PHA 069 Pharmaceutical Manufacturing with Quality Assurance and cGMP PDF

PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: __________________________...

PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ Lesson title: Pharmaceutical Analysis and Quality Control and Stability of Materials: Pharmaceutical Products LAS References: Lesson Objectives: Remington; The Science and Practice of At the end of the activity, the students will be able to: Pharmacy. 22nd edition 1. Understand the concept of pharmaceutical analyses and quality control and Ansel’s Pharmaceutical Dosage Forms and stability of pharmaceutical products Drugs Delivery Systems 9th Edition INTRODUCTION The pharmaceutical industry, as a vital segment of the healthcare system, conducts research and manufactures and markets pharmaceutical and biological products and medical devices used for the acute/chronic treatment and diagnosis of disease. Recent advances in drug discovery, primarily in the field of biotechnology and in the required controls over manufacturing processes, are presenting new challenges to the control of quality and to the systems that operate internally in the industry. The external regulations established by the federal Food and Drug Administration (FDA) and other regulatory bodies also add to these challenges. The evolving role of the industrial quality professional requires more extensive education including food and drug law, business, as well as the traditional science/technology coursework. The pursuit of quality is being approached through the application of quality systems including risk-based assessment and continuous improvement, whereby management and labor join forces to build quality into products while helping to ensure the company’s financial success. This changed emphasis is directed toward defect prevention (proactive) rather than defect detection (after the fact). Quality assurance (QA) and quality control (QC) departments develop and follow standard internal operating procedures directed toward assuring the quality, safety, purity, and effectiveness of drug products. The FDA has issued a primary regulation to the industry entitled Current Good Manufacturing Practice for Finished Pharmaceuticals (commonly referred to as the cGMPs or GMPs). Numerous guidelines have been issued relative to specific dosage forms and operations such as aseptic manufacturing, validation and stability testing, etc., which impose significant compliance requirements. These guidelines also serve as the basis for compliance investigations conducted by the FDA and are used in regulatory agency inspections of facilities and operations. Emphasis is being placed on the inspection of quality systems as part of the regulatory pre-approval program when reviewing New Drug Applications (NDAs) and Biological License Applications (BLAs). Stability of Pharmaceutical Products Stability of a pharmaceutical product may be defined as the capability of a particular formulation, in a specific container/ closure system, to remain within its physical, chemical, microbiological, therapeutic, and toxicological specifications at a defined storage condition. Pharmaceutical products are expected to meet their specifications for identity, purity, quality, and strength throughout their defined storage period at specific storage conditions. Assurances that the packaged product will be stable for its anticipated shelf life must come from an accumulation of valid data on the drug in its commercial package. These stability data include selected parameters that, taken together, form the stability profile. The stability of a pharmaceutical product is investigated throughout the various stages of the development process. The stability of a drug substance is first assessed in the preformulation stage. At this stage, pharmaceutical scientists determine the drug substance and its related salts stability/compatibility with various solvents, buffered solutions and excipients considered for formulation development. Suitable analytical methods must be employed in order to ensure the likelihood that this assessment will be successful. Optimization of a stable formulation of a pharmaceutical product is built (using statistical design) upon the information obtained from the preformulation stage and continues during the formulation development stages. Typically, the first formulation development stage may be for preclinical studies or as late as the preparation of a “first in human” formulation which is often a non-elegant formulation optimized for short-term dose-ranging clinical studies. The second major formulation development stage occurs to support Phase II clinical studies (proof of concept phase). The pharmaceutical product developed at this stage is This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ usually the prototype for the commercial product. Therefore, the pharmaceutical product will be formulated based in part on the stability information obtained from the previous formulations and must meet stability requirements for longer-term clinical studies. In the final formulation development state for Phase III clinical studies, the formulation must be truly representative of what the commercial pharmaceutical product will be in order to avoid delays in approval. In addition to building on the clinical requirements of the drug, the commercial pharmaceutical product must also incorporate the commercial or the final market image of the product, which includes the container closure system. The stability of this product must be demonstrated to the appropriate regulatory agencies in order to assign an expiration period and date for the product. This expiration period allows for the assignment of an expiration date based on the manufacture date of each lot of drug product. Once a pharmaceutical product has gained regulatory approval and is marketed, the pharmacist must understand the proper storage and handling of the drug. In some cases, a pharmacist may need to prepare stable compounded preparations from this product. Most drug products are not shipped directly from the manufacturer to a pharmacy. Typically, a drug product is shipped from a manufacturer to a distribution center. From the distribution center the drug product is then shipped to a wholesaler. From the wholesaler, the drug product may be shipped to the distribution center for a pharmacy chain or directly to the pharmacy. Finally, the drug product is dispensed by the pharmacy to the patient. Dispensing of the drug product may be at a hospital, a clinic, and a traditional “brick and mortar” pharmacy or from a mail-order pharmacy. Therefore, the stability typically must also assess the robustness of the drug product through its supply chain. It is not unusual for temperature excursions to occur during these transfers of control. Inventory control, or holding, of each drug is