Preformulation Guide


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Preformulation Guide

  1. 1. PREFORMULATION GUIDANCE PREFORMULATION GUIDANCE FOR INDUSTRY This guidance document represents the author’s current thinking on preformulation in drug discovery and development. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.
  2. 2. PREFORMULATION GUIDANCE Discovering and developing safe and effective new medicines is a long, difficult, and expensive process. Once a new compound has been identified in the laboratory, it undergoes the drug development process before it can be marketed for public use. The entire drug development process can be summarized in a series of steps or charts. Drug Development Steps:  Preclinical Testing  Investigational New Drug Application (IND).  Clinical Trials  New Drug Application (NDA)  Approval Drug Development Steps: 1. Preclinical Testing Preclinical Testing: The compound is tested for safety and efficacy in laboratory and animal studies. Preformulation studies covering the physical and chemical characterization of the new drug substance are also conducted. Preclinical Testing Involves: 1. Pharmacology 2. Toxicology 3. Preformulation 4. Formulation 5. Analytical
  3. 3. PREFORMULATION GUIDANCE 6. Pharmacokinetics 1. Pharmacology: 2. Toxicology: Toxicology studies in preclinical stage are conducted to: • Select or reject lead candidate • General Indication of suitability • Dose selection and guidance to clinician The basic studies conducted are: • Mutagenicity - In vitro Ames test [ A test used to determine the mutagenic potential of a substance based on the mutation rate of bacteria that are exposed to the substance] . • One-week or Two-week Range Finders:  Mouse or Rat, Dog or Primate • Maximum Tolerated Dose • Gross Effects, Clinical Chemistries - What are the toxicities • Gross Pathology to Indicate Target Organs • Satisfactory Therapeutic Ratio vis-a-vis Animal Efficacy Studies Single Dose Acute Toxicity Testing for Pharmaceuticals (Refer CDER Guidelines) 3. Preformulation : Preformulation involves the application of biopharmaceutical principles to the physicochemical parameters of a drug with the goal of designing an optimum drug delivery system. Characterization of drug molecule is a very important step at the preformulation phase of product development. Following studies are conducted
  4. 4. PREFORMULATION GUIDANCE as basic preformulation studies; special studies are conducted depending on the type of dosage form and the type of drug molecule: 1. Solubility determination 2. pKa determination 3. Partition coefficient 4. Chemical stability profile 5. Crystal Properties and Polymorphism 6. Particle size, shape and surface area 7. Specifications for New Drug Substances and Products 8. Dosage Form Development Chart 1. Solubility determination The solubility of drug is an important physicochemical property because it affects the bioavailability of the drug, the rate of drug release into the dissolution medium, and consequently, the therapeutic efficacy of the pharmaceutical product. The solubility of a molecule in various solvents is determined as a first step. This information is valuable in developing a formulation. Solubility is usually determined in a variety of commonly used solvents and some oils if the molecule is lipophilic. The solubility of a material is usually determined by the equilibrium solubility method, which employs a saturated solution of the material, obtained by stirring an excess of material in the solvent for a prolonged period until equilibrium is achieved.
