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1.
J Med Chem ; 65(1): 37-57, 2022 01 13.
Article in English | MEDLINE | ID: mdl-34931848

ABSTRACT

A bibliometric study of authors across medicinal chemistry journals over 20 years reveals important trends. Most United States (US) based authors are assigned as racially/ethnically Asian or White; few are Black or Hispanic. More US coauthors have the same race/ethnicity as the corresponding author than expected. The percentage of female authors increased globally, but only slowly. Since 2010, the number of female and male authors declined by 9% and 30%, respectively. Geographically, most authors are male except in Italy where there is gender balance. Gender homophily is observed globally. Geographically, the discipline is now more widely practiced. Article output doubled from 2000 to 2010 with a large increase in articles from China. China excepted, output has since declined. The average number of authors per article rose by a third since 2000. The value of high diversity groups in education, research, and industry cannot be overstated. We recommend diversity is addressed by every medicinal chemist.


Subject(s)
Authorship/standards , Chemistry, Pharmaceutical/standards , Ethnicity/statistics & numerical data , Periodicals as Topic/statistics & numerical data , Publications/statistics & numerical data , Racial Groups/statistics & numerical data , Female , Geography , Humans , Male , United States
2.
Eur J Pharm Biopharm ; 169: 292-296, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34757155

ABSTRACT

The residual moisture (RM) level strongly impacts the stability of freeze-dried biopharmaceuticals. On the one hand, the RM should not be too high to keep the reaction potential of water molecules low and to avoid a decrease in the glass transition temperature through the plasticizing effect of water. On the other hand, overdrying has been described to negatively impact protein stability. Consequently, an optimal RM has to be established and justified for approval by authorities. Therefore, end products with different RM are analyzed over storage. The different RM levels are typically obtained by slightly varying the lyophilization process itself; but deviations from the original process are critical. Additionally, samples can be taken during lyophilization runs, e.g. at the end of primary drying or after the ramp into secondary drying. This, however, does not allow for good control over the RM. Here we present the adaption of a headspace water spiking technique using a microliter syringe to precisely increase and adjust the RM. This technique is suitable to reproducibly introduce water in the microliter scale to achieve RM of less than 1% [w/w] with high precision depending on the dry cake weight. In addition, we show that by using different fill volumes and cake densities, an equal three-dimensional water distribution throughout the whole cake can be achieved. Furthermore, potential limitations and risks in manual RM introduction are discussed.


Subject(s)
Drug Compounding/methods , Freeze Drying/methods , Protein Stability , Proteins/pharmacology , Water , Biological Products/pharmacology , Chemistry, Pharmaceutical/methods , Chemistry, Pharmaceutical/standards , Excipients/pharmacology , Humans , Miniaturization , Phase Transition , Reproducibility of Results , Syringes , Transition Temperature , Water/chemistry , Water/pharmacology
3.
J Mater Sci Mater Med ; 32(9): 116, 2021 Aug 30.
Article in English | MEDLINE | ID: mdl-34460000

ABSTRACT

L-glutamate is an important component of protein. It can prevent gastrointestinal damage caused by NSAIDs. We constructed two-phase enteric-coated granules of aspirin and L-glutamate compound by extrusion spheronization method and fluidized bed coating. The subliminal effective dose of L-glutamate is 100 mg/kg tested by model of gastric ulcer of rats induced by aspirin and drug administration. HPLC-UV and UV-Vis methods were adopted to determine content and cumulative release of aspirin and L-glutamate as quality analysis method indexes. The prescription and process optimization were carried out with yield, sphericity and dissolution. The two-phase compound granules have good sphericity of 0.93 ± 0.05 (aspirin pellets) and 0.94 ± 0.02 (L-glutamate pellets), content of salicylic acid (0.24 ± 0.03)%, dissolution of aspirin (2.36 ± 0.11)%. Quality evaluation and preliminary stability meet the commercial requirements. The stored environment of compound preparation should be sealed in a cool and dark place.