important for a wholesaler or pharmacy. A drug must be within its expiration dating throughout its use by the patient. Solid oral dosages may be dispensed in the commercial packaging or in a pharmacy supplied container closure system. Most prescriptions are supplied to patients for up to 30 or 90 days by traditional and mailorder pharmacies, respectively. Inventory control of product by wholesalers and pharmacies must assess how much dating must remain on a product for it to be useful for its customer. This causes the actual holding of a product to be shorter than the expiration date. Under normal circumstances it is unusual for a pharmacy to accept any product with less than 6 month dating remaining on a product. The use of kinetic and predictive studies for establishing credible expiration dating for pharmaceutical products is now accepted worldwide. Scientifically designed studies using reliable, meaningful, and specific stability-indicating assays, appropriate statistical concepts, and a computer to analyze the resulting data are used to determine an accurate and realistic shelf life. In this way the maximum amount of valid information is obtained to establish a reliable, defendable expiration date for each formulation. The assigned expiration date is a direct application and interpretation of the knowledge gained from the stability study. Types of Stability Type of Stability Conditions maintained throughout the shelf life of the Drug Product Chemical Each active ingredient retains its chemical integrity and labelled potency, within the specified limits. Physical The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability are retained. Microbiological Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits. Therapeutic The therapeutic effect remains unchanged. Toxicological No significant increase in toxicity occurs. This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ PRODUCT STABILITY Many factors affect the stability of a pharmaceutical product including the intrinsic stability of the active ingredient(s), the potential interaction between active and inactive ingredients, the manufacturing process, the dosage form, the container liner - closure system and the environmental conditions encountered during shipment, storage and handling and length of time between manufacture and usage. Classically, pharmaceutical product stability evaluations have been separated into studies of chemical (including biochemical) and physical stability of formulations. Realistically, there is no absolute division between these two arbitrary divisions. Physical factors—such as heat, light, and moisture—may initiate or accelerate chemical reactions, whereas every time a measurement is made on a chemical compound, physical dimensions are included in the study. One type of time-related chemical stability failure is a decrease in therapeutic activity of the preparation to below some arbitrary labeled content. A second type of chemical stability failure is the appearance of a toxic substance, formed as a degradation product upon storage of the formulation. The numbers of published cases reflecting this second type are few. However, it is possible, though remote, for both types of stability failures to occur simultaneously within the same pharmaceutical product. Thus, the use of stability studies with the resulting application of expiration dating to pharmaceuticals is an attempt to predict the approximate time at which the probability of occurrence of a stability failure may reach an intolerable level. This estimate is subject to the usual Type 1 or alpha error (setting the expiration too early so that the product will be destroyed or removed from the market appreciably earlier than actually is necessary) and the Type 2 or beta error (setting the date too late so that the failure occurs in an unacceptably large proportion of cases). Thus, it is obligatory that the manufacturer clearly and succinctly defines the method for determining the degree of change in a formulation and the statistical approach to be used in making the shelf life prediction. An intrinsic part of the statistical methodology must be the statements of value for the two types of error. For the safety of the patient a Type 1 error can be accepted, but not a Type 2 error. One type of time related physical stability failures may affect the availability or rate of drug release of a product. This type of physical stability failure may cause the active ingredient not to be released or a higher rate of drug release (dose dumping). Another type of time related physical stability failures are appearance related. These may just cause the drug product not to appear pharmaceutically elegant or may be an artifact of another physical or chemical stability failure. In this treatment, physical and chemical stability are discussed along with those dosage form properties that can be measured and are useful in predicting shelf life. The effect of various physical and chemical phenomena of pharmaceuticals also is treated. Knowledge of the physical stability of a formulation is very important for three primary reasons. First, a pharmaceutical product must appear fresh, elegant, and professional, for as long as it remains on the shelf. Any changes in physical appearance such as color fading or haziness can cause the patient or consumer to lose confidence in the product. Second, since some products are dispensed in multiple-dose containers, potency of the active ingredient over time must be ensured for each individual dose. A cloudy solution or a broken emulsion can lead to a non-uniform dosage pattern. Third, the active ingredient must be bioavailable to the patient throughout the expected shelf life of the preparation. A breakdown in the physical system can lead to non-availability or “dose dumping” of the medication to the patient. In the case of metered-dose inhaler pulmonary aerosols, particle aggregation may result in inadequate lung deposition of the medication. The chemical causes of drug deterioration have been classified as incompatibility, oxidation, reduction, hydrolysis, racemization, and other mechanisms. In the latter category, decarboxylation, deterioration of hydrogen peroxide and hypochlorites and the formation of precipitates have been included. This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ Pharmaceutical Dosage Forms As the various pharmaceutical dosage forms present unique stability problems, they are discussed separately in the following section. Tablets Stable tablets retain their original size, shape, weight, and color under normal handling and storage conditions throughout their shelf life. In addition, the in vitro availability of the active ingredients should not change appreciably with time. Excessive powder or solid particles at the bottom of the container, cracks or chips on the face of a tablet, or appearance