Continuous manufacturing plays a key role in enabling the modernization of pharmaceutical manufac... more Continuous manufacturing plays a key role in enabling the modernization of pharmaceutical manufacturing. The fate of this emerging technology will rely, in large part, on the regulatory implementation of this novel technology. This paper, which is based on the 2nd International Symposium on the Continuous Manufacturing of Pharmaceuticals, describes not only the advances that have taken place since the first International Symposium on Continuous Manufacturing of Pharmaceuticals in 2014, but the regulatory landscape that exists today. Key regulatory concepts including quality risk management, batch definition, control strategy, process monitoring and control, real-time release testing, data processing and management, and process validation/verification are outlined. Support from regulatory agencies, particularly in the form of the harmonization of regulatory expectations, will be crucial to the successful implementation of continuous manufacturing. Collaborative efforts, among academi...
Characterization of currently marketed heparin products: key tests for quality assurance
Analytical and Bioanalytical Chemistry, 2010
Here we report results from the analyses by enzymatic digestion and reversed-phase ion-pairing li... more Here we report results from the analyses by enzymatic digestion and reversed-phase ion-pairing liquid chromatography mass spectrometry (RPIP-LC-MS) of active pharmaceutical ingredient (API) unfractionated heparins (UFHs) from six different manufacturers and one USP standard sample. We employed a reverse phase ion-pairing chromatography method using a C(18) column and hexylamine as the ion-pairing reagent with acetonitrile gradient elution to separate disaccharides generated from the digestion of the heparins by lyase I and III (E.C. 4.2.2.7 and 4.2.2.8) before introduction into an ion-trap mass spectrometer by an electrospray ionization (ESI) interface. Extracted ion chromatograms (EICs) were used to determine the relative abundance of the disaccharides by mass spectrometry. Eight disaccharides were observed and a similar composition profile was observed from digests of 20 UFH samples. The compositional profile determined from these experiments provides a measure of the norm and range of variation in "good" heparin to which future preparations can be compared. Furthermore, the profile obtained in the RPIP-LC-MS assay is sensitive to the presence of the contaminant, oversulfated chondroitin sulfate A (OSCS), in heparin.
AAPS Advances in the Pharmaceutical Sciences Series, 2011
In the past few decades, the development of medicine at the nanoscale has been applied to oral an... more In the past few decades, the development of medicine at the nanoscale has been applied to oral and parenteral dosage forms in a wide range of therapeutic areas to enhance drug delivery and reduce toxicity. An obvious response to these benefits is reflected in higher market shares of complex drug products containing nanomaterials than that of conventional formulations containing the same active ingredient. The surging market interest has encouraged the pharmaceutical industry to develop cost-effective generic versions of complex drug products based on nanotechnology when the associated patent and exclusivity on the reference products have expired. Due to their complex nature, nanotechnology-based drugs present unique challenges in determining equivalence standards between generic and innovator products. This manuscript attempts to provide the scientific rationales and regulatory considerations of key equivalence standards (e.g., in vivo studies and in vitro physicochemical characterization) for oral drugs containing nanomaterials, iron-carbohydrate complexes, liposomes, protein-bound drugs, nanotube-forming drugs, and nano emulsions. It also presents active research studies in bridging regulatory and scientific gaps for establishing equivalence of complex products containing nanomaterials. We hope that open communication among industry, academia, and regulatory agencies will accelerate the development and approval processes of generic complex products based on nanotechnology.
This article describes the U.S. Food and Drug Administration (FDA) methods validation program for... more This article describes the U.S. Food and Drug Administration (FDA) methods validation program for proposed regulatory methods submitted through the New and Abbreviated New Drug Application processes. The program is conducted by the Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs to ensure that scientifically well-founded regulatory methods are available to assess the quality of the CDER-approved products. The industry, FDA, and United States Pharmacopeia and National Formulary have the common objective of ensuring that drugs in the U.S. marketplace have consistent standards for drug substances and drug product regardless of the synthesis and manufacturing process. This may be accomplished by assuring that the analytical methods for new drug products are submitted for adoption as public standards soon after approval for marketing. The public standard provides a yard-stick for the named product which allows conscientious practitioners and consumers ...