Subject(s)
Aspirin , Drug Compounding , Glutamic Acid , Animals , Aspirin/administration & dosage , Aspirin/chemical synthesis , Aspirin/pharmacology , Chemistry, Pharmaceutical/methods , Chemistry, Pharmaceutical/standards , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Compounding/methods , Drug Compounding/standards , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/standards , Gastric Mucosa/drug effects , Gastrointestinal Tract/drug effects , Glutamic Acid/administration & dosage , Glutamic Acid/chemical synthesis , Glutamic Acid/pharmacology , Quality Control , Rats , Rats, Sprague-Dawley , Stomach Ulcer/drug therapy , Stomach Ulcer/pathology , Tablets, Enteric-Coated
4.
AAPS PharmSciTech ; 22(4): 151, 2021 May 11.
Article in English | MEDLINE | ID: mdl-33977355

ABSTRACT

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.


Subject(s)
Chemistry, Pharmaceutical/methods , Compressive Strength , Drug Development/methods , Lubricants/chemical synthesis , Chemistry, Pharmaceutical/standards , Drug Compounding/methods , Drug Development/standards , Ibuprofen/chemical synthesis , Ibuprofen/standards , Lubricants/standards , Stearic Acids/chemical synthesis , Stearic Acids/standards , Surface-Active Agents/chemical synthesis , Surface-Active Agents/standards , Tablets , Tensile Strength
5.
AAPS J ; 23(3): 67, 2021 05 10.
Article in English | MEDLINE | ID: mdl-33973074

ABSTRACT

Drug dosing decisions in clinical medicine and in introducing a drug to market for the past 60 years are based on the pharmacokinetic/clinical pharmacology concept of clearance. We used chemical reaction engineering models to demonstrate the limitations of presently employed clearance measurements based upon systemic blood concentration in reflecting organ clearance. The belief for the last 49 years that in vivo clearance is independent of the mechanistic model for organ clearance is incorrect. There is only one valid definition of clearance. Defining organ clearance solely on the basis of systemic blood concentrations can lead to drug dosing errors when drug effect sites reside either in an eliminating organ exhibiting incremental clearance or in a non-eliminating organ where intraorgan concentration is governed by transporter actions. Attempts to predict clearance are presently hampered by the lack of recognition that what we are trying to predict is a well-stirred model clearance.


Subject(s)
Carrier Proteins/metabolism , Drug Dosage Calculations , Metabolic Clearance Rate , Models, Biological , Pharmacology, Clinical/standards , Chemical Engineering , Chemistry, Pharmaceutical/methods , Chemistry, Pharmaceutical/standards , Dose-Response Relationship, Drug , Humans , Pharmacology, Clinical/methods
6.
AAPS J ; 23(2): 31, 2021 02 22.
Article in English | MEDLINE | ID: mdl-33619657

ABSTRACT

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment.Graphical abstract.


Subject(s)
Drug Approval , Drug Development/methods , Gastrointestinal Absorption/physiology , Models, Biological , United States Food and Drug Administration/standards , Chemistry, Pharmaceutical/standards , Computer Simulation/standards , Drug Development/standards , Drug Liberation/physiology , Humans , Metabolic Clearance Rate/physiology , Tissue Distribution/physiology , United States
7.
Biomed Chromatogr ; 35(1): e5030, 2021 Jan.
Article in English | MEDLINE | ID: mdl-33201529

ABSTRACT

Bioanalysis, a key supporting function for generating data for pre-clinical and clinical studies in drug development, is under the regulation of local agencies as well as global organizations to ensure the data integrity and quality in submission. As major regulatory agencies and organizations, the US Food and Drug Administration, the European Medicines Agency and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use have been updating their industry guidance for bioanalytical method validation, to keep up with the development new modalities, technologies and regulations. This article summarizes the recent updates and any clarifications and controversies triggered by those updates. Perspectives and recommendations are given based on our own experience as well as commonly accepted practice in the bioanalytical community.


