Tadalafil: a case study for the development of stable solution reference standards for pharmaceutical applications

Tadalafil: A Case Study for the Development of Stable Solution Reference
Standards for Pharmaceutical Applications
Lilly Authors: Matthew Borer, Michael Julius, David Lytle
Reprint from 11th International Reference Standard Symposium
Cerilliant Authors: Tamara Tarbox, Isil Dilek, Uma Sreenivasan, Mitzi Rettinger
The Case for Tadalafil
Reference Standards are a critical part of the control strategy to ensure the quality, safety, and efficacy of • Material usage is tightly controlled and requires documentation of secure storage and pharmaceuticals. Routine QC of pharmaceuticals requires preparation of working solutions from powder reference traceability of usage. material on a routine basis. These solutions are typically prepared in volumetric flasks and stored for short intervals in the laboratory. Weighing of materials for standards in the lab can be time consuming, especially when materials • The material is electrostatic and requires special handling during the weighing of assay are hygroscopic, toxic, or controlled. One source of lot-to-lot discrepancies in release testing is variation in the reference standard working solution which can result from weighing and dilution differences between batches. A • An ampouled working solution standard for use in routine QC of tadalafil would provide solution-based reference standard packaged in a format that preserves concentration and integrity of the material cost, efficiency, and security benefits. provides a convenient, consistent and cost-effective alternative to preparation of working reference standard solutions in the analytical lab. By presenting the reference standard as a low concentration solution in acetonitrile, there is a decreased incentive for the reference standard to be diverted for inappropriate uses. For Working solutions prepared from
Alternative Approach: Qualified
example, reference standards are not suitable for human consumption. Materials with a neat reference materials can
working standard solution in
propensity for this type of diversion require special handling requirements, such as chain of present several challenges
inert sealed ampoule format
custody and accountability. These requirements are not required for the solution, resulting in: Reduced employee time completing and verifying paperwork required for special handling.
• Solutions prepared by weighing neat • Larger batches – larger weighings – greater Reduced shipping costs and time due to not needing special tamper-proof packaging for materials and diluting in volumetric flasks accuracy for the filling solution dispensing and shipping.
• Weighing small quantities accurately is time • Ampoule format prevents changes in concentration Reduced analyst time at the bench for completing and verifying paperwork required for consuming and costly (estimated 45 minutes per due to evaporation special handling. This is in addition to reduced analyst time to prepare the sample by method execution) • Inert atmosphere promotes long term – years of weighing rather than a simple serial dilution.
• Accurate weighing of small quantities may require special balance enclosures and micro-balances • Ampoule format prevents cross-contamination Overall cost reduction is estimated as approximately $40,000 per year! • Requires more reference material over time and • Standard preparation time reduced in the analytical more frequent batch replacement – cost impact • Solutions stored in volumetric flasks may have • If prepared at the working concentration, can use limited shelf life due to evaporation and/or directly. If dilution required, preparation is reduced Method considerations: The HPLC/UV method for tadalafil requires two standards to be prepared by weighing a
degradation. Shelf life for most working standards to quantitative transfer from ampoule powder. The working solution requires dissolution in acetonitrile (ACN) followed by dilution with aqueous diluent. is typically days or weeks • Handling: The pre-diluted solution provides safety The volumetric solution has been shown to be stable for two days. The powder is electrostatic and difficult to in handling of toxic, potent, or hazardous materials handle with greater potential for day to day variability in the concentration of the working solution standard.
• Hygroscopic, electrostatic, volatile, and difficult to in the analytical lab handle materials pose handling and repeatability Diluent Selection: Since the method diluent is a mixture of ACN and aqueous buffer; ACN was selected as the
• Qualification to the primary standard provides diluent for the solution standard. The ampoule of Tadalafil stock solution in ACN can then be conveniently and traceability and consistency in results year after • Special handling is also required for toxic, potent, or accurately diluted before use in the analytical lab. hazardous substances • Use of same lot over extended time significantly Preparation: While the method requires a small weight of reference material, the stock solution was prepared on
• Other special equipment such as glove boxes and reduces variability of the reference – particularly for multi-gram scale. Electrostatic controls and larger weights provide greater accuracy. Gravimetric addition of static control may be required difficult to handle materials analyte and diluent eliminates issues with density and volume fluctuations with temperature.
