Product Critical Quality Research Articles

Review on graphene and its derivatives: Synthesis methods and potential industrial implementation

Graphene and its derivatives have gained significant attention of late due to their remarkable physicochemical properties. This review focuses firstly on the synthesis methods of graphene and its derivatives along with their attributes and characterization techniques. This is followed by a discussion of the potential industrial implementation of the synthesis routes. The potential industrial implementation of the graphene synthesis methods are reviewed using the key criteria of cost, process condition, yield, scalability, product quality and environmental impact. The literature data supported that synthesis routes such as oxidative exfoliation-reduction, liquid-phase exfoliation and chemical vapor deposition have the potential to be commercialized due to their ability to produce large amount of high quality graphene. Further development is necessary to overcome barriers such as environmental concerns and the high graphene cost.

Accurate and Rapid Protein Concentration Measurement of In-Process, High Concentration Protein Pools.

Protein concentration is a critical product quality attribute and required for any therapeutic protein. Many commercial and investigational new biologics are now formulated at high concentrations (>100 mg/ml) to achieve successful subcutaneous administration. Assaying protein concentration in high concentration formulations poses a challenge, as traditional absorption spectroscopy and UPLC/HPLC (ultra/high performance liquid chromatography) assays cannot accurately measure such high concentrations without further solution manipulation. However, recent advances in UV/vis technology have led to the creation of instruments that measure samples at relatively short (<1 cm) path lengths, which would allow them to accurately measure high concentration protein samples in accordance with Beer Lambert Law principles. In this research, samples of five different proteins at concentrations ranging from 0.15 to 242 mg/ml (corresponding to OD280 vales of 0.15-315 AU) were measured on two different instruments employing different techniques of low path length UV/vis measurements. In order for the techniques to meet MSD's acceptance criteria for release assays, measurements were required to be accurate to within 10% of a reference measurement (performed on a traditional UV/vis spectrophotometer) and to be precise within 5% CV. The results show that using a technique known as slope spectroscopy, it is possible to measure OD280 from 0.5 to 315 AU with <7% error relative to the reference measurement. If instead measurements are taken using an instrument utilizing a single, small path length, it is possible to measure absorbances from 0.2 to ~75 AU with <7% error. This article concludes that the slope spectroscopy technique performed within the acceptance criteria across the full range of measured absorbances and that the single, short path length measurement performed within the acceptance criteria up to 75 AU.

Differential gene expression of a feed-spiked super-producing CHO cell line

Feed supplements are concentrated cell culture media that contain a variety of nutrients, which can be added during a bioprocess. During fed-batch cultivation, feed media are typically added to a growing cell culture to maximize cell and product concentrations. In this study, only a single shot of feed medium was added on day 0 to a basal cell culture medium and compared to non-supplemented basal medium (feed-spiked at day 0 versus control experiments) by cultivation of a recombinant mAb expressing CHO cell line in batch mode under controlled conditions in a bioreactor. Since the feed-spike at day 0 was based on existing medium components without introducing additional supplements, a desirable process with decreased complexity was generated. Unlike cells in basal medium, feed-spiked cultures reached almost 2× higher peak cell concentrations (10 × 106 c/mL vs. 18 × 106 c/mL) and 3× higher antibody concentrations (0.8 g/L vs. 2.4 g/L). Batch process time and the integral over the viable cell count were similar for both process types. Constantly high cell-specific production rates in feed-spiked cultures (70 pg/cell/day) compared to continuously declining rates in basal medium (from 70 to 10 pg/cell/day) were responsible for an overall 70% higher cell-specific production rate and the higher product concentrations. To associate gene expression patterns to different process proceedings, transcriptome analysis was performed using microarrays. Several transcripts that are involved with glutamine de novo synthesis and citric acid cycle were significantly upregulated on several days in feed-spiked cultures. The top identified gene ontology (GO) terms related well to cell cycle and primary metabolism, cellular division as well as nucleobase formation or regulation, which indicated a more active proliferative state for feed-spiked cultures. KEGG biochemical pathway analysis and Gene set enrichment analysis (GSEA) further confirmed these findings from a complementary perspective. Moreover, several interesting gene targets, which have not yet been associated with recombinant protein expression, were identified that related to a higher proliferative state, growth, protein synthesis, cell-size control, metabolism, cell survival as well as genes that are associated with the control of the mammalian target of rapamycin (mTOR) in feed-spiked cultures. Analysis of critical product quality attributes (i.e. glycosylation, charge variants and size distribution) showed that feed-spiking did not change antibody quality.

