Christopher D. Chiles, MD

• Assistant Professor of Medicine
• Division of Cardiology
• Texas A&M School of Medicine
• Scott and White Memorial Hospital
• Temple, Texas

This equivalence of effects is the basis for the use of electron beam arrhythmia prevalence zestril 10 mg purchase with amex, gamma blood pressure 300200 cheap zestril 10 mg with amex, or X-ray forms of radiation in radiation processing blood pressure chart senior citizens zestril 5 mg on line. However jack mack the heart attack i39m gonna be somebody discount zestril american express, the rate of energy deposition for the different sources of radiation can be quite different blood pressure chart based on height and weight purchase cheap zestril online, and this parameter may play an important role in the resultant effect on materials that are irradiated. Interaction of High-Energy Photons with Materials At intermediate photon energies that characterize the gamma ray and X-ray (Bremsstrahlung) sources of radiation used in the radiation sterilization process, the dominant channel for interaction of the photons with the orbital electrons occurs via a process called Compton inelastic scattering. This method of energy transfer is named after the person that first described the quantum mechanical relationships governing the scattering process [2]. A photon undergoing Compton scattering transfers part of its energy to the orbital electron. The amount of energy transferred to the electron will depend on the quantum mechanical relationships governing the scattering event but is usually sufficient to not only ionize the atom but also leave the electron with significant kinetic energy to continue the ionization process. In fact, the most probable Compton scattering event is a backscatter of the photon, which transfers maximum energy to the electron. For gamma rays emitted by a cobalt-60 source, a backscattered photon will deliver about 1 MeV to the orbital electron. The scattered photon continues to undergo scattering events and generate additional primary electrons until its energy is dissipated. The primary electrons have sufficient energy to ionize other atoms via an electron­electron inelastic scattering process. From a numerical standpoint, it is primarily these secondary electrons that are the source of the physical and chemical events that lead to the radiation-induced changes in materials and sterilization of the medical device/drug product. The photon functions as an initiator of the process that leads to radiation sterilization throughout the bulk of the medical device/drug product. Radiation Absorbed Dose and Measurement Definition of Absorbed Dose Energy must be absorbed by a material to cause change, whether it be sterilization of a drug product or change in a material property. Energy from the incident radiation is transferred to the material by various pathways as discussed in the previous section. The energy that is absorbed in a material from radiation exposure is termed absorbed dose. It is defined as the quantity of ionizing radiation energy imparted per unit mass of a specified material [4]. The previous unit that was used to measure absorbed dose was the rad, which is no longer in use (100 rads = 1 Gy). It is of interest to note that absorbed dose is defined in terms of a specified material. For example, two different materials could be exposed to the same incident radiation field yet receive different absorbed doses. Absorbed dose is measured with well-characterized materials/devices called dosimeters, and dose is normally recorded as dose delivered to the dosimeter. Many well-characterized dosimeters that are commonly used to measure absorbed dose have energy absorption characteristics that are water equivalent, so absorbed doses are effectively reported in terms of absorbed dose in water. In radiation sterilization applications that involve the biocidal action of radiation on microorganisms, the difference in absorbed dose between microorganisms and water is relatively small. However, this may be a moot point because the same dosimeters that are used to measure absorbed dose during routine processing of a product are oftentimes used to validate the acceptable minimum and maximum doses for irradiation of the product. Dosimetry-A Critical Part of the Process Absorbed dose is a critical parameter that impacts the radiation process from its beginning to its end. Accurate measurement of absorbed dose delivered to test samples is a critical part of this validation program. An acceptable maximum dose is determined by irradiation of test samples at specified absorbed doses and postirradiation analysis of the test samples. Doses need to be delivered to the test samples in a precise manner, which requires accurate measurement of the absorbed doses. In dose mapping, the product is loaded into the irradiation containers in accordance with a specified loading pattern and absorbed dose is measured at prescribed locations in the product load. The information from this dose map is used to identify the location and magnitude of the minimum and maximum doses. Upon completion of the dose mapping study, the product is ready for routine processing. During routine processing, absorbed dose is measured at specified locations in the run to confirm that all products in the run received at least the minimum absorbed dose and no product in the run exceeded the established maximum absorbed dose. As a final step, the absorbed dose delivered to product along with its certification is used to release the product. With dosimetric release, there is no requirement or need to perform postirradiation sterility testing. Because of the importance of absorbed dose in the overall radiation sterilization process, we obviously need to have a quantitative tool for its measurement. Furthermore, the measurements need to be accurate, and we must be confident in the measurement results. The quantitative tool that meets these requirements is called a dosimeter and is defined as a device that, when irradiated, exhibits a quantifiable change that can be related to the absorbed dose in a given material using appropriate measurement instruments and procedures. The dosimeter is only one part of the measurement system, which is referred to as the dosimetry system. In addition to the dosimeters, you require a calibrated instrument for measuring the dosimeter response as well as standards and procedures. A dosimetry system is defined as a system used to measure absorbed dose, Method of Measurement the dosimetry systems that are used in the radiation sterilization industry are divided into various classes depending on where they fit in the metrological hierarchy and field of application. Reference standard dosimetry systems are of high metrological quality and are used to calibrate the dosimetry systems that are used for routine measurements of absorbed dose at an irradiator. This class of dosimetry systems may be held at a given location; that is, take the form of transfer standard dosimetry systems operated by a national standards laboratory or an accredited dosimetry calibration laboratory. Transfer standard dosimetry systems are sent to an irradiator for irradiation and then returned to the calibration laboratory for confirmatory measurement. The concept of high metrological quality implies a dosimetry system with low uncertainty and traceability to appropriate national or international standards. A routine dosimetry system, which is used for routine measurements of absorbed dose at an irradiation facility, is calibrated against a reference standard dosimetry system. The dosimeters that are used for calibration purposes have high metrological quality and form a separate class of dosimeters from routine dosimeters that are used to measure absorbed dose at an irradiator. Routine dosimeters are still highly characterized and calibrated devices that provide accurate measurements of absorbed dose, although not to the same degree of precision as transfer