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Anil Kane, executive director, Global Head of Formulation Sciences, Pharmaceutical Development Services at Patheon discusses key parameters in the development and manufacturing of oral solid-dosage forms.
Oral solid-dosage forms (typically, tablets and capsules) are manufactured using conventional manufacturing processes such as direct blending or granulation techniqueswet granulation, dry granulation/roller compaction, or fluid bed granulation followed by fluid bed drying, milling, compression, and coating. It is important to understand the critical processing parameters (CPPs) that impact critical quality attributes (CQA). The CQAs that impact the final outcome (i.e., the therapeutic efficacy of the drug product) usually are parameters such as in-vitro dissolution and drug product stability. In-vitro dissolution of the drug can influence the rate and extent of drug absorption. Drug substance properties such as particle size, morphology, dosage strength, and drug loading have a big impact on the blending process and can influence the homogeneity of the drug substance in the blend. Blending is a critical process that needs to be optimized and is considered a CPP that can impact the potency of the finished product. Similarly, each of the granulation techniques has a processing step that could cause variability and has the potential of impacting the CQAs. Key parameters that need to be optimized (see Table I) will depend on the API properties, its stability, dose, drug loading, and other factors.
Table I: Process and critical process parameters that require optimization.
Critical process parameters
Number of revolutions of the blender
High shear wet granulation
Impeller and chopper speed
Binder addition time
Fluid bed drying
Inlet air temperature
Fluidization air volume
Fluid bed granulation
Inlet air temperature
Inlet air temperature
Speed of encapsulation
A typical process optimization methodology includes a systematic identification of CQAs, CPPs, and a risk assessment to identify the critical selection of key parameters. A plan can then be drawn up, using a statistical design of experiments (DOE), which can be a full- or partial-factorial design, based on the availability of API and the number of runs that can be manufactured. The DOE experiments involve running parameters at high, medium, and low values, as well as running a defined number of control runs at target parameters. By analyzing the data from the DOE runs, a design space can be identified. Knowledge of the design space enables a control strategy to be defined for the manufacture of the product.
A similar approach is taken for formulation optimization, in which critical functional formulation excipients are evaluated with high, medium, and low levels, and the impact of these variables is studied on output parameters of that functionality (e.g., disintegrant levels studies can be done with the rate of disintegration of tablets as the output).
A systematic DOE to optimize the formulation composition in an oral solid-dosage form is important for two main purposes:
Products with multiple doses use a “dose weight proportional” strategyâusing the same formulation composition (drug to excipient ratio) and compressing the larger dose into a larger tablet size. This strategy has the benefit of avoiding a separate stability study as the drug to excipient ratio is the same; however, the disadvantage is that the higher dose becomes a large tablet, which may present “patient compliance” issues because of difficulty in swallowing. The limited time available for developing clinical trial formulations often makes optimization of drug load and tablet size a low priority.
During this stage, however, it is important that the choice of excipients, level of excipients, the drug load, and reduction of pill size and burden are optimized. Polypharmacy is a huge problem, and patients would benefit greatly if better drug products that are easier to swallow can be developed. Optimizing the formulation at the right stage in the development program by increasing the drug load per unit tablet or capsule, thereby, reducing the pill burden, would be beneficial.
Anil Kane is executive director, Global Head of Formulation Sciences, Pharmaceutical Development Services at Patheon.
Vol. 41, No. 4
When referring to this article, please cite it as A. Kane, “Key parameters to be optimized in the development and manufacturing of oral solid-dosage forms” sidebar to “Designing Optimized Formulations," Pharmaceutical Technology 41 (4) 2017.