Unit Dose APIs: Content Uniformity, Testing and Quality Assurance in the Modern Pharmacy

Unit Dose APIs: Content Uniformity, Testing and Quality Assurance in the Modern Pharmacy

i-cadeceusNothing is more important in compound pharmaceuticals than the Active Pharmaceutical Ingredient. The building block of all pharmacologic treatments, any compounded medication is only as effective for a patient as the strength and purity of its foundational APIs. Unit Dose APIs in particular need to undergo testing for content uniformity and pharmacies should have specific quality assurance programs in place for testing unit doses.

By establishing a pharmaceutical quality system, a pharmacy can ensure an ongoing state of control over product quality, establishing the desired level of quality and how to maintain that level of quality while consistently improving when the opportunity arises.

Cracking the Puzzle of Efficient, Non-Destructive Content Uniformity Testing

Traditional content uniformity (CU) testing is called “destructive” testing and actually consumes resources as it’s conducted. Wet chemical analyses and other destructive testing methods can be highly cost-ineffective and actually less indicative of quality than tests that can be performed more frequently and with no destruction of resources.1

Near-infrared spectroscopy, or NIR, can be used as a non-destructive method of measuring content uniformity in doses. For pharmacies that would like to test tablets more frequently than the 10 per batch recommended in the United States Pharmacopeia general chapter <905> guidelines for content uniformity, NIR technology can allow more testing without debilitating cost increases. NIR works based on measuring absorption levels in the near-infrared region between the visible and mid-infrared range.2

Implementing process analytical technologies or real-time release testing can set up a system where your QA specialists and pharmacists can sample more frequently and conveniently for tests, straight from the production line. This increases quality and means that your compounds spend less time off the line being analyzed, keeping all your resources more efficiently in one place.

Should USP <905> Always Be Used for Content Uniformity Testing Standards?

Pharmacy operators should also be aware of potential alternatives to USP <905> that might provide better levels of quality acceptance for certain situations. USP <905> functions as an overall guideline and governs uniformity of dosage units, but the chapter does have some deficiencies and is considered by the FDA to only provide “limited assurance that the batch meets specifications and statistical quality control criteria.”3

USP <905> was written and intended for testing a defined sample, so pharmacies can employ a number of different statistical sampling plans and criteria for batch acceptance to make sure they’re compliant with the CGMPs. A 2013 study in Pharmaceutical Development and Technology concluded that USP <905>’s reliance on a two-stage sampling plan and using the mean to calculate acceptance values indicates that it actually could allow some low-dosage products to go to market with CU and WV values that would actually fail both the USP <905> test and alternative CU tests. USP <905>’s small fixed sample sizes and reliance on the sample mean in its calculations actually creates a 1.5 percent “zone of indifference” where some formulations could respond unexpectedly.4

The FDA encourages pharmacies to use more innovative practices for testing content uniformity, like NIR, and to use stratified sampling plans for batches that contain different locations that should be sampled—this ensures the batch is uniform throughout. For most pharmacies, it’s also recommended to consider alternatives to USP <905> for calculating accepted values of content uniformity and weight variance.

The Large-N approach and Parametric Tolerance Interval Testing could both be used as viable alternatives to USP <905>. A variation on the Large-N method is FDA approved for situations where a large number of tablets are measured using non-destructive means. In this context, Large-N is considered to be a one-tiered, non-parametric counting test to measure CU, rejecting any doses that fall outside its 85-115 percent accepted value claimed on the label. Large-N is typically more conservative than the USP <905> test, or Uniformity of Dosage Units (UDU) test.

Parametric Tolerance Interval Testing (PTIT)’s advantages over USP <905> include more flexible sample sizes and does not create the “zone of indifference” by over-reliance on the sample mean in the calculation. Some studies have found that applying the PTIT can lead to a substantial number of batches that are fit for their purpose being rejected, however, so it’s important for individual pharmacies to look at their analysis practices and use the acceptance value calculation methods that work for their products and their patients.5

What Does Quality Assurance Look Like in the Modern Pharmacy?

The pharmaceutical industry changes fast. Laws and enforcement constantly morph and evolve. There are more opportunities than ever for pharmacists to take an active role in patient care for sufferers of chronic diseases, aging baby boomers and other populations. More and more patients will rely upon pharmacological treatments for pain relief and maintaining their lifestyle. Patients and doctors will increasingly desire treatments for the world’s currently incurable diseases, and those compounded medications will need to be delivered with no question of quality.

Quality assurance is not simply a department or a process implemented at the line level. Quality assurance in the modern pharmacy is a leadership philosophy and a culture of quality from top to bottom. Consider for a moment that in an organization using the six sigma method for eliminating process defects, being at 3.8 sigma is considered to be “good,” catching errors 99 percent of the time. Seems good enough, right? Now consider it in terms of patients. Missing 1 percent of your pharmacy’s formulations leaves thousands of patients at risk.

Pharmacy leadership that believes in QA and rigorous testing not only refuses to accept “good enough”—they will give their staff the tools and resources to reach their QA goals. This includes a defined process for QA, as well as a responsive system for investigating errors, and encouraging reporting and analysis. If you reduce variability in your product and improve quality, you will ultimate decrease costs by having fewer rejected doses, leading to better products and a better reputation.

Pharmacies should evolve with the times as part of their quality assurance practices, including using telepharmacy technology, and improving content uniformity testing using NIR or other technologies. Using the latest innovations and continually improving helps improve one of the two major root causes of pharmacological mistakes: human error.

The other major causes of errors is poor-quality or unpredictable APIs. Improving responsibility for your supply chain can eradicate these issues. This includes working with trusted parties who meet and exceed Current Good Manufacturing Practice (CGMP), not only at the supplier level, but at every point in the process. Everyone who transports, compounds, comes in contact with, stores or administers your pharmacy’s dose is part of that supply chain, with your pharmacy’s reputation and your patients’ well-being on the line.6

Unit dose APIs form the basis of our industry, and while working with a premier provider like Pharmaceutica North America can lower a pharmacy’s risk of API issues, using the latest technology and practices in conjunction with a robust quality assurance culture can help your pharmacy thrive in a modern era that promises great opportunity.

Pharmaceutica North America is a premier provider of Active Pharmaceutical Ingredients, including the highest-quality unit dose APIs. To learn more about how using PNA APIs can help pharmacies stand behind the quality of their compounds or about the specific APIs we offer, please contact us.

Show 6 footnotes

  1. “Content Uniformity (CU) testing for the 21st Century: CDER Perspective,” accessed Nov. 17, 2015, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM341168.pdf
  2. “Near-Infrared Assay and Content Uniformity of Tablets,” April 2, 2007, http://www.pharmtech.com/near-infrared-assay-and-content-uniformity-tablets
  3. “Current Events in Blend and Content Uniformity,” March/April 2014, http://www.ispe.org/index.php/ci_id/46689/la_id/1.htm
  4. “Content uniformity testing: suitability of different approaches for marketed low dose tablets,” Nov/Dec 2013, http://www.ncbi.nlm.nih.gov/pubmed/22324336
  5. “Challenges and Opportunities in Implementing the FDA Default Parametric Tolerance Interval Two One-sided Test for Delivered Dose Uniformity of Orally Inhaled Products,” Sept. 8, 2011, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225528/
  6. “Pharmaceutical Quality Systems: US Perspective,” accessed Nov. 17, 2015, http://www.fda.gov/downloads/drugs/developmentapprovalprocess/manufacturing/ucm288108.pdf
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