Introduction
The process for developing and manufacturing drug delivery systems for human therapeutics has evolved over the past two decades. It now involves collaboration among individuals representing a variety of scientific disciplines, including biology, chemistry, engineering, and pharmaceutics. Drug products are formulations or “dosage forms” used for administering an active pharmaceutical ingredient (API; see Table 7.3.1 for a list of acronyms found in the unit) to assess its safety in preclinical models (toxicology studies), early- to late-phase human clinical trials, and for commercial use. In this overview, drug, compound, and API will be used somewhat interchangeably to refer to the active molecule. Drug formulations can be designed to address several challenges, including:
- Improving the solubility of hydrophobic or sparingly soluble compounds
- Enhancing bioavailability or exposure of drugs by solubilization approaches
- Preserving the physical and chemical stability of drugs in particular dosage forms
- Tailoring the drug release rate and/or targeting to a select location
- Ensuring the ability to scale up the manufacturing of the drug product from the bench to clinical quantities
- Exploring alternative delivery systems and patent extensions (often called life cycle management)Table 7.3.1 List of Acronyms Used in this Unit
ANDA: Abbreviated new drug application API: Active pharmaceutical ingredient AUC: Area under curve BLA: Biologic license application BCS: Biopharmaceutical classification system CDER: Center for Drug Evaluation Research CMC: Chemistry and manufacturing controls CoA: Certificate of analysis CR: Controlled release CTA: Clinical trial application DP: Drug product DOE: Design of experiments EP: European Pharmacopeia FDA: Food and Drug Administration GLP: Good laboratory practices GMP: Good manufacturing practices HDPE: High density polyethylene HPLC: High-performance liquid chromatography HPMC: Hydoxypropylmethylcellulose HPMCAS: Hydoxypropylmethylcellulose acetate succinate HPC: Hydroxypropyl cellulose ICH: International Conference on Harmonization IND: Investigational new drug i.p.: Intraperitoneal IR: Immediate release i.v.: Intravenous JP: Japanese Pharmacopeia LC-MS: Liquid chromatography/mass spectrometry MAD: Multiple ascending dose NDA: New drug application NIR: Near infrared NMR: Nuclear magnetic resonance NOAEL: No observed adverse effects level O/W: Oil in water PAT: Process analytical technology PEG: Polyethylene glycol PEO: Polyethylene oxide PIC: Powder in capsule PTFE: Polytetrafluoroethylene PVP: Polyvinylpyrrolidone SAD: Single ascending dose s.c.: Subcutaneous SEDDS: Self emulsifying drug delivery system SEM: Scanning electron microscopy SMEDDS: Self micro-emulsifying drug delivery system SPIP: Single pass intestinal perfusion TK: Toxicokinetics USP: United States Pharmacopeia
Primary packaging is also important to enhance ease of dosing, safety (tamper and child resistance), maintain shelf life, and preserve brand identity.
The key attributes typically associated with drug product (DP) development are “stability,” “safety,” “manufacturability,” and “bioavailability.” These criteria must be met to design a successful DP. The pharmaceutical industry is undertaking parallel approaches for development of small- and large-molecule active pharmaceutical ingredients (APIs). Small-molecule APIs are organic compounds typically less than 800 Daltons, and small enough to passively transport through cellular membranes. Large-molecule APIs, also called biologics, include peptides and proteins and can be more challenging to deliver, involving different formulation strategies. Most small APIs are crystalline and can be produced in large batch reactors/crystallizers, followed by filtration and drying steps. While some peptides can be produced synthetically, most biologics are isolated from cell lines, using recombinant DNA technology. For biologics, manufacturing operations, such as separation, purification, and filtration can make processing more complex.
Oral delivery is most easily accomplished for small APIs. For large APIs, the destabilizing effects of pH and temperature changes often preclude this route. Peptides and proteins can be subject to denaturation or enzymatic hydrolysis within the gastrointestinal tract, destroying their therapeutic activity (Parkins and Lashmar, 2000). Dosage forms, such as liquid, tablets, transdermal patches, and depots, are suitable for small molecules, as they can remain insoluble or completely solubilized prior to administration.
Primary product packaging can be bottles, blisters, or pouches. Biologic drug products are usually sterile injectables. Those compounds with good aqueous solubility can be supplied as stabilized solutions or lyophilized powders for reconstitution. Some small-molecule APIs, such as anti-infectives and chemotherapeutics, also require injectable formulations to increase their bioavailability in the bloodstream. Primary packaging for injectables include bottles or vials with rubber stoppers for using syringes to remove the product. There are pros and cons for the development of either large or small APIs for a given therapeutic need. For example, small APIs can be produced less expensively at larger scales, and can be formulated with a wider variety of delivery platforms (i.e., oral, transdermal, injectable). Biologics, on the other hand, are often preferred because of their greater target selectivity. However, there are safety concerns with biologics inasmuch as parenteral/intravenous delivery can cause immunological reactions (Callen, 2007).
During the development and commercialization of drug products, technical information packages are submitted to the United States Food and Drug Administration (FDA), or similar regulatory agencies in other countries where clinical studies are to be performed. These are part of the Chemistry and Manufacturing Controls (CMC) sections in the regulatory document. Early submissions include Investigational New Drug applications (INDs) or Clinical Trial Applications (CTAs) in other countries. The New Drug Application (NDA) is filed during the final stages of development in preparation for commercialization. For biologics, a Biologics License Application (BLA) must be filed prior to the NDA. Familiarization with the International Conference for Harmonization (ICH) guidelines is helpful to ensure robustness of the data package for each submission (http://www.fda.gov).
Although individual pharmaceutical and biotech organizations have slightly different paradigms for drug development, the overall scientific strategies are approaching common ground in the use of first principles. This overview includes a summary of approaches used for small-molecule API dosage forms, from preformulation to commercial manufacturing. Additional details on solubility challenges, formulation development, and manufacturing of large-molecule API/biologic formulations are addressed by Parkins and Lashmar (2000), Shahrokh (2007), and Shire (2009).
Delivery Pathways
For small molecules, oral administration is the preferred route, especially in early clinical trials. For this purpose the formulation is typically a capsule, tablet, or suspension. Non-oral, or parenteral, routes of administration include intraperitoneal (i.p.), intravenous (i.v.), subcutaneous (s.c.), transdermal, buccal, nasal, vaginal, and rectal (Table 7.3.2 and Table 7.3.3). Intravenous formulations are used if a rapid onset of action is needed, such as for the treatment of severe pain and microbial infections. Intravenous formulations are often used in clinical studies to quantify the relative bioavailability of other dosage forms. For a given compound, parenteral routes may be preferred for overcoming oral bioavailability or tolerability challenges, or to prepare for alternative marketing strategies in extending the patent life of the formulation (life cycle management).
