As the development team gains more experience with the product during the devel-opment stage, they should always keep in mind the scalability of the product for commercialization. They should keep in mind proper equipment requirements that will assure ease in processing and general stability of the drug product as the manu-facturing passes from each unit operation to the next. In particular, aspects of com-pounding, fi lling, and sterilization should be considered. Unique unit operations like lyophilization or homogenization that might be required should also be reviewed to ensure that the product lends itself to a scalable process.
1.5.1 Compounding
During compounding, many factors can affect the quality of the product. Issues can arise with simple differences in the order of addition, in the temperatures used for processing, in mixing speeds required for dissolution or dispersion, and in the shear stresses associated with the mixing itself. Each factor must be assessed in order to confi rm that the most optimum approach is being employed.
When developing a product, the order in which ingredients are added can have a signifi cant impact on the quality of the active ingredient as well as the overall qual-ity of the product. For example, an antioxidant would be added to nitrogen-sparged water before the active is added to the water in order to ensure the active is protected as much as possible. If the salt of the API is going to be generated in situ, the coun-terion may need to be added fi rst in order to help with solubilization of the active ingredient. Excipients such as surfactants would likewise be added before the active in order to assist in solubilization. In addition, pH adjustment may have to be made early in the process and then verifi ed and adjusted later.
As the materials are added, the time and temperature required for full incorpora-tion should be recorded whether full incorporaincorpora-tion means fully dissolved for solutions or fully dispersed for suspension systems. Sometimes, the processing parameters acceptable to laboratory personnel are not appropriate at all for a pro-duction environment. For example, the propro-duction preference for the compounding steps is often completion within one or two work shifts in order to keep the
bioburden of the drug product to a minimum. Therefore, a formulation in which the dissolution of the drug substance takes several days will not be desirable in produc-tion. Similarly, temperature should also be monitored to assure that the fi nal pro-cessing temperature is optimum for commercialization. For example, if water must be heated to nearly boiling in order to allow for dissolution of the drug substance or other excipients, the production facility might fi nd this diffi cult to accomplish for a pharmaceutical parenteral product.
During the course of the addition of the materials, the mixing speeds and impel-ler types required to incorporate the drug and excipients into the vehicle should also be considered and recorded. Often, the type of mixer used in the laboratory is not similar at all to the impeller systems available in production. The result may be the selection of mixing speeds and times that do not scale well into commercial production.
Mixing speeds and impeller types can be particularly important in the manufac-turing of protein and other biotechnology products. The effect of shear on the dena-turation of proteins is well known. Therefore, care must be taken to assure that the processing steps are robust enough to prevent the aggregation or agglomeration of the protein products. Even small differences in mixing can create subvisible parti-cles in the protein product that can serve as seeds for aggregation over the long-term shelf life of the protein product.
1.5.2 Filling
Several product parameters can affect the effi ciency of the fi lling process. For exam-ple, high viscosity materials can result in large variation in fi ll volumes due to pumping variability. If a product is water-like in viscosity, fi lling is often done eas-ily and accurately. However, some products, such as those with high levels of poly-sorbate 80, polyethylene glycols, or other more viscous materials, are more diffi cult to fi ll accurately. In these cases, special fi lling pumps can assist in maintaining an accurate fi ll volume over the course of the manufacturing. In addition, slower fi lling line speeds can sometimes help in maintaining fi ll accuracy.
In addition to affecting the accuracy of fi lling, the viscosity of the product can also affect the observed shear within the product. Even when viscosity is not an issue, shear effects can be observed during the fi lling process because the fi lling needles used to target the vial or package are usually much smaller than the tubing leading into them. This decrease in diameter has a net effect of increasing the shear stresses in the bulk product solution. Thus, the effect of shear during fi lling should also be monitored for shear-sensitive products, such as proteins, peptides, and other biotechnology drugs.
Filling line speed is often set based on the type of product a manufacturing site has the most experience with. For most parenteral products, this means an aqueous- based vehicle of low viscosity and negligible degradation over the course of com-pounding and fi lling. However, some products are particularly labile and must be
fi lled quickly. In these cases, the batch size and temperature of compounding and fi lling must be optimized with consideration of the time required for completion of these operations. Therefore, it is incumbent upon the formulator to collect data on these factors and provide those data to the production personnel in order to assist in designing an appropriate process.
Another key aspect in the fi lling process is establishing the headspace require-ments. The details of the experiments associated with formulation development were discussed previously in this chapter. The results of these experiments become key because the capability of the fi ll line to maintain the recommended headspace oxygen level is tested at this point. The variables that affect the effi ciency of main-taining headspace oxygen include the vial size, the fi ll volume, the line speed, and the gas used for the overlay. It is helpful for the formulation expert to work in close conjunction with the production personnel in order to ensure that the formulation is suffi ciently stable based on the headspace oxygen results the fi ll line can attain.