CMC Considerations when a Drug Development Project is Assigned Breakthrough Therapy Status
A ssignment of Breakthrough Therapy (BT) designation could lead to accelerated clinical programs,... more A ssignment of Breakthrough Therapy (BT) designation could lead to accelerated clinical programs, which could be two or more years less than a “conventional” development program. Potential accelerated clinical development timelines could lead to insufficient time to complete all “traditional” CMC studies for approval and delivery to the patient within the boundaries of completing the clinical development program, for example:
Recently, certain lots of heparin have been associated with an acute, rapid onset of serious side... more Recently, certain lots of heparin have been associated with an acute, rapid onset of serious side effects indicative of an allergic-type reaction. To identify potential causes for this sudden rise in side effects, we examined lots of heparin that correlated with adverse events using orthogonal high-resolution analytical techniques. Through detailed structural analysis, the contaminant was found to contain a disaccharide repeat unit of glucuronic acid linked β1→3 to a β-N-acetylgalactosamine. The disaccharide unit has an unusual sulfation pattern and is sulfated at the 2-O and 3-O positions of the glucuronic acid as well as at the 4-O and 6-O positions of the galactosamine. Given the nature of this contaminant, traditional screening tests cannot differentiate between affected and unaffected lots. Our analysis suggests effective screening methods that can be used to determine whether or not heparin lots contain the contaminant reported here.
High Performance Liquid Chromatographic Assay of Erythromycin Salts and Esters in Bulk and Pharmaceutical Dosage Forms
Journal of Liquid Chromatography & Related Technologies, 1998
Recently, several liquid chromatographic methods for the assay of erythromycin base were develope... more Recently, several liquid chromatographic methods for the assay of erythromycin base were developed and are being considered for the routine assay of erythromycin. In this study, we developed simple and rugged liquid chromatographic methods for the assay of erythromycin salts and esters, and used these methods for the assay of erythromycin estolate, erythromycin ethylsuccinate, erythromycin stearate, erythromycin gluceptate, and erythromycin lactobionate in bulk and pharmaceutical formulations. The HPLC methods proved to be simple, sensitive, versatile, and rugged. The developed methods provide an attractive alternative to current official microbiological methods. The HPLC assay results for all commercial erythromycin products tested comply with the USP Antibiotics-Microbial assay specification.
Heparin, a widely used anticoagulant primarily extracted from animal sources, contains varying am... more Heparin, a widely used anticoagulant primarily extracted from animal sources, contains varying amounts of galactosamine impurities. Currently, the United States Pharmacopeia (USP) monograph for heparin purity specifies that the weight percent of galactosamine (%Gal) may not exceed 1%. In the present study, multivariate regression (MVR) analysis of 1 H NMR spectral data obtained from heparin samples was employed to build quantitative models for the prediction of %Gal. MVR analysis was conducted using four separate methods: multiple linear regression, ridge regression, partial least squares regression, and support vector regression (SVR). Genetic algorithms and stepwise selection methods were applied for variable selection. In each case, two separate prediction models were constructed: a global model based on dataset A which contained the full range (0-10%) of galactosamine in the samples and a local model based on the subset dataset B for which the galactosamine level (0-2%) spanned the 1% USP limit. All four regression methods performed equally well for dataset A with low prediction errors under optimal conditions, whereas SVR was clearly superior among the four methods for dataset B. The results from this study show that 1 H NMR spectroscopy, already a USP requirement for the screening of contaminants in heparin, may offer utility as a rapid method for quantitative determination of %Gal in heparin samples when used in conjunction with MVR approaches.