of crystals on the surface of tablets or on container walls are indications of physical instability of uncoated tablets. Hence, the effect of mild, uniform, and reproducible shaking and tumbling of tablets should be studied. The recommended test for such studies is the determination of tablet friability as described in the USP. Tablet Friability USP describes the recommended apparatus and the test procedure. After visual observation of the tablets for chips, cracks, and splits, the intact tablets are sorted and weighed to determine the amount of material worn away by abrasion. In general, a maximum weight loss of not more than 1% of the weight of the tablets being tested is considered acceptable for most products. The results of these tests are comparative rather than absolute and should be correlated with actual stress experience. Packaged tablets also should be subjected to cross-country shipping tests as well as to various drop tests. Tablet hardness (or resistance to crushing or fracturing) can be assessed by commercially available hardness testers. As results will vary with the specific make of the test apparatus used, direct comparison of results obtained on different instruments may not necessarily be made. Thus, the same instrument should be used consistently throughout a particular study. Color stability of tablets can be followed by an appropriate colorimeter or reflectometer with heat, sunlight, and intense artificial light employed to accelerate the color deterioration. It is still not unusual for color assessment to be performed visually. Caution must be used in interpreting the elevated temperature data, as the mechanism for degradation at that temperature may differ from that at a lower temperature. It is not always proper to assume that the same changes will occur at elevated temperatures as will be evidenced later at room temperature. Cracks, mottling, or tackiness of the coating indicates evidence of instability of coated tablets. Typically, dissolution is the in vitro test performed to estimate bioavailability for a tablet regardless of the solubility of the active ingredients. Disintegration has been relegated to an in-process test or used to help dissolution. Dissolution tests should be run in an appropriate medium at 37°C. Actual dissolution conditions, including medium, are developed during the clinical development phase of a product. The dissolution method developed has to demonstrate a correlation that is relevant to the bioavailability of the dosage form. Dissolution profiles are examined during development to provide sufficient information to define a single sample time point with a minimum concentration for immediate release product. Controlled release drug products require a dissolution profile with concentration ranges at set sampling points for product assessment. When no significant change (such as a change in the polymorphic form of the crystal) has occurred, an unaltered dissolutionrate profile of a tablet formulation usually indicates constant in vivo bioavailability. Uniformity of weight, odor, texture, drug and moisture contents, and humidity effect may also be studied during a tablet stability test. Gelatin Capsules Hard gelatin capsules are the type used by pharmaceutical manufacturers in the production of the majority of their capsule products. The pharmacist in the extemporaneous compounding of prescriptions may also use hard gelatin capsules. Soft gelatin capsules are prepared from shells of gelatin to which glycerin or a polyhydric alcohol such as sorbitol has been added to render the gelatin elastic or plastic-like. Gelatin is stable in air when dry but is subject to microbial decomposition when it becomes moist or when it is maintained in aqueous solution. Normally hard gelatin capsules contain between 13 and 16% moisture. If stored in a high humidity environment capsule shells may soften, stick together or become distorted and lose their shape. On the other hand, in an environment of extreme dryness, gelatin capsules may harden and crack under slight pressure. Gelatin capsules should be protected from sources of microbial contamination. Encapsulated products, like all other dosage forms, must be packaged properly. Because moisture may be absorbed or released by gelatin capsules depending on the environmental conditions, capsules offer little physical protection This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ to hygroscopic or deliquescent materials enclosed within a capsule when stored in an area of high humidity. It is not uncommon to find capsules packaged in containers along with a packet of desiccant material as a precautionary measure. Dissolution development and requirements for capsules are similar to tablets. The capsule shell can affect dissolution test results but not be relevant to bioavailability. Both hard and soft gelatin capsules exposed to excessive heat and moisture may exhibit delayed or incomplete dissolution due to cross-linking of the gelatin in the capsule shell. The cross-linking of gelatin capsules is an irreversible chemical reaction. Cross-linking may also occur in capsules that are exposed to aldehydes and peroxides. Although cross-linked capsules may fail dissolution due to pellicle formation, digestive enzymes will dissolve the capsules. For hard or soft gelatin capsules that do not conform to the dissolution specification, the dissolution test may be repeated with the addition of enzymes. Where water or a medium with a pH less than 6.8 is specified as the medium in the individual monograph, the same medium specified may be used with the addition of purified pepsin that results in an activity of 750,000 units or less per 1000 mL. For media with a pH of 6.8 or greater, pancreatin can be added to produce not more than 1750 USP units of protease activity per 1000 mL. Suspensions A stable suspension can be redispersed homogeneously with moderate shaking and can be poured easily throughout its shelf life , with neither the particle size distribution, the crystal form, nor the physiological availability of the suspended active ingredient changing appreciably with time. Most stable pharmaceutical suspensions are flocculated; that is, the suspended particles are bonded together physically to form a loose, semi rigid structure. The particles are said to uphold each other while exerting no significant force on the liquid. Sedimented particles of a flocculated suspension can be redispersed easily at any time with only moderate shaking. In non-flocculated suspensions, the particles remain as individuals unaffected by neighboring particles and are affected only by the suspension vehicle. These particles, which are smaller and lighter, settle slowly, Once they have settled, they often form a hard, difficult-to-disperse sediment. Non-flocculated suspensions can be made acceptable by decreasing the particle size