Finished Drug Products Research Articles

Metformin drugs under simulated gastric conditions can generate high nitrite-dependent levels of N-nitrosodimethylamine

N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), group 2A carcinogens, were detected in finished drug products, including metformin, ranitidine, sartans and other drugs which caused multiple recalls in the USA and Europe. Important studies also reported the formation of NDMA when ranitidine and nitrite were added to simulated gastric fluid. Our objective was to screen finished drug products from Europe and USA for nitrosamine impurities and investigate the formation of NDMA in metformin finished drug products when added to simulated gastric fluid. One dosage unit of 30 different commercially available drugs, including metformin, sartans, and ranitidine were tested for NDMA, NDEA, and dimethylformamide (DMF) impurities, using a liquid chromatography-mass spectrometry (LC–MS) method. Then, 6 metformin finished drug products were tested in stomach conditions for 2 h at 37 °C in a 100 mL solution with a pH of 2.5 and different nitrite concentrations (40, 10, 1, 0.1 mM) and tested for NDMA, and DMF using LC–MS. We measured NDMA, NDEA, and DMF in 30 finished drug products. NDMA and DMF were quantified for metformin drug products in simulated gastric fluid with different nitrite concentrations. None of the 30 drugs showed concerning levels of NDMA, NDEA, or DMF when tested as single tablets. However, when metformin tablets are added to simulated gastric fluid solutions with high nitrite concentrations (40 mM and 10 mM), NDMA can reach amounts of thousands of nanograms per tablet. At the closest concentration to physiologic conditions we used, 1 mM, NDMA is still present in the hundreds of nanograms in some metformin products. In this in vitro study, nitrite concentration had a very important effect on NDMA quantification in metformin tablets added to simulated gastric fluid. 1 mM nitrite caused an increase above the acceptable daily intake set by the U.S. Food and Drug Administration (FDA) for some of the metformin drugs. 10 mM, 40 mM nitrite solutions generated NDMA amounts exceeding by more than a hundred times the acceptable daily intake set by the FDA of 96 nanograms. These findings suggest that metformin can react with nitrite in gastric-like conditions and generate NDMA. Thus, patients taking metformin could be exposed to NDMA when high nitrite levels are present in their stomach, and we recommend including a statement within the Patient Package Inserts/Instructions for use.

Evaluation of a Novel LC-MS/MS Based Analytical Method for the Risk Assessment of Nitrosamines in Pharmaceutical Products and Packaging Materials

The detection of nitrosamine impurities, particularly small dialkyl types, which are frequently known to be potent mutagenic carcinogens, in some Sartan group active pharmaceutical ingredients (APIs) and finished drug products caused global regulatory organizations to have concerns. Accordingly, Registration Holders/Applicants, API manufacturers, and their raw material suppliers are required to check the presence of nitrosamines in their products and carry out risk assessments using the quality risk management principles specified in the ICH Q9 guide. In this context, a new LC-MS/MS method has been developed and validated for the simultaneous determination of NDMA, NDEA, NMBA, NDIPA, NEIPA, NDBA, and MeNP nitrosamine compounds in API and finished products as well as in primary packaging materials, one of the risk sources. This validated method was applied to check the nitrosamine content may occur from canister, blister, printed aluminum foil, nasal spray, and eye drop packaging materials as part of the Extractables & Leachables studies arising from interactions between the product and the primary packaging. For the determination and quality control of nitrosamines in sartan group pharmaceutical products and packaging materials, the developed LC-MS/MS analytical method offers highly reliable, fast, high accuracy, good sensitivity and simultaneous detection even at low concentrations.

Exploring the Evolution of Analytical Method Validation: Current Perspectives

In this review, we delve into the critical process of analytical method development and validation within the realm of pharmaceutical drug development. The creation of sound analytical methods stands as a cornerstone from the early stages of drug discovery through to the eventual marketing approval. Our objective is to meticulously examine the methodology behind developing, optimizing, and validating analytical methods, particularly focusing on their application to drug products – from the formulation's developmental stage to the production of commercial batches. We begin by elucidating the significance of method development tailored to the specific components of finished drug products or in-process tests. Additionally, we delve into the intricacies of sample preparation techniques essential for accurate analysis. Central to our discussion are the practical approaches employed to ascertain critical parameters including selectivity, specificity, limit of detection, limit of quantitation, linearity, range accuracy, precision, recovery, solution stability, ruggedness, and robustness of liquid chromatographic methods. These parameters are indispensable for supporting routine, in-process, and stability analyses crucial for ensuring the safety, efficacy, and quality of pharmaceutical products. By dissecting the intricacies of method development and validation, this review aims to provide pharmaceutical researchers and practitioners with valuable insights and practical guidelines to navigate the complex landscape of analytical method validation in drug development.