dosimeters. Gamma Irradiators Irradiator Categories Nuclear regulatory agencies have divided gamma irradiators into four categories according to their design and operation. Because only two of the four categories may find a significant application for irradiation of medical products, the discussion is limited to these categories. This category irradiator was noted in the section on the interaction of radiation with material as a possible source for blood irradiation. Irradiation of blood as well as some types of drug products fits that product profile. Other possible applications for Category I irradiators may include irradiation of test product, clinical studies, research, dose validation, and calibration. The radioactive source in Category I irradiators remains shielded inside a biological shield at all times, and it is not possible for an individual to come in contact with the source at any time. For this reason, the regulatory agencies treat this category irradiator differently from the other category irradiators. Category I irradiators are relatively small, that is, typically less than several feet in diameter and several feet in height, and could easily fit in the space that normally serves as a room in a laboratory. When not in use, the sealed gamma source is stored in a large pool of water within a shielded room that is referred to as the cell. When all personnel have safely exited the cell and a safety system is activated, the sources are automatically raised from the pool of water into the room and irradiate product that is within the cell. First, a source of ionizing radiation comes in the form of a radioisotope, usually cobalt-60 that is doubly encapsulated to form sealed sources. Sources of this type are grouped into racks that are stored in a pool of water inside a shielded room called the cell. Because the radiation levels to kill microorganisms are typically 1,000 times greater than the levels to kill or harm individuals, a biological shield that surrounds the cell is required. The shield is typically built of concrete with walls and ceiling approximately 6 ft in thickness. However, to reduce the size of the cell, the biological shield can be metallic in nature. A redundant safety system to protect personnel and preclude entry to the cell when the sources are exposed is required. A control system that usually takes the form of a programmable logic controller is required, and an air exchange system is also required to remove ozone from the cell-ozone that is produced from interaction of the gamma rays with oxygen molecules in the air. Lastly, a deionized water and chiller system is needed to eliminate ionic decay of equipment and remove excess heat that is transferred to the water when the source is "parked/down" position. For example, these containers may consist of aluminum or stainless steel boxes called totes, carriers, or possibly entire pallets of product. Depending on the irradiator design, totes may vary in length and height from a few feet to as much as 10 ft in height. The width of the tote, which is the dimension through which the gamma rays must penetrate, is typically 2 ft or less in size. A carrier may typically have a footprint similar to a tote but may be several feet taller in height. Some carriers have single shelves to minimize or maximize dose characteristics of the irradiator for more precise dosing. In some irradiators, an entire pallet of product is loaded onto the conveyance system as an entity. Regardless of the size and design of the irradiation container, most gamma irradiators move product through the cell in what is referred to as a "shuffle-dwell" principle. In a shuffle-dwell operation, the irradiation containers shuffle to a location in the cell where they accumulate in rows that surround the source plane. They dwell at each location for a preset time called the cycle time after which they shuffle to the next location, and the operation is repeated until the container has fully traversed all positions in the cell. In a batch mode, the irradiation containers are loaded with product and moved into the cell, where they are positioned around the source location. The source is then raised, and the irradiation containers then proceed to increment around the source in a shuffle-dwell mode until the product has received the required dose. The source is then lowered back into the pool of water and the irradiation containers removed from the cell. In a continuous mode of operation, the irradiation containers continuously move into and out of the cell while the source(s) is in the exposed (up) position. This mode of operation can be accomplished by moving the irradiation containers through a shielding maze before entry to the cell. The irradiation container is typically approximately 3 ft in length by 10 ft in height by 2 ft in width. The irradiation containers are moved into the cell through a maze via a floor or overhead conveyor. Once in the cell, the totes accumulate around the source plane and proceed to increment around the source in a shuffle-dwell mode. This is due to the fact that the radiation field is isotropic in nature; that is, the gamma rays are emitted in all directions from the cobalt-60 source. For this reason, it is important to surround the cobalt-60 source with product containers, thereby capturing as many of the source photons as possible and in the process, increase the intrinsic efficiency of the irradiator. Because of the size of the tote and volume of product in the tote, not all products in the tote will receive the same absorbed dose. Even in an empty tote, the absorbed doses are different at various locations within the tote due to the different distances from the source. A similar effect can be noted from the isotropic emission of optical radiation from a light bulb. Electron Beam Irradiators Design A high-power electron beam accelerator is at the heart of an electron beam irradiator. The accelerator serves as the source of radiation analogous to gamma rays in gamma irradiators. The different types of electron beam accelerators that are used in the radiation sterilization share one common attribute, which is high output power. Power equates to throughput, and electron beam irradiators similar to gamma irradiators are capable of processing millions of cubic feet of product per year. Electron beam irradiators share many of the same design features as gamma irradiators. You need a biological shield to protect individuals from the high levels of radiation that exist in the cell when the accelerator is operational, a conveyance system to transport product in front of the beam of electrons, and a safety system that precludes entry to the cell when the accelerator is operational. In addition, you need a system for controlling the irradiator and an air recirculation system to remove ozone from the cell. In this type of accelerator, electrons are accelerated in a resonant cavity that is cylindrical in geometry. This accelerator design is capable of very high output powers, and depending on the port from which the electrons are extracted, it can deliver different energy electrons up to 10 MeV. Because electrons are charged particles, they can be steered and directed using magnetic fields. Because the electron beam exiting an accelerator is typically only a few cm in diameter, the beam needs to be scanned in a transverse direction to the motion of the product on the conveyance system, thereby ensuring high-energy electrons uniformly irradiate the entire product surface. Magnetic fields can be used to deflect the beam using a device called a scan horn. Beam scan and conveyor motion need to be synchronized to ensure that all parts of the product are irradiated. Alternately, linear accelerators called Linacs may be used as the source of highenergy electrons and product conveyed in carriers horizontally in front of the beam of electrons. Depending on the application and mission of the irradiator, other configurations are also possible.