of the suspended material or by increasing the density and viscosity of the vehicle, thus reducing the possibility of settling. When studying the stability of a suspension, a differential manometer is used to determine if the suspension is flocculated. If the suspension is flocculated, the liquid will travel the same distance in the two side arms. With non-flocculated suspensions, the hydrostatic pressures in the two arms are unequal; hence, the liquids will be at different levels. The history of settling of the particles of a suspension may be followed by a Brookfield viscometer fitted with a Helipath attachment. This instrument consists of a rotating T-bar spindle that descends slowly into the suspension as it rotates. The dial reading on the viscometer is a measure of the resistance that the spindle encounters at various levels of the sedimented suspension. This test must be run only on fresh, undisturbed samples. An electronic particle counter and sizer, such as a Coulter counter, or a microscope may be used to determine changes in particle size distribution. Crystal form alterations may be detected by microscopic, near-IR or Raman examination and, when suspected, must be confirmed by X-ray powder diffraction. All suspensions should be subjected to cycling temperature conditions to determine the tendency for crystal growth to occur within the suspension. Shipping tests, namely transporting bottles across the country by rail or truck are also used to study the stability of suspensions. Solutions A stable solution retains its original clarity, color, and odor throughout its shelf life. Retention of clarity of a solution is a main concern of a physical stability program. As visual observation alone under ordinary light is a poor test of clarity, a microscope light should be projected through a diaphragm into the solution. Undissolved particles will scatter the light, and the solution will appear hazy. Although the Coulter counter also can be used, light-scattering instruments are the most sensitive means of following solution clarity. Solutions should remain clear over a relatively wide temperature range such as 4 to 47°C. At the lower range an ingredient may precipitate due to its lower solubility at that temperature, whereas at the higher temperature the flaking of particles from the glass containers This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ or rubber closures may destroy homogeneity. Thus, solutions should be subjected to cycling temperature conditions. The stability program for solutions also should include a study of pH changes, especially when the active ingredients are soluble salts of insoluble acids or bases. Among other tests are observations for changes in odor, appearance, color, taste, light-stability, pourability, viscosity, isotonicity, gas evolution, microbial stability, specific gravity, surface tension, and pyrogen content, in the case of parenteral products. When solutions are filtered, the filter medium may absorb some of the ingredients from the solution. Thus, the same type of filter should be used for preparing the stability samples as will be used to prepare the production-size batches. For dry-packaged formulations reconstituted prior to use, the visual appearance should be observed on both the original dry material and on the reconstituted preparation. The color and odor of the cake, the color and odor of the solution, the moisture content of the cake, and the rate of reconstitution should be followed as a part of its stability profile. Emulsions A stable emulsion can be redispersed homogeneously to its original state with moderate shaking and can be poured at any stage of its shelf life. Although most of the important pharmaceutical emulsions are of the oil in water (O/W) type, many stability test methods can be applied to either an O/W or water in oil (W/O) emulsion. Two simple tests are used to screen emulsion formulations. First, heating to 50 to 70°C and observing its gross physical stability either visually or by turbidimetric measurements can determine the stability of an emulsion. Usually the emulsion that is the most stable to heat is the one most stable at room temperature. However, this may not be true always, because an emulsion at 60°C may not be the same as it is at room temperature. Second, the stability of the emulsion can be estimated by the coalescence time test. Although this is only a rough quantitative test, it is useful for detecting gross differences in emuls ion stability at room temperature. Emulsions also should be subjected to refrigeration temperatures. An emulsion stable at room temperature has been found to be unstable at 4°C. It was reasoned that an oil-soluble emulsifier precipitated at the lower temperature and disrupted the system. An emulsion chilled to the extent that the aqueous base crystallizes is damaged irreversibly. The ultracentrifuge also is use d to determine emulsion stability. When the amount of separated oil is plotted against the time of centrifugation, a plateau curve is obtained. A linear graph results when the oil flotation (creaming) rate is plotted versus the square of the number of centrifuge revolutions per minute. The flotation rate is represented by the slope of the line resulting when the log distance of emulsion-water boundary from the rotor center is plotted against time for each revolution per minute. For stability studies, two batches of an emulsion should be made at one time on two different sizes of equipment. One should be a bench-size lot and the other a larger, preferably production-size, batch. Different types of homogenizers produce different results, and different sizes of the same kind of homogenizer can yield emulsions with different characteristics. Ointments Ointments have been defined as high-viscosity suspensions of active ingredients in a non-reacting vehicle. A stable ointment is one that retains its homogeneity throughout its shelf life period. The main stability problems observed in ointments are bleeding and changes in consistency due to aging or changes in temperature. When fluid components such as mineral oil separate at the top of an ointment, the phenomenon is known as bleeding and can be observed visually. Unfortunately, as there is no known way to accelerate this event, the tendency to bleed cannot be predicted. An ointment that is too soft is messy to use, whereas one that is very stiff is difficult to extrude and apply. Hence, it is important to be able to define quantitatively the consistency of an ointment. This may be done with a penetrometer, an apparatus that allows a pointed weight to penetrate into the sample under a measurable force. The depth of the penetration is a measure of the consistency of an ointment. Consistency also can be measured by the Helipath attachment to a high-viscosity viscometer or by a Burrell Severs rheometer. In the latter