Frank L. Acosta Jr., MD

• Director of Spine Deformity
• Department of Neurosurgery
• Cedars-Sinai Medical Center
• Los Angeles, California

Each of these materials may be composed of several chemical substances which makes the formulation quite complex erectile dysfunction wiki order levitra professional 20mg free shipping, and as a rule erectile dysfunction from alcohol buy levitra professional 20mg mastercard, it is very difficult to obtain a comprehensive list of adhesive ingredients from label suppliers erectile dysfunction lisinopril discount levitra professional 20mg with visa, making the extractables/leachables process difficult erectile dysfunction medications for sale order generic levitra professional canada. Identification of Extractables from Labels Because of the difficulty in obtaining credible and comprehensive information about the extractable substances from labels suppliers erectile dysfunction treatment without side effects buy levitra professional amex, pharmaceutical companies must perform a controlled extraction study to identify extractable substances erectile dysfunction pump cost purchase 20 mg levitra professional. Extractables and Leachables from Inks, Adhesives, and Coatings Label components such as inks, adhesives, and coatings are not primary packaging materials since they are not in direct contact with drug products or substances. However, substances from the materials may migrate through the walls of plastic containers and appear as leachables. Label Extractables Protocol Before beginning any study, the label supplier should be requested to supply as much information on the label composition as is possible. Discussion with the suppliers/manufacturers of the ink, adhesive, polymer, and paper portions of the label is also desirable. Review of suppliers/manufacturers literature (paper and web based) will prepare the user with the proper questions for suppliers. Any upfront knowledge of the label composition will provide dividends in time and money saved during the extraction study. A controlled extraction study of a packaging label involves exposing a sample to an appropriate solvent system at elevated temperatures to accelerate the extraction process followed by chemical analysis. The label, which is not intended in ordinary applications to be ever exposed to solvents, will not only be subject to extraction but likely will partially dissolve in some solvents. At least two solvents are recommended-water or an aqueous system that mimics the drug product. The extraction is performed by soaking the label in a solvent for a fixed time at a controlled temperature. Extraction profiling of the label is divided into three parts: nonvolatiles, volatiles, and semi-volatiles. Essentially, the high-level process is to understand the chemistry of the materials and components of the containment or delivery and system to target potential leachable under worse-case conditions of use. It is recommended to conduct extractable testing early in the drug product development process, but there is no clear definition of early. Drug and device development is a complex and time-consuming process but there are critical phases of development to guide the degree of testing. Containment and delivery system qualifications based on risk to the specific drug product and patient contact from early development and throughout the product lifecycle. Regardless of the jurisdiction, materials in contact with the drug or patient must be evaluated for safety and compatibility. It is important to integrate potential leachables or chemical migration in early development phases to build in quality and safety, rather than try to mitigate a problem once it has occurred in later stages of development. Although drug product development phases can overlap, in general, research and early development encompasses preclinical and phase 1 studies. Research and early development for medical device would consider feasibility and process development. At this stage, safety is critical for both the drug and delivery device to be able to move into full development. In early stages, material or component compliance with compendia physicochemical and biocompatibility testing will be an important indicator for safety. During clinical phases 1/2 and process development, material chemical profile is an important factor for design inputs to correlate to performance properties and potential safety alerts. It is not until later clinical development phases 2/3 that leachables can be verified and impact to product quality and safety realized. Route of administration, duration of exposure, and patient population are among the variables to be considered. The qualification of leachables is associated not only with the discovery and amount of leachables but also the toxicological impact to the patient. The first step and most vital step of the process is to identify the primary container closure/device components and other critical components to be evaluated for extractables. These materials would then be assessed for potential extractables, starting by obtaining available supplier information on biocompatibility and results of compendia tests for those materials which have an applicable monograph. The compendia tests will not provide adequate information to correlate to patient safety or drug product compatibility, so study would need to be designed to obtain a chemical characterization profile of the potential extractables for all the critical components. The output of the Stage I extractables study should characterize the materials and components to gain a thorough understanding of the chemical profile. The protocol for an extractable characterization study should employ multiple solvents having varying propensity to extract constituents from the container closure materials using Nonvolatile Screen Organic solvent extracts can be analyzed for residual substances. This provides generalized information on the amount of polymers and ingredients present. Extracts can be then directly analyzed for compound-specific semi-volatile, nonvolatile, and inorganic profiles. Information obtained in the general screening studies can be used to guide specific studies. There is a multitude of extractables that can be generated from labels, inks, and adhesives for characterization purposes, but the risk of potential leachables from indirect contact is typically associated with the volatiles since there is a higher likelihood for volatiles to permeate through semipermeable polymers. Qualification of potential leachables should be based on outcome of simulation studies. Process for Managing Packaging Extractables and Leachables There is a logical progression to the framework for identification and control of leachables involving a set of steps to guide the type and degree of qualification relative to the phase of development. The chemical composition of a component will define its performance properties as well as potential for leaching, which can directly or indirectly impact drug product quality and patient safety. The conditions for extractions should be adequate to provide a chemical profile but not so extreme as to create anomalous results. The extracts should then be analyzed using multiple techniques to detect organic and inorganic constituents of the container closure system. The extractable compounds detected during a stage I study are classified as potential leachables. After a chemical profile is obtained, the data can be compared to the supplier information and evaluated for any compounds of concern. In the initial stage of the evaluations, much of the data will be qualitative or at best semiquantitative having only tentative identifications. It is not always evident if there is a toxicological concern until positive identification is made and the compounds measured. Once extractable compounds are identified and quantified, an assessment for safety can be attained and alternative materials may be considered if necessary. The measurement of extractables in container closure systems should be made using well characterized methods in order to have a level of confidence to guide in the decisionmaking process. Measurements should be direct, provide high assurance of reproducibility, have purpose, and be sufficient and timely to provide a meaningful evaluation of quality [76]. The methods should be fully validated if they are to be used to control the container closure materials. Selection of the extractable compounds to be targeted in a leachable study will need to have careful