For example blood pressure 60 over 40 discount zestril 10 mg otc, if sodium hydroxide solution was used for cleaning arteria heel purchase zestril canada, the pH of the cleaning agent could be above pH 12 hypertension 24 hour urine test zestril 2.5 mg purchase fast delivery. At high pH blood pressure normal low pulse rate 5 mg zestril order with mastercard, Compound A is very soluble and Compound B is clearly the worst-case product for cleaning blood pressure 9060 purchase zestril 5 mg free shipping. If the cleaning agent used for these residues is a formulated alkaline cleaning agent containing surfactants, solubility at high pH as well as solubilization by micelle formation should be considered. In either alkaline pH cleaning, Compound B is the worst-case residue and should be selected for cleaning validation in a matrix approach. If products containing sulfamethoxazole were cleaned using an acid cleaning agent, solubility in acid pH should be considered. If products containing sulfamethoxazole were cleaned using water, solubility at neutral pH should be considered. Knowledge of the compound pKa (or multiple pKa), the pH at which 50% ionization occurs, is key information. The selection of a worst-case compound for cleaning validation is a critical element of any cleaning program that supports the cleaning of multiproduct equipment. These assessments must be carefully made considering all relevant technical information, including the physical and chemical properties of the residues. Incorrectly identifying worst-case soils for cleaning validation undermines the entire cleaning program and exposes an organization to significant regulatory risk. If a worst-case compound is incorrectly selected, the cleaning validation of all residues in the matrix may be compromised. This information along with compound structure, pKa, and other pharmaceutics information provides valuable information for worst-case residue selection. Much of this information is always developed during new drug and new product development. This information is valuable for screening drug candidates, prediction of biopharmaceutical properties, formulation development, dissolution testing, and other applications. Cleaning professionals should interact with pharmaceutics scientists to be sure that their technical needs are met when this basic pharmaceutics development work is done. A slight increase in solubility occurred in alkaline surfactant liquid (typical cleaning agent). Solubility in the cleaning agent liquid should be the primary consideration in determining the worst-case compound for cleaning validation. However, cleaning of the entire product matrix, including slow-dissolving polymers or other problem-inactive ingredients, may profoundly affect the choice of cleaning agent. Regulatory considerations: A matrix approach to cleaning is acceptable when the matrix is well defined and considers many parameters in defining the matrix. However, other parameters that should receive consideration include the following: · · · · Pharmacological aspects of the product Known toxicity Potency based upon the dose of the active substance Quantity or percentage of active substance in the formulation · Release mechanism of the product to be cleaned. Parenteral Medications highly prudent to verify the matrix theory by performing cleaning verification studies at periodic frequencies to verify that the cleaning strategy in place is effective. A correctly chosen worst-case product is fundamental for a science-based technical cleaning program. Most toxic residue (or residue with lowest pharmacologic dose) is another consideration. Toxicity (or dosage) is considered in the well-known Fourman and Mullen residue calculation. Another consideration in determining the most-difficult-to-cleaning residue in a cleaning matrix is residue "cleanability," or the ability of the residue to be cleaned. However, if another similar plate (Plate B) from dinner was allowed to rest untouched in the kitchen for several days allowing the residue to dry and harden, the residue would be much more difficult to clean. Relating this example to pharmaceutical cleaning, the cleaning process for Plate B would be much more rigorous than would be required for Plate A to accomplish equivalent cleaning. This analogy has also been used to caution cleaning validation practitioners about rinse samples. A rinse sample from equipment immediately washed after manufacturing is much more meaningful than a rinse sample removed after residue had dried for several hours. Many cleaning practitioners evaluate worst-case residues by considering only the solubility and toxicity of the compound of interest. While this approach may be acceptable when all products manufactured at a site are relatively easily cleaned, such as aqueous parenteral solutions containing water-soluble ingredients, it is not adequate for more complex dosage forms. The cleanability of products containing polymers, such as controlledrelease tablet products, may be significantly affected by inactive excipients. For example, consider two formulations containing the same active ingredient but having different inactive formulations. One may have primarily soluble ingredients and be rapidly dissolving, while the other is designed to slowly dissolve and provide a prolonged release of drug over an extended time period. The "cleanability" of these two formulations could be markedly different even though they contain the same active ingredient- with the same solubility and toxicity. However, the knowledge of pharmacological properties of active substances can provide more meaningful data and should be considered when establishing a matrix. The output of a cleaning matrix is often a numerical value for each active substance. A threshold value is established, and if this value is exceeded, cleaning validation is required. If the value is not exceeded, cleaning validation is not required, based upon the sound scientific principles of the matrix. Notwithstanding, it is Cleaning Validation-Lifecycle Approach product must be considered. Another example is as follows: a set-granulation tablet formulation residue is easily cleaned when cleaning is initiated immediately after manufacturing is completed. However, if residue is allowed to rest in equipment over a weekend and dries and hardens, cleaning becomes much more difficult. Note the similarity between this example and the dried spaghetti sauce residue example described above. Consultation regarding residue "cleanability" with manufacturing personnel who perform actual cleaning is recommended. Manufacturing personnel are often overlooked when determining difficult-to-clean dosage forms. Their input into determining most-difficult-to-clean residues and product groupings can be very valuable. Cleaning procedures should not be developed solely through discussions in conference rooms. Input "from the floor" expressed by people who have experience with doing the actual cleaning coupled with laboratory work, including solubility information, is critical for the determination of worst-case