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Transdermal administration is used for systemic delivery of drugs through the skin barrier (stratum corneum). This mode of delivery, which usually involves the use of an adhesive patch, is convenient, noninvasive, and can accommodate extended delivery of various APIs, e.g., analgesics and contraceptives. For some drugs, hepatic and intestinal metabolism can be avoided by using transdermal systems. However, the molecular weight, solubility, and stability of the compound can affect its suitability for a transdermal formulation.
Other routes of drug administration include nasal, pulmonary, and ocular delivery (Table 7.3.2). Most often these approaches are used for localized delivery of APIs. Injectable and implantable systems (Table 7.3.3), while invasive, can direct drugs to specific locations and afford rapid bioavailability. They also have the added risks of causing inflammation and surgical complications.
Development strategies for any dosage form require an understanding of the physicochemical properties of the compound and its interaction with formulation components and processing methods. In addition, formulations are crucial for bridging toxicology and pharmacokinetic (PK) studies to ensure adequate compound exposure and for calculation of the No Observed Adverse Effect Level (NOAEL), which is used in determining safe drug plasma levels for calculating clinical doses (ICH M3R2 guidance, Jan. 2010). Detailed below are the important stages for drug product development. The scope of this overview is limited to formulation and manufacturing technologies related to oral, injectable, and transdermal dosage forms, to contrast several DP approaches. Emphasis is placed mostly on formulation and manufacturing strategies, with only a brief mention of supporting analytical and packaging technologies.
Preformulation and Characterization
One of the most important steps in dosage form development is preformulation, which begins when the molecule can be scaled up to gram quantities. Usually, a systematic approach is taken for API characterization to provide guidance for the technical strategy used in Phase I development.
A typical preformulation data package for a clinical drug candidate entails an assessment of its physical, chemical, and biopharmaceutical properties to enable development of a robust DP that provides optimum exposure in the clinic. A basic review of preformulation can be found in Carstensen (2000). Important compound physicochemical properties include pH solubility profile, solubility in various solvents, pK
Physicochemical Properties
Crystals and polymorphs: Small molecule APIs are typically crystalline powders that are weak acids, bases, zwitterions, or even neutral molecules. The advantages of crystallinity are good physical and chemical stability, purity, and mechanical properties. It is also easier to control particle size and shape with the formation of crystals. In some cases, an amorphous API may be desirable, especially when crystalline materials have poor aqueous solubility, thereby limiting in vivo absorption. However, there are risks with physical stability where amorphous materials may re-crystallize after aging (time, temperature, and relative humidity) or exhibit enhanced rates of chemical degradation. Crystalline APIs that are highly polymorphic (i.e., having many solid state forms) may also have poor physical stability, leading to form conversion during processing and storage. Properties of both crystalline and amorphous API can be optimized using various methods, such as salt and polymorph screening for the former, and polymer/excipient stabilization approaches for the latter.
Chemical stability: The chemical stability of most APIs is evaluated both in solution and in the solid state at various temperatures and under accelerated conditions. Forced degradation studies are also conducted, which probe various degradation reaction mechanisms, such as hydrolysis and oxidation. Some common chemical degradation mechanisms encountered with pharmaceuticals are discussed by Waterman et al. (2002a,b). Strickley and Oliyai (2007) also review reaction mechanisms unique to pro-drugs (precursor molecules converted to the active compound in vivo) and methods for their stabilization. The size and morphology of the API are also characterized using microscopy and particle sizing methods (i.e., laser diffraction, image analysis). This information is used to predict dissolution kinetics and suitability for various DP manufacturing operations.
Salt selection and polymorph screening: Salt selection and polymorph screening for crystalline drugs are important to ensure that the most stable and bioavailable form is nominated for development. Crystalline structure can affect the stability of the molecule. Forms with higher melting temperatures tend to be more physically and chemically stable under accelerated conditions and resistant to phase transitions (i.e., polymorph changes) during DP manufacturing. Salts are often more soluble than their free acids or bases. This makes them more suitable for liquid formulations and also more bioavailable in solid drug products. Recent reviews by Serajuddin (2007) and Llinas and Goodman (2008) detail the mechanisms and advancements in salt selection and polymorph screening. Serajuddin (2007) describes the use of acid-base equilibria, the relationships between pH, pK
Similar to salt screening, polymorph screening techniques have evolved over the last decade. Llinas and Goodman (2008) review several methods to elucidate polymorphs, such as seeding, anti-solvent addition, mechanical grinding, supersaturation, ultrasonication, and high-throughput techniques. All these can be used to rapidly identify stable forms. Other approaches include formation of co-crystals, where the molecule crystallizes by associating with nonionic or multiple species, unlike conventional salts, yielding unique properties. Highly polymorphic drugs may be challenging to formulate, especially if the forms are labile and have drastic differences in solubility and chemical stability.
Solubility and dissolution: Techniques to measure the solubility and dissolution rate of poorly soluble, ionizable compounds are reviewed by Avdeef (2007). Shake-flask, titration, and microdissolution methods are compared and contrasted, and the pH-solubility curves for many drug compounds are featured. Dai (2010) discusses methods for predicting the precipitation of drug forms in vivo using bio-relevant aqueous media. Although many drugs can be dissolved, their rapid rate of precipitation may compromise bioavailability and safety, especially in IV preparations. Stabilizing agents, such as surfactants and polymers, may prevent drug forms from rapidly “crashing out” of solution. To simulate drug precipitation on injection, a syringe connected to a flow-through apparatus is used where the formulation passes through a buffer and into an ultraviolet cell for detection of the API concentration over time. Other USP-type dissolution methods may be modified to monitor dissolution and precipitation in simulated stomach versus intestinal fluids (i.e., at pH 1.2 versus 6.5), as well as fed and fasted states. Further details on these methods are provided in the analytical section below.