A Workflow-Based Framework for Curating Product Analytical Data and Statistical Results for Lot Release

Purpose Demonstrate the use of a knowledge management and data curation (KProMS) system to support a collaborative research project involving the generation of extensive critical product quality data and the investigation of alternative statistical sampling/analysis strategies for product release.

Quality-by-design approach for the development of telmisartan potassium tablets

A quality-by-design approach was adopted to develop telmisartan potassium (TP) tablets, which were bioequivalent with the commercially available Micardis® (telmisartan free base) tablets. The dissolution pattern and impurity profile of TP tablets differed from those of Micardis® tablets because telmisartan free base is poorly soluble in water. After identifying the quality target product profile and critical quality attributes (CQAs), drug dissolution, and impurities were predicted to be risky CQAs. To determine the exact range and cause of risks, we used the risk assessment (RA) tools, preliminary hazard analysis and failure mode and effect analysis to determine the parameters affecting drug dissolution, impurities, and formulation. The range of the design space was optimized using the face-centered central composite design among the design of experiment (DOE) methods. The binder, disintegrant, and kneading time in the wet granulation were identified as X values affecting Y values (disintegration, hardness, friability, dissolution, and impurities). After determining the design space with the desired Y values, the TP tablets were formulated and their dissolution pattern was compared with that of the reference tablet. The selected TP tablet formulated using design space showed a similar dissolution to that of Micardis® tablets at pH 7.5. The QbD approach TP tablet was bioequivalent to Micardis® tablets in beagle dogs.

Quality by design approach in the development of an ultra-high-performance liquid chromatography method for Bexsero meningococcal group B vaccine

Bexsero is the first approved vaccine for active immunization of individuals from 2 months of age and older to prevent invasive disease caused by Neisseria meningitidis serogroup B. The active components of the vaccine are Neisseria Heparin Binding Antigen, factor H binding protein, Neisseria adhesin A, produced in Escherichia coli cells by recombinant DNA technology, and Outer Membrane Vesicles (expressing Porin A and Porin B), produced by fermentation of Neisseria meningitidis strain NZ98/254. All the Bexsero active components are adsorbed on aluminum hydroxide and the unadsorbed antigens content is a product critical quality attribute. In this paper the development of a fast, selective and sensitive ultra-high-performance liquid chromatography (UHPLC) method for the determination of the Bexsero antigens in the vaccine supernatant is presented. For the first time in the literature, the Quality by Design (QbD) principles were applied to the development of an analytical method aimed to the quality control of a vaccine product. The UHPLC method was fully developed within the QbD framework, the new paradigm of quality outlined in International Conference on Harmonisation guidelines. Critical method attributes (CMAs) were identified with the capacity factor of Neisseria Heparin Binding Antigen, antigens resolution and peak areas. After a scouting phase, aimed at selecting a suitable and fast UHPLC operative mode for the vaccine antigens separation, risk assessment tools were employed to define the critical method parameters to be considered in the screening phase. Screening designs were applied for investigating at first the effects of vial type and sample concentration, and then the effects of injection volume, column type, organic phase starting concentration, ramp time and temperature. Response Surface Methodology pointed out the presence of several significant interaction effects, and with the support of Monte-Carlo simulations led to map out the design space, at a selected probability level, for the desired CMAs. The selected working conditions gave a complete separation of the antigens in about 5min. Robustness testing was carried out by a multivariate approach and a control strategy was implemented by defining system suitability tests. The method was qualified for the analysis of the Bexsero vaccine.