Subject(s)
Chemistry, Pharmaceutical , Chromatography , Chemistry, Pharmaceutical/legislation & jurisprudence , Chemistry, Pharmaceutical/standards , Chromatography/methods , Chromatography/standards , Clinical Trials as Topic , Humans , Pharmaceutical Preparations/blood , Pharmaceutical Preparations/urine , Reproducibility of Results , Sensitivity and Specificity , United States , United States Food and Drug Administration
8.
PLoS One ; 15(12): e0243428, 2020.
Article in English | MEDLINE | ID: mdl-33270800

ABSTRACT

BACKGROUND: Quality-assured medicines are a principal means of achieving health-related Sustainable Development Goals. An example of quality assurance/quality control (QA/QC) procedures in drug procurement is provided by the operation of the Global Drug Facility (GDF) of the Stop TB Partnership, the largest provider of tuberculosis (TB) medicines to the public sector worldwide. METHODS: Procedures and results of GDF's quality assurance/quality control (QA/QC) over the five-year period 2013-2017 were analysed retrospectively. 13,999 batches of 51 different medicines had been procured and reviewed within this period. 1,388 of these batches had been analysed in the laboratories of GDF's external quality control agent (QCA). Assay and dissolution results determined by the manufacturers and by the external QCA were compared using Bland-Altman analysis. RESULTS: All investigated batches of medicines were in specifications at the time of shipment. The costs for QA/QC were 0.8% of purchase costs. The median time required for chemical analysis was 10 working days. Comparison of the medicine quality analysis results showed for the poorly water-soluble compound rifampicin a bias of 4.4%, with the manufacturers reporting higher values than the external QCA, most likely due to different methods employed for the analysis. Overall 95% limits of agreement (LOAs) were -6.7 to +8.0% for assay, and -10.1 to +11.8% for dissolution. In case of kanamycin injections, 95% LOAs for assay reached -14.5 to +13.2%, largely attributable to samples from one manufacturer who had used a microbiological assay while the external QCA had used an HPLC assay. CONCLUSIONS: GDF's procedures represent a useful benchmark when evaluating QA/QC procedures of other medicine procurement operations. Inter-laboratory comparison using Bland-Altman plots allows to investigate bias and variability in medicine quality control and should be considered as a routine procedure by drug procurement agencies, to identify priorities for further improvements.


Subject(s)
Antitubercular Agents/standards , Public-Private Sector Partnerships/standards , Quality Control , Sustainable Development , Tuberculosis/drug therapy , Antitubercular Agents/chemistry , Antitubercular Agents/therapeutic use , Chemistry, Pharmaceutical/economics , Chemistry, Pharmaceutical/methods , Chemistry, Pharmaceutical/standards , Costs and Cost Analysis , Humans , Retrospective Studies , Solubility
9.
Pharmazie ; 75(11): 540-547, 2020 11 01.
Article in English | MEDLINE | ID: mdl-33239126

ABSTRACT

Chinese materia medica decoction pieces (CMMDPs), one of the three pillars of the Chinese materia medica industry, are a key link in the Chinese materia medica industrial chain. Industrialization is the only way for the modernization of CMMDPs. This review mainly summarizes the characteristics, history, current situation and prospect of CMMDPs industry, providing a new reference for promoting the flourishing development of the industrialization of CMMDPs and for serving massive health industry. The literature was collected from databases including Web of Science, PubMed, Elsevier and CNKI (Chinese). CMMDPs industry has the characteristics of regionalism, resource dependency, customer diversity and low industrial concentration. Deeply processed products include traditional Chinese medicine (TCM) formula granules, small-packed decoction pieces, ultrafine decoction pieces, puffed decoction pieces, compressed decoction pieces and instant decoction pieces. Integration of treatment and processing at the place of origin is emerging. However, there is still room for improvement, for example, the manufacturing technologies of CMMDPs industry need to be continually improved. The management of CMMDPs' normalized production also needs to be strengthened. The quality of CMMDPs should be strengthened supervision and it should establish the objective and feasible quality evaluation system for CMMDPs. At present, China has attached unprecedented importance to the development of TCM, and issued a number of supporting policies, sparing no effort to support its development.