Chemometric analysis of a set of one-dimensional (1D) 1 H nuclear magnetic resonance (NMR) spectr... more Chemometric analysis of a set of one-dimensional (1D) 1 H nuclear magnetic resonance (NMR) spectral data for heparin sodium active pharmaceutical ingredient (API) samples was employed to distinguish USP-grade heparin samples from those containing oversulfated chondroitin sulfate (OSCS) contaminant and/or unacceptable levels of dermatan sulfate (DS) impurity. Three chemometric pattern recognition approaches were implemented: classification and regression tree (CART), artificial neural network (ANN), and support vector machine (SVM). Heparin sodium samples from various manufacturers were analyzed in 2008 and 2009 by 1D 1 H NMR, strong anion-exchange high-performance liquid chromatography, and percent galactosamine in total hexosamine tests. Based on these data, the samples were divided into three groups: Heparin, DS≤1.0% and OSCS= 0%; DS, DS>1.0% and OSCS=0%; and OSCS, OSCS>0% with any content of DS. Three data sets corresponding to different chemical shift regions (1.95-2.20, 3.10-5.70, and 1.95-5.70 ppm) were evaluated. While all three chemometric approaches were able to effectively model the data in the 1.95-2.20 ppm region, SVM was found to substantially outperform CART and ANN for data in the 3.10-5.70 ppm region in terms of classification success rate. A 100% prediction rate was frequently achieved for discrimination between heparin and OSCS samples. The majority of classification errors between heparin and DS involved cases where the DS content was close to the 1.0% DS borderline between the two classes. When these borderline samples were removed, nearly perfect classification results were attained. Satisfactory results were achieved when the resulting models were challenged by test samples containing blends of heparin APIs spiked with non-, partially, or fully oversulfated chondroitin sulfate A, heparan sulfate, or DS at the 1.0%, 5.0%, and 10.0% (w/w) levels. This study demonstrated that the combination of 1D 1 H NMR spectroscopy with multivariate chemometric methods is a nonsubjective, statistics-based approach for heparin quality control and purity assessment that, once standardized, minimizes the need for expert analysts. Keywords Heparin . Proton nuclear magnetic resonance ( 1 H NMR) . Pattern recognition . Classification and regression tree (CART) . Artificial neural network (ANN) . FDA disclaimer The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.
Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture
A model is a representation of an underlying physical-chemical phenomenon. In the pharmaceutical ... more A model is a representation of an underlying physical-chemical phenomenon. In the pharmaceutical industry, mathematical-based models can be applied at all stages of development, starting with formulation design, continuing through process development and scale-up, and extending into process monitoring and control of the commercial process. Implementation of models offers many benefits. These include, but are not limited to, (i) enhanced process understanding, (ii) reduction of experimentation cost, and (iii) improvement of productivity and product quality. 2.2 Overview of Models Models can be broadly categorized as either qualitative or quantitative. The focus of this chapter is quantitative models. These can be classified into three broad areas: mechanistic, empirical, and hybrid. As illustrated in the knowledge pyramid in Figure 2.1, overall understanding and the information needed to derive from these models increases from empirical to mechanistic models. Mechanistic models are based on first principles, capture the underlying physical/chemical phenomena through sets of equations, and can be time independent (i.e., steady-state) or dynamic. As indicated by Singh et al. [1], mechanistic models can be an excellent way to represent process knowledge. In such models, the input-output dynamics in a unit operation can be represented by a set of differential equations. Model building necessitates the
Effect of formulation factors on the observed bounce in cascade impactors used to measure the spray particle size of metered dose inhalers
International Journal of Pharmaceutics, 1998
... a, Nephele Enterprises, 12746 Ethan Avenue North, White Bear Lake, MN 55110, USA. b, Inhalati... more ... a, Nephele Enterprises, 12746 Ethan Avenue North, White Bear Lake, MN 55110, USA. b, Inhalation Drug Delivery Laboratory, 3M Pharmaceuticals, St. Paul, MN, USA. c, US Food and Drug Administration, CDER, Division of Testing ...