LogP and permeability: The pH-solubility information generated for API during the preformulation stage can be also combined with logP and permeability data (generated by in vitro or in vivo methods) to determine a biopharmaceutical classification system (BCS) rating. This system, introduced in 1995, has refined formulation strategies. Lindenberg et al. (2004) provide a review of various drug molecules and their BCS ratings. logP values are an indication of the hydrophilicity or hydrophobicity of a molecule. High values (greater than 4) imply lipophilicity and high affinity for biological membranes (i.e., skin or gut). The converse is true for low logP values. While permeability data for APIs are required to complete the BCS scheme and can be estimated by Caco-2 cell plates, rat single-pass intestinal perfusion (SPIP) data may more accurately represent gastrointestinal transit (Zakeri-Milani et al., 2009). There are four BCS classes ranked against permeability and solubility (Fig. 7.3.1). BCS 1 compounds (high solubility/high permeability) are the most bioavailable. High solubility is defined as complete dissolution of the desired dose in 250 ml of aqueous media over the pH ranges 1.0 to 7.5. Permeability values may vary based on SPIP or Caco-2 (unit 7.2) techniques, as described in Zakeri-Milani et al. (2009) and Lindenberg et al. (2004). Ranges include <1 × 10
 | Figure 7.3.1 Biopharmaceutical classification system (BCS) solubility grid. |
Forced Degradation Studies
The chemical stability of the API within the DP is important to maintain its quality over the defined shelf life. Forced degradation studies are typically conducted under controlled conditions (temperature, relative humidity, molar ratios, and light exposure) to test the susceptibility of the compound for reacting with any species or impurities that might be present. For example, if a compound is prone to oxidation by exposure to peroxides, one might consider adding antioxidants or radical scavengers, or even avoiding sources of these impurities when choosing excipients for the DP. As excipients, such as polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP), may be sources of peroxides and free radicals (Waterman et al., 2002b), they should not be intimately combined with oxidatively labile API. If the API is prone to photodegradation, special precautions may be needed to block out certain wavelengths of light during DP manufacturing and storage. Forced degradation studies also help in developing the analytical method for the API and DP, and in monitoring key degradation species. Waterman and Adami (2005) and Alsante et al. (2007) review methods to predict degradation and aging of compounds by using reactive species, such as free radical initiators, to promote oxidation, and acidic or basic reagents to facilitate hydrolysis. Software tools can be useful for making important predictions. Darrington and Jiao (2004) explain the adaptation of high-performance liquid chromatography-mass spectrometry techniques to more accurately measure reaction rates, instead of assuming simple Arrhenius-type behaviors for degradation where the natural log of the reaction rate constant is proportional to the inverse of temperature. Once degradation species are identified, it is important to assess their toxicity to determine whether they can be qualified to acceptable levels within the DP based on the maximum dose projected and the duration of a clinical study. The ICH guidelines are used for establishing acceptable levels (http://www.fda.gov).
Excipient Selection and Compatibility
Excipients are inactive ingredients that help control the delivery of the API, and may improve the solubility, stability, and manufacturability of formulations. These materials must be well characterized for impurities, toxicological profiles, and relevant physicochemical properties pertaining to their function in the formulation. To ensure compliance with various regulatory guidelines, ingredients are usually selected that are classified as “Generally Recognized as Safe” and that have passed specifications, which are clearly defined in monographs, such as the United States, European, and Japanese Pharmacopeias (USP, EP and JP, respectively). The International Pharmaceutical Excipients Council provides a more detailed definition of excipients and their properties. Special guidance can be obtained from the FDA and USP Web sites (http://www.fda.gov and http://www.usp.org). Vendors are required to disclose regulatory information on pharmaceutical excipients, and with which pharmacopeia monographs they comply (thus, if a compound is being formulated for a Japanese clinic or market, it is imperative that the excipients used be listed within the Japanese Pharmacopeia monograph).
Liquid formulations: Excipients in liquid formulations help solubilize or suspend the drug, prolong shelf life, and mask taste. Liquids are used mostly in toxicity studies or early clinical trials for ease of administration in selected increments and for minimizing development time. Buffering agents may be required in i.v./parenteral formulations to prevent the API from precipitating or to reduce discomfort upon injection. Preservatives and antioxidants prevent microbial growth and compound degradation, respectively, to enhance shelf life. Liquid DPs may consist of aqueous ingredients, oils, or emulsions. Reviews of liquid formulations are found in Kipp (2007) and Brewster et al. (2007). Shown in Table 7.3.4 are some of the most commonly used excipients and their functions in liquids.
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Solid oral formulations: In contrast to liquids, solid formulations (i.e., tablets, capsules) are more dependent upon the material properties of excipients. When high drug loading is necessary (for large doses or low potency compounds), the formulation can “inherit” poor API properties in terms of its flowability, compactability, and disintegration/dissolution in aqueous media. Excipients for solid DPs include gelatin- or polysaccharide-based capsules, brittle/ductile fillers, binders, surfactants, film coatings, and flavorings. Many polymers are used to stabilize amorphous forms of the drug or to inhibit precipitation. Over the years, excipient properties have been characterized with the aim of optimizing material selection for challenging API. Alderborn and Nyström (1996) summarized important properties of various excipients used in solid oral formulations. Some of the more useful solid excipients and their functions are listed in Table 7.3.5.
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Transdermal formulations: Excipients are essential in transdermal formulations for improving API solubility, flux and permeability, and adhesion of the DP to the skin. For a matrix patch, excipients may consist of a mixture of polymeric adhesives, permeation enhancers, and solubilizers. Other components include nonwoven backing materials and release liners to protect the adhesive. Because patches may be used for extended drug delivery, close monitoring of the physical stability of the API is important to ensure a steady flux through the skin. Problems, such as recrystallization, may occur in supersaturated matrices. Reviews of adhesives and enhancers are found in Tan and Pfister (1999), Qvist et al. (2002), and Karande et al. (2006). Table 7.3.6 lists some of the important transdermal excipients.
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API and excipient compatibility
API and excipient compatibility studies are conducted to ensure that the compound is stable in the presence of the excipient within the desired concentration ranges. The test includes preparing an excipient/API ratio higher (typically 5- to 10-fold) than in the final formulation. This ensures that impurities or reactive species are in excess of the API, which would tend to make degradation mechanisms more easily detectable. Studies can be conducted on small scale using about 5 grams or less of API for all tests. Accelerated stability testing is conducted at conditions defined in the ICH guidelines, such as 5°C, 25°C/60%RH, 30°C/65%RH, and 40°C/75%RH. Samples of the API and excipient are mixed intimately (i.e., triturated) in wet or dry conditions or compacted together, then placed in representative packaging, such as bottles or pouches in accelerated stability chambers. While the use of binary mixtures probes direct interactions, “mock” formulations are useful if the degradation mechanisms of several components are known, or multiple interactions are suspected.