QbD for pediatric oral lyophilisates development: risk assessment followed by screening and optimization

Objective: This study proposed the development of oral lyophilisates with respect to pediatric medicine development guidelines, by applying risk management strategies and DoE as an integrated QbD approach.Methods: Product critical quality attributes were overviewed by generating Ishikawa diagrams for risk assessment purposes, considering process, formulation and methodology related parameters. Failure Mode Effect Analysis was applied to highlight critical formulation and process parameters with an increased probability of occurrence and with a high impact on the product performance. To investigate the effect of qualitative and quantitative formulation variables D-optimal designs were used for screening and optimization purposes.Results: Process parameters related to suspension preparation and lyophilization were classified as significant factors, and were controlled by implementing risk mitigation strategies. Both quantitative and qualitative formulation variables introduced in the experimental design influenced the product’s disintegration time, mechanical resistance and dissolution properties selected as CQAs. The optimum formulation selected through Design Space presented ultra-fast disintegration time (5 seconds), a good dissolution rate (above 90%) combined with a high mechanical resistance (above 600 g load).Conclusions: Combining FMEA and DoE allowed the science based development of a product with respect to the defined quality target profile by providing better insights on the relevant parameters throughout development process. The utility of risk management tools in pharmaceutical development was demonstrated.

Modulation and modeling of monoclonal antibody N-linked glycosylation in mammalian cell perfusion reactors.

Mammalian cell perfusion cultures are gaining renewed interest as an alternative to traditional fed-batch processes for the production of therapeutic proteins, such as monoclonal antibodies (mAb). The steady state operation at high viable cell density allows the continuous delivery of antibody product with increased space-time yield and reduced in-process variability of critical product quality attributes (CQA). In particular, the production of a confined mAb N-linked glycosylation pattern has the potential to increase therapeutic efficacy and bioactivity. In this study, we show that accurate control of flow rates, media composition and cell density of a Chinese hamster ovary (CHO) cell perfusion bioreactor allowed the production of a constant glycosylation profile for over 20 days. Steady state was reached after an initial transition phase of 6 days required for the stabilization of extra- and intracellular processes. The possibility to modulate the glycosylation profile was further investigated in a Design of Experiment (DoE), at different viable cell density and media supplement concentrations. This strategy was implemented in a sequential screening approach, where various steady states were achieved sequentially during one culture. It was found that, whereas high ammonia levels reached at high viable cell densities (VCD) values inhibited the processing to complex glycan structures, the supplementation of either galactose, or manganese as well as their synergy significantly increased the proportion of complex forms. The obtained experimental data set was used to compare the reliability of a statistical response surface model (RSM) to a mechanistic model of N-linked glycosylation. The latter outperformed the response surface predictions with respect to its capability and reliability in predicting the system behavior (i.e., glycosylation pattern) outside the experimental space covered by the DoE design used for the model parameter estimation. Therefore, we can conclude that the modulation of glycosylation in a sequential steady state approach in combination with mechanistic model represents an efficient and rational strategy to develop continuous processes with desired N-linked glycosylation patterns. Biotechnol. Bioeng. 2017;114: 1978-1990. © 2017 Wiley Periodicals, Inc.

Questions and Challenges in the Development of Mesenchymal Stromal/Stem Cell-Based Therapies in Veterinary Medicine.