residues. The mostdifficult-to-clean residue is a key determination for a cleaning validation program. It is critical that it be done correctly for a successful cleaning validation program. If worst-case locations on equipment pass cleaning validation, it may be assumed that all other locations on equipment are clean. Identifying worst-case locations on equipment by careful and deliberate analysis is vital for a cleaning validation program. There is general agreement that most-difficult-to-clean areas of equipment must receive maximum attention in the cleaning process and be appropriately tested (swab or rinse sampling) in cleaning validation. How these locations are determined has not been thoroughly discussed in the literature. Often selections of sampling sites are arbitrary and based on the expertise of one or more individuals. The approach to determine the most-difficult-to-clean sites should be documented in policy or procedure. Thereafter, the actual determination of sampling sites for each system along with appropriate justification should be documented. The following briefly describes specific steps to determine worst-case locations for cleaning and cleaning validation: 1. Equipment technical analysis: the design, structure, and function of the equipment are considered in the equipment technical analysis. This analysis should yield a theoretical analysis by expert individuals about potentially difficult-to-clean areas on equipment. Observation of equipment after processing: the equipment is observed after processing typical pharmaceutical products. Observation of multiple product lots is recommended, especially if different products are manufactured on the same equipment. Manufacturing operators who clean equipment can recommend products to be observed. This analysis yields practical information about residue accumulation based on actual manufacturing performance. Equipment technical analysis Observation of equipment after processing Equipment disassembly review Cleaning procedure review Operator interviews Analysis and evaluation of above information Preparation of sampling documents for cleaning validation Documentation of above Equipment Considerations Equipment considerations are fundamental to cleaning and cleaning validation-dirty equipment is cleaned by the validated cleaning process. It is these areas of the equipment that should receive appropriate emphasis in the cleaning procedure. These areas must also be tested in cleaning validation-if the highest risk areas of equipment can be adequately cleaned, then all other less difficult areas of equipment are considered to be clean. Two equipment-related areas that are often overlooked or not well defined in cleaning validation programs are discussed. They include the following: · Most-difficult-to-clean locations on equipment: these are areas of greatest concern in the cleaning process and that should be specifically tested in cleaning validation. If most-difficult-to-clean sites are able to be cleaned, other locations on equipment are assumed to be clean. Most-Difficult-to-Clean Locations in Equipment Most-difficult-to-clean locations on equipment are worst-case locations. Equipment components that are disassembled for cleaning and subsequent evaluation pose a much lower risk than components that are part of the equipment main assembly and are cleaned in place. Parts and equipment locations previously identified as difficult to clean may not be difficult to clean after equipment disassembly. Operator interviews: Discussions with operators experienced with cleaning the equipment of interest are utilized to determine difficult-to-clean locations. Their recommendations of difficult-to-clean areas of the equipment based on actual experience are noted. Analysis and evaluation of above information: All of the above information is integrated and evaluated. Judgments are made to finalize the selection of mostdifficult-to-clean locations on equipment. These determinations must then be considered in development of the cleaning procedure and selection of sampling sites for cleaning validation. Preparation of sampling documents for cleaning validation: All of the above information is used to prepare sampling pages for use in cleaning validation. These documents are then submitted to the validation approval committee as supporting justification for the equipment sampling pages. Sampling pages and designated sampling sites are then used for all cleaning validations. When auditors review cleaning validation, rationale for the selection of sampling locations is a logical question. This documentation package supports the selection of sampling locations on equipment. A cleaning validation program should include a technical and science-based approach for identifying worst-case locations for cleaning and for sampling. Correctly identifying worst-case locations for sampling is essential for a credible cleaning validation program. If worst-case locations are not correctly identified and are, thus, not sampled in cleaning validation, assumptions about the entire equipment being clean cannot be made. This is especially the case when certain parts of equipment are not disassembled but are cleaned as-is. Cleaning Validation-Lifecycle Approach When items of equipment such as pieces of pipework that are connected by triclover or other clamps or gaskets are not disassembled during cleaning, the rationale for adopting this approach should be documented and the effectiveness of the cleaning process demonstrated. This can be done during cleaning validation exercises or when cleaning verification studies are performed-the items should be disassembled and inspected/swabbed to determine their level of cleanliness. Assuming that material simply cannot enter the space between the individual items of equipment is not an acceptable approach, and it can lead to significant patient risk, as well as significant deficiencies during regulatory inspections. Another area that can lead to deficiencies during regulatory inspections is the documentation of swab locations on equipment. While the determination of the sites for swabbing might have been performed well, the documentation of such locations is often inadequate and not specific enough for the item of equipment in question. Swab locations are sometimes documented using wording such as "swab at the base of the dryer" or "swab near the valve on equipment. Another factor that can limit the effectiveness of worst-case sampling studies relates to how equipment is described (or drawn) in cleaning validation procedures/reports. Often only very simplistic drawings of vessels, dryers, filters, filling equipment, encapsulators, etc. For example, the amount of residual active ingredient from the previous product is not uniformly transferred to subsequent product in a liquid-filling process. Residue is transferred nonuniformly to the first part of the lot when the next product initially contacts filling equipment. Product A manufacturing: Product A is manufactured in the mixing tank and filled into vials using filling equipment.

