TECH OUTLOOK 8NOVEMBER 2023IN MY OPINIONWithin the pharmaceutical industry, there exists combination products which combine aspects of medical devices and pharmaceuticals. For example, a Transdermal Drug Delivery System (TDDS) is a device that adheres to the patient's skin and delivers active pharmaceutical ingredients (API) to the patient via passage through the skin. In the process to manufacture a TDDS, much like most manufacturing processes, there are multiple unit operations with intermediate steps. The Stacked Control Assessment (SCA) approach consists of stacking the sources of variation for a particular finished product's critical quality attribute (CQA), which is controlled by a product specification. In this article we will use the example of product potency as the CQA. Since product potency can change throughout a product's shelf life, sources of variation to potency during shelf life must also be considered.The SCA approach defines the largest potential sources of variation and represents a measure of process ability to meet specifications for each process step. The analysis also provides insight into the historical performance of raw material controls and provides visibility to which specification ranges can be tightened with the least risk to raw material specification non-conformance. This is a critical step in determining the overall control strategy. It encompasses all controls, both product and process related.Specific to TDDS manufacturing, there are three main unit operations that provide sources of variation to product potency. These are the intermediate unit operations of Blending, Coating, and Pouching. Each of these unit operations have sources of variation for potency that will stack cumulatively in the finished product form, determining the overall stacked control for potency. Adding sources of variability throughout shelf life depicts the potential extent of potency variability at the end of product shelf life. An example of SCA by potency variation stacking is provided to better understand the mechanism for the cumulative stacking approach. For simplicity, we will only describe the first unit operation equation in detail and later show the mathematical relationship accumulating the variation for each unit operation. An example for the sources of variation to blend potency is provided below in Figure 1.Figure 1: SCA Equation for Blend PotencyBlend Potency as % of Target = (API Assay * (API Weight (mg) /(API Weight (g) + Other Ingredient Weight (g))) / Blend Potency Target (mg/g)) * 100The API concentration ratio represents the process variation caused by the addition of an API to the process kettle. We will assume for this exercise that the weights of all ingredients added were at target values making this ratio equal to 1. The raw material control in this equation is API assay. The acceptance criteria defined by the specification determines the potential variation allowed by this control. In this example, we will assume the allowable API assay acceptance criteria varies from 98-102% purity. According to the equation in figure 1, the ratio of API assay to target is utilized, therefore 0.98-1.02 are the potential inputs to the equation. In the case of the above equation, the raw material control of API assay has a direct 1:1 impact on blend potency if the correct ingredient weights are added to the blend. In other situations, there may be more than one raw material or process control affecting the CQA and these would accumulate mathematically to affect blend potency.STACKED CONTROL ASSESSMENT (SCA) APPROACH FOR PRODUCTION OPTIMIZATIONBy Robert Lambert, Director Of Technical Services, Noven PharmaceuticalsRobert Lambert
< Page 7 | Page 9 >