consideration; an extractable will not necessarily become a leachable. Complex extraction media are not recommended for simulation studies, but if necessary, the challenges associated with interfering species or masking probable leachables would require some degree of targeted method development. The compounds detected during a simulation study are classified as probable leachables. It is also conceivable that an extractable may form an interaction product or degradation products once in contact with the drug product. Migration of extractables or interaction products may occur under certain conditions relative to the drug product which may take place over a period of time. It is necessary that the leachable methods have the appropriate sensitivity and specificity as well as be free of interferences from the drug product. The next step in the process is to identify leachable targets and develop and validate analytical methods to quantify target leachables. These methods are drug product specific and must be validated under the guidelines provided by the regulatory agencies. The drug products can then be set up on stability and evaluated at the specified time points. Assessments of the toxicological impact should be made throughout the stability studies and a correlation between extractables and leachables should be made to enable control of leachable compounds. A toxicologist will evaluate any confirmed leachable compound detected from a safety perspective. The impact to drug product quality and potential impurities would be assessed in parallel. As the last step in the process, the chemical profiles should be monitored throughout the product lifecycle to establish a baseline and enable a control strategy. Changes in leachables may arise due to any planned or unplanned changes related to containment and delivery system, drug product, or conditions of use. Managing Extractables and Leachables from Single-Use and Process Components There is a potential for pharmaceutical products to be contaminated from contact materials during any phase of production or storage. While it is true that the guidance documents use the term container closure systems, evaluation of these systems are not limited to only the primary containers; secondary and ancillary materials can also contribute to leachables as well as any materials that may be in intermediate contact with the pharmaceutical product during manufacture. The process materials and equipment used in manufacturing biopharmaceutical products fall into this category and can introduce leachables, albeit the intermediate or upstream nature of the processing materials. Certain bioprocess conditions may serve to filter or concentrate a given extractable compound introducing a leachable into the drug product with potential to cause harm to a patient. This presents the challenge to the manufacturer of biopharmaceutical products such that the critical materials to be evaluated for extractables must be understood early in the pharmaceutical development process so that this can be incorporated into leachable studies. General conditions of drug product exposure to a final container closure system compared to that of a disposable or process component is shown in Table 25. The likelihood of interaction of single-use or process components with a biopharmaceutical product will depend on four major conditions: (i) the direct contact to the actual drug product, (ii) indirect contact of solutions or materials that are precursors to the drug product, (iii) immediate contact of the drug product or precursor that is not processed further after contact, and (iv) remote contact of the drug product or precursor that is processed further after contact [77]. Contamination of a biopharmaceutical product can pose a safety risk to a patient causing a toxic or allergic effect; contamination can also change the properties of the drug product having a negative impact to the product and putting the patient at risk by not receiving intended therapy. The risk of constituents migrating from the contact material into the drug product or the precursors must take into consideration the compatibility of the component materials, proximity of the component to the final product, the product or precursor composition, the surface area of the contact material, the contact time, and the temperature. Other issues of concern are possible pretreatments and intended use, such as exposure of the components to steam sterilization or gamma radiation and if the components will be rinsed and reused. All of these factors combined create a dilemma when designing a process for qualification and validation of surface contact and in process materials. The chapters detail the use of risk-based assessments to determine the degree of testing based on the contact area and type of media. The outcome of this assessment establishes three levels of risk: low, moderate, and high. There is also a provision for a material, component, or system that has been previously used and found equivalent to a comparator. A risk score can be developed based on the probability of extractables occurring relative to the severity of harm caused from contamination of the biopharmaceutical. Like the final container closure system, disposables and process components also require extractables assessment and leachables control. Manufactures of processing materials and equipment may provide baseline information on extractables, but the materials suitability for one process may not be valid for a different biopharmaceutical product. The degree of scrutiny for single-use and processing components depends on several factors, and a risk assessment is commonly used to identify and prioritize studies to qualify and control the materials and components. Risk scores are generally based on predictive models developed for particular materials in a particular system and would need to be developed for each specific application. Although there will always be a degree of uncertainty in the risk values, an informed decision can be made by considering each material and potential for migration. Once the surface contact materials from processing equipment and components are evaluated for the potential to contaminate the biopharmaceutical product, a decision can be made as to whether an alternative material should be considered or to proceed with an extraction study. The use of multiple solvents should include clean solvents to provide a chemical profile as well as solution simulating the drug product. Conditions of exposure should be exaggerated to indicate worst case and provide data for the chemical profile. Based on the extractables data, constituents would be evaluated for potential impact to patient safety as well as to the drug product. At this point, another decision can be made to seek alternative material or to proceed to a leachable assessment [80]. The target analytes for leachable studies, derived from the extraction of the surface contact materials from processing equipment and components, can be combined with those from the primary container closure system to understand the required sensitivity, those that are in common or may interfere with the drug product or other target analytes before developing the leachable study plan. Several methods may need to be developed and validated in order to encompass all of the constituents of interest. There are different study approaches for conducting extraction studies depending on the intended outcome of the study. This is an informational chapter intended to provide a framework for the design, justification, and execution of extractables studies for pharmaceutical packaging systems. They do not present specific experimental conditions, specific tests, analytical procedures, or acceptance limits for packaging systems or products but provide the basis for selecting appropriate methodology. The choice of extraction conditions and analysis techniques can be relative to the goal of obtaining qualitative profiles, quantitative profiles, predictive modeling, and/or actual conditions of exposure. A comprehensive extractable study can entail a combination of all the above objectives. Inhalation and injectable dosage forms are among the highest level of concern having the greatest degree of scrutiny. A systematic approach is detailed for investigation and control of leachables by employing controlled extraction studies followed by correlation to leachables and control. These recommendations incorporated threshold values to answer the question of "how low to go.