Decisions regarding commercialization of a product must be balanced with technical and regulatory expectations blood pressure chart high diastolic generic 5 mg zestril otc. Quality Target Product Profile the importance of understanding the therapeutic expectations for the product cannot be underestimated pulse pressure 16 zestril 5 mg buy cheap. The connection between the quality of the product and its impact on safety and efficacy for the patient is paramount blood pressure zona plus discount zestril 2.5 mg fast delivery. Certainly blood pressure chart jpg effective zestril 2.5 mg, there are physical and chemical properties of the product that influence quality attributes required to ensure safety and efficacy are important blood pressure medication edema order 10 mg zestril visa. However, other relationships between product quality and patient need should also be considered. A portion of the intended patient population may have tolerability or allergic responses to specific components typically used in a product or formulation. The inherent complexity of developing a drug product that behaves identically for each individual is a daunting challenge. Understanding risk and assessing which risks are important are at the core of QbD. In fact, it is the process of assessing, controlling, and reviewing risks throughout a product lifecycle that instigates a systematic approach to developing process understanding and generates the development of design space and results in the establishment of a robust control strategy. A robust quality risk management process typically requires the collaboration of a cross-functional team of experts from a variety of pharmaceutical science disciplines. Evaluating risk based on scientific knowledge that may reflect their collective prior experience or theoretical or conceptual analysis is extremely important to adequately address all of the potential sources of variability in a manufacturing process. Understanding what is known and recognizing and acknowledging uncertainty about what is not known is the beginning of the risk management process and can only be adequately addressed by adhering to the primary principles of quality risk management: · the evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient. Certainly, an increase in the level of risk warrants concomitant and proportionate diligence in characterizing and evaluating and managing risk. In addition, transparency in describing and conveying the judgment basis of risk assessments, regardless of the level of risk, is useful for anticipating and potentially preventing failure. Risk Assessments Variables evaluated in a risk assessment should be judged relative to the following questions [10,29]: · · · · What might go wrong Answers to these questions provide the relevant criteria by which risk is judged, namely, the severity, uncertainty, and probability that a risk may pose and whether or not a risk can be detected. Many companies in the industry employ a scale that differentiates catastrophic from a negligible impact [30]. Uncertainty is the unknown level of understanding for which the variability of a process parameter or quality attribute influences the severity and/or probability of risk to the safety, efficacy, and quality of the product. Probability is the likely occurrence of impact on the safety, efficacy, and quality of a product. Probability is generally characterized by an estimate of the degree of variability of a parameter or attribute to impact quality and may consider the combination of operational controls in place that reduces the level of probability. Detectability is the ability to discover or determine the existence, presence, or fact of a hazard [10]. The ability to detect variability of a parameter or attribute and the relative sensitivity to variability can provide appropriate mitigation for a risk. The combination of these criteria is used together to assess the risk parameters and attributes that may pose the quality of the product. They may rely on a combination of prior knowledge, experience, and/or experimentation. A vast variable space exists, often referred to as "knowledge space", that contains inputs and outputs which can be described and labeled as process parameters and quality attributes, respectively. Through a risk assessment, what is not known is identified from what is known or judged to be understood. In this step of the process, the question of what can go wrong is addressed and a list of potential hazards is cataloged. Risk Identification and Analysis An estimation of the risk may be qualitative or semiquantitative and may be the result of ranking risks in a "cause and effect" (C&E) matrix, or other tools associating process parameters with their potential impact on quality attributes. The objective is to establish the functional relationship between quality attribute (y) and process parameters (x). Each quality attribute is assigned a "weight" score based on its potential impact to product quality, safety, or efficacy. A cumulative score is then calculated for each parameter using the following equation: Cumulative score = (Impact of parameter × Weight of quality or process performance attribute) C&E Matrices A C&E risk assessment is performed to capture the current process understanding and to prioritize the process parameters that require further study or experimentation. Identify and rank attributes (quality and process) for each focus area/unit operation. The quality attributes for the final drug product should be identified prior to the creation of C&E matrix. Each process parameter (input) is assessed based on the potential impact on the outputs of a particular focus area, including quality attributes or process performance attributes. The inputs are process parameters that can be people, equipment, measurements, process, materials, environment, etc. The maximum cumulative score will vary by focus area and will depend on the number of attributes scored. The cumulative score represents the relative importance of a process parameter for the focus area (or unit operations), so parameters with high scores could potentially be of high risk to product quality or process performance and should have supporting process understanding. Quality attributes specific to process intermediates, product specification, or quality targets are considered. Process performance should be focused primarily on important performance indicators. The Severity assessment is conducted with the primary input from process experts using prior knowledge gained from process characterization pilot-scale and full-scale process batches. The scoring scale is consistent with Severity (1­9) with the highest Occurrence assigned to parameters with the greatest likelihood of a deviation. Other considerations may include prior knowledge, manufacturing history, equipment failure, and human error. The scoring range was consistent with scores assigned for Severity and Occurrence with the highest scores assigned to process parameters with limited or no means of Detection. Considerations include equipment control capabilities, deviation alarms, and tracking. A final Risk Priority Number is assigned based on multiplying the scores for Severity, Occurrence, and Detection (S × O × D) with appropriate rationales for each process parameter described. The analysis of functional relationships can distinguish the level of risk and serves to prioritize relevant studies or experiments required to evaluate the risk. Another way to identify and analyze risks and organize them in an orderly fashion is to use an Ishikawa Diagram. Frequently, Ishikawa diagrams are used to identify the potential causes of a specific problem. For example, the risk of having production defects in a tablet can be traced to the potential sources of variability that create that risk. Each of these tools alone or in combination with one another can provide a preliminary and systematic assessment of risk. However, it is subsequent evaluation of risk where scientific experiments, models, and simulations can increase understanding of the risk and lead to design space to describe the area within which risk can be controlled. Subsequent assessments may distinguish acceptable risks from risks that require controls and/or methods for measuring control. Parenteral Medications · Use of formal risk assessment criteria to identify and differentiate