• Regulatory requirements may require detailed and • Fewer failed batches due to variability of the Fill volume: 3 mL. Fill volume was selected for convenience of volumetric transfer and dilution of the stock at time
time consuming paperwork to track material usage standard – critical for high dollar and/or difficult to Container: Unsilanized 5 mL wide-bore amber ampoules. Large enough to accommodate the volume required
• Correct preparation of the standard can be a factor • Less paperwork associated with handling the pre- for dilution; wide bore allows use of volumetric pipettes. Flame sealed under argon – protects against oxidative in inter-lab variability diluted solution – convenience and cost savings and evaporative changes.
• Inconsistent preparation of working standards can • Exemptions can be obtained for US DEA & Health lead to incorrect failure of a production lot, OOS Canada regulated materials when in solution format Baseline qualification: Potency and impurities by the validated method, assaying against the powdered
investigations and batch rejection. Significant – reduced paperwork eliminates regulatory burden reference material.
Stability: Short-term and long-term stability were evaluated by testing the solution for potency and impurities.
• Proven track record in other industries ‒ clinical/forensic toxicology, clinical diagnostic, and environmental Development Solution – Proof of Concept
A solution was gravimetrically prepared for Stress Degradation Controlled Storage Impurities Stress Degradation Plan Stress Degradation Controlled Storage Assay Results development purposes at 1 mg/mL in acetonitrile, a volume of 3 mL filled into 5 mL ampoules, and flame-sealed under argon. Total # of # Ampoules tested for each
Potency in mg/mL (RSD)
% Impurities
This standard was subjected to short-term stress degradation conditions for 30 days. Control samples were stored in the sub-freezer. Stability samples were stored at sub- freezer, freezer, refrigerator, room 15 to 30°C with Exposure up temperature, 40°C, and 80°C conditions as well as photostability conditions and sampled at specified Interval samples were transferred to the freezer and analyzed together at the end of the study. Potency and impurities were determined by the established methods. Stress Degradation Photostability Stress Degradation Photostability Stress Degradation HPLC Assay Results
Stress Degradation HPLC Impurities Results
Impurities Results Exposure
% Impurities
% Impurities
Cerilliant (ICH 2) Cerilliant (ICH 2) Cerilliant Control (ICH 2) Cerilliant Control (ICH 2) Lilly Xenon (ICH 1) Lilly Xenon (ICH 1) otal
Lilly Xenon Control (ICH 1) Lilly Xenon Control (ICH 1) Lilly Fluorescent (ICH 2) Lilly Fluorescent (ICH 2) Lilly Fluorescent Control (ICH 2) Lilly Fluorescent Control (ICH 2) Potency was maintained under the conditions of the study. Photostability results indicated the solution was stable at normal laboratory use conditions.
Long-term storage was assigned as refrigerated.
The development solution was put on long-term stability under refrigerator and freezer conditions for two years. Neat reference material was used as assay standard in the potency measurement.
Real Time HPLC Assay Results
Real Time HPLC Impurities Results
2°C to 8°C
-10°C to -25°C
Potency in
Potency in
A solution based assay standard was developed for Tadalafil. This standard replaced neat Tadalafil reference material for use in routine QC of Tadalafil.
Data from 15 months of storage to date shows no loss
of potency or increase in impurities.
The solution reference standard was prepared in a diluent compatible with the HPLC method and packaged under argon in flame-sealed amber ampoules. The solution was stable under ambient handling conditions, stress degradation, and long-term up to 15 months to date. The assay standard prepared from neat, in contrast, has only been shown valid for two days.
The solution format eliminated documentation and storage requirements related to traceability of usage for special security substances. Time and efficiency in routine QC was improved by elimination of need for special procedures for handling of electrostatic materials during the weighing of assay standards. Day to day variability in assay standard preparation was reduced.
The study demonstrates that efficiencies can be gained by careful development of reference standards in formats that meet methodrequirements and also promote efficiency and consistency. 2012 Cerilliant Corporation 811 Paloma Drive Round Rock, TX 78665

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