Expectations for patient-focused drug development erectile dysfunction washington dc buy levitra professional 20mg low price, device innovations erectile dysfunction causes and treatment buy cheap levitra professional 20 mg online, and new expedited drug development designations have influenced the way packaging and delivery system should be qualified for use erectile dysfunction treatment japan buy levitra professional 20mg on-line. This law was further enhanced supporting patient-centered medical product development in December 2016 when the 21st century cures act was passed to facilitate faster drug clearances [22] erectile dysfunction protocol free copy purchase genuine levitra professional on line. The type and amount of container closure information required in each application can vary erectile dysfunction on prozac order levitra professional 20 mg overnight delivery, and the interpretation of the requirements will depend on various factors impotence vacuum pumps buy levitra professional 20 mg on line. Regardless of the product jurisdiction, the underlying principle of risk management applies. Specifications for packaging materials and components are found in chapters under 1,000. Parenteral Medications However, these are only a starting point for qualifying a finished system for intended use. Guidance documents do not suggest a comprehensive list of tests, specific test methods, or acceptance criteria. Batch to batch consistency of packaging components and acceptance criteria should be based on good scientific principles for each specific system and product [15]. The market package for a drug product includes the primary packaging components, secondary package, external packaging, and associated components. Each suitability category has associated levels of testing; level 1 indicates the greatest degree of evaluation required. The suitability category for level 1 safety includes extraction/ toxicological evaluation, limits on extractables, and batch to batch monitoring. It is not clear from the guidance document if migrated substances refers to leachables or extractables; however, it is implied that toxicological evaluation should be conducted on all extractables. The premise was predicated on the fact that all chemicals can be toxic to some degree, but it is only those extractables that become leachables that are of concern [24]. Extractables do not become leachables in many cases, and it can depend on how the products are assessed. Extractions can be performed under harsh conditions, such as strong solvents at high temperatures or mild conditions, which may or may not reflect the actual conditions of the final drug product. Since human toxicity data on most industrialized chemicals are limited, it is not practical to conduct a toxicological evaluation on extractables and would not necessarily provide information needed to ensure patient safety. It is not a simple process to determine that a material of construction or packaging component is safe for its intended use, and a standardized approach has not been established. The packaging guidance provides rationale for a comprehensive study of high-risk dosage forms such as an injection, inhalation, ophthalmic, or transdermal. It involves two parts: an extraction study on the packaging component to determine which chemical species may migrate into the dosage form (and at what concentration) and a toxicological evaluation of those substances which are extracted to determine the safe level of exposure via the label specified route of administration. The approach for toxicological evaluation of the safety of extractables should be based on good scientific principles and consider the specific container closure system, drug product formulation, dosage form, route of administration, and dose regimen [15]. A specific section on container closure systems recommends a thorough analysis of leachables and extractables to evaluate the capacity of container closure materials to interact with and modify the therapeutic protein 543 product. The expectation is to conduct a risk assessment to mitigate and control leachables as appropriate. Leachables studies should be performed on the product under stress conditions as well as under real-time storage conditions because in some cases the amount of leachables increases dramatically over time and at elevated temperatures. Product compatibility testing should be performed to assess the effects of container closure system materials and all leachables on product quality. A comprehensive extractables and leachables assessment should include multiple analytical techniques to assess the attributes of the container closure system that could interact with and degrade protein therapeutic products [25]. Since the packaging guidance was issued, the concept of risk-based assessments brought to bear new insights on how to manage extractable and leachable studies. It is understood that this guidance is currently being updated to clarify and reflect current day best practices. In essence, pharmaceutical development can be adapted to a quality by design (QbD) process. This starts with defining the quality target profile, which includes the container closure and delivery system. Attributes that are critical to product quality should be identified, justified, and controlled. The concept of design space and building quality in through-process development and improvements can result in a degree of regulatory flexibility. The critical parameters for selection of container closure and delivery systems should be part of quality risk management process. Extractable studies should be designed to estimate the probability and amount of chemical entities migrating into the drug product to be prioritized for leachable studies. Extractable data can be leveraged to validate leachable methods to determine occurrence and amount of leaching substances with regard to product quality and patient safety. Leachable substances should be mitigated and controlled as appropriate for a particular drug product. The knowledge collected should be used to establish acceptance criteria, maintain a state of control, and enable continuous improvement [29]. The development and manufacturing process of the drug substance will have the same philosophy as drug product, including the presence of steps designed to reduce impurities. A scientifically justified model can enable a prediction of quality and can be used to support the extrapolation of operating conditions across multiple scales and equipment. Adoption of this guideline will promote innovation and continual improvement and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments. Leachables and extractables, although not specifically mentioned, are key in achieving these same overall quality objectives. Another aspect of risk to product quality and safety is related to the potential for drug product impurities arising from interrelation with packaging systems. Impurities are an important class of critical quality attributes of finished drug or biologic products. Management of Extractables and Leachables They can include organic and inorganic impurities. In the case of synthetic molecules, a chemical migrant is only considered to be a leachable if it is a degradation or reaction product of the drug product or substance with immediate container closure system [4,32]; whereas impurities in biologics are different. Leachables are considered impurities in biologics as product-related substances that are molecular variants of the desired product. Process-related impurities can also exist from manufacture equipment and include downstream-derived impurities such as column leachables [5,6]. The biocompatibility guidance includes a matrix for selecting appropriate tests based on various endpoints. These endpoints include cytotoxicity, sensitization, irritation, or intracutaneous reactivity, acute systemic toxicity, material-mediated pyrogenicity, subacute/subchronic