  5. 5. PREFORMULATION GUIDANCE Common solvents used for solubility determination are: I. Water II. Polyethylene Glycols III. Propylene Glycol IV. Glycerin V. Sorbitol VI. Ethyl Alcohol VII. Methanol VIII. Benzyl Alcohol IX. Isopropyl Alcohol X. Tweens XI. Polysorbates XII. Castor Oil XIII. Peanut Oil XIV. Sesame Oil XV. Buffers at various pHs 2. pKa determination Determination of the dissociation constant for a drug capable of ionization within a pH range of 1 to 10 is important since solubility, and consequently absorption, can be altered by orders of magnitude with changing pH. The Henderson-Hasselbalch equation provides an estimate of the ionized and un-ionized drug concentration at a particular pH. For acidic compounds: pH = pKa + log ([ionized drug]/[un-ionized drug]) For basic compounds: pH = pKa + log ([un-ionized drug]/[ionized drug])
  6. 6. PREFORMULATION GUIDANCE pKa of a compound is thus a measure of drug un-ionized at a certain pH pKa = -log K a , where Ka is the acidity or ionization constant of a weak acid. (K w=[H 3 O+] For a weak base, K a = K w/K b , where K w is the ionic product of water x [OH-]) and K b is the basicity or ionization constant of the weak 3. Partition coefficient Partition coefficient (oil/water) is a measure of a drug's lipophilicity and an indication of its ability to cross cell membranes. It is defined as the ratio of un- ionized drug distributed between the organic and aqueous phases at equilibrium. P o/w = (C oil /C water ) equilibrium For series of compounds, the partition coefficient can provide an empiric handle in screening for some biologic properties. For drug delivery, the lipophilic/hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption. Although partition coefficient data alone does not provide understanding of in vivo absorption, it does provide a means of characterizing the lipophilic/hydrophilic nature of the drug. Since biological membranes are lipoidal in nature, the rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the moleucle. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water. Drugs having values of P much greater than 1 are classified as lipophilic, whereas those with partition coefficients much less than 1 are indicative of a hydrophilic drug. Although it appears that the partition coefficient may be the best predictor of absorption rate, the effect of dissolution rate, pKa, and solubility on absorption must not be neglected.
  7. 7. PREFORMULATION GUIDANCE 4. Chemical stability profile Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug. These studies include both solution and solid state experiments under conditions typical for the handling, formulation, storage, and administration of a drug candidate as well as stability in presence of other excipients. Factors affecting chemical stability critical in rational dosage form design include temperature, pH and dosage form diluent. The method of sterilization of parenteral products will be largely dependent on the temperature stability of the drug. Drugs having decreased stability at elevated temperatures cannot be sterilized by autoclaving but must be sterilized by another means, e.g., filtration. The effect of pH on drug stability is important in the development of both oral and parenteral dosage forms; acid labile drugs intended for oral administration must be protected from the highly acidic environment of the stomach. Buffer selection for parenteral dosage forms will be largely based on the stability characteristics of the drug. • Solid-State Stability • Solution-Phase Stability • Compatibility Studies: Stability in the Presence of Excipients • Typical Stability Protocol for a New Chemical Entity
  8. 8. PREFORMULATION GUIDANCE • Solid-State Stability The primary objectives of this investigation are identification of stable storage conditions for drug in the solid state and identification of compatible excipients for a formulation. Solid state studies may be severely affected by changes in purity and crystallinity, which often result from process improvements. Repetitive testing of the initial bulk lot in parallel with newer bulk lots should be expected, and adequate material should be set aside for these studies. In general, solid state reactions are much slower and more difficult to interpret than solution state reactions, and it is customary to use stress conditions in the investigation of stability. The data obtained under stress conditions are then extrapolated to make a prediction of stability under appropriate storage conditions. Stress conditions utilized by the scientists are: • Elevated temperature Studies • Stability under High-Humidity Conditions • Photolytic Stability • Oxidative Stability • Elevated temperature Studies The elevated temperatures most commonly used are 40°, 50° and 60° C in conjunction with ambient humidity. Occasionally, higher temperatures are used. The samples stored at the highest temperature should be examined for physical and chemical changes at weekly intervals, and any change, when compared to an appropriate control (usually a sample stored at 5°C), should be noted. If a substantial change is seen, samples stored at lower temperatures are examined. If no change is seen after 30 days at 60°C, the stability prognosis is excellent. Corroborative evidence must be obtained by monitoring the samples stored at lower temperatures for longer durations. Samples stored at room