Practice of quality control circle activities to reduce the errors in rechecking of finished drug products in pharmacy intravenous admixture service

Practice of quality control circle activities to reduce the errors in rechecking of finished drug products in pharmacy intravenous admixture service

Parts per billion of nitrite in microcrystalline cellulose by ion chromatography mass spectrometry with isotope labeled internal standard

Regulatory authorities like the U.S. Food and Drug Administration (FDA) have set strict specification levels for N-nitrosamines in finished drug products. Nitrite is a potential precursor for the formation of probable carcinogenic N-nitrosamines when secondary or tertiary amines are also present in the active pharmaceutical ingredient (API) synthesis or drug formulation process. An accurate and sensitive determination of nitrite will be useful when a drug product manufacturer chooses to investigate the reaction kinetics between nitrite and amines or to select appropriate excipients for its drug formulation. Pharmaceutical excipient manufacturers may also need an accurate nitrite measurement to investigate the nitrite content in their excipients. This study details the development and validation of an ion chromatography mass spectrometry (IC-MS) method for trace nitrite determination in microcrystalline cellulose materials, one of the important pharmaceutical excipients used in many drug formulations. MS operated under selected ion monitoring mode was used to solve the commonly encountered interference issue with conductivity detection, and nitrite isotope internal standard was employed to address the ion suppression issue with MS detection. The installation of an after-column “jumper” to flush water with an auxiliary pump through the MS when it is not used for data collection avoided sensitivity loss due to trace salt accumulation in the ion source. Validation of the optimized method was satisfactory, with linearity of nitrite in the concentration range of 0.02–7.50 ppm (µg/g) having a regression coefficient of > 0.999, precision of RSD < 9.5% at 0.03 ppm and RSD < 3.4% at 0.4 ppm and recovery of 92.0–103.0%. The limit of detection and limit of quantitation were 0.005 and 0.016 ppm, respectively.

Assessment on compatibility and safety of labels for pharmaceutical packaging

Although the secondary packing materials do not directly contact the finished drug products, compound migration may still happen between them. To ensure drug quality and safety, extractables and leachables of the packing materials should be analyzed. In this study, 2,6-di-tert-butyl-4-methylphenol (BHT) was first found in the labels for pharmaceutical packaging. For the identification of the compound, a strategy combining high performance liquid chromatography (HPLC), ultra-performance liquid chromatography-quadrupole time-of-flight mass (UPLC-Q-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy was utilized. Afterwards, a effective and sensitive HPLC method for quantification of BHT was developed and validated. Finally, a toxicological risk assessment of BHT was performed to ensure the safety of drugs.

Development of a Simple Extraction Procedure and an HPLC Method for the Determination of Delmopinol in a Challenging Rubbery Dental Chew.

Delmopinol hydrochloride (delmopinol) is widely used in oral hygiene products such as dental chews for preventing dental plaque buildup and gingivitis. This study aimed to develop a simple and inexpensive extraction method, followed by a stability-indicating reversed-phase HPLC (RP-HPLC) method for the determination of delmopinol from rubbery dental chews. The extraction method was optimized in terms of pH, temperature, solvents, repeatability, and reproducibility. Delmopinol was extracted from the rubbery dental chews using 6 N NaOH-MeOH (1 + 1, v/v) at 65°C. The delmopinol peak was eluted in about 7 min by gradient elution on a pH-stable (alkaline) Phenomenex Gemini-NX-C18 column (50 × 4.6 mm id, 110 Å, 3 µm particle size) maintained at 50°C. Mobile phase A was composed of aqueous 10 mM ammonium hydroxide and mobile phase B was acetonitrile. The analyte was monitored by UV detection at 220 nm with a flow rate of 2.0 mL/min. The method was successfully validated as per the current International Conference on Harmonization guidelines for delmopinol with respect to specificity, linearity (R2 >0.999), accuracy, precision, LOQ (2 µg/mL), LOD (0.6 µg/mL), and robustness. The reliability of the method was also demonstrated by batch analysis of 132 dental chews. A simple extraction method and RP-HPLC method were successfully developed and validated for the determination of delmopinol from rubbery dental chews. The overall method was demonstrated to be accurate, robust, specific, and stability-indicating. Therefore, the developed method is suitable and highly desirable for routine analysis of delmopinol in its finished drug products.

