourth and final essay reviews the current state of the art and assesses the pros and cons as well as the difficulties in deploying pre sterilized single use filling systems for biopharmaceutical drug product (DP) that is filled into vials or prefilled syringes.
To begin, let us review the final stage of bulk drug substance manufacture in biopharmaceuticals. Typically, the drug substance will be produced in its final formulation or very close to its final formulation. In a majority of cases, the biological drug substance is also formulated to have a two or three year shelf life as frozen bulk in an intermediate stage of the drug. The vast majority of bulk storage tanks are fabricated from 316L stainless steel, in case when the drug substance is more corrosive more expensive super high performance alloys. The stainless steel bulk storage tanks will also contain the following elements in the alloy: molybdenum, chromium, cobalt, iron, copper, manganese, titanium, zirconium, aluminum, carbon, and tungsten. These elements may have an adverse effect on the drug quality.
These bulk storage tanks are very expensive. A three hundred liter bulk drug substance storage tank has a cost approaching two hundred thousand dollars. A single tank is as expensive as an Aston Martin. The holding cost on this amount of capital if the biopharmaceutical drug substance is held in a frozen state for two years can approach eighty thousand dollars if the drug manufacturer typically funds capital projects that pay out in five years. If the manufacturer has faster payout expectations for its capital deployed, the holding cost is even higher. An alternate to stainless or bulk storage tanks is to store the drug substance in single use plastic tank bags. Of course the bag will need to be tested for chemical compatibility with the drug that will be stored in it and there are some engineering problems to overcome with the speed and uniformity of the freezing process of the drug substance, however there is a significant economic driver for biopharmaceutical drug manufacturers not to tie up much capital in a fleet of stainless steel tanks.
If the drug substance is stored as frozen bulk in single use plastic bags, then there are also cost advantages to the final fill operation. I will now discuss these advantages. As the first example let us assume that the bulk drug substance produced is in the exact same formulation as the filled drug product that will be sold. Using the traditional method of storing the bulk drug substance in stainless steel tanks (sometimes referred to as cryogenic tanks) the fill plant has to have an incoming storage tanks where the thawed drug substance is transferred from the cryogenic tank and received into the fill plant’s incoming tank. This tank is also fabricated from stainless steel and the tank has to be washed, sanitized and prepped for each batch of drug product to be filled. The use of single use plastic bags for frozen bulk storage eliminated the need for the fill plant’s incoming storage tank. This will save capital costs, operating costs for the cleaning and sterilization, as well as have a significant improvement in the carbon and water footprints of the filling plants operation.
As previously stated, there are limitations in the size and geometry of the plastic single use bulk drug substance bags that are used for storage. These constraints will determine the lot size of the filling operation. If the contents of several stainless steel cryogenic storage vessels are normally pooled in the fill operation, this again places a constraint on the use of single use plastic bags without having an incoming traditional storage vessel in the fill facility. Likewise if the bulk drug substance does not have the equivalent formulation as the final as sold drug product filled in the vial or pre-filled syringe, then the fill facility will need an incoming tank to accommodate the process steps need to accomplish the change to the final formulation. To recap: in instances where the bulk drug substance is already at the final formulation and the lots sizes of vials or prefilled syringes are not large, significant economic and ecologic advantages are gained using single use plastic storage bags. This scenario will often apply in the supply of drug product used for clinical trials.
Now that we have comprehended the storage of frozen drug substances and the first process step of thawing and transferring the drug into the filling operation, I will describe the other uses of single use components in a fill operation. As an alternate to the traditional rigid and in place transfer piping between the incoming tanks and the fill line, there is the possibility to use single use pre-sterilized flexible plastic (silicone) tubing and associated plastic fittings. The single use systems eliminate the need to wash and sanitize the transfer piping. Piping is typically more difficult to wash and sanitize than are tanks. This is due to the smaller dimensions and more convoluted geometry of the piping compared with a storage tank as well as the shutoff valves that are part of the piping. Eliminating the need for cleaning and sterilization of product contacting transfer piping and fittings will save labor, CIP and SIP costs, and also lessen the cycle time needed for the fill operation.