Continuous manufacturing plays a key role in enabling the modernization of pharmaceutical manufac... more Continuous manufacturing plays a key role in enabling the modernization of pharmaceutical manufacturing. The fate of this emerging technology will rely, in large part, on the regulatory implementation of this novel technology. This paper, which is based on the 2nd International Symposium on the Continuous Manufacturing of Pharmaceuticals, describes not only the advances that have taken place since the first International Symposium on Continuous Manufacturing of Pharmaceuticals in 2014, but the regulatory landscape that exists today. Key regulatory concepts including quality risk management, batch definition, control strategy, process monitoring and control, real-time release testing, data processing and management, and process validation/verification are outlined. Support from regulatory agencies, particularly in the form of the harmonization of regulatory expectations, will be crucial to the successful implementation of continuous manufacturing. Collaborative efforts, among academi...
Characterization of currently marketed heparin products: key tests for quality assurance
Analytical and Bioanalytical Chemistry, 2010
Here we report results from the analyses by enzymatic digestion and reversed-phase ion-pairing li... more Here we report results from the analyses by enzymatic digestion and reversed-phase ion-pairing liquid chromatography mass spectrometry (RPIP-LC-MS) of active pharmaceutical ingredient (API) unfractionated heparins (UFHs) from six different manufacturers and one USP standard sample. We employed a reverse phase ion-pairing chromatography method using a C(18) column and hexylamine as the ion-pairing reagent with acetonitrile gradient elution to separate disaccharides generated from the digestion of the heparins by lyase I and III (E.C. 4.2.2.7 and 4.2.2.8) before introduction into an ion-trap mass spectrometer by an electrospray ionization (ESI) interface. Extracted ion chromatograms (EICs) were used to determine the relative abundance of the disaccharides by mass spectrometry. Eight disaccharides were observed and a similar composition profile was observed from digests of 20 UFH samples. The compositional profile determined from these experiments provides a measure of the norm and range of variation in "good" heparin to which future preparations can be compared. Furthermore, the profile obtained in the RPIP-LC-MS assay is sensitive to the presence of the contaminant, oversulfated chondroitin sulfate A (OSCS), in heparin.
AAPS Advances in the Pharmaceutical Sciences Series, 2011
In the past few decades, the development of medicine at the nanoscale has been applied to oral an... more In the past few decades, the development of medicine at the nanoscale has been applied to oral and parenteral dosage forms in a wide range of therapeutic areas to enhance drug delivery and reduce toxicity. An obvious response to these benefits is reflected in higher market shares of complex drug products containing nanomaterials than that of conventional formulations containing the same active ingredient. The surging market interest has encouraged the pharmaceutical industry to develop cost-effective generic versions of complex drug products based on nanotechnology when the associated patent and exclusivity on the reference products have expired. Due to their complex nature, nanotechnology-based drugs present unique challenges in determining equivalence standards between generic and innovator products. This manuscript attempts to provide the scientific rationales and regulatory considerations of key equivalence standards (e.g., in vivo studies and in vitro physicochemical characterization) for oral drugs containing nanomaterials, iron-carbohydrate complexes, liposomes, protein-bound drugs, nanotube-forming drugs, and nano emulsions. It also presents active research studies in bridging regulatory and scientific gaps for establishing equivalence of complex products containing nanomaterials. We hope that open communication among industry, academia, and regulatory agencies will accelerate the development and approval processes of generic complex products based on nanotechnology.
This article describes the U.S. Food and Drug Administration (FDA) methods validation program for... more This article describes the U.S. Food and Drug Administration (FDA) methods validation program for proposed regulatory methods submitted through the New and Abbreviated New Drug Application processes. The program is conducted by the Center for Drug Evaluation and Research (CDER) and the Office of Regulatory Affairs to ensure that scientifically well-founded regulatory methods are available to assess the quality of the CDER-approved products. The industry, FDA, and United States Pharmacopeia and National Formulary have the common objective of ensuring that drugs in the U.S. marketplace have consistent standards for drug substances and drug product regardless of the synthesis and manufacturing process. This may be accomplished by assuring that the analytical methods for new drug products are submitted for adoption as public standards soon after approval for marketing. The public standard provides a yard-stick for the named product which allows conscientious practitioners and consumers ...