  9. 9. PREFORMULATION GUIDANCE temperature and at 5°C may be followed for as long as 6 months. The data obtained at elevated temperatures may be extrapolated using the Arrhenius treatment to determine the degradation rate at a lower temperature. Arrhenius Equation: K = A e-Ea/RT E : activation energy; R: gas constant a logK = logA - (E a /2.303RT) Plotting the rate of reaction (K) against 1/T allows the calculation of rate at any temperature and therefore a prediction of shelf-life (t 90 , time to 90% potency). This forms the basis of many accelerated stability tests. Not all solid-state reactions are amenable to Arrhenius treatment. Their heterogeneous nature makes elucidation of the kinetic order and prediction difficult. Long-term lower temperature studies are, therefore, an essential part of a good stability program. • Stability under High-Humidity Conditions In the presence of moisture, many drug substances hydrolyze, react with other excipeints, or oxidize. These reactions can be accelerated by exposing the solid drug to different relative-humidity conditions. Controlled humidity environments can be readily obtained using laboratory desiccators containing saturated solutions of various salts. Preformulation data of this nature are useful in determining if the material should be protected and stored in a controlled low-humidity environment, or if the use of an aqueous-based granulation system, in the case of a solid dosage form, should
  10. 10. PREFORMULATION GUIDANCE be avoided. They may also caution against the use of excipients that absorb moisure significantly. • Photolytic Stability Many drug substances fade or darken on exposure to light. Usually the extent of degradation is small and limited to the exposed surface area. This can be controlled by using amber glass or an opaque container or by incorporating a dye in the product to mask the discoloration (if the only issue is aesthetics). Exposure of the drug substance to 400 and 900 footcandles of illumination for 4- and 2-week periods, respectively, is adequate to provide some idea of photosensitivity. Over these periods, the samples should be examined frequently for change in appearance and for chemical loss, and they should be compared against samples stored under the same conditions but protected from light. Source : ICH
  11. 11. PREFORMULATION GUIDANCE • Oxidative Stability The sensitivity of each new drug entity to atmospheric oxygen must be evaluated to establish if the final product should be packaged under inert atmospheric conditions and if it should contain an antioxidant. Sensitivity to oxidation of a solid drug can be ascertained by investigating its stability in an atmosphere of high oxygen tension. Usually a 40% oxygen atmosphere allows for a rapid evaluation. Results should be compared against those obtained under inert or ambient atmospheres. • Solution-Phase Stability The primary objective of this phase of preformulation research is identification of conditions necessary to form a stable solution. These studies should include the effects of pH, ionic strength, cosolvent, light, temperature and oxygen. Solution stability investigations usually commence with probing experiments to confirm decay at the extremes of pH and temperature (e.g., 0.1N HCl, water, and 0.1N NaOH all at 90°C). These intentionally degraded samples may be used to confirm assay specificity as well as to provide estimates for maximum rates of degradation. This initial experiment should be followed by the generation of a complete pH-rate profile to identify the pH of maximum stability. Aqueous buffers are used to produce solutions over a wide range of pH values with constant levels of drug, cosolvent and ionic strength. Reactions in solutions proceed considerably more rapidly than the corresponding solid-state reactions. Degradation in solution thus offers a rapid method for the generation of degradation products. The latter are often needed for the purpose of identification (to study their toxicity) and the development of analytical methods. Even for a drug substance intended to be formulated into a solid dosage form such as a tablet, a limited solution-phase stability study must be undertaken. Among others, these studies are necessary to assure that the drug substance does not
  12. 12. PREFORMULATION GUIDANCE degrade intolerably when exposed to gastrointestinal fluids. Thus, the stability of drug in buffers ranging from pH 1 to 8 should be investigated. If the drug is observed to degrade rapidly in acidic solutions, a less soluble or less susceptible chemical form may show increased relative bioavailability. Alternately, an enteric dosage form may be recommended for such a compound. The availability of pH-rate profile data is sometimes useful in predicting the solid- state stability of salt forms or the stability of a drug in the presence of acidic and basic excipients. If a drug substance is adjudged to be physically or chemically unstable when exposed to moisture, a direct compression or nonaqueous-solvent granulation procedure is to be recommended for the preparation of tablets. Before using a nonaqueous solvent for this purpose, stability of the drug in the solvent must be ascertained. Light Stability: Some solution samples should be subjected to a light stability test, which includes protective packaging in amber glass containers. Control samples for this light test may be stored in cardboard packages or wrapped in aluminum foil. Oxidation: Some of the solution samples should also be subjected to further testing with: • Excessive headspace of oxygen • Headspace of an inert gas such as helium or nitrogen • Inorganic antioxidant such as sodium metabisulfite • Organic antioxidant such as butylated hyrdroxytoluene-BHT Analysis of these samples will give an idea of oxidation potential of the drug.