Subject(s)
Drug Industry/standards , Drugs, Chinese Herbal/standards , Medicine, Chinese Traditional/standards , Chemistry, Pharmaceutical/standards , Drug Packaging/standards , Drugs, Chinese Herbal/chemistry , Humans , Industrial Development , Quality Control
10.
Pharmacol Res Perspect ; 8(6): e00668, 2020 12.
Article in English | MEDLINE | ID: mdl-33090729

ABSTRACT

Benzathine penicillin G (BPG) is used as first-line treatment for most forms of syphilis and as secondary prophylaxis against rheumatic heart disease (RHD). Perceptions that poor quality of BPG is linked to reported adverse effects and therapeutic failure may impact syphilis and RHD control programs. Clinical networks and web-based advertising were used to obtain vials of BPG from a wide range of countries. The quality of BPG was assessed using a high performance liquid chromatography assay capable of detecting relevant impurities and degradation products. Tests for water content, presence of heavy metals and physical characteristics of BPG, including particle size analysis and optical microscopy, also were conducted. Thirty-five batches of BPG were sourced from 16 countries across 4 WHO regions. All batches passed the US Pharmacopeia requirements for BPG injection (content), with no evidence of breakdown products or other detected contaminants. Water content and heavy metal analysis (n = 11) indicated adherence to regulatory standards and Good Manufacturing Practice. Particle size analysis (n = 20) found two batches with aggregated particles (>400 µm) that were dispersed following sonication. Current batches of BPG were of satisfactory pharmaceutical quality but aggregated particles were found in a modest proportion of samples. Future studies should focus on the physical characteristics of BPG which may contribute to variations in plasma penicillin concentrations an observed needle blockages in clinical practice. Pharmacopeial monographs could be revised to include standards on particle size and crystal morphology of BPG.


Subject(s)
Anti-Bacterial Agents/standards , Chemistry, Pharmaceutical/standards , Internationality , Penicillin G Benzathine/standards , Quality Control , Anti-Bacterial Agents/therapeutic use , Chemistry, Pharmaceutical/methods , Cross-Sectional Studies , Humans , Penicillin G Benzathine/therapeutic use , Rheumatic Heart Disease/drug therapy
11.
Biologicals ; 67: 9-20, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32665104

ABSTRACT

Identification of Critical Quality Attributes (CQAs) and subsequent characterization in process development studies are the key elements of quality by design (QbD) for biopharmaceutical products. Since the inception of ICH Q8R2, several articles have been published on approaches to conducting CQA risk assessments as well as the application to process understanding. A survey was conducted by multiple companies participating in an International Consortium working group on the best practices for identifying CQAs with linkages to process characterization (PC) studies. The results indicate that the companies surveyed are using similar approaches/timing to identify CQAs during process development. Consensus was also observed among the companies surveyed with approaches to linkage of CQAs to process characterization studies leading to impact to control strategies and lifecycle management.


Subject(s)
Benchmarking/methods , Biological Products/chemistry , Chemistry, Pharmaceutical/methods , Drug Industry/methods , Surveys and Questionnaires , Technology, Pharmaceutical/methods , Benchmarking/standards , Benchmarking/statistics & numerical data , Biological Products/standards , Biological Products/therapeutic use , Chemistry, Pharmaceutical/standards , Chemistry, Pharmaceutical/statistics & numerical data , Drug Design , Drug Industry/standards , Drug Industry/statistics & numerical data , Humans , Quality Control , Research Design , Risk Assessment/methods , Risk Assessment/statistics & numerical data , Technology, Pharmaceutical/standards , Technology, Pharmaceutical/statistics & numerical data
13.
AAPS J ; 22(4): 74, 2020 05 19.
Article in English | MEDLINE | ID: mdl-32430592