toxicity, genotoxicity, implantation, hemocompatibility, chronic toxicity, carcinogenicity, reproductive/developmental toxicity, and degradation. Relevant endpoints should consider the nature of body contact, degree, frequency, duration (limited/ prolonged/permanent), and conditions of exposure of the device materials to the body. The level of toxicological concern should be based on patient exposure to the chemical entity and the available toxicological data. One approach is to consider the total patient exposure of the device or device component chemical in relation to the amount at which toxicities are known or probably exist. Extraction solvents should be selected to optimize compatibility with the device materials and provide information on the types of chemicals that are likely to be extracted in clinical use. Thus, the risk assessment should consider what is known about the additional material, the base material, and the potential chemical interactions between the two. The level of toxicological concern should be based on patient exposure to the chemical [33,34]. The requirements will vary depending on the product jurisdiction, drug/biologic product characteristics, and intended use. Regardless of the approach, the choice and rationale for the container closure systems and qualification should be consistent with the Common Technical Document format. Information on both leachables and extractables should be included in Module 3 (Quality) Manufacturing Process Development section under Container Closure System (3. When warranted, extractable- and leachable-related impurities, the correlations, and specifications should be included, if leachables are confirmed through shelf life. Individual elements of the control strategy would include container closure system (3. Implementation throughout the product life cycle should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities [31]. Considerations for Safety Risk Assessments Evaluation of leachables and extractables safety is conducted to inform on toxicological hazards or potential for a compound to cause an adverse biological reaction, considering the nature of the reaction and the dose required. Biocompatibility testing is intended to indicate that a device material will perform with an appropriate host response in a specific situation. Safety risk assessments will cover a wide range of biocompatibility testing, which should be consistent with quality risk management goals. The type and degree of testing will depend on many factors, such as phase of development, materials/systems, in use application, previous knowledge/ experience, regulatory jurisdiction, type and proximity of components to drug product, and patient/tissue. The purpose of this section is to bring awareness to various tests and application. The reader is advised to reference the appropriate standards for specific details. The packaging guidance has a greater emphasis on chemical assessments (extractables) and drug product interactions (leachables) followed by safety evaluations. In contrast, device materials may need to be qualified for direct as well as indirect contact with the human body and prioritize biocompatibility testing supported by chemical analysis of the materials. Sources of relevant information include: literature, clinical experience, animal study experience, and medical device standards. Guidelines for generating qualitative and quantitative extractable profiles are also available. While this appears to be an enigma, compendial methods denote that a standardized approach can be used to provide general baseline information to identify certain characteristics of the materials and the physicochemical nature of the materials. There are specifications associated with many of the monographs, and those specified materials must be compliant to indicate suitability for use with a pharmaceutical product. Standardized tests indicating biological responses to the component materials as well as certain functional tests are also included in the compendia. Data from compendia tests are limited and considered as first-line information to be acquired when qualifying a container closure system. Complete stability, compatibility, and a safety assessment of the container closure system is necessary to ensure it is appropriate for the intended use. Materials that are in contact with pharmaceutical container closure systems must comply with the appropriate pharmacopeia monographs as required by regulatory agencies around the world. Unfortunately, there are no global specifications for container closure systems, and requirements are enforced according to the terms of each country. Even though the materials of construction may have general characteristics that are standard, these attributes are not necessarily consistent on a global level. A single container closure system may be comprised of several different materials types, and these materials types can be intended for different uses. The extraction procedures, analysis, and specifications vary according to each monograph within Ph. There have been efforts to harmonize compendia, but the impact of changing test criteria and specifications for marketed container closure systems are far reaching, and consensus is challenging. In addition, containment/delivery systems and testing technologies have been advancing, but compendia methods have not kept pace. One notable example is the heavy metals test that was consistent across all pharmacopeias but inadequate for detection and recovery of elements of interest. This is no longer consistent across all pharmacopeias and problematic for all packaging chapters since extractable heavy metals were analyzed using <231> methodology. So, the question lingers, what data are meaningful, useful, and scientifically sound for the initial testing phase The specificity of standardized tests presents a challenge when qualifying materials on a global basis because it is difficult to standardize acceptance criteria when test procedures are not consistent. The sampling, extraction conditions (solvents and exposure), and analysis conditions (techniques and conditions) vary, and results are specific to those conditions. The pharmacopeia monographs provide wide-ranging standards and are intended for materials used within a certain context. As a result of some of the generalities, often these tests can be applied to materials that may not fall into the intent of the specification. There are also new-or combinations of- materials being used in container closures system that may not have existed when specifications were set. As old materials may be discontinued or new materials enter the market, updates of the compendia may not keep pace, and standardization will become more challenging. Type I is highly resistant borosilicate glass used for parenteral preparations of all pH values. The classification for glass is based on the characteristic of the solubility of glass in water when autoclaved. The procedures between pharmacopeias are different, but the solubility for all is measured based on titration of water, after exposure to glass, with a weak acid to detect the amount of alkali (base) present. There are other pertinent tests and specifications for glass in each of the pharmacopeias, but these are not factored in to the classification scheme. Plastics Pharmaceutical products and container closure systems continue to evolve to meet the needs of patients and caregivers. Packaging is no longer limited to the protection and storage of a drug product, with the rising demand for innovative delivery and administration devices the boundaries for regulation between container closure systems and devices have blurred. Regulatory controls for device materials are grounded in biological reactivity tests, and the degree of testing is linked to the material classifications. The numerical class increases relative to the duration (risk) of contact between the body and device.