  13. 13. PREFORMULATION GUIDANCE pH-Rate Profile: To generate a pH-rate profile, stability data generated at each pH and temperature condition are analyzed kinetically to yield the apparent decay rate constants. All of the rate constants at a single temperature are then plotted as a function of pH. The minimum in this curve is the pH of maximum stability. An Arrhenius plot is constructed by plotting the logarithm of the apparent decay rate constant versus the reciprocal of the absolute temperature at which each particular buffer solution was stored during the stability test. If this relationship is linear, one may assume a constant decay mechanism over this temperature range and calculate an activation energy (E a ) from the slope (-E a/R) of the line described by: ln k = - (E a /R)(1/T) + C Where C is a constant of integration and R is the gas constant. A broken or nonlinear Arrhenius plot suggests a change in the rate-limiting step of the reaction or a change in decay mechanism, thus making extrapolation unreliable.
  14. 14. PREFORMULATION GUIDANCE • Compatibility Studies: Stability in the Presence of Excipients Compatibility Studies: In the tablet dosage form the drug is in intimate contact with one or more excipients; the latter could affect the stability of the drug. Knowledge of drug- excipient interactions is therefore very useful to the formulator in selecting appropriate excipients. Example: A typical tablet contains binders, disintegrants, lubricants, and fillers. Compatibility screening for a new drug must consider two or more excipients from each class. The ratio of drug to excipient used in these tests is very much at the discretion of the preformulation scientist. The three techniques commonly employed in drug-excipient compatibility screening are: • Thin-layer chromatography • Differential thermal analysis • Diffuse reflectance sprectroscop Thin-Layer Chromatography: This involves storage of drug-excipients mixture both quot;as isquot; and granulated with water at elevated temperatures. The granulation may be carried out so that the mixture contains fixed amounts (e.g., 5%) of moisture. The mixtures are sealed in ampoules to prevent any escape of moisture at elevated temperatures. The samples are examined periodically for appearance and analyzed for any decomposition using thin-layer chromatography. Unstressed samples are used as controls. Any change in the chromatograph such as the appearance of a new spot
  15. 15. PREFORMULATION GUIDANCE or a change in the RF values [The distance (d s ) traveled by a sample, relative to the solvent front (d e ) which is compound specific in each chromatographic system. The ratio is termed the R f value or resolution factor. This is sometimes known as relative to front.] of the components is indicative of an interaction. The technique may be quantities if deemed necessary. If significant interaction is noticed at elevated temperatures, corroborative evidence must be obtained by examining mixtures stored at lower temperatures for longer durations. If no interaction is observed at 60 or 70°C, especially in the presence of moisture, none can be expected at lower temperatures. Among the advantages of thin-layer chromatographies in this application are: • Evidence of degradation is unequivocal. • The spots corresponding to degradation products can be eluted for possible identification. The technique can be quantitated to obtain kinetic data. • Differential Thermal Analysis: Thermal Analysis is useful in the investigation of solid-state interactions. It is also useful in the detection of eutectics. Thermograms are generated for pure components and their physical mixtures with other components. In the absence of any interaction, the thermograms of mixtures show patterns corresponding to those of the individual components. In the event that interaction occurs, this is indicated in the thermogram of a mixture by the appearance of one or more new peaks or the disappearance of one or more peaks corresponding to those of the components.
