Process Challenges and Solutions
The delivery of complex injectables requires tailor-made solutions, and that calls for not only a perfect match between the active substance and the administration system, but also a close working relationship between the vendor and the pharmaceutical company.
The development of sophisticated medications for unmet medical needs has created a whole new breed of challenges for the pharmaceutical industry. The sophistication of these new drugs has dramatically changed the processes required to produce them. By the same token, the products themselves must be differentiated on the marketplace in order to achieve commercial success. The standard ampoule, for example, might still be appropriate for a low-priced, generic drug that is widely known and has attained general acceptance.
Innovative drugs, on the other hand, such as recombinant proteins, monoclonal antibodies, etc., require much more sophisticated packaging and presentations if they are to achieve breakthrough. A number of solutions have been developed, and the following case studies provide good illustrations of platforms that were constructed with the customer.
The Process of Syringe Filling
While the filling of vials and bottles is a well known process in both the food and pharma industry, the filling of syringes is something different.
Both syringe barrels and rubber stoppers and closure parts have to be washed and cleaned before sterilization. Ordinarily, this is done in washing machines using purified water for first washing steps, followed by final rinse with water for injection. The final step of this process is the lubrication of the parts. Lubrication is in most cases based on medical grade silicone oil. Processes have been fine-tuned to provide enough silicone to allow movement of the stopper in the syringe, while at the same time keeping the quantity to the absolute minimum.
If possible, the sterilization of the syringes is done using dry heat tunnels since this also de-pyrogenizes, or removes pyrogens which could cause patients to run fevers. If this is not possible, for example when the syringe has a staked needle, steam sterilization is used. In this case, a more sophisticated washing process is needed that already reduced pyrogens on the glass. In one case study, the pyrogen removal has been validated by demonstrating an endotoxin removal exceeding 3 log.
The filling can be done using various pumping technologies and is suited to the product's needs: rotary piston pumps, rolling diaphragm pumps, or peristaltic pumps are some of the possibilities. As a principle, an inline filtration of the product on the filling line is applied as close as possible to the point of fill. This reduces the critical area within the cleanroom to a minimum.
The stopper is introduced into the syringe using a stopper placement tube with a slightly smaller diameter than the syringe. The stopper is compressed through the tube with a placement pin. When the stopper has reached it's final position, the tube is retracted first, letting the stopper expand. With this technology, no overpressure is created within the syringe.
Case Study 1: Microparticles
Microparticles as a dosage form have been developed as depot for long-release of drug substances. These microparticles are typically based on biodegradable macromolecules such as lactic and glycolic acid copolymers. The manufacturing of these microparticles can be done by either spray-drying under aseptic conditions, or using solvent-detergent based processes. For the fill-finish section of the process, the challenge lies in the aseptic transfer into the classified area (Class A/B) with subsequent re-suspension.
In this particular case, the microparticles manufactured by spray-drying are collected in a small stainless steel vessel which is then transferred into a minienvironment. This box is transported to the site of filling and coupled to the cleanroom wall. During this step, the outer side of the clean-room door is fixed tightly to the outer side of the transfer box, therefore sealing the unsterile faces of both doors. The door then opens into the cleanroom providing access to the stainless steel vessel. The vessel is transferred into an aseptic work place equipped with RABS (restricted access barrier system). Here, the microparticles are re-suspended into a buffer solution just prior to filling.
Case Study 2: Dual-chamber Syringes
The second part of the process above is the filling of the microparticle-suspension into dual-chamber syringes, especially developed to meet the requirements of certain types of drugs that need to be combined prior to administration, such as a freeze-dried active substance and its diluent. The system involves placing a stopper inside a syringe. The diluent is then filled into the top segment, the active substance in the bottom one. Prior to administering the drug, the doctor or nurse activates a mechanism on the plunger to mix the two substances.
The steps involved are depicted in the following illustration [insert pdf-illustration].
The special challenge in filling the suspension is the sedimentation of the suspension when the filling is interrupted. All connections have to be performed with special care as the suspension cannot be filtered. For the sedimentation, a special recirculation from the filling needles to the product holding tank was developed providing conforming product throughout the fill. Also, due to the abrasive nature of the particles, ceramic pumps have to be used instead of the usual stainless steel ones. This particular product has been in commercial production for seven.
Case Study 3: Oxygen Sensitive Products
For oxygen sensitive products, the filling has to be done under protective atmosphere. In most cases, the air bubble in the filled syringe is replaced by a nitrogen-rich gas-mix. Depending on the detailed layout and construction of the filling machine, this can be done on various work stations. For some processes, it is sufficient to provide nitrogen into the stopper placement tube during sealing of the syringe. For others, pre-purging of the empty syringes coupled with filling under nitrogen might be called for. Using this technique, oxygen levels of less then 8 percent in the air bubble are obtained. Final proof for the effectiveness of these steps however can only be shown in stability studies.
As shown in the case studies, the delivery of complex injectables requires tailor-made solutions. In order to provide the perfect match between the active substance and the administration system, there must be a close working relationship between the vendor and the pharmaceutical company, especially when it comes to conducting feasibility analyses and determination of which injection system best suits the drug to be produced. During the clinical production phase, all necessary tests must be carried out on the product to ensure sterility, stability and even viability for up-scaling. All documentation necessary for international approvals must also be prepared during this phase. �Joerg Zimmermann is head of product