Temperature measurements are typically performed using thermocouples positioned in slow to heat zones with the load items erectile dysfunction yoga purchase levitra professional 20mg free shipping. The use of specialized fittings to permit thermocouple access without compromising the integrity of the item and any wrapping material is strongly recommended erectile dysfunction caused by stroke order online levitra professional. Where this is not the case erectile dysfunction journals cheap levitra professional 20 mg on-line, the physical data should be considered suspect as air removal and steam penetration may be improved relative to unprobed load items erectile dysfunction treatment massage buy discount levitra professional 20mg line. In evaluating the physical data erectile dysfunction in diabetes medscape levitra professional 20mg amex, the location with the lowest overall F0 is considered to be of the greatest concern erectile dysfunction under 35 20mg levitra professional for sale. The load in which the lowest F0 is demonstrated is conventionally utilized in annual re-evaluation of the sterilizer. In considering the loads to evaluate, the maximum load of mixed items is most appropriate as a "worst case" challenge for each unique sterilization process. The large mass of the maximum load will entail greater steam to bring the items to sterilizing conditions resulting in more condensate than would be encountered with smaller loads. The choice of the largest load Terminal Sterilization Sterilization of products entails consideration of both sterility and stability; a two sided concern that essentially doubles the work required relative to parts sterilization. The free water in the formulation is necessary to sterilize both the liquid phase and the headspace above the liquid (a portion of the free water converts to steam to accomplish this). The biological challenge for terminal sterilization must be considered with some caution. Its resistance to steam sterilization is such that the minimum F0 with which it can be comfortably used (assuming a D121 of 2 min and a challenge level of 106 spores per container) is 18 min. As that amount of heat input is excessive for many materials, alternative indicator spore forming microorganisms are often chosen. Those organisms and others are appropriate choices provided the resistance of the chosen spore is evaluated in the product. Where either the containers or closures are not sterilized prior to filling, a further complication ensues. Assuming a 9 log reduction is required to provide a 1 in 1,000 chance of a survivor in the validation studies. The use of selfcontained probes that can individually record data can be used in very large sterilizers or continuous sterilizers where the use of wired thermocouples is problematic. Biological challenge units in product filled containers are positioned across the load pattern, with emphasis on the cool point determined during the load mapping studies. Thermocouples are positioned in separate containers next to those with the biological challenge. The entire sterilizer load for validation need not utilize product containers; the use of placebo filled containers is commonplace, provided that the placebo units approach the tested product in fill volume, viscosity, and heat capacity. In each load size, consistency of minimum and maximum delivered F0 is the key requirement. Parenteral Medications must be formally evaluated for its potential impact on the performance of the system. The review must consider the extent to which the repair and/or the condition prior to the repair could alter the effectiveness of the cycle. The evaluation might require a repetition of one or more of the elements of the equipment qualification, or in extreme cases, the performance qualification of the sterilizer itself. Record review is a requirement for the release of materials produced by any process. In steam sterilization, the records of individual cycles must be carefully reviewed to determine their conformance to process requirements. Many firms establish formalized review sheets defining the expected conditions to be attained and the tolerance around them for ease of record review. Conclusion Steam sterilization is a relatively simple process; its criticality and universal use suggest that individuals working in this industry must have a thorough understanding of the principles associated with its use and validation. There is perhaps more information available on this process than any other in our industry. The reader is encouraged to explore that information, if the information provided within this effort proves inadequate. Ongoing Control Steam sterilizers share many considerations with other pieces of pharmaceutical process equipment. As microbiological kill is logarithmically related to the sterilizing temperature, slight variations in temperature can have a substantial effect on process lethality. The calibration must consider the entire control system from point of measurement to the process recorder [28]. Instrumentation utilized for the validation of the process must be calibrated as well. Preventive maintenance as defined by the sterilizer manufacturer is intended to keep the sterilizer in proper working condition. There should be a defined schedule for its execution using methods and parts provided by the vendor. This form of maintenance is presumed to have no adverse impact on the sterilization process, and while records of it must be maintained, evaluation of the change is normally not indicated. Corrective change that repairs malfunctions of the equipment presents quite a different situation. Each repair, whether planned or unplanned, * the location should have been determined in the mapping studies described earlier. Biological comparative analysis in various product formulations and closure sites. The simplicity and speed of heat (moist or dry) and radiation sterilization ordinarily makes those the methods of choice; however, the effects of these sterilization processes on many materials are detrimental to essential material properties. When faced with these circumstances, the practitioner often turns to chemical methods where microorganisms are destroyed by exposure to chemical agents in gas, vapor, or liquid form. This article will review the available processes for these chemical agents, outline their development, describe suitable validation approaches, and delineate the necessary routine process control requirements. While all of these processes rely on a chemical action against microorganisms, there are meaningful differences in their application to each phase that must be understood in order to use them effectively. The same chemical agent will require differing controls when delivered in a different manner. The processes for sterilization by the varying agents that operate in a particular phase are all similar, and resemble each other more than the processes for a single agent applied in different phases. This can perhaps be better understood by a rapid review of the relevant aspects of physical chemistry. The basic definitions of gases, liquids, and vapors are presented below: Gas-a substance possessing perfect molecular mobility, and the property of indefinite expansion, as opposed to a solid or liquid [1] Liquid-composed of molecules that move freely among themselves, but do not tend to separate like those of gases, either gaseous or solid [1] Vapor-visible exhalation, as fog, mist, steam, smoke, or noxious gas, diffused through or suspended in the air [1] All materials in a liquid state have some tendency to evaporate into the gaseous form. At any fixed temperature of a liquid, there is a vapor pressure created by the gas in equilibrium with that