ABSTRACT

The pharmaceutical industry and regulatory agencies rely on dissolution similarity testing to make critical product performance decisions as part of drug product life cycle management. Accordingly, the application of mathematical approaches to evaluate dissolution profile similarity is described in regulatory guidance. However, the requirements (e.g., which time points, number of time points, %CV) to apply the widely known similarity factor f2 and other alternative statistical approaches diverge noticeably across regulatory agencies. In an effort to highlight current practices to assess dissolution profile similarity and to strive towards global harmonization, a workshop entitled "in vitro dissolution similarity assessment in support of drug product quality: what, how, when" was held May 21-22, 2019, at the University of Maryland, Baltimore. This article summarizes key points from the podium presentations and breakout (BO) sessions focusing on (1) contrasting the advantages and disadvantages of several statistical methods; (2) the importance of experimental design for successful similarity evaluation; (3) the value of similarity evaluation in light of clinically relevant specifications; and (4) the need for creating a robust and scientifically appropriate path (e.g., non-prescriptive decision tree) for dissolution profile similarity assessment as a stepping stone for global harmonization.


Subject(s)
Chemistry, Pharmaceutical/trends , Congresses as Topic/trends , Drug Development/trends , Education/trends , Pharmaceutical Preparations/chemistry , Research Report/trends , Animals , Baltimore , Bayes Theorem , Chemistry, Pharmaceutical/methods , Chemistry, Pharmaceutical/standards , Drug Development/methods , Drug Development/standards , Humans , Pharmaceutical Preparations/metabolism , Pharmaceutical Preparations/standards , Research Report/standards , Solubility
14.
PDA J Pharm Sci Technol ; 74(3): 348-358, 2020.
Article in English | MEDLINE | ID: mdl-32295860

ABSTRACT

It is generally acknowledged that quantitation in extractables and leachables (E&L) can be variably reproducible and accurate, depending on the quantitation approach taken. This is especially true for "simple" quantitation, which is the practice of estimating an analyte's concentration based on its response relative to that of an internal standard that has been added to the sample in a known amount. Simple quantitation is prone to error and variation as it is based on the largely false premise that the response factors for all extractables, leachables, and internal standard candidates are the same. It has been proposed that this uncertainty (inaccuracy and variation) be accounted for by adjusting two key parameters in E&L assessment, the reported concentrations themselves and the analytical evaluation threshold (AET) via an uncertainty factor (UF). This paper examines quantitation variation and discusses the means of establishing and utilizing the UF to adjust the AET to lower values and to adjust reported concentrations to higher values, enabling an impact assessment performed with this data to be more protective of patient safety. Although adjustment of the AET lower with the UF is supported, flaws in the concept of using the UF to adjust reported concentrations upward are considered, and it is recommended that the UF not be used in this manner. Rather, E&L quantitation should be based on compound-specific relative response factors, collected and collated in an E&L database.


Subject(s)
Chemistry, Pharmaceutical/standards , Drug Contamination/prevention & control , Drug Packaging/standards , Pharmaceutical Preparations/analysis , Pharmaceutical Preparations/standards , Uncertainty , Analytic Hierarchy Process , Chemistry, Pharmaceutical/methods , Chromatography/methods , Chromatography/standards , Drug Packaging/methods , Humans , Risk Assessment/methods , Risk Assessment/standards
15.
Curr Pharm Teach Learn ; 12(3): 339-346, 2020 03.
Article in English | MEDLINE | ID: mdl-32273073