CMC Considerations when a Drug Development Project is Assigned Breakthrough Therapy Status
A ssignment of Breakthrough Therapy (BT) designation could lead to accelerated clinical programs,... more A ssignment of Breakthrough Therapy (BT) designation could lead to accelerated clinical programs, which could be two or more years less than a “conventional” development program. Potential accelerated clinical development timelines could lead to insufficient time to complete all “traditional” CMC studies for approval and delivery to the patient within the boundaries of completing the clinical development program, for example:
Recently, certain lots of heparin have been associated with an acute, rapid onset of serious side... more Recently, certain lots of heparin have been associated with an acute, rapid onset of serious side effects indicative of an allergic-type reaction. To identify potential causes for this sudden rise in side effects, we examined lots of heparin that correlated with adverse events using orthogonal high-resolution analytical techniques. Through detailed structural analysis, the contaminant was found to contain a disaccharide repeat unit of glucuronic acid linked β1→3 to a β-N-acetylgalactosamine. The disaccharide unit has an unusual sulfation pattern and is sulfated at the 2-O and 3-O positions of the glucuronic acid as well as at the 4-O and 6-O positions of the galactosamine. Given the nature of this contaminant, traditional screening tests cannot differentiate between affected and unaffected lots. Our analysis suggests effective screening methods that can be used to determine whether or not heparin lots contain the contaminant reported here.
High Performance Liquid Chromatographic Assay of Erythromycin Salts and Esters in Bulk and Pharmaceutical Dosage Forms
Journal of Liquid Chromatography & Related Technologies, 1998
Recently, several liquid chromatographic methods for the assay of erythromycin base were develope... more Recently, several liquid chromatographic methods for the assay of erythromycin base were developed and are being considered for the routine assay of erythromycin. In this study, we developed simple and rugged liquid chromatographic methods for the assay of erythromycin salts and esters, and used these methods for the assay of erythromycin estolate, erythromycin ethylsuccinate, erythromycin stearate, erythromycin gluceptate, and erythromycin lactobionate in bulk and pharmaceutical formulations. The HPLC methods proved to be simple, sensitive, versatile, and rugged. The developed methods provide an attractive alternative to current official microbiological methods. The HPLC assay results for all commercial erythromycin products tested comply with the USP Antibiotics-Microbial assay specification.
Heparin, a widely used anticoagulant primarily extracted from animal sources, contains varying am... more Heparin, a widely used anticoagulant primarily extracted from animal sources, contains varying amounts of galactosamine impurities. Currently, the United States Pharmacopeia (USP) monograph for heparin purity specifies that the weight percent of galactosamine (%Gal) may not exceed 1%. In the present study, multivariate regression (MVR) analysis of 1 H NMR spectral data obtained from heparin samples was employed to build quantitative models for the prediction of %Gal. MVR analysis was conducted using four separate methods: multiple linear regression, ridge regression, partial least squares regression, and support vector regression (SVR). Genetic algorithms and stepwise selection methods were applied for variable selection. In each case, two separate prediction models were constructed: a global model based on dataset A which contained the full range (0-10%) of galactosamine in the samples and a local model based on the subset dataset B for which the galactosamine level (0-2%) spanned the 1% USP limit. All four regression methods performed equally well for dataset A with low prediction errors under optimal conditions, whereas SVR was clearly superior among the four methods for dataset B. The results from this study show that 1 H NMR spectroscopy, already a USP requirement for the screening of contaminants in heparin, may offer utility as a rapid method for quantitative determination of %Gal in heparin samples when used in conjunction with MVR approaches.