liquid. As the temperature increases, so does the vapor pressure, corresponding to a higher concentration of the material in 711 712 the gas phase in equilibrium with the liquid phase. When gases are cooled, they may reach their dew point at which temperature a portion of the gas reverts (condenses) to the liquid state. Chemical agents such as hydrogen peroxide and peracetic acid are utilized for sterilization in ways where both liquid and gas phases may be present simultaneously and are termed a vapor. The laws of physics mandate that both gases and liquids be uniform in the concentration of all components present in each. As a consequence, these processes are relatively simple to develop, validate, and operate. The premise behind many vapor sterilization processes is that by rapidly increasing the temperature of the liquid, all components of the liquid are converted into a gas and maintain the same concentration of each component despite the phase change. This may result in a metastable situation with localized condensation of the material at locations where the surface temperature is less than the dew point temperature of the materials in the vapor. Variations in temperature across a chamber will result in different amounts of condensation at each location. All of this tends to make sterilization using vapors far more problematic than either gas or liquid sterilization. The situation is actually Parenteral Medications even more complex, as introducing a hot vapor into an ambient temperature chamber will result in a gradual temperature rise over the course of the process and across the chamber itself. The concentration of the chemical agent has the largest impact on the effectiveness of the sterilization process regardless of the phase present. Of course, substantially higher concentrations of a chemical agent are possible in the liquid phase relative to the gas phase. Therefore, in vapor sterilization processes, the sterilizing effect on the microorganisms will differ in the gas, vapor and liquid phases due to localized differences in concentration, and adsorption of the agent from each phase to the microorganism. There are other important factors essential for effective sterilization of microorganisms by chemical agents. Moisture must be present as well for effective sterilization to assist in penetration of the agent through the spore coat [2]. In gas sterilization, moisture is provided by the humidity present in the gas phase. For gas sterilization processes used for medical devices that have many protective layers surrounding the device, an extensive pre-humidification of the load is performed to assure adequate humidity at the device target location. For vapor sterilization, the moisture necessary for effective sterilization may be present as either a gas or liquid depending upon the temperature at the target location. Just as the amount of chemical agent may vary during vapor sterilization, the moisture level will also be different in each phase. In the context of gas, liquid, and vapor sterilization, the essential process parameters are comparatively easily determined for both gases and liquids, whereas vapors present all manner of measurement uncertainties. With vapors, the agent concentration and humidity levels are neither constant across the processing environment (and process cycle), and measurement of one phase to calculate the equilibrium concentration in the other is only useful where the entire process is isothermal given that the antimicrobial agent and water are present in both phases. As vapors are either introduced as hot gases or derived from hot liquids and introduced into ambient temperature chambers, the process temperature is rarely constant, and thus, concentration measurement is at best a locally correct number, and at worst near useless in establishing process conditions and relating them to lethality. Sterilization Basics Sterilization is a process that completely destroys or removes microorganisms. The agents described in this chapter when applied without adequate control measures should not be considered sterilizing. Gas, Vapor, and Liquid Phase Sterilization the logarithmic number of microorganisms remaining alive [3]. The slope (the inverse of which defines the D-value) of the microbial death curve is an inherent property of the microorganism and the conditions of the sterilization treatment itself. The slope of the curve is related to the time in minutes for the microbial population to be reduced by 90% (or 1 logarithm) and is commonly termed the D-value [3]. Accurate determination of the D-value requires precise measurement of the lethal conditions to which the microorganism is exposed and must be reported with the D-value. D-values for vapor sterilization processes are not possible, as the sterilizing conditions to which the microorganisms are exposed cannot be accurately determined. The validation exercise supports the efficacy of the sterilization process against the microorganisms present during routine processing. Depending upon whether the sterilization process is gaseous, liquid, or vapor, the details of the validation will vary; however, the basic principles described above remain the same. A sterilizing agent will require different instrumentation, equipment, and controls for effective usage depending upon the phase(s) in which it is delivered. Gas, vapor, and liquid sterilization processes are not exempt from this phenomenon, and material evaluation is required. The strong oxidative powers of many chemical agents, pH extremes of acids and bases, and the presence of substantial moisture can all lead to significant changes in the materials being sterilized. The typical sterilizing chamber is comprised of many different materials, all of which must be tolerant of the sterilizing conditions. Consideration of each of these possible adverse consequences must be an integral part of process selection, equipment design, cycle development, and process validation. Process Equipment Gas, liquid, and vapor sterilizations are ordinarily carried out in jacketed vessels or chambers much like those utilized for steam sterilization. The jacket provides improved temperature control, while the pressure (and vacuumrated) chamber serves to contain the potent chemicals employed for the sterilization process. These systems have various features including operator interface, recipe management, process execution and control capability, documentation, and interfaces with surrounding systems. A well-designed control system facilitates operation of the system and is essential to maintaining a compliant sterilization process. It is critical for providing the control necessary to support and maintain a validated sterilization process. There are vendors that supply stand-alone control systems that can be used to supply and in some instances, exhaust simple vessels for sterilization. In these instances, the end user is responsible for interfacing their process equipment with the freestanding control system. Temperature regulation, pressure/vacuum capabilities, and other operational features must be provided independent of the vendor-provided controller. The range of process equipment that can be sterilized with these units varies from the complexity of a freeze dryer to the simplicity of a stirred tank. Large commercial systems might use a jacketed stirred tank, the liquid-phase counterpart of the sterilizing chamber used for gases and vapors. For smaller scale processes, the equipment might be as simple as a nonpressure-rated container where the items to be sterilized are submerged. Agitation, temperature control, and sequencing would be provided by the operator using laboratory apparatus and/or room environmental controls.