critical from noncritical sources of variability and determine which variables are important to study and control. As the lifecycle of a product evolves from pharmaceutical development through technology transfer, during commercial manufacture and with the introduction of product enhancements and alternative formulations, the functional relationships between parameters and attributes and quality attributes of the product may change. Reassessment of functional relationships, adjusting design space boundaries to accommodate changes in the manufacturing process, and establishing new design space increase process understanding and product knowledge and provide improved quality assurance of the product. Risk Evaluation Identifying the sources of variability among process parameters that may pose risk to quality attributes allows for an analysis of the impact and probability of that risk causing harm. The importance or magnitude a risk poses often leads to the development of an experimental strategy to evaluate the level of risk. The functional relationships between process parameters and quality attributes within the focus areas of a manufacturing process provide the opportunity to evaluate the risk quantitatively and characterize boundaries of that risk through experimentation. Design of Experiments DoE is a structured and statistical approach to evaluating the interactions of process parameters and their impact on quality attributes [31­36]. Multiple parameters are studied simultaneously, which allows the estimation of interactions between factors. The designs can be structured to specific objectives, that is, factor screening or response surface exploration as well as identifying resource constraints. The use of DoE offers efficiency for estimating parameter effects and control over precision of response prediction in the case of response surface designs. They are comprehensive in nature, eliminate subjective assessments, and provide data with a wide inductive basis. Model building can be used to condense the raw data into systems of equations, which describe relationships and thereby facilitate interpretation. Sequential experimentation provides incremental understanding of the relationship between parameters and quality attributes by converging to conditions which produce the desired product. Estimation of all effects including interactions provides a wider inductive basis for the experiment. The statistical approach to DoE is useful in quantitatively characterizing the level of risk that any given parameter or attribute may pose in a multivariate expression. The variety of statistical approaches generate data that can be used to optimize the understanding of the boundaries of parameters and attributes in a design space and thereby improve the understanding their relative risk may have on quality of the product. Scientific and risk-based assessments meet several fundamental objectives of QbD: · Risk assessments are useful for characterizing and ranking attributes process parameters semiquantitatively relative to their impact on safety and efficacy. Risk Control Decisions on what level of risk is acceptable have frequently centered on which parameters and attributes are "critical. For example, genotoxic impurities can be purged and controlled in the third step of a six-step synthesis of a drug substance. Stoichiometry, temperature, and pH of the reaction have been demonstrated to impact control of genotoxic impurities. Subsequent demonstration that the process consistently operates within the design space reduces the risk. In many instances, an appropriate risk management strategy will reduce the risk to an acceptable level where severity and probability may be mitigated by adherence to parameter and attribute boundaries. The acceptability of risk is often a decision that balances the presumed impact of the risk relative to appropriate controls to mitigate that impact. However, if the drug itself is mutagenic and is indicated for firstline therapy for breast cancer, the presence of these impurities should be balanced with the benefit of the drug and its duration of use. If reduction or elimination of genotoxic impurities is cost prohibitive or results in other quality issues, then acceptance of limits for these impurities that exceed the standard regulatory expectation may be justified. The inability to associate quality attributes with safety and efficacy increases the level of uncertainty in assessing risk. Furthermore, the inherent difficulty to precisely characterize many biological molecules reduces the opportunities to develop concrete process understanding. However, examples and case studies describing the application of QbD principles and, in particular, quality risk management approaches have demonstrated limited success [38­42]. QbD principles can be utilized for large-molecule drug product development (formulation and process) can be performed and are illustrated in sections below. Design Space for Drug Product Drug product development typically includes an assessment of the formulation (via a DoE study) and the manufacturing process. In this section, an example of a formulation DoE is provided, which defines the factors that impact the quality attributes. This will be followed with an assessment of one unit operation lyophilization where the important parameters that impact quality attributes are defined. Based on the assessment of prior knowledge, impact of formulation excipients on the quality attributes during storage needs to be assessed. A formulation DoE design was prepared for a protein at a concentration of 150 mg/mL. The study was performed with 1 mL fill volume in a prefilled syringe with a coated plunger for closure. A full-factorial experimental design was utilized, for studying each factor individually and the interactions between the factors. A total of 15 different formulations including the formulations with varying excipient levels, and dual center point formulation were evaluated during the stability study. The stability study was performed at 5°C (intended storage condition), 25°C (stress condition), and 40°C (accelerated stress condition), and quality attributes such as total impurities, protein concentration, pH, and subvisible particles (10 µm and 25 µm) per container were assessed. The data at 25°C for 6 months were obtained, and the resulting analyses are provided in this section. A significant change in percent total impurities was seen in samples at the high and low pH conditions during storage for up to 6 months. Risks should be characterized by their respective and relevant relationship to quality attributes and process parameters and documented in a logical manner that shows the relationships between product quality and the attributes and parameters that influence quality. A general summary of the risk assessment approach and justifications for decisions regarding the attributes and parameters that warrant concern is helpful to regulatory authorities and should be transparent and reproducible. In a regulatory submission, a description of the process used to evaluate and characterize risks should be provided. Regulators are keen to understand how a sponsor distinguishes which attributes and parameters to study from those parameters and attributes that are noncritical [12,13,17­19]. Use of QbD Principles in Protein Drug Product Development QbD principles are applicable to both small-molecule drugs and large molecular biologics. However, the challenges of executing risk assessments are greater for a biological because the large size molecule (biological molecule) is vastly more complex and the impact of attributes and process parameters on product quality attributes is generally more uncertain than for small molecules. In addition, the complicated nature of generating biological molecules from living organisms can lead to significant product heterogeneity. The inherent complexity of biological 820 showed a variation which is expected for proteins stored at stress conditions. The slope is linear for the impact of sucrose on pH, percentrelated impurities, protein concentration, and subvisible particles (25 µm) per container. The impact of sucrose on subvisible particles (10 µm) per container showed a slight increase with moderate impact on p-value, which can be attributed to the variability in the data seen for subvisible particles (10 µm) per container.