In a multiproduct biopharmaceutical drug product fill facility, the manufacturer has dedicated sets of fills nozzles (also referred to as needles or injectors) that are particular to a single drug. When the filling line is switched from one product to the next, the fill nozzles are changed. The removed fill nozzles are then washed and sanitized for later use. An alternate to reusable fill nozzles that are typically fabricated in a machine shop out of stainless steel is to fabricate single use nozzles that are injection molded from plastic. An economic cost analysis may show that the single use pre sterilized plastic parts is competitive with reusable nozzles due to the cleaning and sterilization saving as well as the possible improvement in cycle time that could arise in removal and reinsertion of the nozzles. A problem with single use plastic nozzles is that they are often too wide to penetrate small vials or syringe openings and are also too short to be used in bottom up filling. Bottom up filling is deployed to reduce splashing and foaming. The nozzles also must prevent drips forming between dosing of the vials. The wider the needle the higher the propensity for drips to form. The cost of single use stainless steel nozzles are likely to be prohibitive, hence in most cases the drug product manufacturer will continue to use reusable stainless steel nozzles in their filling operation.
Another limitation in fill operations deploying single use pre sterilized systems is when the operation is filling at high speed large batches of a single product in a repetitive campaign to fill the same product. In the case where the manufacturer is performing high speed and large lot size filling the single use pre sterilized systems may not adequately support the filling operation.
In order for filling systems to be able to perform high-speed operations, there are many obstacles and major technical efforts that must come to fruition. This is not a new thought, nor a new undertaking; rather this task has proven to be a difficult one. Current systems are equipped to perform low speed, small batching filling procedures, and the scale up, high-speed filling systems, while sound like a perfect, durable solution, only create addition problems, such as a fairly slow dosing speed, somewhat of a loss of filling accuracy and precision, and difficulty dosing products with variable temperature and viscosity attributes.
There is quite a bit of light at the end of the tunnel though as more and more of the biopharmaceutical drugs that are coming to market are for the treatment of diseases affecting a small population of patients. The likely vial size for many of these drugs is greater than 10 ml and the lot sizes may only be several thousand vials per lot. In this situation, and also in the case of clinical drug product manufacture, single use pre sterilized filling components will offer biopharmaceutical drug manufacturers economic and ecologic advantages.
If all of the technical achievements can be solved, and a system can be scaled up to a high-speed filling operation, then there will be an overwhelming amount of advantages for the use of single-use systems such as efficiency and consolidation of tasks and steps.
As a conclusion to this series of four essays, biopharmaceutical drug manufacturers do have the choice to deploy single use systems as an alternate to traditional stainless steel systems in their fermentation, purification and recovery, and filling operations. The manufacturers of such single use systems will not capture a vast market, but will enjoy a high level of acceptance in certain segments such as the manufacture of a specialized drug to treat a small number of patients and certainly in the manufacture of drugs to support clinical trials. I want to thank you all for reading the series of essays and want to remind you that the opinions I have expressed in the series are personal and not those of my employer Genentech.
Lindsay Leveen, “The Green Machine”, has worked with and consulted to major corporations in areas of energy deregulation, fuel cells, biotech, telecommunication, alternate fuels, power generation, transmission and distribution, as well as a variety of other process based technologies. Lindsay now works at Genentech as the Product Management Team leader for Lytics (Activase, TNKase and Cathflo) and was the Associate Director of Strategic Planning for this leading Biotech Company. Lindsay has lectured on sustainable development at leading universities and numerous industry conferences. He has written a book that is now used as a university text in Japan for energy policy and sustainable development. Lindsay has a knack to simplify and explain thermodynamics in everyday terms. He studied thermodynamics for his graduate thesis in Chemical Engineering at Iowa State University.