The therapeutic potential of stem cells has fascinated those interested in treating diseases in both human and animal subjects. Although the exact mechanism of action and the definitive effectiveness of stem cell therapies remain unclear, animal owner perceptions and a desire for improved treatment options have fueled the interest of clinicians and stakeholders. Standards do not yet exist to define the critical attributes of mesenchymal stem/stromal cell (MSC)-based products derived from veterinary species such as the dog, cat, and horse. This has led veterinary stakeholders to adopt those guidelines and criteria set forth for human MSC-based products; however, these criteria are not always applicable to MSCs from dogs, cats, and horses (e.g., variability in species-specific cell surface marker expression and antibody cross reactivity). Establishing useful standards and meaningful product quality criteria as well as the understanding of full spectrum of MSC functions and preclinical evidence for safety and therapeutic efficacy for veterinary (companion and recreational animals) MSC-based-products will be critical to furthering product development, and may ultimately facilitate the availability of FDA-approved MSC-based products for use in veterinary medicine.

A variation risk management methodology for an interactive pharmaceutical design and manufacturing environment

The pharmaceutical manufacturing field is one of the most challenging fields due to stringent regulations, global harmonization and tough competition. It has been realized that quality, safety and efficacy of pharmaceutical drug products are key elements for success in market. However, improving quality requires better understanding of the product and process critical quality attributes (CQAs). The utmost goal is to build quality upfront during early design stages by implementing guidelines such as quality by design which focuses on targeting design quality into the ingredients, formulation and manufacturing process to deliver the intended performance of the drug product. Achieving such goal is possible by integrating important tools and functions in one interactive usable model. One significant opportunity has been found in the effective utilization of data gathered during different activities such as sampling and testing of pharmaceutical ingredients and products. Extracting patterns of interest of such data can be essential in targeting problems such as variation initiation and variation propagation. Variations are those unwanted deviations from nominal values which greatly impact the final quality and efficacy of products. Manufacturers face some challenges due to lack of quantitative models to prioritize CQAs and quantify their associated risk of variation. Therefore, there is a need for proactive quantitative mechanisms usable during the early design stages to reduce design’s sensitivity to manufacturing variations. The work here introduces a systematic interactive environment that integrates together the design model and the current process capabilities to capture the impact of manufacturing variations on top performance function. A case study on tablet’s crushing strength, expressed by tablet’s tensile strength, has been carried out successfully to prove the effectiveness of the proposed methodology in identifying design’s CQAs and assessing their risk of variation. Moreover, it introduces the mechanism for a quantitative ongoing monitoring of the risk of variation and decision making regarding manufacturers selection.

The influence of direct compression powder blend transfer method from the container to the tablet press on product critical quality attributes: a case study

Objective: The aim of this article is to compare the gravitational powder blend loading method to the tablet press and manual loading in terms of their influence on tablets’ critical quality attributes (CQA).Significance: The results of the study can be of practical relevance to the pharmaceutical industry in the area of direct compression of low-dose formulations, which could be prone to content uniformity (CU) issues.Methods: In the preliminary study, particle size distribution (PSD) and surface energy of raw materials were determined using laser diffraction method and inverse gas chromatography, respectively. For trials purpose, a formulation containing two pharmaceutical ingredients (APIs) was used. Tablet samples were collected during the compression progress to analyze their CQAs, namely assay and CU.Results: Results obtained during trials indicate that tested direct compression powder blend is sensitive to applied powder handling method. Mild increase in both APIs content was observed during manual scooping. Gravitational approach (based on discharge into the drum) resulted in a decrease in CU, which is connected to a more pronounced assay increase at the end of tableting than in the case of manual loading.Conclusions: The correct design of blend transfer over single unit processes is an important issue and should be investigated during the development phase since it may influence the final product CQAs. The manual scooping method, although simplistic, can be a temporary solution to improve the results of API’s content and uniformity when compared to industrial gravitational transfer.

Inhalable Ipratropium Bromide Particle Engineering with Multicriteria Optimization.