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Selecting the right antigen that is hopefully differentially expressed on tumor tissues is rather important erectile dysfunction research generic levitra professional 20mg without prescription. Selecting the Antibody Since the initial advent of mAbs for cancer therapy erectile dysfunction nursing interventions levitra professional 20 mg without a prescription, there has been an increase in our knowledge on selecting an antibody herbal remedies erectile dysfunction causes purchase levitra professional discount. The basic principles of antibody selection include targeting the tumor tissue with high selectivity over healthy tissues erectile dysfunction disorder cheap levitra professional 20 mg online, binding tumor cells with high avidity and/or affinity erectile dysfunction drugs india order discount levitra professional line, and ultimately binding antigens that are expressed in high enough amounts on a tumor cell impotence news buy levitra professional 20 mg with amex. With immunogenicity of therapeutic proteins always being a concern,6 it is also recommended that humanized antibodies be selected over murine or chimeric forms. Ultimately, the right choice of an antibody is also not solely based on activity but also on process development. For example, it is important to get an early read on the physical and chemical stability of the antibody after the disulfides are reduced and used in cytotoxin conjugation via cysteine (Cys) chemistries. The electrostatic properties of the antibody intermediate are greatly modified after chemical conjugation on Lys as recently reported by Boylan et al. Cleavable linkers are of two types-based on whether they are enzymatic or chemically hydrolyzed. Acid-labile linkers are meant to keep the linker stable under the pH conditions in the blood or plasma and cleave under acidic conditions that are typically encountered in the lysosomes. A protease cleavable linker also has the advantage of stability in blood or plasma and is selectively cleaved when it encounters a lysosomal enzyme. One of the best known examples of a successful non-cleavable linker used in clinical studies is that of Kadcyla. While it is not possible to cover all of the different linkers and linker chemistry in great detail, the reader is referred to an interesting review by McCombs and Owen. Selecting the Drug the drugs attached to the antibody are also referred to as the payload. Payloads are typically small-molecule chemo-toxic agents that have shown some initial promise in in vitro and in vivo cancer models. Some of the important chemical attributes of these payloads or drugs include potency in sub-nanomolar concentrations, solubility, conjugatability, and stability. The synthesis and characterization of these small-molecule toxins are not in scope for this chapter. Interestingly, a moderately toxic irinotecan derivative targeting Trop-2 is also under clinical development for various cancers. This unnatural amino acid was selectively conjugated to an alkoxy-amine derivatized auristatin through an oxime ligation reaction. As such, specialized equipment and personnel training is required to achieve high quality product. This is encountered during conjugation, formulation, and analytical development of these molecules as underlined below. Conjugation Development As mentioned previously in the "Selecting the Linker" section, conjugation of the payload occurs via existing lysines, cysteines, engineered cysteines, or unnatural amino acids. While mutant glycotransferases add specific activated sugar moieties to the mAbs at select glycosylation positions,24 transglutaminases link an amine group of the linker to an engineered glutamine residue on the mAb. However, conjugation development also involves handling of extremely toxic material that requires special handling equipment and personnel training that may not be feasible in every manufacturing facility. Highly potent active ingredients are usually categorized as health hazard class 3 or 4. While handling these compounds, operators may be required to wear respiratory protective procedures in addition to any other protective gowning procedures. Some of the toxic payloads are powders that need to be handled in an isolator under negative pressure to prevent them to be released into the environment. While the handling procedures of the payloads require special attention because they are in the powder form, the conjugation reaction must still take place in a closed system even if it is conducted in solution phase. Since it is not financially feasible to have molecule-specific suites, it is imperative that decontamination processes are in place to reuse equipment and facilities for various development projects and/or implement single-use equipment where feasible after addressing compatibility with disposable equipment. Complete and effective decontamination procedures need to be developed and validated to prevent carryover between projects. Decontamination procedures for highly toxic material need specialized training and protective equipment including selfcontained breathing apparatus. No significant aggregation was noticed in the corresponding unconjugated mAbs under the same conditions. The local surface around the conjugation sites was considerably more hydrophobic as expected. Specifically, since the hydrophobic toxins decrease the melting onset temperature (Tmonset), stability studies at elevated temperatures need to be carefully addressed for both International Council for Harmonisation requirements as well as comparability studies (both of which are out of scope for this chapter). Chemical hot spots, such as deamidation, isomerization, and/or oxidation sites in the unconjugated mAb still pose a problem for chemical instability. Lyophilized products in general have greater stability when compared to the liquid counter parts, though significant process development work is needed to ensure a stable lyophilized cake. As with a liquid protein drug product, developing a lyophilized product requires understanding of the basic rules of protein stabilization. General philosophies and rational design of lyophilized drug product are discussed by Carpenter et al. These doses translate to lower volume requirements in the vial, and hence, there is a need to understand the impact of drug product vial configurations in order to minimize waste and maximize convenience to the caregiver. Lower protein content in the vials also means that the total amount of protein in the vial will not contribute to overall structural stability of the lyophilized cake. A specific molar ratio of sugar to protein was shown to be necessary to provide storage stability of the antibody after lyophilization with various cryoprotectants. In contrast to conjugation development, which needs to occur under negative pressure, drug product needs to be filled under positive pressure to prevent the contaminants such as microbes and particulates in the final drug product vial. Similar to decontamination procedures for conjugation, specific procedures and analytical methods need to be developed for drug product processing and need to be considered prior to fill/finish activities for clinical purposes. The amino acids on the parent mAb are likely to undergo chemical modifications. Other methods using luminescence assays or fluorescence-based methods have also been developed that are capable of measuring living cells and provide a quantitative assessment of cell viability. Several studies have reported that after conjugating a hydrophobic drug to the antibody, no changes were noticed on antigen binding. It was concluded from this study that secondary structure is not altered by conjugation to any measurable extent. Intrinsic fluorescence of the protein can also be used to probe tertiary structure of the protein, especially in the regions close to the aromatic rings such as tryptophan. These Trp residues absorb around 295 nm and fluoresce between 330 and 350 nm, and any shift in the peak absorbance or fluorescence would indicate a change in structure. In addition to increased stability due to succinimide ring hydrolysis, Lyon et al. The small-molecule toxin adds significant challenges to both physical and chemical stability of the overall molecule as discussed previously in the "Formulation Development" section. In addition to the hydrophobicity of the toxin, the linker chemistry adds to the in vitro and in vivo stability as well. Deliberate hydrolysis of the succinimide ring by chemical hydrolytic pathways51 or self-hydrolyzing maleimides by incorporating a basic amino group next to the maleimide ring52 have been reported. Each