This can be a useful starting point demi lovato heart attack buy zestril 2.5 mg low cost, if the planned cleaning regime is to be conducted at those temperatures blood pressure chart home use buy zestril on line. If a substance is deemed to be poorly or sparingly soluble at 20°C­25°C blood pressure bottom number best order for zestril, one cannot assume improved and increased solubility at higher temperatures blood pressure 8555 purchase zestril 5 mg without a prescription. It is important to consider the following factors when considering using a detergent: · Solubility of the active substance in the detergent must be studied and quantified blood pressure medication depression side effects purchase zestril overnight. For example, it is conceivable that the detergent could bring about the degradation of the active substance into a pharmacologically active species, which is both (i) more difficult to clean than the active substance (based upon solubility) and (ii) nondetectable by the analytical test method chosen to measure Parenteral Medications residual active substance. This will require validation or verification using an appropriately validated analytical test method. The knowledge of basic solubility studies forms the backbone of any cleaning strategy. Poor solubility will have a potential effect in poor analytical recovery studies and ultimately, poor cleaning cycles. Residue Solubility of Most-Difficultto-Clean Residue Matrix Facilities in which multiple products are manufactured on the same equipment minimize the work of cleaning validation by conducting cleaning validation on the most-difficult-to-clean residue, that is, a matrix approach to cleaning. If the worst-case residue is demonstrated in validation that it can be successfully cleaned, it is assumed that all other easier-to-clean residues are able to be cleaned. All products in the comparison group must be cleaned by the same cleaning procedure. Determining the mostdifficult-to-clean residue is thus a key determination for a site cleaning program. Comparison of respective product residue solubilities is a key factor used to determine worst-case residue for cleaning validation. Other references may provide more extensive solubility data in different pH solutions and in solvents such as alcohols and organic solvents. Compound A contains an ionizable acid moiety that is soluble in alkaline solutions. Compound B has essentially the same solubility at all pH conditions (acid, neutral, and basic). If the equipment used to manufacture these products was cleaned using only water, Compound A has lower solubility and would be considered the worst-case residue. However, if the equipment was cleaned with an alkaline cleaning agent, solubility in the cleaning agent liquid should be considered. Completion of Product A manufacturing: After completion of manufacturing and filling, Product A residue is present in the equipment. Equipment cleaning: the equipment is then cleaned using the validated cleaning process. Product A residue: Remaining Product A residue is below the calculated maximum residue limit on mixing tank and on filling equipment. Product A residue in Product B: Product A residue (remaining in tank after cleaning) in the tank is uniformly transferred to Product B. Product B filling: When filling of Product B is initiated, Product B enters filling lines and filling equipment. Product A residue in first vials of Product B: Product A residue is nonuniformly flushed into Product B containers-first containers of Product B will have maximum Product A residue. Equipment with potential for nonuniform contamination of the subsequent lot poses the greatest risk to the patient. This includes equipment after the final mixing/blending step in the equipment process Nonuniform Contamination Transfer Contamination may be transferred uniformly or nonuniformly from equipment into product. Uniform transfer occurs when all residues on shared equipment are completely transferred to the next product lot to be manufactured. In contrast, the residue on equipment such as transfer lines and filling equipment (postmixing tank) is transferred to the next batch when the product initially contacts the equipment, that is, nonuniformly. Both uniform and nonuniform transfer of residue must be considered in cleaning validation. Nonuniform contamination sites are the highest risk sites on equipment to be cleaned. Cleaning validation focuses on the minimization of carryover between successive products manufactured on the same equipment. The amount of a contaminant from one product lot transferred into a subsequent different product manufactured in the same equipment must be less than a predetermined acceptable limit. Calculation of the maximum residue level acceptable for transfer is based on the approach of Fourman and Mullen where the shared surface area of manufacturing equipment is used to estimate the maximum allowable carryover. This approach assumes uniform contamination across all shared surfaces, and quantitative transfer of the first product residue into the subsequent product to be manufactured. For example, all product residues in a mixing tank are uniformly transferred to the next batch that is mixed in the same tank. This equipment nonuniformly transfers residue to the first containers or units of subsequent product. Nonuniform contamination may be easily addressed by calculating the maximum residue in the nonuniform equipment surfaces. The initial volume or units of subsequent product containing high levels of residue are then discarded. Losses in equipment setup, fill volume adjustment, or weight adjustment at the start of manufacturing often serves to eliminate high-residue units. Cleaning professionals must be aware of nonuniform contamination and must be certain that setup rejects are sufficient to eliminate highly contaminated product. This is potentially a serious risk, with respect to both patient safety and regulatory compliance. Organizations that base their entire programs on the Fourman and Mullen calculation are overlooking the potential for nonuniform contamination. When the potential for nonuniform contamination is considered, it is sometimes done in an unscientific manner and is easily challenged on inspection. One such scenario is when a company sets an arbitrary number of filled units to be discarded immediately after the start of filling, such as the discarding of the first five bottles filled. The scientific basis for the number of units that are to be discarded is something that should be based on a worstcase calculation of the extent of the nonuniform contamination. Parenteral Medications validation must be appropriate for the actual residue present on the equipment surface. Most cleaning validation protocols require quantitative analytical determination of the analyte of interest, and subsequent comparison of the