  16. 16. PREFORMULATION GUIDANCE Diffuse Reflectance Spectroscopy: Diffuse reflectance spectroscopy is gaining increasing popularity among preformulation scientists as a tool to detect and monitor drug-excipient interactions. In this technique solid drug, excipients, and their physical mixtures are exposed to incident radiation. A portion of the incident radiation is partly absorbed and partly reflected in a diffuse manner. The diffuse reflectance depends on the packing density of the solid, its particle size, and its crystal form, among other factors. When these factors are adequately controlled, diffuse reflectance spectroscopy can be used to investigate physical and chemical changes occurring on solid surfaces. A shift in the diffuse reflectance spectrum of the drug due to the presence of the excipient indicates physical adsorption, whereas the appearance of a new peak indicates chemisorption or formation of a degradation product.
  17. 17. PREFORMULATION GUIDANCE Typical Stability Protocol for a New Chemical Entity
  19. 19. PREFORMULATION GUIDANCE 5. Crystal Properties and Polymorphism Many drug substances can exist in more than one crystalline form with different space lattice arrangements. This property is known as polymorphism. Polymorphs generally have different melting points, x-ray diffraction patterns, and solubilities, even though they are chemically identical. Differences in the dissolution rates and solubilities of different polymorphic forms of a given drug are very commonly observed. When the absorption of a drug is dissolution rate limited, a more soluble and faster-dissolving form may be utilized to improve the rate and extent of bioavailability. For drugs prone to degradation in the solid state, the physical form of the drug influences degradation. Selection of a polymorph that is chemically more stable is a solution in many cases. Different polymorphs also lead to different morphology, tensile strength and density of powder bed which all contribute to compression characteristics of materials. Some investigation of polymorphism and crystal habit of a drug substance as it relates to pharmaceutical processing is desirable during its preformulation evaluation, especially when the active ingredient is expected to constitute the bulk of the tablet mass. Although a drug substance may exist in two or more polymorphic forms, only one form is thermodynamically stable at a given temperature and pressure. The other forms would convert to the stable form with time. In general, the stable polymorph exhibits the highest melting point, the lowest solubility, and the maximum chemical stability. Various techniques are available for the investigation of the solid state. These include microscopy (including hot-stage microscopy), infrared spectrophotometry, single-crystal X-ray and X-ray powder diffraction, thermal analysis, and dilatometry.
  20. 20. PREFORMULATION GUIDANCE Chart for Setting Acceptance Criteria For Polymorphism in Drug Substances and Drug Product Source: ICH
  21. 21. PREFORMULATION GUIDANCE 6. Particle size, shape and surface area Bulk flow, formulation homogeneity, and surface-area controlled processes such as dissolution and chemical reactivity are directly affected by size, shape and surface morphology of the drug particles. In general, each new drug candidate should be tested during preformulation with the smallest particle size as is practical to facilitate preparation of homogeneous samples and maximize the drug's surface area for interactions. Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior. It is generally recognized that poorly soluble drugs showing a dissolution-rate limiting step in the absorption process will be more readily bioavailable when administered in a finely subdivided state rather than as a coarse material. In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules. Size can also be a factor in stability; fine materials are relatively more open to attack from atmospheric oxygen, the humidity, and interacting excipients than are coarse materials. 1. Determination of particle size Classical methods for measuring particle size Microscopy Optical microscopy is generally used as the first tool to see and measure sizes of particles ranging in size from 0.2 microns to 100 microns.