Chemometric analysis of a set of one-dimensional (1D) 1 H nuclear magnetic resonance (NMR) spectr... more Chemometric analysis of a set of one-dimensional (1D) 1 H nuclear magnetic resonance (NMR) spectral data for heparin sodium active pharmaceutical ingredient (API) samples was employed to distinguish USP-grade heparin samples from those containing oversulfated chondroitin sulfate (OSCS) contaminant and/or unacceptable levels of dermatan sulfate (DS) impurity. Three chemometric pattern recognition approaches were implemented: classification and regression tree (CART), artificial neural network (ANN), and support vector machine (SVM). Heparin sodium samples from various manufacturers were analyzed in 2008 and 2009 by 1D 1 H NMR, strong anion-exchange high-performance liquid chromatography, and percent galactosamine in total hexosamine tests. Based on these data, the samples were divided into three groups: Heparin, DS≤1.0% and OSCS= 0%; DS, DS>1.0% and OSCS=0%; and OSCS, OSCS>0% with any content of DS. Three data sets corresponding to different chemical shift regions (1.95-2.20, 3.10-5.70, and 1.95-5.70 ppm) were evaluated. While all three chemometric approaches were able to effectively model the data in the 1.95-2.20 ppm region, SVM was found to substantially outperform CART and ANN for data in the 3.10-5.70 ppm region in terms of classification success rate. A 100% prediction rate was frequently achieved for discrimination between heparin and OSCS samples. The majority of classification errors between heparin and DS involved cases where the DS content was close to the 1.0% DS borderline between the two classes. When these borderline samples were removed, nearly perfect classification results were attained. Satisfactory results were achieved when the resulting models were challenged by test samples containing blends of heparin APIs spiked with non-, partially, or fully oversulfated chondroitin sulfate A, heparan sulfate, or DS at the 1.0%, 5.0%, and 10.0% (w/w) levels. This study demonstrated that the combination of 1D 1 H NMR spectroscopy with multivariate chemometric methods is a nonsubjective, statistics-based approach for heparin quality control and purity assessment that, once standardized, minimizes the need for expert analysts. Keywords Heparin . Proton nuclear magnetic resonance ( 1 H NMR) . Pattern recognition . Classification and regression tree (CART) . Artificial neural network (ANN) . FDA disclaimer The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.
Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture
A model is a representation of an underlying physical-chemical phenomenon. In the pharmaceutical ... more A model is a representation of an underlying physical-chemical phenomenon. In the pharmaceutical industry, mathematical-based models can be applied at all stages of development, starting with formulation design, continuing through process development and scale-up, and extending into process monitoring and control of the commercial process. Implementation of models offers many benefits. These include, but are not limited to, (i) enhanced process understanding, (ii) reduction of experimentation cost, and (iii) improvement of productivity and product quality. 2.2 Overview of Models Models can be broadly categorized as either qualitative or quantitative. The focus of this chapter is quantitative models. These can be classified into three broad areas: mechanistic, empirical, and hybrid. As illustrated in the knowledge pyramid in Figure 2.1, overall understanding and the information needed to derive from these models increases from empirical to mechanistic models. Mechanistic models are based on first principles, capture the underlying physical/chemical phenomena through sets of equations, and can be time independent (i.e., steady-state) or dynamic. As indicated by Singh et al. [1], mechanistic models can be an excellent way to represent process knowledge. In such models, the input-output dynamics in a unit operation can be represented by a set of differential equations. Model building necessitates the
Effect of formulation factors on the observed bounce in cascade impactors used to measure the spray particle size of metered dose inhalers
International Journal of Pharmaceutics, 1998
... a, Nephele Enterprises, 12746 Ethan Avenue North, White Bear Lake, MN 55110, USA. b, Inhalati... more ... a, Nephele Enterprises, 12746 Ethan Avenue North, White Bear Lake, MN 55110, USA. b, Inhalation Drug Delivery Laboratory, 3M Pharmaceuticals, St. Paul, MN, USA. c, US Food and Drug Administration, CDER, Division of Testing ...
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