METHOD DEVELOPMENT AND VALIDATION FOR THE ESTIMATION OF CLASS-I ELEMENTAL IMPURITIES IN PROPOFOL EMULSION USING ICP-MS

Elemental impurities are the traces of metals that can be found in finished drug products which may enter through various sources like excipients, and active pharmaceutical ingredients etc., their toxicity is to be estimated as they may pose serious toxicological effects to patients. The aim of this work is to estimate Class-I elements (Cd, Pb, As, Hg) simultaneously in Propofol 10 mg/mL Emulsion for Injection or Infusion using modern technique Inductively coupled plasma mass spectrometry, employing microwave-assisted digestion of sample. The developed method was validated for various parameters according to ICHQ2(R1) to prove that the developed method is fit for the required purpose and can be adaptable regularly. Validation results showed that the method was linear over the range of LOQ to 250%, with a good linearity correlation factor of R≥0.99, the method was found to be robust against the deliberate changes in sample preparation and uptake speed.

Liquid chromatographic methods for the analysis of canagliflozin: concise overview and greener assessment.

There is a pressing need for the development of greener liquid chromatographic bioanalytical methods for antidiabetic drugs for plasma monitoring and revisiting patients' dosage regimens. Besides, analytical methods are also needed for the quality assurance of finished drug products and regulatory approval. Therefore, the present review focuses on the reported liquid chromatographic methods (LC and LC-MS/MS) that are applied for quality control, forced degradation, and pharmacokinetic studies of a newer antidiabetic agent, canagliflozin (CNG). These reported studies are summarized based on liquid chromatographic separation parameters, such as column dimensions, mobile-phase compositions, flow rate, and use of different detection systems (UV, PDA, and mass spectrometry). The sample pretreatment of biological fluids, which is important for minimizing the matrix effect, is dealt with separately. Liquid-liquid extraction was found to be the most preferred methodology adopted for sample pretreatment followed by the solid-phase extraction technique. However, miniaturized novel pretreatment methods are untraceable in the literature for the extraction of CNG. Special emphasis is paid to the assessment of the greenness profiles of the reported analytical methods for the consideration of sustainable development and green analytical chemistry. Based on the National Environmental Method Index (NEMI) assessment tool, most of the reported studies fulfilled around half of the parameters and were found to be about 50% greener. It is proposed that toxic or hazardous solvents, such as acetonitrile or methanol, should be replaced with greener and environmentally friendly solvents. Thus, there is a need to develop more robust, efficient, and greener liquid chromatographic methods for the determination of CNG in biological fluids and drug products.

Ultra-High Performance Liquid Chromatography (UHPLC) for Quantification of Gabapentin in Granules and Capsules

Ultra-High Performance Liquid Chromatography (UHPLC) has become the modern standard HPLC platform in recent years. UHPLC as an ideal separation tool for the analysis of complex mixtures with a shorter analysis time is very suitable to be used as a fast and precise method. This study aims to determine the quantitative determination of gabapentin in the form of intermediate products, namely granules and finished products, namely capsules from 1 production batch using the UHPLC method. The results of the quantitative examination of the average content (% recovery) of gabapentin in granule and capsule samples quantified by the UHPLC method met the compendial requirements and internal specifications compared to the standard gabapentin recovery values. The % recovery obtained is 98.254% for gabapentin granules and 97.784% for gabapentin capsules, which means it is still in the 95%-105% range. While the %RSD value is 0.735 for granules and 0.839 for capsules, which means it has an RSD value of &lt;2%. % precision of gabapentin granules was 99.558% with %RSD 0.407, and % intermediate precision gabapentin capsules was obtained 98.845% with %RSD 0.678. In conclusion, based on the quantitative results obtained meet the expected specifications, so it can be considered for use for routine analysis and quality control of medicinal ingredients, in the inspection of intermediate products and other finished drug products in the pharmaceutical industry quickly and accurately.

