The term Reference Standard Qualifications (RSQ) “is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria,”1 and incorporate these quantitative reference standards to do so: purity, potency, identification, impurities content, and generally full characterization.
Identity Testing
There are a range of tests to ensure the identity of the drug product or drug substance. These can be done by a variety of equipment, including LC-MS, 1H NMR, 13C NMR, FTIR (Fourier Transform Infrared Spectroscopy), TGA (Thermal Gravimetric Analysis)/DSC (Differential Scanning Calorimetry), and UV-Vis. Appearance testing can be achieved by chiral or ion chromatography, elemental analysis (identifying C, H, and N), TGA/DSC, and XRPD.
Quantitative Testing For quantitative reference standards, there is a standard formula that should utilized (HPLC Purity) x (100% − % Residual Solvents − % Inorganic Impurities)= The Determination and Confirmation of the Assay Value % (i.e., weight %). These component values can be quantified by using HPLC for the purity analysis, residual solvents by LOD or KF Water Content and HSGC, and inorganic impurities by ROI (Residue on Ignition), ICP-MS/OES ((Inductively Coupled Plasma Mass Spectrometry or Inductively Coupled Plasma Optical Emission Spectroscopy). (For a limited number of sample quantities of both residual solvent or inorganic impurities, they can alternatively be tested by TGA.) Finally, to access the weight percentage confirmation, titration and qNMR are excellent techniques.
Concurrent with identity and quantitative testing, storage conditions and stability should be established. This includes storage (container/closure), expiration dating, re-testing procedures, and usage and tracking.
We Can Assist with your Reference Standard Qualifications Needs
SK pharmteco has years of experience and numerous experts in Reference Standard Qualifications. Compendia methods (USP/EP/BP/JP) are utilized in tandem with analytical method development, validation, and transfer to ensure optimal success with your drug substances and drug products. Please contact us with any specific questions or to receive a quote for your RSQ needs.
Dynamic Vapor Sorption (DVS) is a gravimetric technique used to measure the change in mass of a material in response to changes to surrounding conditions such as temperature or humidity. DVS is primarily used with water vapor but can be applied to other organic solvents as well for the physicochemical characterization of solids.
DVS was developed by Daryl Williams, the founder of Surface Measurement Systems Ltd., in 1991. The company then delivered the first working DVS instrument to Pfizer in 1992.1 Since then, many other equipment manufacturers have entered the field.
Figure 1: A DVS isotherm plot indicating sorption and desorption rates and hysteresis. The isotherm shows a typical hysteresis curve where the adsorption phase is almost identical to the desorption phase (i.e. reversible). Note that at 80 %RH, there is net sorption of 0.9% between adsorption and desorption traces. The material appears to be slightly hygroscopic according to the definition in Ph. Eur.2
Sorption, Desorption, Absorption, and Adsorption There are five main physical processes that occur during the DVS experiment. The first, sorption, is when a material takes on moisture due to increased humidity. Conversely, desorption is the process that occurs when the material loses moisture due to decreasing humidity. Sorption can be classified as one of two types. Adsorption is moisture that is observed on a surface of a material, while absorption is moisture that has penetrated the surface of a material. The fifth term and the term that relates sorption and desorption is called hysteresis. The overall chart that includes and tracks the sorption and desorption rates and hysteresis is called the isotherm. These curves are crucial for understanding the physicochemical characteristics of a solid, such as porosity, polymorphic change, or liquefying of a sample.2
Applications
There are numerous reasons to utilize DVS, and some of the most common within the active pharmaceutical ingredient (API) industry are:
To determine the sorption isotherm;
To evaluate the hygroscopicity of an API powder;
To compare the hygroscopicity of different solid-state forms: solvates, polymorphs, salts, amorphicity, and cocrystals;
To determine the deliquescence point of a material;
To quantify and qualify the amorphous content in drug substance orexcipient,3 and
To evaluate packaging materials.