Strickley and Oliyai (2007) performed studies to investigate both excipient and processing effects on the stability of some prodrugs. Water addition, compression, and high shear mixing of blends can help reveal unique degradation mechanisms, based on the morphology of the mixture. Stability testing should be adapted to represent the desired shelf life and storage of the DP. For early clinical studies, 8 to 12 weeks of data are often sufficient to rank order excipients. Arrhenius or other models are used to approximate the degradation rate at various times and temperatures. In some cases, two-week accelerated data at 60°C may be used as a highly discriminating method to rule out many species. The criteria for determining compatibility include levels of degradants formed, physical stability (changes in solid-state properties, i.e., crystallinity), and dissolution (in cases of poorly soluble API). Predictions of stability are best if the batch of API utilized is representative of clinical manufacturing. In many cases, early material obtained from discovery chemists is utilized for this purpose.
Preclinical Formulation Development
Before a compound is introduced into the clinic, exposure and safety studies must be conducted in various animal models. The ICH M3R2 guideline lists the requirements for nonclinical studies (ICH M3R2, Jan. 2010). Pharmacokinetic studies are usually performed early in the discovery program to compare the performance of various formulations and to optimize the exposure of the API. Factors related to compound dissolution and metabolism that are important for developing toxicological formulations may be identified at this stage.
Exposure and PK studies
Liquid formulations are the best to use for preclinical studies as they are easy to develop and to administer. While water is the best diluent for hydrophilic API, polyethylene glycol (PEG) and oils with surfactants are often used for solubilizing BCS 2/4 type compounds. Ethanol is used as a co-solvent in some cases. The same animal species used in toxicity studies are also employed for defining pharmacokinetics. Comparison studies are typically performed in three species, such as rats, dogs, and monkeys. For transdermal products, porcine models are used to more closely mimic transport through human skin. Dose ranges for study typically include those above and below values proposed for therapeutic use. The pharmacokinetic data, including plasma concentrations versus time, area under curve (AUC), and half-life are obtained to further guide formulation development. Compounds with very short half-lives are good candidates for controlled release tablets or transdermal patches. Low C
Toxicological Formulations
The best formulation, usually a solution (i.v., oral) or suspension (oral), is scaled up and undergoes accelerated stability studies. Depending on the complexity of the formulation, the development time can be rapid (within 1 month). The FDA considers transdermal formulations combination products because they represent a drug compound combined with a device. Often, transdermal development is a second-generation development following preparation of oral or injectable dosage forms. Accordingly, prior toxicological data generated from i.v. formulations of the compound can be used when developing subsequent dosage forms. In early development, subcutaneous injections and transdermal solutions or gels allow assessment of skin irritation potential (Ozguney et al., 2006). For initial safety and dose escalation studies, it may be necessary to use prototype patches (Office of Combination Products guidance, Sept. 2006).
For oral suspensions in either aqueous or oil media, high shear mixing or homogenization may be required to ensure consistency in the dose administered per unit of volume. Dispersants and co-solvents, as discussed in the excipients section above, may assist with high API loading. Because the duration of a toxicity study must match that of the intended clinical study, the manufacturing procedure and stability should be suitable for that time period. Ideally the formulation is prepared in advance and stored for the duration of the study. Frequently, the API lacks long-term chemical and physical stability in the presence of liquid, despite the presence of stabilizing excipients. Precipitation and/or degradation may be observed within 24 hr or under accelerated conditions. Temperature cycling (between refrigeration and ambient) could also compromise compound stability. In these cases, daily preparation of the liquid formulation may be required. While this may be acceptable for short-term studies, reformulation will be necessary to support longer preclinical and clinical trials. For i.v. and injectable formulations, the API must be readily solubilized or emulsified and reconstituted in sterile media (i.e., saline, water for injection). Transdermal gels or emulsions are selected using similar criteria.
The manufacture of the final formulation for toxicology studies is conducted under Good Laboratory Practice (GLP) requirements (ICH M3R2 Guidance, 2010). If required for scale-up, larger batches may be prepared in a Good Manufacturing Practice (cGMP) facility, which is also used for clinical manufacturing. The FDA regulates the procedures for the manufacture, testing, packaging, labeling, storage, and distribution of DPs for preclinical and clinical use. Proper documentation is required during manufacture, including batch records, analytical test procedures, and labeling. The GLP batches are tested for API potency, purity, and dose delivery. If the results meet requirements, the batch is released by analytical and quality personnel for GLP use. A detailed compound dose-testing protocol is usually written by the formulator and provided to the site performing the toxicology studies. After completion of the study, information about the absorption profiles (toxicokinetics, or TK), NOAEL, and other adverse events encountered in the tests subjects is used to estimate dose ranges for studies in humans. Allometric scaling, which takes into consideration factors, such as body surface area to volume ratios, blood volume, and other metabolic parameters, is conducted to convert data from preclinical animal models to humans in assessing API plasma concentration ranges for safety and efficacy (Feng et al., 2000).
Drug Product Technologies
Described in this section are key technologies used in formulation development and manufacturing of oral, parenteral, and transdermal dosage forms.
Material Property Assessment
The mechanical properties of APIs and excipients are important in developing solid dosage forms. Particle morphology, flow, and compaction behavior are some of the factors that influence processing and performance. Laser diffraction and scanning electron microscopy (SEM) are often used to assess particle characteristics. Size and shape can influence compound dissolution, flow/cohesion, and powder compaction. Finer particles tend to be more cohesive, and therefore generally have poor flow behavior. However, they may have improved mixing characteristics in low dose formulations and better dissolution rates in aqueous media. Tools such as the Jenike and Schulze shear cells can assess the flow, frictional, and cohesive behavior of most powders, and aid in the design of particle handling processes (Carson and Wilms, 2006; Schulze, 2011). The former is a linear displacement tester and the latter an annular or “ring” configuration. In both cases the powder is sheared between two metal cells, one of which is stationary. The angles of internal and wall friction are determined for materials, as well as their flow functions. Segregation tests are used to assess the potential of API and excipients to separate during blending and for overcoming problems with content uniformity. Commercial testers are available to measure sifting, fluidization, and vibrational segregation of blends and granules. Deng et al. (2010) investigated the flow and air-induced segregation of several active blends. Matching the size, shape, and true density of powders helps prevent segregation problems upon scale-up. Finally, characterizing the compaction behavior of powders predicts their performance during granulation and tableting. Hiestand parameters, such as hardness, tensile strength, elastic modulus, and brittle fracture index (Hiestand, 1996) provide an indication of the feasibility of compact formation from various API and excipients. Test methods include using pendulum impact for ductility, and compressive failure (crushing) of compacts for tensile strength. For example, materials with high hardness and elasticity may be more difficult to compact because of problems with elastic recovery. By classifying various API and excipient materials as “brittle” or “ductile,” the formulator can choose fillers to complement the properties of the API (Rowe and Roberts, 1996). Examples of mechanical property testing of pharmaceutical powders are found in Mullarney and Hancock (2006) and Cao et al. (2010).