Analysis of genotoxic N-nitrosamines in active pharmaceutical ingredients and market authorized products in low abundance by means of liquid chromatography – tandem mass spectrometry

In 2018, high levels of the IARC class IIA carcinogen N-nitrosodimethylamine (NDMA) were analytically verified in the active pharmaceutical ingredient (API) valsartan, resulting in extensive regulatory action on angiotensin-II-receptor antagonists and recall of finished drug products by the pharmaceutical industry to ensure patient safety. The root cause of contamination was the unintended reaction of common reagents utilized during drug synthesis. This lead to serious effects on drug quality and immediate regulatory action. Thus, routine analysis of drug product contents are inevitable and necessitate thoroughly performed work up procedures of the product as well as adequate validated analytical methods. The nature of N-nitrosamines (NA), ranging from small, semi-volatile compounds up to highly polar molecules, effort sophisticated requirements in terms of instrumental analysis. Up today, gas as well as liquid chromatographic devices coupled to mass spectrometers are the most widespread systems for analysis. Gas chromatographic – mass spectrometric (GC-MS) systems, obviously superior towards liquid chromatography – mass spectrometry (LC-MS) for detecting small volatile compounds like NDMA, reach their limits for broadly designed studies including polar or acidic NA. In this study, a complementary and highly sensitive approach by means of liquid chromatography – tandem mass spectrometry (LC-MS/MS) is presented, including detection of 13 NA deduced from major classes of secondary amines. Thereby, the fully validated approach was performed in accordance to ICH and European Medicines Agency (EMA) guidelines. Quantitative proof-of-concept measurements with various APIs and market authorized tablets as representative drug formulations conclude applicability for further presumably contaminated substances. The approach employs organic or inorganic extraction steps with solid phase extraction (SPE). The limit of detection for the most prominent NA, NDMA and N-diethylnitrosamine (NDEA), were both 0.025 parts-per-billion (ppb) per matrix, respectively.

Development and Evaluation of Vasoactive Intestinal Peptide Freeze-Dried Injection

Introduction: Vasoactive intestinal peptide (VIP), a ubiquitous, naturally synthesized human peptide is extensively documented to have diverse physiological effects like anti-inflammatory, immune-modulatory, anti-hypertensive, stimulation of contractility in the heart, vasodilation, and promoting neuroendocrine-immune communication. The synthetic form of VIP is called aviptadil (AVP). The main objective of this research was to develop a novel stable lyophilized dosage of VIP (Aviptadil) using sucrose as a bulking agent. AVP is a peptide with known concern for aqueous stability, which seems to be challenging for storing finished drug products and supply chain management. The VIP injection was developed using the lyophilization technique in the presence of bulking agent and some other pH-adjusting agent. The bulking agent and solvent system selection depends upon the solubility, stability of the drug substance, and feasibility during manufacturing. During product formulation development, the bulk solution was evaluated for processing time and temperature impact. The lyophilization cycle was developed using the most advanced freeze-drying technology. Result and discussion: With the usage of bulking agent (sucrose) as may act as a cryoprotectant for peptide, the formulated bulk solution was freeze-dried, and primary drying was done at-25°C (below than critical product temperature) followed by secondary drying at 25°C. The critical quality attributes of lyophilized drug products like the description of lyophilized cake/powder, moisture content, reconstitution time, active drug content and color of the solution were evaluated. The developed formulation bulk solution was stable and compatible with contact materials like SS vessels when hold up to 24 hours at 2 to 8°C. The optimized freeze-dried product meets the predefined acceptance criteria as part of the quality target product profile. Conclusions: It can be concluded from the research work carried out that a stable lyophilized parenteral formulation containing VIP (AVP) was developed using sucrose as a bulking agent. These findings show that the freeze-dried formulation is an appropriate technological remedy for stabilizing VIP in lyophilized injectable dosage form.