instrument the ointment is loaded into a cylinder and extruded with a measured force. The amount extruded is a measure of the consistency of the ointment. Ointments have a considerable degree of structure that requires a minimum of 48 hours to develop after preparation. As rheological data on a freshly made ointment may be erroneous, such tests should be performed only after the ointment has achieved equilibrium. Slight This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ changes in temperature (1 or 2°C) can affect the consistency of an ointment greatly; hence, rheological studies on ointments must be performed only at constant and controlled temperatures. Among the other tests performed during the stability study of an ointment are a check of visual appearance, color, odor, viscosity, softening range, consistency, homogeneity, particle size distribution, and sterility. Undissolved components of an ointment may change in crystal form or in size with time. Microscopic examination or an X-ray diffraction measurement may be used to monitor these parameters. In some instances it is necessary to use an ointment base that is less than ideal, to achieve the required stability. For example, drugs that hydrolyze rapidly are more stable in a hydrocarbon base than in a base containing water, even though they may be more effective in the latter. Transdermal Patches A typical transdermal patches consist of a protective backing, a matrix containing active drug, an adhesive that allows the patch to adhere to the skin and a release liner to protect the skin adhering adhesive. Therefore, the transdermal patch must deliver drug as labeled, adhere properly to both the backing and to the patient’s skin. In addition, the transdermal patch must be pharmaceutically elegant through the shelf life of the product. For a transdermal patch, this means that the release line peels easily with minimal transfer of adhesive onto the release liner and that the adhesive does not ooze from the sides of the patch. Therefore, the typical stability related tests for transdermal patches are appearance, assay, impurities, drug release per USP, and backing peel force. Metered-Dose Aerosols Drug Products A metered dose inhalation product comprises an aerosol can containing a propellant and drug, and a mouthpiece used to present an aerosolized drug to the patient. There are many drug contact components in a metered-dose inhalation product. Therefore, the drug may be in contact with materials that could allow plasticizer leach into the propellant. The typical stability related tests for metered-dose aerosols include appearance, assay, impurities, plume geometry, emitted dose, particle size distribution of the emitted dose, and number of doses per unit. In addition, stability studies on leachables may be required. Shelf life of metered-dose aerosols drug products may also be dependent on the orientation that the drug product is stored. Typically most canister type products are tested at least in the upright orientation. Dry-Powdered Inhalation Products A dry-powdered inhalation product consists of drug with excipients delivered in a dry powdered form. The delivery system for a dry- powdered inhalation product may be a separate device or integrated with the active. A dry-powdered dosage must reproducibly deliver a specific amount of drug at a particle size that can be deposited into the lungs. Particles too large will get trapped in the throats and particles too small will just be carried out of the lungs on the next expiration. The typical stability related tests for dry powder inhalation products include appearance, assay, impurities, emitted dose, particle size distribution of the emitted dose, and water content. Nasal Inhalation Products A nasal inhalation product consists of drug with excipients delivered from a delivery system. The delivery system for a nasal inhalation product may be a separate device or integrated with the active. A nasal inhalation product must reproducibly deliver a specific amount of drug at a particle size and plume that can be deposited into the nasal membrane. Particles too large will not be absorbed into nasal membrane or run out of the nose; and poor spray pattern will deposit the drug ineffective in the nasal cavity. The typical stability related tests for nasal inhalation products include appearance, assay, impurities, spray content uniformity, particle (droplet) size distribution of the emitted dose, spray pattern or /and plume geometry, leachables, weight loss and preservative content. Sterility and microbial testing may be required periodically for stability testing. Incompatibility Typically, physicochemical stability is assessed at the preformulation stage of development. A drug substance candidate is treated with acid, base, heat, light, and oxidative conditions to assess its inherent chemical stability. Binary mixtures of the drug substance with This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ individual excipients are also investigated at the preformulation stage. These tests are performed to determine the drug substance sensitivity to degrade or reactivity with common pharmaceutical excipients. The most common reactions observed for drug substances from these tests include: hydrolysis, epimerization (racemization), decarboxylation, dehydration, oxidation, polymerization, photochemical decomposition and addition. All drug substances have the potential to degrade by at least one of the reactions mentioned above. With an understanding of the stability/reactivity of a drug substance in the preformulation stage, it is possible to formulate the drug product to minimize drug decomposition. Numerous examples are described in other sections of this book, and the literature is replete with illustrations. Although undesirable reactions between two or more drugs are said to result in a physical, chemical, or therapeutic incompatibility, physical incompatibility is somewhat of a misnomer. It has been defined as a physical or chemical interaction between two or more ingredients that leads to a visibly recognizable change. The latter may be in the form of a gross precipitate, haze, or color change. On the other hand, a chemical incompatibility is classified as a reaction in which a visible change is not necessarily observed. Since there is no visible evidence of deterioration, this type of incompatibility requires trained, knowledgeable personnel to recognize it. A therapeutic incompatibility has been defined as an undesirable pharmacological interaction between two or more ingredients that leads to: 1. Potentiation of the therapeutic effects of the ingredients. 2. Destruction of the effectiveness of one or more of the ingredients. 