ABSTRACT

BACKGROUND AND PURPOSE: Courses that integrate pharmacology, medicinal chemistry, and pharmacotherapy are widely implemented in pharmacy curriculums. The integration of medicinal chemistry is often challenging given the difficulty of material and time constraints. The objective of this pedagogical approach is to utilize structure activity relationship (SAR) maps as visual aids to teach students medicinal chemistry in an integrated course. EDUCATIONAL SETTING: SAR maps were designed and implemented within an integrated course focusing on cardiopulmonary diseases. Specific SAR maps used in lecture and class activities included phenylethylamines (adrenergic agonists (i.e. bronchodilators)) and aryloxypropanolamines (beta blockers). Students were assessed in class activities (formative) and exams (high stakes) for specific information surrounding drug structure and the SAR map. Drug properties assessed included essential pharmacophores, pharmacodynamics, physiochemical properties, metabolism, duration of action, and decision-making. FINDINGS: Results from assessment item analysis reveal that students performed well on medicinal chemistry questions related to the SAR maps (~90% correct on first exam). Students revealed in a survey that the SAR maps enhanced their understanding of medicinal chemistry concepts. SUMMARY: SAR maps are effective tools that visually teach students key concepts in medicinal chemistry. This millennial student-friendly tool is time-effective and promotes learning as opposed to drug structure memorization. The SAR map can be easily implemented in other integrated courses focused on various disease states.


Subject(s)
Chemistry, Pharmaceutical/education , Chemistry, Pharmaceutical/standards , Drug Therapy/instrumentation , Structure-Activity Relationship , Students/statistics & numerical data , Chemistry, Pharmaceutical/methods , Curriculum/standards , Drug Therapy/methods , Drug Therapy/statistics & numerical data , Humans , Students/psychology , Surveys and Questionnaires
16.
J Pharm Biomed Anal ; 185: 113235, 2020 Jun 05.
Article in English | MEDLINE | ID: mdl-32182447

ABSTRACT

Polysaccharides have broad bioactivities and are major components of water decoction of herb formulae. However, the quality control of polysaccharides remains a challenge. Oligosaccharide-fragment approach has been considered in elucidating chemical structures of polysaccharides, but never been used for quantitation. Using reference chemicals and a real sample Danggui Buxue Tang (DBT) in this study, an oligosaccharide-marker approach was established to quantify specific polysaccharides. Firstly, linear relationships between parent polysaccharides and hydrolysis-produced daughter oligosaccharides were verified using reference polysaccharides. Then in case of DBT, two fluorescence-labeled oligosaccharides with high specificity to individual parent polysaccharides were selected as markers. They were easily isolated and identified. Their potential in quantification of parent polysaccharides were satisfactorily validated in terms of linearity (r≥0.99), repeatability (RSD ≤ 8.4 %), and spike recovery (≥80 %). This method could be a promising approach for quality assessment of polysaccharides in herbal formulae.


Subject(s)
Chemistry, Pharmaceutical/methods , Drugs, Chinese Herbal/analysis , Oligosaccharides/analysis , Quality Control , Chemistry, Pharmaceutical/standards , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Drugs, Chinese Herbal/chemistry , Reference Standards , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization/methods , Spectrometry, Mass, Electrospray Ionization/standards , Tandem Mass Spectrometry/methods , Tandem Mass Spectrometry/standards
17.
PDA J Pharm Sci Technol ; 74(2): 286-288, 2020.
Article in English | MEDLINE | ID: mdl-32179712

ABSTRACT

It is important to identify, assess, and address current barriers to implementation of post-approval changes that are intended to ensure continued (uninterrupted) operations and drive innovation and continual improvement in a maximally efficient, agile, and flexible pharmaceutical manufacturing sector. Leveraging the International Conference for Harmonisation Quality Guideline Q10 provides regulatory relief when it comes to addressing changes related to excipients, specifically excipient supplier's name and address changes, which will ensure a sustainable, reliable global supply and the availability of high quality product to patients through the entire commercial lifecycle of a product without extensive regulatory oversight.