Bioavailability Enhancement
Formulation technologies improve the bioavailability of a compound by increasing its solubility or dissolution rate in the body. Because for oral dosage forms the presence of food may affect absorption, solubility enhancement can bridge the gap between fasted and fed conditions. In transdermal dosage forms, skin permeability and diffusion may be enhanced with certain excipients that have affinity for the stratum corneum. Strategies can be selected for poorly soluble compounds based on their compatibility and scalability. Screening of these platforms are conducted in bio-relevant media and buffers (Jantratid et al., 2009) to mimic the pH and ionic strength conditions in oral, parenteral, and transdermal routes.
Precipitation inhibition: Many crystalline APIs display increased solubility in physiological media as salts, rather than as free acids or bases. In certain cases, the solubility may be kinetically unstable, especially near the limit of supersaturation for high-dose formulations. The ionized form can precipitate, leaving the counter-ion to dissociate. This problem is common within the gastrointestinal tract, limiting oral absorption. In these cases, various surfactants may be used to enhance solubility, paired with a water-dispersible polymer, to inhibit precipitation of the API (reducing mobility of the ionic species) in gastric or intestinal media. Guzman et al. (2007) demonstrate a “spring and parachute” concept where various surfactants are combined with hydroxypropyl cellulose (HPC) to solubilize and delay precipitation of celecoxib salts. Screening for various API/surfactant/polymer combinations is critical for optimization.
Amorphous dispersions: In many cases, APIs may be more soluble as a stable amorphous form if crystalline options are not viable. The largest challenge with amorphous materials is that they can be less physically and chemically stable than crystals. To overcome this, APIs are molecularly dispersed within a polymer matrix, preventing crystallization by limiting mobility and nucleation. Spray drying a solution of API and polymer together can yield amorphous powders, which can be further processed into solid DP. Freisen et al. (2008) describe using hydroxypropyl methylcellulose acetate succinate (HPMCAS) to stabilize various APIs using spray dried dispersion technology. Accelerated aging studies and thermal characterization are important to ensure the matrix is stable over the shelf life of the DP. For transdermal systems, adhesive polymers function as crystallization inhibitors for supersaturated matrix patches.
Coatings: Enteric coatings are present in delayed-release capsule and tablet formulations to prevent compound solubilization in the stomach. In case a compound is poorly absorbed, or precipitates at the low pH present in the stomach and upper gastrointestinal tract, coating polymers are used that are insoluble below pH 5, thereby improving bioavailability by targeting solubilization and absorption within the small intestine. Coatings can be present on tablets or individual pellets filled into a capsule. Coated multi-particulates may reduce the impact of food effects on bioavailability as their gastrointestinal transit is less dependent upon variations in motility compared to larger coated tablets. Liu et al. (2009) demonstrated the use of Eudragit polymers to target drug absorption in the intestine. A coating can be a simple means to improve bioavailability.
Nanosuspensions: For many crystalline APIs, particle size reduction to the micron range is achieved by using conventional techniques such as jet-milling. This can significantly improve dissolution rates. However, when micronizing, amorphous, and solubilization strategies are unsuccessful, it is possible to reduce the API size to the nanoscale for improving bioavailability. Wet milling technologies can be adapted using stabilizers and grinding media to accomplish size reduction without compromising physical and chemical stability. The nanosuspensions are spray dried or coated onto beads for suitability in solid formulations. Rabinow (2004) provides a comprehensive review of nanosuspension technologies.
Lipid systems: API molecules that are extremely hydrophobic (i.e., logP >4) can present significant challenges with dissolution and food effects for oral dosage forms. In the fed state, bile salts are typically present in the intestine, which improves drug solubility. Hydrophobic compounds could be more suitable for transdermal drug delivery if they are able to diffuse through the skin. Compounds that are soluble in oil phases or lipids can be emulsified to improve transport in the gastrointestinal tract or following parenteral delivery. For oral DPs, compounds may be solubilized in a lipid containing a surfactant. Upon contact with aqueous media, the oil phase spontaneously forms an emulsion that is stabilized by micelles. These are referred to as self-emulsifying or micro-emulsifying drug delivery systems (SEDDS or SMEDDS). Porter et al. (2008) and Trevaskis et al. (2008) describe lipid-based technologies for enhancing API absorption. Drug/lipid mixtures may be filled into hard or soft gelatin capsules for oral delivery. In parenteral/injectable systems, liposomes or microemulsions are sometimes used to prevent precipitation and to ensure delivery into the bloodstream.
Permeation enhancers: As mentioned above, enhancer molecules are used to improve transport of drug through the skin from transdermal formulations. These are small molecule lipids or co-solvents that disrupt the lipids and proteins within the stratum corneum to increase drug permeability. Selection of components should be made to minimize skin irritation. Enhancers may be screened in preclinical models to assess the irritation potential for human skin.
Solid Dosage Formulation Platforms
Although manufacturing technologies for capsule and tablet formulations are standardized within the pharmaceutical industry, they include the broad requirements for immediate release (IR) and controlled release (CR) dosage forms. Most of the unit operations are based on industrial powder processing/agglomeration methods.
Direct compression: The simplest process, with this approach the drug and excipient powders are dry mixed together at the desired concentrations and directly conveyed to a tableting or capsule-filling operation. Mixing methods include low shear rotating twin shell (or “V”) and bin blenders, or medium to high shear ribbon and impeller blade blenders. High shear methods are used to improve dispersion in low dose formulations, or to break up heavy agglomerates. Blends may also be passed through a low-impact mill (Fitzmill or Comil) for uniform dispersion. The final blends are conveyed to a tablet press or a capsule-filling machine to produce the final DP. Although this process train is most desirable for scale-up, it poses many challenges. The largest risks are segregation, poor flow, and problems with bulk density, all of which can compromise DP quality. Low bulk density may prevent consistent filling of capsules and tablet dies, limiting dose ranges and throughput. Direct compression is practical for medium to high dose formulations if the API properties can be optimized to maintain good flow and content uniformity.
