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In the entries below, we’ll share our thoughts and comments on these areas and other topics of interest. Please feel free to contact us to suggest topics of interest.
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Forced Degradation Studies Can Reduce Stress(ors)
Forced Degradation is an important addendum to our previous post on Stability and Storage. Stressors are applied to new APIs and drug products to determine their degradation pathways and products under a variety of environmental conditions, including acid, base, light, heat, and oxidation. Forced degradation studies are also known as stress testing, stress studies, stress decomposition studies, and forced decomposition studies. These conditions “…are more severe than accelerated (stability) conditions and thus generate degradation products that can be studied to determine the stability of the molecule.”1 ... (Read More)
The Background, Advantages of, and Considerations for Radiolabeled Peptides
The use of radiolabeled peptides is a well-established tool in researching and treating many diseases and conditions. Selective receptor-targeting peptides are utilized as agents due to their rapid circulatory and tissue clearance and the high affinity and specificity to their targets. Peptides also have a relatively small size and low molecular weight compared to proteins and antibodies. There have been innovations and improvements in the design of peptides that incorporate chemical modifications with “impressive diagnostic accuracy and sensitivity.”1 Coupling these peptides with radiolabeling for peptide receptor radionuclide imaging (PRRI) and therapy (PRRT) has yielded remarkable results. In fact, a historical summary of radiolabeled peptides asserts, “The emergence of radiolabeled peptides for use with PET/CT such as 68Ga, 18F, and 64Cu, and the use of new receptor binding ligands…, have revolutionized PRRI and improved its diagnostic power beyond expectation.”2... (Read More)
Raw Materials Testing: Trust – and Verify – Your Sources
The CGMP guidance for APIs from the FDA states that raw material specifications should be established and documented. The guide’s key line states, “Quality measures should include a system for testing raw materials, packaging materials, intermediates, and APIs. (19.23)”1
All raw materials used in producing APIs for clinical trials must be evaluated by testing or received from the supplier with accompanying analysis and subsequently subjected to identity testing. Raw materials and intermediates need to be designated by names and/or specific codes so that any special quality characteristics can be readily identified. Furthermore, written procedures should provide for the identification, documentation, appropriate review, and approval of any changes to raw materials. Additionally, changes to supply sources of critical raw materials should be treated according to the FDA’s established change control guidelines.…(Read More)
Extractables and Leachables
Extractables and Leachables (E&L) are essential areas of concern for the pharmaceutical and food industries, specifically regarding their packaging, usage components (e.g., medical devices or syringes), and the manufacturing chain. We will examine testing of analysis of them within pharmaceutical applications. The two terms are related but distinct, each with its own analytical requirements.
A handy article published in Pharmaceutical Engineering by the International Society for Pharmaceutical Engineering (ISPE) explains that “Extractables are chemical compounds that migrate from single-use systems (SUS) into model solvent solutions under controlled and exaggerated conditions depending on temperature, pH, polarity, and time.” In other words, this happens when using strong solvents. They note that “SUS are normally not exposed to such conditions in biopharmaceutical processes.”1
ISPE’s article defines leachables as “chemical compounds that migrate from SUS into process solutions under normal biopharmaceutical process conditions. They further clarify that these compounds “may end up in the final drug product formulation. For the most part, leachables are a subset of extractables, although interaction with product components may produce leachables not seen as extractables.”1 …(Read More)
A special thanks to Matt Webberley, Associate Director, Analytical Research and Development at our sister company, SK biotek Ireland Limited, for his assistance with the profiles of AAS, ICP-OES, ICP-MS, and XRD.
Nitrosamines in Food and Beverages
This is the third in a series of entries examining nitrosamines in a range of products. Our first of two previous articles presented an overview of nitrosamines, including a historical look at their implication as a probable carcinogen. In the second entry, we reviewed their presence in active pharmaceutical ingredients (APIs), and how to remove them.
Nitrosamines are organic compounds found in the human diet and other environmental sources. These highly potent carcinogens can cause tumors in nearly all organs and have been classified as genotoxic impurities (GTI)… (Read More)
Nitrosamines in Active Pharmaceutical Ingredients
The linkage between cancer and a large class of chemical compounds known as nitrosamines were postulated by William Lijinsky in 1970.1 Then, in June 2018, their presence (specifically, N-nitroso-dimethylamine (NDMA)) was detected in the API Valsartan, an Angiotensin-II-receptor antagonist.
It later became “obvious that the issue may not only occur with sartans but, in principle, with any API containing a vulnerable amine and a nitrosation source. Hence not only NDMA but a plethora of potential nitrosamines could be created.”2 They have been subsequently detected in other medicines resulting in 250 product recalls, affecting more than 1400 lots.3,4 The cost of recalls could be high.5 APIs or their impurities can become nitrosated “during the later stages of the synthetic process of the drug product manufacturing or even while in the completed, packaged product.”6 … (Read More)
Nitrosamines: An Overview
Nitrosamines are organic compounds found in the human diet and other environmental outlets. Being potent carcinogens that can cause tumors in nearly all organs, they have been classified as genotoxic impurities (GTIs). There are guidelines and rulings by various regulatory organizations, including the FDA, EPA, EMA, and the IARC (International Agency for Research on Cancer). Their presence and attendant concerns have been noted for many years. A.J. Gushgari and R.U. Halden wrote in Chemosphere, Nitrosamines were first proposed as “environmental carcinogens by William Lijinsky in 1970… (Read More)