Cost-effective, green HPLC determination of losartan, valsartan and their nitrosodiethylamine impurity: application to pharmaceutical dosage forms.

Angiotensin-converting enzyme inhibitors are one of the most widely used anti-hypertensive drugs which are used to reduce hypertension. In 2018, the United States Food and Drug Administration together with the European Medicine Agency declared the presence of carcinogenic nitrosamine impurities such as nitrosodiethylamine (NDEA) in some of the products, including valsartan (VLS) and losartan (LOS), and drugs' recall procedures were started. Thus, they should be controlled to be below the acceptable cancer risk level to ensure safety of the pharmaceutical products. Therefore, sensitive and reliable analytical methods were required for detection and quantitation of NDEA in bulk and finished drug products. Green analytical chemistry has received great interest to minimize the amount of organic solvents consumed without loss in chromatographic performance. A green and sensitive HPLC method was developed for the determination of NDEA in LOS and VLS using mobile phase of 0.02 M ammonium acetate adjusted to pH 7.2 and ethanol in gradient manner. Limits of detection and limits of quantification for NDEA were estimated to be 0.2 and 0.5 µg ml−1, respectively. The standardized limits of NDEA impurity in drug substances were set as 0.56 ppm, which indicates the feasibility of its determination by the proposed conventional method without need for expensive instrumentations (e.g. MS/MS detectors) that are not found in most pharmaceutical quality control laboratories.

Quality Standards in State Programs Permitting Cannabis for Medical Uses.

Currently in the United States, there exists a patchwork of state-level laws and regulations surrounding cannabis use. Although cannabis (excluding hemp under the Agricultural Improvement Act of 2018, Public Law 115-334) is illegal at the federal level and is not FDA (U.S. Food and Drug Administration) approved for any indication, many states allow patients with qualifying conditions to register for their medical cannabis program (MCP). To better understand the quality of cannabis found in these programs, we collected laws, regulations, and guidance documents available on public state-run websites and compared them with current good manufacturing practices (CGMPs) applicable to finished drug products. CGMPs for human drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packaging of a drug product to assure it is safe for use. Such a comparison will aid the development of consistent quality standards that could, in turn, improve the quality of a wide range of cannabis medical products in development that may be sold in the United States. States may likewise choose to have the cannabis and cannabis-derived products that fall within their MCP to follow quality-focused guidelines, such as those listed in CGMPs, to ensure the quality of these products and promote public health. This study further solidifies the need for standardized testing protocols and methodologies to keep consumers safe.

Planning pharmaceutical manufacturing networks in the light of uncertain production approval times

In the light of shortening product life cycles and growing competition, supply chain efficiency has become a priority for researching pharmaceutical companies. Improving capacity management through dynamic product (re-)allocations is a widely acknowledged lever to achieve significant efficiency gains. However, product allocations in the pharmaceutical industry are subject to a specific source of uncertainty. Any facility that is to manufacture a given product for the very first time requires a production approval from regulatory authorities. The duration of the approval process is highly uncertain and can delay the completion of product allocations by several years. This implicitly affects decisions about outsourcing to contract manufacturing organizations (CMOs) who play an essential role in pharmaceutical supply chains (PSCs). Outsourcing is typically based on long-term contractual agreements and thus should be considered in a strategic time frame. To address these issues, we develop a two-stage stochastic MILP model for PSC network design under demand and approval time uncertainty. More specifically, we focus on the secondary manufacturing stage, which comprises all processes converting active pharmaceutical ingredients into finished drug products. A numerical study based on a real-life case of a global pharmaceutical company is presented to validate the applicability of our approach. The results show that approval times drive optimal allocation strategies and may induce different degrees of decentralization at upstream and downstream manufacturing stages. Furthermore, they are guiding make-or-buy decisions while uncertain demands mainly affect global capacity provisioning.