  22. 22. PREFORMULATION GUIDANCE Advantages • Easy and convenient • A size-frequency distribution curve can be plotted by counting the number of particles in a size range • Can detect the presence of agglomerates and particles of more than one component Disadvantages • Diameter is obtained from only two dimensions - length and breadth • No estimation of the depth (thickness) of particle is available • The number of particles that must be counted to get a good estimate of the distribution makes the method slow and tedious Sieving or screening This method utilizes a series of standard sieves calibrated by the National Bureau of Standards. Sieves are generally used for grading coarser particles. Sieves produced by photoetching and electroforming techniques are now available with apertures from 90 microns down to as low as 5 microns. Method: According to the method of the U.S. Pharmacopoeia for testing powder fineness, a definite mass of sample is placed on the proper sieve in a mechanical shaker. The powder is shaken for a definite period of time, and the material that passes through one sieve and is retained on the next finer sieve is collected and weighed.
  23. 23. PREFORMULATION GUIDANCE Sedimentation A number of classical techniques based on sedimentation methods, utilizing devices such as the Andreasen pipette or recording balances that continuously collect a settling suspension are known. However, these methods are now in general disfavor because of their tedious nature. o Commonly used instruments:  Royco (based on light scattering)  Hiac (based on light blockage)  Coulter Counter (based on blockage of an electrical conductivity path)
  25. 25. PREFORMULATION GUIDANCE Determination of surface area The determination of the surface areas of powders has been getting increasing attention in recent years. The techniques employed are relatively simple and convenient to use, and the data obtained reflect the particle size. The relationship between the two parameters is an inverse one, in that a grinding operation that reduces the particle size leads to an increase in the surface area. Two commonly available methods for determining surface area are: Adsorption Method Air Permeability Method 2.1 Adsorption Method This method is based on the Brunauer, Emmett, Teller (BET) theory of adsorption. Briefly, the theory states that most substances will adsorb a monomolecular layer of a gas under certain conditions of partial pressure (of the gas) and temperature. Knowing the monolayer capacity of an adsorbent (i.e., the quantity of adsorbate which can be accommodated as a monolayer on the surface of a solid, the adsorbent) and the area of the adsorbate molecule, the surface area can, in principle, be calculated. 2.2 Air Permeability Method The principle resistance to the flow of a fluid, such as air, through a plug of compacted powder is the surface area of the powder. The greater the surface area per gram of powder, the greater the resistance to flow. Hence permeability, for a given pressure drop across the plug, is inversely proportional to specific surface; measurement of the former provides a means of estimating this parameter. Because of the simple instrumentation and the speed with which determinations can be made, permeability methods are widely used pharmaceutically for specific surface determinations, especially when the aim is to control batch-to-batch variations. When using this technique for more fundamental studies, it would seem prudent to calibrate the instrument.
  26. 26. PREFORMULATION GUIDANCE 7. Specifications for New Drug Substances and Products 7.1 Setting Acceptance Criterion for Impurity & Degradation in a New Drug Product
  27. 27. PREFORMULATION GUIDANCE 7.2 Establishing Identity, Assay And Enantiomeric Impurity Procedures for Chiral New Drug Substances and New Drug Products containing Chiral Drug Substances Source: ICH
  28. 28. PREFORMULATION GUIDANCE 7.3 Microbiological Quality Attributes of Drug Substance and Excipients Source: ICH
  29. 29. PREFORMULATION GUIDANCE 7.4 Setting Acceptance Criteria for Drug Product Dissolution  Appropriate type of drug release acceptance criteria Source: ICH
  30. 30. PREFORMULATION GUIDANCE  Appropriate test conditions and acceptance criteria Source: ICH