Of course, there are a variety of other applications in other industries, including for building materials, food science, cosmetics, coatings, and sealants.
DVS Analysis of APIs For pharmaceutical development, DVS is used for a variety of applications, including screening early drug and excipient candidates, establishing processing parameters, and identifying packaging and storage requirements (Figure 2).4,5
Figure 2: A DVS isotherm of an API showing that the material started to gain significant mass after exposure to relative humidity values of more than 60 %RH. The change here was irreversible, as demonstrated by the desorption curve. DVS could be a useful tool to suggest storage conditions in terms of humidity contents in the surrounding environment.
However, due “to the typically slow establishment of an equilibrium, DVS experiments are rather time-consuming.”4 Nevertheless, “water content of solid active pharmaceutical ingredients and excipients, individually and when formulated in pharmaceutical dosage forms, is a parameter that should be monitored throughout the drug lifecycle.”5
As an analytical technique for APIs, DVS has become a necessary step within drug development and production, reducing issues that can arise during manufacturing, packaging, transportation, solubility, dissolution rate, stability, or storage. AMPAC Analytical’s sister company, SK biotek Ireland Analytical Services, has the experience, technology (including a Surface Measurement System’s DVS Resolution Dual Vapor Gravimetric Sorption Analyser), and support, to assist with this vital testing. Both companies are part of SK pharmteco and can easily transfer your project from either business unit to ensure the most optimal solution and logistical support are provided to meet your product timeline. We invite you to contact our team members and discuss how we can assist with your sorption testing requirements.
Figure 3: A SMS DVS instrument like the one located at SK biotek Ireland.
Effective method development is crucial for the quality control of Active Pharmaceutical Ingredients (API) and Drug Products (DP). Thorough method development enables successful downstream method validation.
The regulatory guidance specifies that:
Method development and validation vary by application (quantitative, qualitative, etc.).
It is phase appropriate.
The client may provide additional guidance/validation criteria.
The validation guidance directs how AMD (analytical method development) is conducted.
Early Adoption of Forced Degradation Analysis It is recommended that forced degradation be performed early in the method development lifecycle and that method parameters are suitable for mass spectrometry. This will prevent many issues that could occur in later stages and ensures the primary purity method is stability-indicating (specificity). When performing forced degradation, these considerations should be weighed:
Always utilize a control sample without exposure to stressors.
The stressors generally consist of acid, base, peroxide, heat, and photolytic conditions. Other stressors may be used based on known material incompatibility
After exposing the compound to these stressors, target 5-20% degradation of the main peak.
If degradation is not observed under reasonable conditions, then the material can be considered stable under those conditions.
Impurity Genesis and Identification Assessment Acceptance criteria should be scaled to impurity levels. How can the method unequivocally assess the analyte of interest in the presence of likely impurities, degradants, and the sample matrix? Additional considerations include:
Is themethod capable of identifying and/or quantifying a specific compound?
Are there solvents present that can interfere with potential impurities?
Known impurities? Are the known impurities stable under the method conditions?
Is the method specific for degradation byproducts for stability-indicating methods?
Cross-Platform Method Robustness Robustness refers to a method’s ability to meet its analytical requirements (system suitability requirements) despite small variations of the method’s parameters, such as discrete changes to a column or sample tray temperature, percent organic modifier, flow rate, and detector wavelength. This capability is typically built into the method during method development.
Precision or Accuracy – You Need Both in Strong AMD AMPAC Analytical development strategy involves the early adoption of forced degradation studies with the goal of every primary purity method being stability-indicating (specificity) and mass spectrometry compatible. The validation strategy is phase-appropriate and application-specific and guides the development strategy. The validation acceptance criteria guidelines are specific to the test methodology, intended use, and level. Finally, method lifecycle performance is assessed, and reevaluation or revalidation can occur.
Contact us today to learn how we can create accurate, precise method development for your API and DP pipeline.
Effective method development is crucial for the quality control of 