Dry granulation: To minimize the risks associated with direct compression, dry granulation methods promote the adhesion of drug and excipient particles and provide larger and denser granules that are easier to process, compared to primary particles. Segregation of components is also minimized because of the broader size distribution of the resulting powder. Dry blending of ingredients takes place, followed by roller compaction. This operation involves passing the blend through a screw feeder, which delivers densified powder between two rolls. The rolls compact the powder, continuously forming a ribbon, which is passed through a low-impact screen mill that breaks it into particles ranging between 100 µm and 1 mm in size. Factors such as roll pressure, roll speed, and powder feed rates control the solid fraction and tensile strength of the ribbon, which affect milling behavior. The final granules are conveyed to tableting or capsule operations. This process is particularly useful for moisture-sensitive compounds and those in early development. High-dose formulations may be challenging to process if the API has poor mechanical properties. Ribbons may stick to the rolls or become extremely brittle, diminishing the benefits for dry granulation. Zinchuk et al. (2004) describes methods for optimizing ribbons on a small scale using a compaction simulator, and Cunningham et al. (2010) details finite element modeling approaches to improve process understanding.
Wet granulation: In cases where dry processing fails to produce densified granules because of the mechanical properties of the blends, wet methods can be utilized if the compound is physically and chemically stable. High shear methods involve dry blending of powders in a vessel containing a binder, followed by water addition at a controlled rate until the granulation endpoint is reached. This is monitored by recording torque outputs or particle growth. The wet material is dried in small batches with tray dryers or the process is scaled up to fluid bed drying. The granules may be milled to reduce large aggregates. In fluid bed granulation, powders are fluidized in a column with heated air, and then granulated with a binder solution or water. After the desired endpoint is attained, the spray is halted and the wet material is dried in the stream of heated air. High-shear wet granules tend to be more dense than fluid bed-processed materials. Fluid bed granulation is preferable for scale-up because it is a “one-pot” process. Mort (2005) reviews the mechanisms of wet granulation processes in industrial applications.
Tableting/capsule filling: Tableting of the final granules or blends can be conducted at small scale using a single station press, or a rotary press with multiple stations for large scale and commercial manufacture. Powders may be gravity fed or force fed through hoppers into the press. Tooling size and shape are selected based on the desired image and convenience of dosing. Compression profiles are generated to optimize hardness, friability, and disintegration time (or dissolution for CR tablets) over a range of tableting forces. Scale-up is conducted on the basis of the dwell time of the punches, taking into consideration the powder and flow properties of the final active blend. Single or multiple layer tablets can be manufactured depending upon the application. Some examples for multiple layers include formulating two chemically incompatible APIs in the same tablet, combining an IR and CR layer for meeting a target release profile, and osmotic tablet delivery systems. For these systems, tablet presses contain multiple feed hoppers to fill the die prior to compression. Capsule filling is conducted with automated machines where powders are fed through a hopper and filled to target weight. Capsule size is determined by the bulk density of the granulation or blend that is needed to accommodate the desired dose range.
Film coating: Tablets or pellets may be coated for cosmetic or functional reasons for IR or CR applications. Most processes take place in a rotating pan coater where coating solution is sprayed onto a bed of tablets while heated air is circulated through the coater. The coating may consist of polymer, plasticizer, and approved pigments (see USP, EP, or JP monographs) dissolved in aqueous or organic solvents. Atomization of the solution takes place until the target weight gain is desired, after which the tablets are dried for several minutes. In CR formulations, the coating thickness may be adjusted to tailor compound release rates. Coating processes may be challenging for complex tablet shapes where edge erosion and sticking of tablets together can occur.
Hot melt extrusion: Extrusion processes can take the place of granulations for certain drug/excipient combinations by intimately mixing and producing pellets or matrices. This technology is suitable for making solid dispersions of crystalline drugs and polymers for bioavailability enhancement or sustained release dosage forms. Powders are fed from a hopper and blended together within screw feeding systems. The mixture is passed through a heated barrel into a die for extrusion into the final tablet or pellet form. A review of hot melt processing can be found in Breitenbach (2002).
Controlled Release Dosage Forms
There are technologies used specifically for oral CR dosage forms, for which the selection depends upon the desired release profile, risks with gastrointestinal transit variability, and cost. Figure 7.3.2 shows examples of CR dosage forms. Each of these options may be viable with careful formulation design and sound pharmacokinetic models.
Matrix: Matrix tablets are monolithic devices that control drug release based on erosion and diffusion mechanisms. They are prepared by compressing swellable or cross-linked hydrophilic polymers, such as hypromellose (HPMC), polyethylene oxide (PEO), and polyvinylpyrrolidone (PVP), into tablets. The API is dispersed as solid particles within the matrix. When the tablet is hydrated, a gel layer is formed, which acts as a diffusion barrier for soluble drug and, over time and with exposure to shear, the gel layer erodes. When the diffusion and erosion rates are equal, drug release follows a zero-order profile, where the concentration of drug (C) released as a function of time (t) is linear, where dC/dt = k. Most matrix tablets tend, however, to follow first-order release profiles, where rate of drug release follows the equation dC/dt = kC. Korsemeyer and Peppas (1981) and Bettinia et al. (2001) describe release mechanisms for matrix tablets. Advantages of matrix tablets are simplicity of manufacture, established models for predicting drug release, and low cost. However, challenges exist with gastrointestinal transit variability, food effects, “dose dumping” (undesirable burst release of drug), or incomplete release if tablet size, shape, and polymer molecular weights are not optimized.
Multiparticulates: An alternative to matrix tablets are multiparticulates that are placed into a capsule. In this preparation the API is spray coated onto nonpareils (sugar or cellulose spheres) or extruded into mini matrices (Ishida et al., 2008). A polymer barrier may then be coated around the beads to control the rate of release. Wurster/fluidized bed-coating processes are typically used for this purpose. See Nikowitz et al. (2011) for manufacturing methods. The advantages of this dosage form are flexibility in mixing various rate-controlling beads to achieve unique release profiles, and the fact that it allows for continuous gastrointestinal transit of particles. Zero- and first-order profiles can be achieved. Wilding et al. (1991) compares the pharmacokinetic profiles of various CR dosage forms. Challenges include accommodation of high drug loads, and interactions of polymeric membranes with lipids and alcohol, which may affect fed/fasted release and dose dumping.
