Leveraging Your NSF Certification: Now that you've received NSF Certification ... why not leverage the Mark to your advantage.
by Tom Savage, Director of Scientific and Regulatory Compliance at NSF Reference Standards
Since 2008, when patient deaths were first linked to tainted raw materials used in manufacturing heparin, the U.S. Food and Drug Administration (FDA) and other regulatory agencies have taken a much closer look at drug manufacturing supply chains. Pharmaceutical manufacturers frequently outsource the development and production of excipients, which adds a variable of uncertainty to the manufacturing process and can potentially compromise the quality of finished products. An investigation into the heparin incident eventually traced the source of contamination to a manufacturing facility in Changzhou, China.
Since then, the U.S. FDA has opened field offices in China and India to more closely monitor the manufacturing practices of suppliers in those countries. But, U.S. and European regulators’ increased scrutiny of excipients is not limited to products manufactured in lower-cost labor markets. In the wake of the high-profile heparin contamination, it’s safe to assume that regulators are reviewing all excipients — wherever they are manufactured — and scrutinizing their quality and purity like never before.
Your organization may have the best intentions of producing a high-quality pharmaceutical product, but will your current quality assurance practices stand up to the higher scrutiny of regulatory agencies in the United States and Europe?
In general, regulatory bodies in the United States and Europe require that excipients:
Compendial monographs play an important role in determining the acceptability of an excipient. They set the minimum critical quality attributes for each material and list the required tests, methods and acceptance criteria for quality assurance. Comparisons against reference standards are frequently required as part of this process.
A reference standard is a standardized substance used as a measurement base for similar substances. Used in both qualitative and quantitative analyses, the reference standard must be highly pure and well characterized. For example, if a pharmaceutical product includes benzoic acid, the supply chain source of this ingredient must be tested for purity and consistency against a recognized reference standard for benzoic acid.
While primary reference standards can be purchased from the United States Pharmacopeia (USP) and European Pharmacopeia (EP), regulatory agencies worldwide (including the FDA and the European Medicines Agency) recognize that the use of secondary reference standards is an accepted industry practice. Whether produced in-house by the manufacturer or purchased from an independent source like NSF International, secondary reference standards must be traceable to the primary USP and EP standards through comparative laboratory testing.
While regulators allow the use of in-house reference standards (developed and used internally by the pharmaceutical manufacturer), they are held to a high level of scrutiny and may put your organization at an increased risk of non-compliance citations. Typically, in-house reference standards are characterized by only one laboratory and only against one primary reference standard, either USP or EP.
In contrast, secondary reference standards procured from an independent organization like NSF International are tested by a minimum of three independent laboratories using GMP procedures. They are packaged and labeled according to GMP requirements and proven traceable to both USP and EP primary reference standards. Complete traceability documentation, including all raw data, is provided to meet regulatory requirements. When a regulatory auditor takes a close look at your excipient supply chain, the use of an independently-produced secondary reference standard provides valuable evidence of your organization’s efforts to assure product quality and purity.
Whether your organization develops in-house standards or purchases secondary reference standards from an independent source, regulators require evidence of traceability to the primary reference standard. NSF reference standards are recognized by U.S. and European regulators as traceable and can be used in place of primary standards for qualitative and quantitative tests such as identification, impurity determinations, chromatographic system suitability, assays, uniformity tests and determinations on dosage forms. They can also be used for total organic content determinations and physical tests, such as melting point.
NSF reference standards are packaged and labeled in the United States at NSF’s Ann Arbor, Michigan facility in accordance with the principles of cGMPs. The packaging environment is determined by the ingredients in each reference standard and is based on factors such as light sensitivity, humidity, oxidation potential and toxicity.
Every NSF reference standard undergoes a rigorous qualification process to ensure its quality, purity and suitability for compendial use. The steps in this process include:
The independent labs perform appropriate tests using cGMP processes and documentation, and submit their independent lab reports, including all raw data and results, to NSF who then:
The technical review board reviews, discusses and, if appropriate, approves secondary reference standard status. Unanimous approval is required for NSF to create a certificate of analysis package and release the product as an NSF reference standard.
Use of NFS reference standards is a simple and cost-effective way to reduce your organization’s risk of regulatory actions. If your excipient manufacturing operation is audited by a regulatory agency, the investigator will want to see:
NSF reference standards continue to be developed. For more information please visit the NSF Reference Standards website.
Tom Savage, Director of Scientific and Regulatory Compliance at NSF Reference Standards, has more than 35 years of experience working for the U.S. FDA in laboratory management and regulatory compliance.