Nutraceutical manufacturers have had many issues to consider since FDA released the GMP (good manufacturing practice) guidelines for the dietary supplement industry last summer. Among these concerns is the definition or application of a “scientifically valid argument,” a concept presented in the GMPs.
The intent of the phrase is to establish, as a minimum requirement, a documented explanation of well-grounded logic which justifies how and why one conducts a key manufacturing process, material qualification or analytical test using science. The scientific portion of the explanation should be a combination of theory, experimentation and test results. An example of applying this concept is given below for the addition of magnesium stearate (as a lubricant) to a homogenous nutraceutical powder blend.
Magnesium stearate is the most common ingredient used in tablet formulations. For nutraceutical tablet manufacturing, it is the lubricant of choice. It is common manufacturing behavior to add a minimum amount after first achieving a homogenous powder blend of all other ingredients and additionally mixing-in the lubricant for a brief period of time. This enables the powder blend particle surface to be sufficiently coated while limiting penetration of the lubricant within the particle matrix. Within the FDA concept, this is part of the theoretical explanation.
There are several problems associated with incorrect lubrication in tablet compression. Under-lubricating a powder blend leads to adherence of material on the metal surfaces of the punches and die walls of the tablet press. Over-lubrication leads to soft tablets and poor disintegration and/or dissolution. These are some of the experimental outcomes to be used in determining an optimal level of magnesium stearate in a formulation.
Other variables to address when determining magnesium stearate concentration and blend time experiments include:
- Powder blend particle size distribution,
- Powder blend bulk and tapped density,
- Powder blend moisture content,
- Powder blend chemical nature,
- Powder blend filler/component solubility,
- Powder blend filler/component cohesive nature,
- Blender type, and
- Powder blend fill percentage vs. blender capacity.
These variables have different impacts on this experimental model, and can become part of analytical tests. For example, powder blend particle size distribution provides powder flow insight, as poor powder flow characteristics can reduce formation of a lubricant film. Powder blend bulk and tapped density will affect powder flow and blender capacity, and the addition of magnesium stearate will densify the blend. As far as moisture content, the amount of moisture can affect lubricant concentration due to hydrophobic nature. The chemical nature of the powder blend can be defined as the sum of the chemical tendencies of the powder blend ingredients toward being hydrophobic, hydrophilic or a mixture of the two.
The solubility and cohesive nature of the filler and components in the powder blend are related concerns. Solubility addresses the tendencies of the powder blend ingredients to interact with either water-soluble or fat-soluble solvents, while the cohesive nature refers to the chemical and/or physical attributes of certain molecules (such as MCC, DCP, lactose, etc.) in which the material cohesion properties vary (plastic or brittle deformation, etc.).
Regarding blender issues, looking at blender type means examining the mixing profile relative to the amount of horizontal vs. vertical mixing capabilities. Consider how as the fill percentage increases, the mixing efficiency decreases and extends mixing time. The concept of blender validation should also be considered in study design.
To complete the “argument,” consider the collection, comparison and analysis of the variables listed above to characterize the formulation. Make determinations from this to set a target amount of lubricant with statistically significant variations of concentration. Set a minimum mixing time, pull blender samples and analyze for magnesium stearate concentration. An FT-NIR can be used for this measurement. More than one source of magnesium stearate should be used. Positive performance results can be used to qualify a source. Negative performance results can disqualify a source. Evaluation of performance can be determined several ways: by using an instrumented tablet press to evaluate ejection and compression forces, tablet hardness measurements and by conducting disintegration/dissolution tests. Powder blend without lubrication should be included within the testing matrix and compared to samples with multiple levels of lubricant. The totality of the work should be organized in a style similar to a laboratory experiment while having a documented format with change control similar to an SOP. This report should be filed with the master file for audit purposes.
A simple style such as the following would suffice:
- Header with the title and any applicable experiment numbering references with date.
- Introduction that incorporates the purpose, scope and background.
- Study design.
- Experimental details, including materials and methods.
- Results with discussion.
- Summary and conclusions.
- Footer and ending approval, which should contain the signatures of the author and reviewer for quality purposes.
Development of “scientifically valid process steps” enables a company to be compliant with GMP guidelines. Performing this process optimizes tableting blends and minimizes associated processing problems. As this methodology is required for compliance, it should become routine in the future.