Spray-dried ipratropium bromide (IPB) microspheres for oral inhalation were engineered using Quality by Design. The interrogation of material properties, process parameters, and critical product quality attributes interplay enabled rational product design. A 27-3 screening design exhibited the Maillard reaction between L-leucine (LL) and lactose at studied outlet temperatures (OT) >130°C. A response surface custom design was used in conjunction with multicriteria optimization to determine the operating design space to achieve inhalable microparticles. Statistically significant predictive models were developed for volume median diameter (p = 0.0001, adjusted R 2 = 0.9938), span (p = 0.0278, adjusted R 2 = 0.7912), yield (p = 0.0020, adjusted R 2 = 0.9320), and OT (p = 0.0082, adjusted R 2 = 0.8768). An independent verification batch confirmed the model's predictive capability. The prediction and actual values were in good agreement. Particle size and span were 3.32 ± 0.09μm and 1.71 ± 0.18, which were 4.7 and 5.3% higher than the predicted values. The process yield was 50.3%, compared to the predicted value of 65.3%. The OT was 100°C versus the predicted value of 105°C. The label strength of IPB microparticles was 99.0 to 105.9% w/w suggesting that enrichment occurred during the spray-drying process. The present study can be utilized to initiate the design of the first commercial IPB dry powder inhaler.

Investigation of the interactions of critical scale-up parameters (pH, pO2 and pCO2) on CHO batch performance and critical quality attributes

Understanding process parameter interactions and their effects on mammalian cell cultivations is an essential requirement for robust process scale-up. Furthermore, knowledge of the relationship between the process parameters and the product critical quality attributes (CQAs) is necessary to satisfy quality by design guidelines. So far, mainly the effect of single parameters on CQAs was investigated. Here, we present a comprehensive study to investigate the interactions of scale-up relevant parameters as pH, pO2 and pCO2 on CHO cell physiology, process performance and CQAs, which was based on design of experiments and extended product quality analytics. The study used a novel control strategy in which process parameters were decoupled from each other, and thus allowed their individual control at defined set points. Besides having identified the impact of single parameters on process performance and product quality, further significant interaction effects of process parameters on specific cell growth, specific productivity and amino acid metabolism could be derived using this method. Concerning single parameter effects, several monoclonal antibody (mAb) charge variants were affected by process pCO2 and pH. N-glycosylation analysis showed positive correlations between mAb sialylation and high pH values as well as a relationship between high mannose variants and process pH. This study additionally revealed several interaction effects as process pH and pCO2 interactions on mAb charge variants and N-glycosylation pattern. Hence, through our process control strategy and multivariate investigation, novel significant process parameter interactions and single effects were identified which have to be taken into account especially for process scale-up.

Outlining critical quality attributes (CQAs) as guidance for the development of orodispersible films

Context: Orodispersible films have gained increasing relevance as a novel dosage form. Associated to their particular processing and multicomponent composition, there are a vast number of reasons to establish helpful development guidance, gathering simultaneously the recent pharmaceutical regulatory trends.Objective: This study aimed characterize marketed orodispersible films in order to provide essential information about a clear definition of product critical quality attributes (CQAs).Materials and methods: Several commercial orodispersible films were evaluated in terms of thickness, residual water content, disintegration time and mechanical and thermal properties.Results: The orodispersible films exhibit a broad range of thickness [40–140 μm], probably associated with the height gap used on the cast of orodispersible films production. The majority of orodispersible films dissolved within [32–105s]. In general, a broad range of values were found for all the properties studied, residual water content [2.91–9.75%], Young’s Modulus [51.25–1827 Mpa], tensile strength [1.47–33.91 Mpa] and tensile strain [0.32–38.2%].Discussion and conclusions: Despite the orodispersible films’ complex composition, it was possible to establish correlations about the impact of the main excipients on the final product characteristics. Acceptable values for the CQAs were also defined, working as acceptance criteria for the development of new oral film formulations.

