The objective of this study is to explore the understanding of Blend Uniformity in the manufacture of solid oral dosage forms under current Good Manufacturing Practices (cGMP). For many years particle size has been recognized as a key parameter in the development and manufacture of a wide range of pharmaceutical materials and is routinely measured and controlled at many different stages of research, development, manufacture and quality control. This article highlights the importance and development of blend uniformity.

Introduction

Blend uniformity is a function of both the formulation and mixing action. Once the formulation is optimized from a theoretical process standpoint, blend uniformity must be validated during piloting and scale-up. From a manufacturer’s perspective; poor uniformity generates unacceptable amounts of discarded products, resulting in significant loss of revenue. However, no method currently exists that detects uniformity during the blending process, and as a result the true optimum endpoint is realized rarely.

The US Department of Health and Human Services Food and Drug Administration Centre for Drug Evaluation and Research (CDER) states in the Draft Guidance X:/CDERGUID/2882DFT.WPD (AUG. 1999) that

“Under current Good Manufacturing Practices (cGMP), an applicant is required to perform a test or examination on each commercial batch of all products to monitor the output and validate the performance of processes that could be responsible for causing variability, which includes adequacy of mixing to ensure uniformity and homogeneity”.

21 CFR 211.110 (a) (3)

Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes, also very fine materials are difficult to handle. When large difference in size exists between the active components and excipients, demixing effects can occur making thorough mixing difficult. This effect is greater when the diluents and active raw materials are of significantly different sizes. Not only size but shape too influences the flow and mixing efficiency of powders and granules. Fine materials are relatively more open to attack from atmospheric oxygen, heat, light, humidity and interacting excipients.

It is insufficient to show that adequate distribution of the drug is obtained in the final product; it must be demonstrated within the blend also. The FDA Guidelines states that the USP criteria for content uniformity as 85-115%. But the industry standard for content uniformity is 90-110%.

Blend sampling errors play an important role in formulation of dosage form where homogeneity is must. In a well controlled manufacturing processes, a firm may be able to justify using a batch or lot representative Assay and Assay Range approach to justify the release of final Powder Blend to the dosage-forming step provided  a post-release conformity content uniformity evaluation on the formed dosage units.

The root causes of blend or product content uniformity problems are as follows –

• Non-optimum blending.
• Thief sampling error.
• Segregation.
• Weight control.
• Loss of component.
• Analytical errors.
• Insufficient particle distribution.

Consider the following points during blend uniformity development –

• Keep particle size distribution of granulate material as narrow as possible because fines percolating through coarser material may well result in non-representative final blend assay values.
• Changing mesh size of the mill screen after Fluid Bed Drying will impact on granule particle size and affect bulk density and hardness range.
• Formulate the material/product with appropriate glidants to keep the flow attributes of all the ingredients similar, this prevents differential flow properties.
• Develop the drug-product production process to the point; that the firm has built in with rigorous controls on the critical physical and chemical variables and process steps. If these parameters are not controlled, may adversely impact the content uniformity of the in-process powder from which the dosage units are fabricated.
• The post-blending handling, equipment loading procedures and equipment should be optimized to minimize demixing of the blend being formed into the dosage units.
• Conduct a suitable blend uniformity evaluation whenever the uniformity of the content at the Formed Dosage Unit stage is outside of its established expectations.

Conclusion

Testing final blend uniformity as a suitable in-process control may well evaluate and highlight the incoming ingredient batch-to-batch differences as well as the physical variations in different lots of active materials. Routine blend uniformity testing may eventually be a cGMP requirement even though blending is not the final unit process. A manufacturer who wishes to minimize inspection overhead is encouraged to use dedicated production facilities and in any case produce drug product batches or lots in campaigns that are steady.

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