USP 905: Content Uniformity of Dosage Units and Sampling of Powder Blends
Ensuring the uniformity of powder blends is of paramount importance for the successful production of safe, effective, USP 905-compliant pharmaceuticals. Particle size reduction has long been a focus for process engineers, as smaller particles typically offer certain advantages in terms of key properties, such as dissolvability, bioavailability and even shelf stability. Indeed, individual particle sizes and particle size distributions may both affect the ultimate physiochemical properties of the final product.
When particles of different sizes or shapes are blended, however, there’s a risk of poor uniformity, due to de-mixing effects. APIs and excipients may possess different shapes or sizes, which could affect characteristics relevant to the mixing process itself — such as flow, blending ability and the propensity to undergo degradation due to exposure to environmental factors. These include heat, light or humidity. One obvious solution is to ensure that particulates possess the narrowest possible particle size distributions.
DOSAGE UNITY UNIFORMITY TESTING AT EVERY STAGE
GMP compliance requires testing to confirm the content uniformity of ingredients in a given dosage unit. The goal of these cGMP guidelines is to ensure that APIs are consistently distributed, so that each dose possesses a precise amount of active drug. Yet this end-stage testing is deemed inadequate. FDA requests that powder blends be tested for content uniformity at every stage of manufacturing. Assaying for final blend uniformity may serve as a sensible in-process control that could identify batch-to-batch differences.
Some potential causes of uniformity errors in blends or final products include the following:
- Inadequate blending
- Segregation of constituents
- Fluctuations in weight control
- Component losses
- Analytical errors
- Insufficiently narrow particle size distributions
A review of these potential sources of error suggests several proactive approaches that may be taken to prevent such problems before they occur. This includes the use of milling equipment that is capable of producing carefully controlled particle size distributions. Keep in mind that mixing fines with larger particles is a recipe for segregation, and may result in disappointing final blend assay values. To this end, we suggest manufacturers invest in the kind of carefully engineered process and size reduction equipment available through Quadro Engineering.
BETTER EQUIPMENT FOR TIGHTER CONTROL
We offer tighter particle size distributions, seamless scalability, OEB5 level containment and the wealth of our experts’ combined expertise to assist formulators, process engineers, validation specialists and quality-assurance personnel in arriving at working solutions. Among other industry-leading machines, we offer the High Efficiency Comil® U21. This revolutionary machine, featuring our innovative redesign of the traditional conical mill, yields significant reductions in the production of “fines” and “overs,” ensuring uniformity of powder blends. The U21 also provides greater throughput capacity, reduced noise and superior containment.
Quadro Engineering’s product line has been designed with scalability in mind. This is an important feature, because uniformity testing should produce consistent results — regardless of volume — from pilot through production runs. Keep in mind that quality assurance personnel should conduct a suitable blend uniformity evaluation whenever Formed Dosage Unit uniformity fails to meet established expectations. Indeed, it’s wise to establish a sampling plan and cGMP-compliant inspection plan for powder blends, including a routine manufacturing and maintenance qualification inspection in order to minimize the potential for problems down the line.
EMERGING RECOMMENDATIONS FOR USP 905 COMPLIANCE US
FDA notes that the use of powder-thief sampling may result in unintended inconsistencies in some instances. More innovative approaches to ensuring adequate powder blend mixing include the implementation of PAT real-time monitoring and feed-forward controlling of the powder blending process.
In 2013, FDA withdrew its draft guidance for the pharmaceutical industry. In response, industry representatives published recommendations for changes to the withdrawn guidance document in 2014. As members of the International Society of Pharmaceutical Engineering (ISPE), these industry stakeholders suggested modifications that would further ensure the “adequacy of mixing to assure uniformity and homogeneity.”
Would you like to learn more about how Quadro Engineering can facilitate your GMP manufacturing? Quadro Engineering supplies superior manufacturing equipment for the pharmaceutical industry. To learn more about our world-class machinery, contact us here, call us or fill out this form to request a quote. A member of our highly trained sales staff will contact you promptly.