Osmotic: In addition to diffusion and erosion, drug release may be based on osmotic pressure. With this system, unique profiles can be achieved, provided the dosage form has the appropriate residence time in the lower gastrointestinal tract. Osmotic dosage forms have been commercially developed as multiple layer tablets with one compartment containing only a swelling polymer, such as PEO mixed with salts, and a second layer with the API and polymer. The layered tablet is coated with a nondisintegrating semi-permeable membrane. A small hole is drilled into the top of the tablet to allow for the extrusion of the drug-rich contents caused by the bottom-swelling layer (Malaterre et al., 2009). Because the tablet does not erode throughout the gastrointestinal tract, delivery is localized to the intestine and colon where the osmotic load is greater. This makes the release less sensitive to the presence of food. However, like matrix tablets, the size and shape of osmotic systems must be optimized to avoid variability with gastrointestinal transit. Recently, efforts have been conducted to make single-layer osmotic tablets to minimize the size in an extrudable system (Waterman et al., 2009). Malaterre et al. (2009) provides a review of various osmotic systems. The manufacturing cost of this approach can be higher than matrix or multiparticulate systems, although the need for unique profiles, in addition to zero-order release, can justify the cost.
Parenteral Platforms
The manufacture of liquids for parenterals/injectable involves solutions, colloidal suspensions, or emulsions. Emulsions and suspensions require more complex processing technologies for maintaining fine dispersions or controlling droplet size, and to ensure stability for the product shelf life. An oil-in-water (O/W) emulsion is prepared by mixing two phases under high shear, such as high-pressure homogenization or microfluidic mixing, in the presence of a surfactant. Oil-soluble compounds can be formulated into sustained-release emulsions for parenteral delivery, where diffusion into the aqueous phase is rate controlling. Factors such as addition rate of the oil phase, pH, and temperature can affect the final droplet size. Zeta potential measurements, which characterize the charge distributions around particles or droplets in polar media, may be used to indicate suspension or emulsion stability based on the magnitude of the charge. Highly charged emulsions or suspensions are more stable than those with charges closer to zero, where aggregation of droplets or particles can occur. Filtration is used in the final step for sterilization and emulsion droplet size control (Floyd, 1999). Novel block copolymers, such as PEG constructs, have been developed to form micelles and to entrap drugs for solubilization and emulsification (Richter et al., 2010). Aqueous solutions, suspensions, or emulsions may be filled into vials and lyophilized (freeze-dried) to a dry cake to facilitate long-term storage, then reconstituted with water or saline prior to administration by injection. The formulation components and lyophilization conditions affect the quality of cake formation (Bedu-Addo, 2004). Collapse of the cake during lyophilization is undesirable as it adversely affects the rate of drying due to changes in porosity, gives poor appearance of the final product, and may hinder dissolution upon reconstitution.
Transdermal Platforms
Transdermal patch systems are used for daily or longer-term drug release. The most significant challenge is transport of drug across the skin barrier. The most common platforms are reviewed below. However, there are continuous improvements in this type of delivery system. Some technologies are reviewed in detail by Prausnitz and Langer (2008) and Wang et al. (2005).
Matrix: In this, the simplest and most common system, the API is dispersed within a polymeric matrix either as a “solid solution” or particle suspension. A film is made of the mixture by casting it from a solvent onto a substrate. The polymer functions as the rate-controlling device, as well as a skin adhesive. Backing materials are laminated onto the matrix to protect the surface. The transport of the API across the skin is diffusion controlled and its flux depends on its thermodynamic activity coefficient and solubility within the matrix. Supersaturated systems can maintain a high flux, although there may be risks with physical stability where recrystallization of the drug can occur. Permeation enhancers may be added into soluble matrices to improve transport. With suspended particles in the matrix, a high thermodynamic activity of compound can be maintained as its solubilized form is depleted from the patch.
Reservoir: In this variant of the matrix patch the API is contained within a gel or solubilized layer and embedded between a backing layer and the adhesive. The API must have favorable partitioning into the adhesive from its reservoir to enter the skin. Lamination or coating steps are used to embed the reservoir within the polymer adhesive layer. This helps keep the API solubilized if it is incompatible with the adhesive polymer. Because of their complexity, reservoirs are more difficult to manufacture than a simple matrix.
Iontophoresis: APIs may have limited transport due to solubilization and diffusion, and permeation enhancers can cause skin irritation. To overcome these issues, iontophoretic devices deliver drugs by inducing charges on the molecule and forcing transport through an anode and cathode within the skin surface. The drug is solubilized in an electrolyte solution or gel within an anode or cathode, based on its native charge. An electric field is applied that induces a charge that is similar to the compound and opposite in polarity to the skin surface. The repulsion of the drug forces it through the skin. This process can also enhance transport for neutral molecules, if the electro-osmotic flow of ingredients can occur across the skin (Wang et al., 2005). A patch can be designed to contain a battery, electrodes, and compound reservoir. More expensive than matrix systems, these devices are generally employed only for hydrophilic drugs.
Microneedles: Permeability enhancement may be achieved mechanically by adding an array of micron-sized needles on the adhesive section of a patch. The small needles (approximately 100 to 500 microns in length) can be either solid to simply penetrate the skin, or hollow to control drug delivery. They are designed to be short enough to disrupt the skin barrier without damaging nerves, and preventing discomfort with use. Large molecules, such as vaccines and other peptidic/DNA constructs, can also be delivered through the skin using this approach (Prausnitz and Langer 2008; Wang et al., 2005).
Clinical Formulation Development
The development of clinical dosage forms occurs in parallel to the preformulation and toxicology studies. The first in-human part of the Phase I study is most critical for new molecules to assess safety and tolerability. Phase I includes two components: single ascending dose (SAD) and multiple ascending dose (MAD) studies. These are conducted to determine the maximum tolerated dose in one day, and over several weeks of compound administration, respectively. Formulators work closely with the toxicologists and clinicians to finalize the doses selected for these clinical studies.
Once successful exposure and safety of the compound are defined in Phase I, Phase II (IIa and IIb) is initiated. This series of studies focuses on the efficacy of the test compound for its intended use. Once Phase IIb is undertaken, a close to commercial DP image is necessary to enable a smooth and cost effective transition to Phase III studies. Rarely do formulation challenges prevent a drug compound from being commercialized. However, ease of formulation is important for ensuring consistent DP quality and safety and to avoid excess costs and time in redesigning the formulation. Data generated in each development stage are used to support regulatory filings. As accelerated development has become more important, rapid screening of formulation options and identification of biomarkers for efficacy studies occur in Phase I. This helps identify a mature DP as early as possible in the development process. The overall sequence for DP development for each phase/clinical trial can be summarized as follows:
• Define the best formulation, with the choice of excipients based on maximizing the physical and chemical stability of the API
• Ensure the formulation provides the desired in vitro release of drug
• Conduct pharmacokinetic studies in animals if models are available that are known to predict clinical responses.