analytical result to predetermined acceptance criteria. Analytical methods for residues must have appropriate specificity and sensitivity as required by residue calculations. However, is the measured quantity of the residue actually present on the equipment, or has it been destroyed Residues may remain in the equipment for an extended period of time before cleaning is initiated. Depending on its stability, the residue may undergo hydrolytic, oxidative, or photolytic decomposition prior to initiation of cleaning. Residues may be wet or dry; decomposition is more likely if moisture is available for reaction. Cleaning liquid pH may be acidic or alkaline depending on the type and concentration of cleaning agent used. There must be good understanding of the stability properties of residues so that appropriate analytical methods are developed. The analytical methods must be able to detect degradation products if the cleaning conditions (such as high temperature or extreme pH) may cause degradation of the active ingredient. The stability properties of a compound are fundamental information in pharmaceutical development. This information is always developed during new drug and new product development or is available in technical literature. Cleaning professionals should interact with pharmaceutics scientists to be sure that their technical needs are met when this basic development work is done. Timely collaboration between pharmaceutics scientists, analytical scientists, and cleaning professionals should enable the development of analytical methods appropriate for cleaning validation. There is little value in testing for an active ingredient that is known to completely degrade when exposed to cleaning conditions. Laboratory Considerations Laboratory analysis is extremely important in cleaning validation programs. Procedures associated with testing of cleaning validation samples must be science based, robust, reliable, and reproducible. Sampling personnel performing sampling procedures must be knowledgeable, well trained, dexterous, and fastidious in attention to detail. Considerations related to laboratory testing of cleaning validation samples that are overlooked or poorly executed include the following: · Stability of the residue in developing analytical methods: Residue stability. Residue must be able to be quantitatively recovered (or adjusted mathematically) for analysis. Sampling personnel must correctly execute sampling procedures for analyses to be accurate and precise. Residue Recovery Studies Residue recovery studies are studies that demonstrate known amounts of residue on specific materials may be quantitatively recovered in sampling and analytical testing. Known amounts for residue are applied to a material surface, for example, 316 stainless steel. Ideally, the amount of recovered residue is equal to the original amount applied to the material. Understanding residue solubility properties is key to successful recovery studies. Residue Stability in Cleaning Residue Analysis the stability of the residue to be measured in cleaning validation must be understood. The analytical method used in cleaning Cleaning Validation-Lifecycle Approach Recovery studies must be done to prove that residue can be quantitatively recovered from equipment surfaces as part of cleaning validation. Considerations in recovery studies that are often overlooked include the need to perform studies on predominant materials of product contact that are swabbed or rinsed. Recoveries from electropolished stainless steel surfaces should not be assumed to be representative of recoveries from cast iron, elastomers, and other materials in the equipment train. Recovery studies should be conducted on materials provided by the equipment manufacturer-ideally, these materials should be identical to actual equipment components. Variability in recovery is more likely with "soft" or porous materials such as elastomers. Solubility properties of the residue analyte are critically important for recovery studies. In swab sampling, extractants such as alcohol or organic solvents wet the swab to dissolve residue from the material surface. Residue may not be soluble in water and thus may not be recoverable in the rinsing solvent. Recovery studies must be conducted on all product-contact materials that are swabbed or rinsed in cleaning validation. Without recovery studies that prove residue can be quantitatively recovered, cleaning validation is meaningless. Often recovery studies demonstrate that residue may be only partially recovered from equipment surfaces. When this occurs, the amount recovered in cleaning validation is adjusted based on recovery study data. Residue recovery studies are the basis for swab and rinse sampling in cleaning validation. If recovery studies are not done on all materials of product contact that are tested in cleaning validation, the cleaning validation is meaningless. If personnel performing swab sampling are not qualified through appropriate training, test results from swab samples are questionable and cleaning validation is suspect. Case Study D: New Product Cleaning Validation-False-Negative Results Company A was conducting process validation and cleaning validation on an important new product. Cleaning was successful on the first two lots-process residue was not detected in any samples. When lot #3 of the cleaning validation was planned to be sampled, the technician who had done lots #1 and #2 was not available. The supervisor and a second individual performed all sampling, paperwork, and sample delivery. Results indicated failing levels of residue on equipment- completely unexpected results in light of the successful cleaning on lots #1 and #2. Results of the investigation indicated that technician error was the most likely cause of the residue problem-not on the failed data, but rather on the acceptable residue data in lots #1 and #2. Evaluation of the sample process revealed the cause of acceptable-but erroneous-results in lots #1 and #2. When swabbing was conducted, there was insufficient alcohol to completely recover all residues. The value was below acceptance criteria, apparently indicating acceptable cleaning. However, poor technique by the sampling technician allows alcohol to evaporate potentially creating a false-negative result. After the unacceptable data were confirmed, the product cleaning procedure was revised. The original sampling technician was retrained to ensure rapid performance of sampling to minimize ethanol evaporation. Swab Sampling Technique, Reliability, and Training Swab sampling must be reliable for cleaning validation to be valid. If swab sampling is not reliable, data in cleaning validation will not be meaningful. Swab sampling is reliable when technicians who do sampling are trained and demonstrate competency.

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