3. Occurrence of a toxic manifestation within the patient. Chemical reactions The most frequently encountered chemical reactions, which may occur within a pharmaceutical product, are described below. Oxidation-Reduction Oxidation is a prime cause of product instability, and often, but not always, the addition of oxygen or the removal of hydrogen is involved. When molecular oxygen is involved, the reaction is known as auto-oxidation because it occurs spontaneously, though slowly, at room temperature. Oxidation, or the loss of electrons from an atom, frequently involves free radicals and subsequent chain reactions. Only a very small amount of oxygen is required to initiate a chain reaction. In practice, it is easy to remove most of the oxygen from a container, but very difficult to remove it all. Hence, nitrogen and carbon dioxide frequently are used to displace the headspace air in pharmaceutical containers to help minimize deterioration by oxidation. As an oxidation reaction is complicated, it is difficult to perform a kinetic study on oxidative processes within a general stability program. The redox potential, which is constant and relatively easy to determine, can, however, provide valuable predictive information. In many oxidative reactions, the rate is proportional to the concentration of the oxidizing species but may be independent of the concentration of the oxygen present. The rate is influenced by temperature, radiation, and the presence of a catalyst. An increase in temperature leads to an acceleration in the rate of oxidation. If the storage temperature of a preparation can be reduced to between 0-5° C, usually it can be assumed that the rate of oxidation will be at least halved. The molecular structures most likely to oxidize are those with a hydroxyl group directly bonded to an aromatic ring (e.g., phenol derivatives such as catecholamines and morphine), conjugated dienes (e.g., vitamin A and unsaturated free fatty acids), heterocyclic aromatic rings, nitroso and nitrite derivatives, and aldehydes (e.g., flavorings). Products of oxidation usually lack therapeutic activity. Visual identification of oxidation, for example, the change from colorless epinephrine to its amber colored products, may not be visible in some dilutions or to some eyes. Oxidation is catalyzed by pH values that are higher than optimum, polyvalent heavy metal ions (e.g., copper and iron), and exposure to oxygen and UV illumination. The latter two causes of oxidation justify the use of antioxidant chemicals, nitrogen atmospheres during ampoule and vial filling, opaque external packaging, and transparent amber glass or plastic containers. Trace amounts of heavy metals such as cupric, chromic, ferrous, or ferric ions may catalyze oxidation reactions. As little as 0.2 mg of copper ion per liter considerably reduces the stability of penicillin. This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ Similar examples include the deterioration of epinephrine, phenylephrine, lincomycin, isoprenaline, and procaine hydrochloride. Adding chelating agents to water to sequester heavy metals and working in special manufacturing equipment (e.g., glass) are some means used to reduce the influence of heavy metals on a formulation. Parenteral formulations should not come in contact with heavy metal ions during their manufacture, packaging, or storage. Hydronium and hydroxyl ions catalyze oxidative reactions. The rate of decomposition for epinephrine, for example, is more rapid in a neutral or alkaline solution with maximum stability (minimum oxidative decomposition) at pH 3.4. There is a pH range for maximum stability for any antibiotic and vitamin preparation, which usually can be achieved by adding an acid, alkali, or buffer. Oxidation may be inhibited by the use of antioxidants, called negative catalysts. They are very effective in stabilizing pharmaceutical products undergoing a free-radical-mediated chain reaction. These substances, which are easily oxidizable, act by possessing lower oxidation potentials than the active ingredient. Thus, they undergo preferential degradation or act as chain inhibitors of free radicals by providing an electron and receiving the excess energy possessed by the activated molecule. The ideal antioxidant should be stable and effective over a wide pH range, soluble in its oxidized form, colorless, nontoxic, nonvolatile, nonirritating, effective in low concentrations, thermostable, and compatible with the container- closure system and formulation ingredients. The commonly used antioxidants for aqueous systems include sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, and ascorbic acid. For oil systems, ascorbyl palmitate, hydroquinone, propyl gallate, nordihydroguaiaretic acid, butylated hydroxytoluene, butylated hydroxyanisole, and alpha-tocopherol are employed. Synergists, which increase the activity of antioxidants, are generally organic compounds that complex small amounts of heavy metal ions. These include the ethylenediamine tetraacetic acid (EDTA) derivatives, dihydroethylglycine, and citric, tartaric, gluconic, and saccharic acids. EDTA has been used to stabilize ascorbic acid, oxytetracycline, penicillin, epinephrine, and prednisolone. Reduction reactions are much less common than oxidative processes in pharmaceutical practice. Examples include the reduction of gold, silver, or mercury salts by light to form the corresponding free metal. Hydrolysis Drugs containing esters (e.g., cocaine, physostigmine, aspirin, tetracaine, procaine, and methyldopa), amides (e.g., dibucaine), imides (e.g., amobarbital), imines (e.g., diazepam), and lactam (e.g., penicillins, cephalosporins) functional groups are among those prone to hydrolysis. Hydrolysis reactions are often pH dependent and are catalyzed by either hydronium ion or hydroxide ions (specific-acid or specific- base catalysis, respectively). Hydrolysis reactions can also be catalyzed by either a Brønsted acid or a Brønsted base (general-acid or general- base catalysis, respectively). Sources of Brønsted acid or base include buffers and some excipients. Sometimes, it is necessary to compromise between the optimum pH for stability and that for pharmacological activity. For example, several local anesthetics are most stable at a distinctly acid pH, whereas for maximum activity they should be neutral or slightly alkaline. Small amounts of acids, alkalines, or buffers are used to adjust the pH of a formulation. Buffers are used when small changes in pH are likely to cause major degradation of the active ingredient. Obviously, the amount of water present can have a profound effect on the rate of a hydrolysis reaction. When the reaction takes place fairly rapidly in water, other solvents sometimes can be substituted. For example, barbiturates are much more stable at room temperature in propylene glycol–water than in water alone. Modification of chemical structure may be used to retard hydrolysis. In general, as it is only the fraction of the drug in solution that hydrolyzes, a compound