  31. 31. PREFORMULATION GUIDANCE  Appropriate acceptance ranges (extended release) Source: ICH
  32. 32. PREFORMULATION GUIDANCE  Microbiological Attributes of Non-Sterile Drug Products Source: ICH
  33. 33. PREFORMULATION GUIDANCE 8. Dosage Form Development Chart Source: Modified from quot;Pharmaceutical Preformulation: The Physicochemical Properties of Drug Substancesquot;
  34. 34. PREFORMULATION GUIDANCE 4. Formulation : Formulation Developments starts immediately after or concurrently with preformulation studies. Depending on the dosage form selected, various studies are conducted to accomplish the goal. Formulations developed are tested for both physical and chemical stability at accelerated temperatures. To determine the chemical stability of the formulations, an analytical method needs to be in place (usually an HPLC method) to identify and quantify the active compound. Care should be taken to see that the method is selective and specific for the active molecule. • Solid Dosage Form • Tablets • Capsules • Suppositories • Liquid Dosage Form • Parenteral • Emulsions & Suspensions • Solutions
  35. 35. PREFORMULATION GUIDANCE • Semisolid Dosage Form • Creams • Gels • Ointments • Special Drug Delivery Technologies • Ophthalmic Delivery • Nasal Delivery • Transdermal Delivery • Microencapsulation
  36. 36. PREFORMULATION GUIDANCE 5. Analytical: 5.1 Validation of Chromatographic Methods 5.2 Stability Testing of Drug Substances and Drug Products (FDA) 5.3 Stability Testing of New Drugs and Products (ICH) 5.4 Validation of Analytical Procedures 5.5 Bioanalytical Methods Validation for Human Studies 5.6 Specifications for New Drug Substances and Products
  37. 37. PREFORMULATION GUIDANCE 6. Pharmacokinetic: The primary objective of pharmacokinetics is to quantify drug absorption, distribution, biotransformation and excretion of the drug. Based on pharmacokinetics:  The performance of dosage forms can be evaluated in terms of rate and amount of drug delivered to the blood  The dosage regimen of a drug can be adjusted to produce and maintain therapeutically effective blood concentrations with little or no toxicity Studies in Preclinical Stage: Drug metabolism in animals in the preclinical stage includes characterization of ADME (Absorption, Distribution, Metabolism and Excretion) for a single compound. Studies conducted include:  Mass balance studies (Radiolabeled drug) in toxicology species 1. Tissue distribution and accumulation  Dose proportionality kinetics to support toxicology doses selected 1. Plasma concentration increases linearly with dose of drug 2. Lower limit threshold, upper limit plasma concentration 3. Plasma protein binding - % bound vs. Plasma concentration  Multiple dose kinetics in toxicology species (Toxicokinetics) 1. Plasma and/or tissue accumulation with multiple doses 2. Induction / Inhibition of metabolizing enzymes (Cytochrome P450) A. Lower plasma conc. with time B. Toxicity from increased/decreased endogenous molecules  Metabolite profile, gender differences, interspecies scaling  Support formulation development
  38. 38. PREFORMULATION GUIDANCE 2. Investigational New Drug Application (IND) After completing preclinical testing, a company files an IND with the U.S. Food and Drug Administration (FDA) to begin to test the drug in people. The IND enables a sponsor to ship an unapproved drug in interstate commerce. Clinical trials may proceed 30 days after filing unless the FDA places a hold on the proposal. In many ways, the investigational new drug (IND) application is the result of a successful preclinical development program. The IND is also the vehicle through which a sponsor advances to the next stage of drug development known as clinical trials (human trials). During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies. Generally, this includes data and information in three broad areas: • Animal Pharmacology and Toxicology Studies Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. • Manufacturing Information Information pertaining to the composition, manufacture, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed as to ensure the company can adequately produce and supply consistent batches of the drug.