Regulatory 101: Bulk Holding Time Requirements

The FDA website provides guidance on various CGMP topics. The focus of this installment of Regulatory 101 is on the topic of bulk holding requirements. The question posed via the Q&amp;A on CGMP’s is stated as “How long may a firm store in-process/intermediate powder blends and triturations, sustained-release pellets/beads, and tablet cores, absent separate stability studies, before using them in finished drug products?” Additional considerations are provided to further analyze this frequently asked question. Pharmaceutical products are manufactured to ensure safety, effectiveness, and quality for their intended use. As part of the product development process, stability studies are conducted to determine the appropriate shelf life for the product under specified storage conditions. These studies ensure all product specifications are met up to the assigned expiration date.

Metallic Impurities in Pharmaceuticals: An Overview

Backgroun:Metallic impurities are the traces of metals that can be found in finished drug products. Description:These metallic impurities in pharmaceutical preparations can enter from formulation ingredients, catalysts, and process equipment, containers and closures. They are not completely removed from the product by practical manufacturing techniques and should be evaluated relative to safetybased limits. They can affect drug efficacy or produce direct toxic effect on the patient. Methods:In this paper, an attempt has been made to review these metallic impurities including potential sources and analytical procedures to quantify these impurities. ICH guideline on these impurities and measures to control impurities has also been discussed in the paper. Results:The implementation of ICH Q3D guideline with the quality risk assessment approach is an important milestone to harmonize control of elements worldwide. Conclusion:This approach allows manufacturers to provide vital information about the contribution of impurities in the drug product.

DIR reform, supply chain security, and more

DIR reform, supply chain security, and more

Importance of a High Performing GC-MS Based Screening Method for Testing Stability Samples for Volatile and Semi-Volatile Leachable Impurities

Leachable testing for finished pharmaceutical products is an important part of the regulatory filing and is under more regulatory scrutiny than ever before. Leachable testing for multiple finished drug products such as biologics, large volume parenterals, and polymer-based finished products requires analysis at trace levels with a high level of confidence. A high level of analytical expertise and top-of-the-line analytical instrumentation is required for work at trace levels. (The definition of trace level analytical testing has not been accurately defined; however, to have a sense of the “trace-level”-associated testing issues, we are arbitrarily assigning levels below 100 ng/mL as trace level and below 1 ng/mL as ultra-trace level in this paper). Leachable testing ideally should be performed on a targeted list of analytes compiled from an extractable study and an extractable and leachable correlation study, along with a general non-targeted screening evaluation to avoid any undetected leachables. For targeted screening, analytical testing is more straightforward and can typically detect targets at ppb or sub-ppb levels without issue. However, for a general screening method, this can be difficult, and many times requires special sample preparation combined with high-resolution accurate-mass detection. Case studies will be presented to demonstrate the importance of high-performance and highly sensitive screening methods in detecting unexpected leachables, and in supporting related quality investigations. The importance of well-designed and executed system suitability will also be discussed in this paper.

The U.S. medicine chest: Understanding the U.S. pharmaceutical supply chain and the role of the pharmacist

The U.S. capacity to manufacture key essential medications has diminished. The U.S. pharmaceutical supply chain (USPSC) has diversified and now relies on international sources of active pharmaceutical ingredients and finished drug products (FDPs). Despite years of effort raising concerns about the USPSC, pharmacists and pharmacy technicians continue to spend a substantial amount of time and energy responding to, and mitigating the impact of, medication shortages, drug recalls, and the adverse outcomes related to low-quality medications. The extent of U.S. reliance on foreign sources of medications is largely unknown. Pharmacists do not have a reliable way to determine the country of origin (i.e., source), capacity, or geographic location of pharmaceutical manufacturers, limiting our ability to anticipate challenges or mitigate risks to our Nation’s drug supply. The U.S. Food and Drug Administration’s task of regulating quality and safety is challenging and will likely require additional safeguards and resources. In addition to pharmacists’ engagement, solutions will likely need to leverage a mix of policy, economic incentives, and expanded objective surveillance testing. The U.S. pharmaceutical supply chain is complex, global, and goes beyond FDPs. The 2020 American Pharmacists Association House of Delegates has rightly asserted that “The quality and safety of pharmaceutical and other medical products and the global pharmaceutical and medical product supply chain are essential to the United States national security and public health.” Pharmacy professionals on the front line engage with patients, identify medication-related issues, and engage in drug-procurement decisions. Pharmacists are essential to our nation’s overall health and must be engaged in the development and implementation of strategies to safeguard the USPSC.