Subject(s)
Chemistry, Pharmaceutical/standards , Drug Industry/standards , Equipment and Supplies Utilization/standards , Excipients/standards , Quality Control , Chemistry, Pharmaceutical/methods , Drug Industry/methods , Humans
19.
PDA J Pharm Sci Technol ; 74(3): 309-317, 2020.
Article in English | MEDLINE | ID: mdl-31941794

ABSTRACT

Eye drops are sterile preparations intended for instillation into the eye. All major pharmacopoeias require these products to pass the antimicrobial effectiveness test (AET). This test is similar to that used for an oral dosage form despite the fact that both product categories differ in their microbiological specifications. The eye drops might pass the official requirements of the AET, but in practice, contaminants introduced into the preparation might not be killed before its next use by the patient and this may compromise ocular health. The objective of this work was to investigate the possible application of a limited sterility testing in a multichallenge test that mimics more closely real life use of eye drops. The AET was performed on 12 brands of eye drops, and results were compared with the suggested pass criteria of various pharmacopoeias. The multichallenge test was designed and used to demonstrate the ability of each tested product to kill the entire challenge organism population within a few hours. The results demonstrated that all products investigated complied with the AET acceptance requirements of the USP <51> and the "B" criteria of the European Pharmacopoeia (Ph Eur) <5.1.3>. Only two of the tested products did not comply with the no recovery term of Ph Eur <5.1.3> "A" criteria. Products repeatedly challenged with Pseudomonas aeruginosa ATCC 9027 (103 CFU/mL) were found to be self-sterilizing within 2 h of each inoculation. In conclusion, all tested products passed the acceptance criteria of the USP <51>, class B of the Ph Eur <5.1.3>, and the multichallenge test. The size of the challenge organism population in the AET seems to be severe for eye drops, and the pass criteria of the British Pharmacopoeia Appendix XVI are the most stringent. The no recovery term given in the Ph Eur <5.1.3> should be defined to a specified range.


Subject(s)
Anti-Infective Agents/standards , Chemistry, Pharmaceutical/standards , Drug Contamination/prevention & control , Ophthalmic Solutions/standards , Pseudomonas aeruginosa/drug effects , Sterilization/standards , Anti-Infective Agents/administration & dosage , Chemistry, Pharmaceutical/methods , Colony Count, Microbial/standards , Humans , Ophthalmic Solutions/administration & dosage , Preservatives, Pharmaceutical/administration & dosage , Pseudomonas aeruginosa/physiology , Sterilization/methods
20.
PDA J Pharm Sci Technol ; 74(1): 108-133, 2020.
Article in English | MEDLINE | ID: mdl-31308065

ABSTRACT

Patients can be exposed to leachables derived from pharmaceutical manufacturing systems, packages, and/or medical devices during a clinical therapy. These leachables can adversely decrease the therapy's effectiveness and/or adversely impact patient safety. Thus, extracts or drug products are chromatographically screened to discover, identify, and quantify organic extractables or leachables. Although screening methods have achieved a high degree of technical and practical sophistication, they are not without issues in terms of accomplishing these three functions. In this Part 2 of our three-part series, errors of inexact identification and inaccurate quantitation are addressed. An error of inexact identification occurs when a screening method fails to produce an analyte response that can be used to secure the analyte's identity. The error may be that the response contains insufficient information to interpret, in which case the analyte cannot be identified or that the interpretation of the response produces an incorrect identity. In either case, proper use of an internal extractables and leachables database can decrease the frequency of encountering unidentifiable analytes and increase the confidence that identities that are secured are correct. Cases of identification errors are provided, illustrating the use of multidimensional analysis to increase confidence in procured identities. An error of inaccurate quantitation occurs when an analyte's concentration is estimated by correlating the responses of the analyte and an internal standard and arises because of response differences between analytes and internal standards. The use of a database containing relative response factors or relative response functions to secure more accurate analyte quantities is discussed and demonstrated.


Subject(s)
Chemistry, Pharmaceutical/standards , Drug Contamination/prevention & control , Pharmaceutical Preparations/analysis , Research Design/standards , Chemistry, Pharmaceutical/methods , Drug Packaging/methods , Drug Packaging/standards , Humans , Pharmaceutical Preparations/chemistry
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