of them brings a unique solution to a problem and will have to be tested in clinic. However, it was fully active when internalized by the host cells, and the linker was cleaved by intracellular proteases that release the active antibiotic. The use of site-specific conjugations and radiolabeling may provide a more uniform product with potential benefits in the clinic. As required under this approval process, a randomized phase 3 clinical study was later conducted in 2004. Certainly, the use of engineered amino acids for site-specific conjugation seems to lead the way and will herald in novel cancer therapies in the future. The expiry or impending expiry of patent(s) and data exclusivity periods for these already-licensed biopharmaceuticals permit potential introduction to the market of lower-cost "copies" of these biologically produced molecules. Government bodies, academic institutions, and medical practitioners have all shown great interest in bringing "copies" (called biosimilar products) of biopharmaceuticals expeditiously to market post-loss of exclusivity of the original product in order to enhance patient access to these efficacious-but, very expensive-drugs while concurrently reducing costs incurred by healthcare systems. The arrival of biosimilars requires engagement between pharmaceutical scientists and healthcare professionals to cascade an understanding of the science underpinning the regulatory approval of a biosimilar product [1]. Elsewhere in the world, the first biosimilars have already been approved, or the regulatory framework needed to approve biosimilars is in advanced stages of enactment. The approval of biosimilars is a highly regulated process which includes extensive similarity assessments (direct comparisons with the originator or reference product) that feed into the "totality of evidence," demonstrating biosimilarity and, ultimately, in gaining regulatory approval or licensure [2,6,7]. This is a paradigm shift in thinking compared to novel (non-biosimilar) product development. As a consequence, the demonstration of analytical similarity with a high degree of confidence using state-of-the-art methodologies enables reduced nonclinical and clinical data packages. The heightened importance of the analytical similarity assessment using sensitive state-of-the-art methodologies to detect minor differences in structure and function in head-to-head comparisons between the proposed biosimilar and its reference product requires that state-of-the-art analytical techniques, expertise, and adequate manpower be available to the developer for the successful conduct of biosimilar product development programs. Naming of biosimilars and interchangeability/automatic substitution are topics currently under discussion and debate. Biosimilar Development Paradigm Overview In developing a biosimilar for the global market, the first step for a developer is to gain a thorough understanding of the evolving regulatory requirements as well as the expectations of national regulatory agencies in regions of the world where the product is expected to be marketed. Biopharmaceuticals are made by living cells and have intrinsic structural complexities. Since no two cell lines that were developed independently can be expected to produce a biological product that is structurally identical, biopharmaceuticals cannot be copied exactly. Additionally, product- or process-related impurities can provoke an immune response [8]. A biosimilar is required to have the same route of administration, dosage form, and strength as its reference product as laid out in the definition of a biosimilar found in the Biologics Price Competition and Innovation Act of 2009 [12], which enabled the biosimilar regulatory pathway in the United States. Glycosylated biosimilars require special attention to the structure and function of their complex carbohydrate moieties as they can be involved in the MoA for these medicines such as increase or decrease cell signaling, enzyme activity, or gene expression. Biosimilars can be developed during the period in which the originator product (reference product) is still protected by patent exclusivity, but they can only be marketed after the patents and data exclusivity protecting the originator product have expired or, in the case of patents, successfully challenged [17,18]. In general, this means that the originator biological product must have been authorized for marketing for at least 10 years before a biosimilar can be made available by another company [3]. The European Commission Consensus Paper "What you need to know about Biosimilar Medicinal Products" provides a useful source of further information about biosimilars [15]. Parenteral Medications the proposed biosimilar product to the reference product [6,22]. The expectation for a full Module 3 reflects the fact that the biosimilar product will likely have unique manufacturing processes and control procedures, different from that of the reference product. For example, the biosimilar product will likely use different raw materials, equipment, process controls, and acceptance criteria, and potentially establish a different formulation and possibly a different shelf life [6]. When changes to the manufacturing process (active substance and/or finished product) are introduced, there is no regulatory requirement for re-demonstration of biosimilarity once the Marketing Authorization is granted" [4]. Initial Considerations the paradigm shift in the product development process for biosimilar products necessitates consideration of unique requirements. Originators may not have submitted a license application for a particular product in every country. From a regulatory perspective, a biosimilar may only be submitted for approval through the biosimilar pathway if the reference product is approved in that country [7,23]. Understanding the markets in which the reference product is approved for marketing helps answer the additional questions that follow in this section. While regulators require that a biosimilar has the same strength and dosage form as the reference product, they may not require Drug Substance and Drug Product Process Development Strategy the process development for a biosimilar product follows the same principles as that of a novel biopharmaceutical. Genotropin is currently marketed in two strengths as auto-injectors, ten strengths as prefilled dual-chamber syringes, and two strengths in vials [27]. In contrast, Omnitrope, an approved human growth hormone biosimilar to Genotropin from Sandoz, is currently marketed in three strengths as auto-injectors, two syringes, and two strengths in vials [28]. Obtaining Health Authority agreement early in development for demonstrating comparability between dosage forms and strengths, as well as the number of strengths/ dosage forms to develop for each market, is strongly recommended. Originators may use multiple manufacturing facilities to cover the global distribution of approved/licensed products. An assessment should be conducted both as a paper exercise through researching published information on originator facility locations and registered production sites for specific products as well as experimentally through the analytical characterization of the reference product purchased from various regions. Due to the complexity of biologics and the highly specialized processes and equipment needed to manufacture them, drug substance production sites are typically limited to one to a few per product. Typically, the biosimilar pathway requires a biosimilar to be similar to the licensed product sold in that country. However, a full development program utilizing reference products acquired from multiple markets would make the global development of a biosimilar product extremely challenging from resourcing, budgetary, and logistical perspectives. Many country regulations or guidances have enabled an avenue for developers to utilize a single reference product source in each of the stages of the stepwise development including global clinical trials by demonstrating similarity of the single selected reference product for global trials to a country/ regionally relevant reference product [3]. Parenteral Medications Sourcing strategies for acquiring reference product for both surveillance and clinical testing can range from placing orders directly with the originator company to open market purchases. Sourcing from the open market may lead to increased number of reference product lots being characterized, which can add to the analytical data set but impose greater burden on human resources in analytical laboratories to perform the additional testing and tracking of samples that would be required.