may be stabilized by reducing its solubility. This can be done by adding various substituents to the alkyl or acyl chain of aliphatic or aromatic esters or to the ring of an aromatic ester. In some cases le ss-soluble salts or esters of the parent compound have been found to aid product stability. Steric and polar complexation has also been employed to alter the rate of hydrolysis. Caffeine reduces the rate of hydrolysis and thus promotes stability by complexation with local anesthetics such as benzocaine, procaine, or tetracaine. Esters and β-lactams are the chemical bonds that are most likely to hydrolyze in the presence of water. For example, the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of moisture, but in a dry environment the hydrolysis of aspirin is negligible. The aspirin hydrolysis rate increases in direct proportion to the water vapor pressure in an environment. This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ The amide bond also hydrolyzes, though generally at a slower rate than comparable esters. For example, procaine (an ester) will hydrolyze upon autoclaving, but procainamide will not. The amide or peptide bond in peptides and proteins varies in the labiality to hydrolysis. The lactam and azomethine (or imine) bonds in benzodiazepines are also labile to hydrolysis. The major chemical accelerators or catalysts of hydrolysis are adverse pH and specific chemicals (e.g., dextrose and copper in the case of ampicillin hydrolysis). The rate of hydrolysis depends on the temperature and the pH of the solution. A much-quoted estimation is that for each 10°C rise in storage temperature, the rate of reaction doubles or triples. As this is an empiricism, it is not always applicable. When hydrolysis occurs, the concentration of the active ingredient decreases while the concentration of the decomposition products increases. The effect of this change on the rate of the reaction depends on the order of the reaction. With zero-order reactions the rate of decomposition is independent of concentration of the ingredient. Although weak solutions decompose at the same absolute rate as stronger ones, the weaker the solution, the greater the proportion of active ingredient destroyed in a given time; i.e., the percentage of decomposition is greater in weaker solutions. Increasing the concentration of an active ingredient that is hydrolyzing by zero-order kinetics will slow the percentage decomposition. With first-order reactions, which occur frequently in the hydrolysis of drugs, the rate of change is directly proportional to the concentration of the reactive substance. Thus, changes in the concentration of the active ingredient have no influence on the percentage decomposition. The degradation of many drugs in solution accelerates or decelerates exponentially as the pH is decreased or increased over a specific range of pH values. Improper pH ranks with exposure to elevated temperature as a factor most likely to cause a clinically significant loss of drug, resulting from hydrolysis and oxidation reactions. A drug solution or suspension, for example, may be stable for days, weeks, or even years in its original formulation, but when mixed with another liquid that changes the pH, it may degrade in minutes or days. It is possible that a pH change of only one unit (e.g., from 4 to 3 or 8 to 9) could decrease drug stability by a factor of ten or greater. A pH-buffer system, which is usually a weak acid or base and its salt, are common excipients used in liquid preparations to maintain the pH in a range that minimizes the drug degradation rate. The pH of drug solutions may also be either buffered or adjusted to achieve drug solubility. For example, pH in relation to pKa controls the fractions of the usually more soluble ionized and less soluble nonionized species of weak organic electrolytes. Decarboxylation Pyrolytic solid-state degradation through decarboxylation usually is not encountered in pharmacy, as relatively high heats of activation (25 to 30 kcal) are required for the reaction. However, solid p-aminosalicylic acid undergoes pyrolytic degradation to m- aminophenol and carbon dioxide. The reaction, which follows first-order kinetics, is highly pH-dependent and is catalyzed by hydronium ions. The decarboxylation of p-aminobenzoic acid occurs only at extremely low pH values and at high temperatures. Some dissolved carboxylic acids, such as p-aminosalicylic acid, lose carbon dioxide from the carboxyl group when heated. The resulting product has reduced pharmacological potency. β-Keto decarboxylation can occur in some solid antibiotics that have a carbonyl group on the β-carbon of a carboxylic acid or a carboxylate anion. Such decarboxylations will occur in the following antibiotics: carbenicillin sodium, carbenicillin free acid, ticarcillin sodium, and ticarcillin free acid. Racemization Racemization, or the action or process of changing from an optically active compound into a racemic compound or an optically inactive mixture of corresponding R (rectus) and S (sinister) forms, is a major consideration in pharmaceutical stability. Optical activity of a compound may be monitored by polarimetry and reported in terms of specific rotation. Chiral high performance liquid chromatography (HPLC) has been used in addition to polarimetry to confirm the enantiomeric purity of a sample. This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ Epimerization Members of the tetracycline family are most likely to incur epimerization. This reaction occurs rapidly when the dissolved drug is exposed to a pH of an intermediate range (higher than 3), and it results in the steric rearrangement of the dimethylamino group. The epimer of tetracycline, epitetracycline, has little or no antibacterial activity. In general, racemization follows first-order kinetics and depends on temperature, solvent, catalyst, and the presence or absence of light. Racemization appears to depend on the functional group bound to the asymmetric carbon atom, with aromatic groups tending to accelerate the process. PHARMACEUTICAL CONTAINERS The official standards for containers apply to articles packaged by either the pharmaceutical manufacturer or the dispensing pharmacist unless otherwise indicated in a compendial monograph. In general, repackaging of pharmaceuticals is inadvisable. However, if repackaging is necessary, the manufacturer of the product should be consulted for potential stability problems. A pharmaceutical container has been defined as a device that holds the drug and is, or may be, in direct contact with the preparation. The immediate container is described as that which is in direct contact with the drug at all times. The liner and closure traditionally have been considered to be part of the container system. The container should not interact physically or chemically with the formulation so as to alter