Effect of Freezing on Lyophilization Process Performance and Drug Product Cake Appearance

This study highlights the significance of the freezing step and the critical role it can play in modulating process performance and product quality during freeze-drying. For the model protein formulation evaluated, the mechanism of freezing had a significant impact on cake appearance, a potential critical product quality attribute for a lyophilized drug product. Contrary to common knowledge, a freezing step with annealing resulted in 20% increase in primary drying time compared to without annealing. In addition, annealing resulted in poor cake appearance with shrinkage, cracks, and formation of a distinct skin at the top surface of the cake. Finally, higher product resistance (7.5 cm2.Torr.hr/g) was observed in the case of annealing compared to when annealing was not included (5 cm2.Torr.hr/g), which explains the longer primary drying time due to reduced sublimation rates. An alternative freezing option using controlled ice nucleation resulted in reduced primary drying time (i.e., 30% reduction compared to annealing) and a more homogenous batch with elegant uniform (i.e., significantly improved) cake appearance. Here, a mechanistic understanding of the distinct differences in cake appearance as a function of freezing mechanism is proposed within the context of ice nucleation temperature, ice crystal growth, and presumed solute distribution within the frozen matrix.

Quality by Design Approaches to Formulation Robustness—An Antibody Case Study

The International Conference on Harmonization Q8 (R2) includes a requirement that “Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can impact the quality of the drug product,” that is, the need to assess the robustness of a formulation. In this article, a quality-by-design–based definition of a “robust formulation” for a biopharmaceutical product is proposed and illustrated with a case study. A multivariate formulation robustness study was performed for a selected formulation of a monoclonal antibody to demonstrate acceptable quality at the target composition as well as at the edges of the allowable composition ranges and fulfillment of the end-of-shelf-life stability requirements of 36 months at the intended storage temperature (2°C-8°C). Extrapolation of 24 months' formulation robustness data to end of shelf life showed that the MAb formulation was robust within the claimed formulation composition ranges. Based on this case study, we propose that a formulation can be claimed as “robust” if all drug substance and drug product critical quality attributes remain within their respective end-of-shelf-life critical quality attribute–acceptance criteria throughout the entire claimed formulation composition range.

Integrated Application of Quality-by-Design Principles to Drug Product Development: A Case Study of Brivanib Alaninate Film–Coated Tablets

Modern drug product development is expected to follow quality-by-design (QbD) paradigm. At the same time, although there are several issue-specific examples in the literature that demonstrate the application of QbD principles, a holistic demonstration of the application of QbD principles to drug product development and control strategy, is lacking. This article provides an integrated case study on the systematic application of QbD to product development and demonstrates the implementation of QbD concepts in the different aspects of product and process design for brivanib alaninate film–coated tablets. Using a risk-based approach, the strategy for development entailed identification of product critical quality attributes (CQAs), assessment of risks to the CQAs, and performing experiments to understand and mitigate identified risks. Quality risk assessments and design of experiments were performed to understand the quality of the input raw materials required for a robust formulation and the impact of manufacturing process parameters on CQAs. In addition to the material property and process parameter controls, the proposed control strategy includes use of process analytical technology and conventional analytical tests to control in-process material attributes and ensure quality of the final product.

Process Analytical Technology for High Shear Wet Granulation: Wet Mass Consistency Reported by In-Line Drag Flow Force Sensor Is Consistent With Powder Rheology Measured by At-Line FT4 Powder Rheometer®

Drag flow force (DFF) sensor that measures the force exerted by wet mass in a granulator on a thin cylindrical probe was shown as a promising process analytical technology for real-time in-line high-resolution monitoring of wet mass consistency during high shear wet granulation. Our previous studies indicated that this process analytical technology tool could be correlated to granulation end point established independently through drug product critical quality attributes. In this study, the measurements of flow force by a DFF sensor, taken during wet granulation of 3 placebo formulations with different binder content, are compared with concurrent at line FT4 Powder Rheometer® characterization of wet granules collected at different time points of the processing. The wet mass consistency measured by the DFF sensor correlated well with the granulation's resistance to flow and interparticulate interactions as measured by FT4 Powder Rheometer®. This indicated that the force pulse magnitude measured by the DFF sensor was indicative of fundamental material properties (e.g., shear viscosity and granule size/density), as they were changing during the granulation process. These studies indicate that DFF sensor can be a valuable tool for wet granulation formulation and process development and scale up, as well as for routine monitoring and control during manufacturing.