1.5.3 Sterilization
As previously discussed, the Health Authorities prefer that products are terminally sterilized. Therefore, the formulator must make an assessment of the robustness of the product when exposed to terminal sterilization. This process is typically per-formed via moist heat sterilization (autoclaving), but it can also be accomplished via gamma irradiation, electron beam, ethylene oxide, or other methods. Regardless of sterilization method, the formulator must confi rm that the degradation profi le is acceptable.
For cases in which terminal sterilization is not possible, aseptic fi ltration is per-formed. Formulations that are sterile fi ltered must have a low enough viscosity that the bulk solution can be passed through a sterile fi lter that has at least a 0.2 μm membrane. In some cases, a 0.1 μm membrane may be required. In addition, formu-lations must also be compatible with the materials making up the fi lter membrane and housing. The formulation must not affect the integrity of the membrane or the housing, and the fi lter must not affect the quality of the formulation. These concerns were also previously discussed in this chapter.
1.5.4 General Processing Requirements
In addition to the requirements associated with the unit operations discussed above, the formulation expert must also keep in mind other aspects of the production requirements. These include:
• The general overall time and temperatures required for processing relative to the stability and degradation of the product
• The light sensitivities in the production facility
• And any relative humidity requirements or sensitivities
In addition, the formulator must work with the production personnel to address any requirements associated with unit operations such as lyophilization or high- pressure homogenization, depending on the product.
Clearly, the temperature under which a unit operation is completed is coupled with the time required for that step to be completed. As discussed above, for exam-ple, a dissolution step must be performed to complete dissolution. However, for an active ingredient that also degrades readily, this step may need to be performed at lower temperatures, which may also slow the dissolution itself. Usually, jacketing the vessel with coolant is suffi cient control; however, sometimes compounding a cold room may be required. Clearly, optimization of this mixing time and tempera-ture must be established, and often the formulation chemist is at hand assisting the process engineer in these studies.
Light sensitivity can also require similar studies in order to answer questions like the following:
• What wavelength of light is the drug most sensitive to?
• How long of an exposure is acceptable and at what light intensity?
• What types of changes in the production environment are required to meet the specifi cations for the product?
Though the fi rst two of the above questions are in the realm of the formulation expert, the results of the formulator’s studies will assist in answering the third ques-tion. For example, for some drugs, simply minimizing white light exposure is suf-fi cient. This can be done by covering the vessels, tubing, or other transparent apparatus with opaque material and keeping fi nished vials in opaque bins. In other cases, the use of yellow light is required in order to minimize or prevent the degra-dation of the compounds.
The relative humidity of the production environment can also present a chal-lenge. Sometimes, the drug substance and/or drug product may be very hydroscopic or hydrolytically labile. When the drug substance is highly hygroscopic, strict con-trol of the relative humidity must be enforced in order to, at the very least, ensure that the proper amount of drug substance is added to the batch. For example, drug substances that deliquesce often require tightly controlled low-humidity environ-ments in order to ensure that the drug does not liquefy prior to addition. Other drugs that readily absorb moisture in the atmosphere might require a specifi c standard humidity for the weighing out of the compound in order to control the moisture content for reproducibility of the fi nal assay. In each of these cases, the formulation chemist is responsible for establishing what the limits of the relative humidity should be to ensure quality.
In the case of a hydrolytically labile drug substance, the product is usually manu-factured as a lyophilized product in order to ensure minimal hydrolytic degradation over the course of the shelf life of the product. Here, it is up to the formulator to establish the lyophilization parameters under which production occurs. The details
of this development are addressed in a separate chapter. Suffi ce it to say that the thermal properties that govern lyophilization are part of the requirements. Thermal properties include glass transition, eutectic melt, and robustness to thermal cycling, which includes adequate freezing, potential pH shifts, and overall stability of the drug substance throughout production.
Not all formulations, however, are solutions. Some are micellar, emulsion, or even liposomal systems. Some products are drug substance particulate or suspen-sion systems. Each of these unique formulation types has unique unit operations associated with it. In each case, the formulation expert must defi ne a formulation that is robust enough to be scaled to commercial quantities. Less typical unit opera-tions such as homogenization may require formulaopera-tions that can be pumped at extremely high pressures—perhaps tens of thousands of pounds per square inch for hours at a time. High-pressure homogenization used for emulsions and suspensions is an example. Sometimes, in particular in drug substance suspensions, the pressure and time can create different polymorphs of the drug itself, rendering the entire formulation unprocessable.
Clearly, the formulation development does not end once a preliminary formula-tion has been defi ned. Many addiformula-tional parameters must also be considered as they relate to the fi nal production process.