  39. 39. PREFORMULATION GUIDANCE • Clinical Protocols and Investigator Information Detailed protocols for proposed clinical studies to assess whether the initial- phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. The IND is not an application for marketing approval. Rather, it is a request for an exemption from the Federal statute that prohibits an unapproved drug from being shipped in interstate commerce. Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA; however, its main purpose is to detail the data that provide documentation that it is indeed reasonable to proceed with certain human trials with the drug. Types of INDs quot;Commercial INDsquot; are applications that are submitted primarily by companies whose ultimate goal is to obtain marketing approval for a new product. However, there is another class of filings broadly known as quot;noncommercialquot; INDs. The vast majority of INDs are, in fact, filed for noncommercial research. These types of INDs include quot;Investigator INDs,quot; quot;Emergency Use INDs,quot; and quot;Treatment INDs.quot; For Application Process refer CDER web site
  40. 40. PREFORMULATION GUIDANCE 3. Clinical Trials Clinical Trials involve the following phases: Testing in Humans Number of Percent of Drugs Length Purpose Patients Successfully Tested Several Phase I 20 - 100 Mainly safety 70 percent months Upto Several Some short-term Phase II several months to safety, but mainly 33 percent hundred 2 years effectiveness Several Safety, hundred to Phase III 1 - 4 years effectiveness, 25 - 30 percent several dosage thousand Phase IV Post-marketing surveillance For example, of 100 drugs for which Investigational New Drug applications are submitted to FDA, about 70 percent will successfully complete Phase I and go on to Phase II; about 33 percent of the original 100 will complete Phase II and go to Phase III; and 25 to 30 of the original 100 will clear Phase III (and, on average, about 20 of the original 100 will ultimately be approved for marketing).
  41. 41. PREFORMULATION GUIDANCE Phase I Clinical Trials are to determine safety of the new drug entity, including the safe dosage range. Phase I includes the initial introduction of an investigational new drug into humans. These studies are closely monitored and may be conducted in patients, but are usually conducted in healthy volunteer subjects, and typically last 3-6 months. These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase I, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase II studies. Phase I studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. These studies also determine which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects included in Phase I studies varies with the drug, but is generally in the range of twenty to eighty. In Phase I studies, CDER can impose a clinical hold (i.e., prohibit the study from proceeding or stop a trial that has started) for reasons of safety, or because of a sponsor's failure to accurately disclose the risk of study to investigators. Although CDER routinely provides advice in such cases, investigators may choose to ignore any advice regarding the design of Phase I studies in areas other than patient safety. Phase II Clinical Trials assess the drug's effectiveness. Phase II includes the early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. This phase of testing also helps determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well-controlled, closely monitored, and
  42. 42. PREFORMULATION GUIDANCE conducted in a relatively small number of patients, usually involving several hundred people. Phase II Trials may last from 6 months to 2 years. Trials may be conducted in a blind or non-blind manner. Phase III Clinical Trials determine efficacy and identify adverse reactions in large populations. Phase III studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase II, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Phase III studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Phase III studies usually include several hundred to several thousand people. In both Phase II and III, CDER can impose a clinical hold if a study is unsafe (as in Phase I), or if the protocol is clearly deficient in design in meeting its stated objectives. Great care is taken to ensure that this determination is not made in isolation, but reflects current scientific knowledge, agency experience with the design of clinical trials, and experience with the class of drugs under investigation. Phase IV (Post-marketing surveillance) The objectives of post-marketing surveillance are to identify rare adverse reactions not detected during pre-licensure studies, monitor increases in known reactions, identify risk factors or pre-existing conditions that may promote reactions, and identify particular lots with unusually high rates or types of events.
  43. 43. PREFORMULATION GUIDANCE 4. New Drug Application (NDA) Following the completion of all three phases of clinical trials, a company analyzes all of the data and files an NDA with FDA if the data successfully demonstrate both safety and effectiveness. The NDA contains all of the scientific information that the company has gathered. NDAs typically run 100,000 pages or more. By law, FDA is allowed six months to review an NDA. The average NDA review time for new molecular entities approved was 16.2 months. 5. Approval Once FDA approves an NDA, the new medicine becomes available for physicians to prescribe. A company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate quality-control records. For some medicines, FDA requires additional trials (Phase IV) to evaluate long-term effects.  Drug Approval Application Process  Post-Drug Approval Activities  Post Marketing Surveillance Program