the strength, quality, or purity of its contents beyond permissible limits. The choice of containers and closures can have a profound effect on the stability of many pharmaceuticals. Now that a large variety of glass, plastics, rubber closures, tubes, tube liners, etc are available, the possibilities for interaction between the packaging components and the formulation ingredients are immense. Some of the packaging elements themselves are subject to physical and chemical changes that may be time temperature dependent. Frequently, it is necessary to use a well-closed or a tight container to protect a pharmaceutical product. A well-closed container is used to protect the contents from extraneous solids or a loss in potency of the active ingredient under normal commercial conditions. A tight container protects the contents from contamination by extraneous materials, loss of contents, efflorescence, deliquescence, or evaporation and is capable of tight re-closure. When the packaging and storage of an official article in a well-closed or tight container is specified, water- permeation tests should be performed on the selected container. In a stability program, the appearance of the container, with special emphasis on the inner walls, the migration of ingredients onto/into the plastic or into the rubber closure, the migration of plasticizer or components from the rubber closure into the formulation, the possibility of two-way moisture penetration through the container walls, the integrity of the tac-seal, and the back-off torque of the cap, must be studied. The containers include glass, plastics, metals, and closures. (You may refer to your lecture SAS) CHECK FOR UNDERSTANDING MULTIPLE CHOICE QUESTIONS: Write the letter of your answer before the number. 1. What is the primary purpose of the stability studies conducted during the pharmaceutical product development process? a. To enhance the marketing strategies of the pharmaceutical product b. To ensure that the pharmaceutical product remains within its physical, chemical, microbiological, therapeutic, and toxicological specifications throughout its defined storage period c. To validate the aesthetic appeal of the pharmaceutical product's packaging d. To determine the cost-effectiveness of the pharmaceutical product in the market 2. In the context of pharmaceutical product stability, what does the "expiration date" represent? a. The date after which the drug product is no longer legally marketable b. The date until which the drug product is guaranteed to maintain its quality, safety, and efficacy as demonstrated by stability studies c. The date on which the drug product was first manufactured d. The date when the drug product will start to become ineffective This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ 3. What is the primary purpose of performing a tablet friability test according to USP guidelines? a. To assess the color stability of tablets under various light conditions b. To determine the amount of material worn away by abrasion and ensure tablet integrity c. To measure the dissolution rate of the active ingredient in the tablet d. To evaluate the impact of temperature on the tablet’s bioavailability 4. What is a common indicator of physical instability in uncoated tablets? a. Uniform weight across all tablets b. Excessive powder or solid particles at the bottom of the container c. Proper color and appearance as specified in the product label d. Consistent dissolution rates across different batches 5. How does the presence of moisture affect hard gelatin capsules? a. It may cause the capsules to become too hard and brittle b. It may lead to softening, sticking together, or distortion of the capsules c. It will have no effect on the physical properties of the capsules d. It will enhance the protective barrier of the capsules against microbial contamination 6. Which method is used to assess whether a suspension is flocculated or non-flocculated? a. Brookfield viscometer with a Helipath attachment b. Differential manometer c. Coulter counter d. X-ray powder diffraction 7. What is the primary concern when evaluating the stability of a pharmaceutical solution? a. The ability of the solution to maintain its clarity, color, and odor throughout its shelf life b. The strength of the active ingredient in the solution c. The type of container used for packaging the solution d. The initial cost of manufacturing the solution 8. In the context of dissolution testing for tablets, what does a consistent dissolution rate profile indicate? a. The tablet’s stability across different environmental conditions b. The tablet’s bioavailability remains constant in vivo c. The tablet’s resistance to physical damage during shipping d. The tablet’s color stability under various light conditions 9. Which of the following tests is not typically used for assessing the stability of emulsions? a. Coalescence time test b. Ultracentrifuge for plotting oil flotation rate c. Measurement of penetration depth using a penetrometer d. Heating to 50 to 70°C and observing gross physical stability 10. For an ointment to be considered stable, which of the following characteristics is not typically evaluated? a. Softening range b. Visual appearance c. Particle size distribution d. Drug release rate per USP This document is the property of PHINMA EDUCATION  PHA 069: Pharmaceutical Manufacturing with Quality Assurance and cGMP Laboratory Activity Sheet 10 Name: ________________________________________________ Class number: ____ Section: ____________ Schedule: _________________________ Date: _____________ 11. What stability-related test is crucial for ensuring that a dry-powdered inhalation product delivers the correct amount of drug? a. Appearance b. Assay c. Particle size distribution of the emitted dose d. Plume geometry 12. In the context of metered-dose aerosol drug products, which stability-related test would be least likely to include a concern about plasticizer leach? a. Appearance b. Emitted dose c. Plume geometry d. Number of doses per unit 13. Which of the following is not a method used to minimize oxidation in pharmaceutical products? a. Storing the product at high temperatures b. Employing nitrogen atmospheres during filling c. Using opaque external packaging or amber glass d. Using antioxidants like sodium sulfite or ascorbic acid 14. What is a common characteristic of drugs prone to hydrolysis? a. Presence of a conjugated diene structure b. Presence of a nitroso or nitrite derivative c. Presence of an ester, amide, or lactam functional group d. Presence of a hydroxyl group directly bonded to an aromatic ring 15. Which type of chemical reaction is catalyzed by hydronium ions and often involves drugs with ester or amide functional groups? a. Hydrolysis b. Racemization c. Decarboxylation d. Oxidation-Reduction This document is the property of PHINMA EDUCATION