Process design and control of a twin screw hot melt extrusion for continuous pharmaceutical tamper-resistant tablet production

Hot melt extrusion (HME) is a well-known process within the plastic and food industries that has been utilized for the past several decades and is increasingly accepted by the pharmaceutical industry for continuous manufacturing. For tamper-resistant formulations of e.g. opioids, HME is the most efficient production technique. The focus of this study is thus to evaluate the manufacturability of the HME process for tamper-resistant formulations. Parameters such as the specific mechanical energy (SME), as well as the melt pressure and its standard deviation, are important and will be discussed in this study.In the first step, the existing process data are analyzed by means of multivariate data analysis. Key critical process parameters such as feed rate, screw speed, and the concentration of the API in the polymers are identified, and critical quality parameters of the tablet are defined. In the second step, a relationship between the critical material, product and process quality attributes are established by means of Design of Experiments (DoEs). The resulting SME and the temperature at the die are essential data points needed to indirectly qualify the degradation of the API, which should be minimal. NIR-spectroscopy is used to monitor the material during the extrusion process. In contrast to most applications in which the probe is directly integrated into the die, the optical sensor is integrated into the cooling line of the strands. This saves costs in the probe design and maintenance and increases the robustness of the chemometric models. Finally, a process measurement system is installed to monitor and control all of the critical attributes in real-time by means of first principles, DoE models, soft sensor models, and spectroscopic information. Overall, the process is very robust as long as the screw speed is kept low.

Regulation in the face of uncertainty: the evidence on electronic nicotine delivery systems (e-cigarettes).

Tobacco smoking is the largest single preventable cause of many chronic diseases and death. Effective treatments exist; however, few smokers use them and most try to quit by themselves. Most of the tobacco cigarette’s toxicity is related to the combustion process. Models of harm reduction applied to tobacco suggest that switching from inhalation of combustible products to a noncombustible nicotine delivery product would likely result in a vast reduction in tobacco-related death and illness. Currently available evidence raises no doubt that electronic cigarettes (e-cigs) are by far less harmful than smoking (although probably not absolutely safe) and have the potential to be the most effective tobacco harm reduction products due to their unique property of resembling smoking and providing satisfaction to the user. A lot of controversy is surrounding e-cigs and their regulation, much of which is based on the precautionary principle. Although monitoring and further research is definitely needed, the arguments used to implement severe restrictions or bans are mostly hypothetical, weakly supported by evidence, and, in some cases, derived from mispresentation or misinterpretation of the study findings. Regulators should keep in mind that the target population is smokers who want to reduce or quit their deadly tobacco consumption. To achieve this goal, smokers should be honestly informed on the relative harmfulness of the different products. E-cigs are not tobacco products and are not used as medications. For this reason, a specific regulatory scheme is needed, separate from tobacco or medicinal products regulation. Regulation should implement specific quality criteria for products, rules for the exclusion of chemicals of reasonable concern, and appropriate testing for possible contaminants. Additionally, manufacturing standards derived from the food industry should be implemented and adjusted for specific conditions related to e-cigs. Finding the appropriate balance between safety and acceptability of use by smokers will be important in achieving the maximum public health benefit. Labeling should be specified, with warnings about exposure to skin or through ingestion and discouragement of use by nonsmokers, related to the presence of nicotine. Finally, advertising and marketing should not be banned, but appropriately regulated in order to encourage use by the intended population while avoiding use by never-smokers. E-cigs should be appealing to smokers (but not to nonsmokers), while availability and pricing should be strong competitive advantages of e-cigs relative to tobacco cigarettes.