• Define the best manufacturing process for DP
• Place the final DP prototype on accelerated stability in intended packaging
• Conduct GMP manufacture and packaging of clinical DP
• Generate batch release data and certificate of analysis (CoA) for clinical DP
• Initiate an accelerated stability program for clinical DP (batch made at full scale)
• Submit supporting formulation and analytical data as part of the regulatory filing to request approval (i.e., from the FDA, EU, etc.) for using the DP in a clinical study
As indicated above, drug delivery technologies involve rigorous attention to the biological sciences, chemistry, and engineering. Detailed in the following sections are clinical and commercial development strategies for oral, parenteral, and transdermal dosage forms.
Oral Development
In most pharmaceutical companies, the timeline to develop a dosage form for a Phase I clinical trial is relatively short, where the strategy is to evaluate the safety and tolerability of a new molecule as quickly as possible, before proceeding to further studies. The main challenge in Phase I studies is often a limited supply of API. However, because the patient population in Phase I trials is relatively small (50 to 100 subjects), only small batch sizes of DP are typically required. If the compound is soluble and stable, it is possible that a toxicological solution or suspension formulation can be manufactured for clinical use, assuming all the excipients are at safe levels. Corresponding placebos can be manufactured using the vehicle and a bitter flavoring agent, such as denatonium benzoate (Bitrex), to mimic the taste of an active compound. This approach minimizes development time, generation of extra stability information, and it allows limited resource investment if the compound fails in clinical trials. Daily preparation of a marginally stable oral solution or suspension could be tedious at a clinical site if special mixing or processing is required. This is especially true for viscous diluents or poorly dispersing particles. Solid formulation alternatives should be considered in these cases. For BCS 2 or 4 compounds, solubility/bioavailability enhancement may be challenging and require longer development times. However, introducing a solid formulation in Phase I provides a “close to commercial” concept, making it possible to study dissolution challenges and food effects earlier in the development process. Although IR concepts are the focus in early clinical trials to maximize exposure, in later stages a CR option may be investigated, especially for compounds with very short in vivo half lives or which cause adverse effects when administered systemically.
Many in the industry are introducing Phase I capsules or tablets. Some of the simpler approaches involve adding pure API or a formulated powder into a capsule (PIC). Capsules can be suboptimal for very high doses, poorly wetting API, or interactions with gelatin. The API may not be sufficiently free flowing for capsule filling. Blending or granulating the API with dispersants and disintegrants may improve flow properties. If challenges cannot be overcome by simple processing means, it may be necessary to resort to tablet development. Excipients are sometimes added to tablets to improve manufacturing and performance. Flexibility with tablet size and shape is important for high API loads. Matching placebo tablets can be made for each strength of active compound using a standard set of excipients. A common blend approach is often used where two or more doses are made using weight multiples of the final blend or granulation. To prevent the manufacture of extremely large capsules or tablets, the formulator can select which strengths to bracket, based on the API loading within the formulation.
Because most Phase I studies involve subjects administered compound in a clinical setting, refrigerator storage may be necessary to avoid stability problems if the formulation has not been fully optimized for room temperature conditions. As discussed above, processing technologies for tablets are often more rigorous and time consuming than for capsules or liquids. Knowledge about API and excipient physical and chemical properties can help in predicting the manufacturability of solid dosage forms. Material-sparing methods take advantage of instrumented simulators for compaction or granulation and are used to predict large-scale behavior, thus reducing the consumption of API and development time. Small-scale in vitro dissolution tests may be designed to rank order formulation options. Occasionally, a solution or capsule formulation used in a SAD clinical study may be bridged to a tablet during the MAD study to expedite its introduction into Phase I. In this case, clinical studies can be performed with one dose group to compare the pharmacokinetics between the first- and second-generation formulations.
Processing methods chosen for Phase I are typically simple and suitable for small batch sizes, i.e., less than 5 kg. For solid dosage forms, high shear wet granulation or roller compaction (dry) methods are commonly used to improve content uniformity as the API particle morphology may not be optimized for flow and adhesion to the excipients. The typical image of an early solid DP is an opaque capsule or white, uncoated tablet. For tablets, coatings may be used if blinding is required, especially if the API is colored, or a barrier is needed to mask taste. White film coatings are suitable and simplest for early studies, with film coat color compatibility studies performed later to address marketing needs. The final Phase I prototype tablet is placed on an extended stability program to generate data prior to large-scale manufacturing. The clinical DP is produced in a GMP facility, packaged (typically in bottles), labeled, and shipped to the test site. The batch is tested for purity, potency and release-based criteria as specified in the USP/EP monographs. Formulation information, certificate of analysis for manufacturing, and supporting data are usually included in the IND or CTA application depending upon the country hosting the clinical trial. Once the development stage reaches Phase IIa, a room temperature-stable, solid dosage form is most desirable. These clinical studies tend to be longer than Phase I and may require patients to take the DP home. Larger batch sizes are required, typically about five-fold greater than for Phase I. To meet accelerated timelines, the same Phase I tablet or capsule may be used for Phase II, although the formulation usually needs to be optimized for larger scale manufacturing or changes in the API. As more detailed pharmacokinetic data are made available from the Phase I study, dosage strengths and ranges are fine tuned for Phase II. For BCS class 2 or 4 compounds, clinical bioequivalency studies may be needed to bridge exposure between old and new formulations, if animal pharmacokinetic studies alone are not predictive.
For IR tablets, fillers may be optimized to prolong shelf life, binders may be added to improve granulation efficiency, and solubilizers screened for improving bioavailability. Granulation processes may be changed from wet to dry methods, or vice versa, depending on feasibility, based on long-term stability data generated with the Phase I formulation. For a difficult compound, the formulator may not change the process until a later stage (Phase IIb) to conserve development time, and generate more supporting data. Process unit operations are adapted to larger scale in selecting proper blending, granulation, and film coating equipment. Using compaction simulators for small-scale predictive experiments minimizes API consumption by almost ten-fold to adapt the process for both roller compaction and tableting operations. Direct compression approaches for tableting may be explored, provided future batches of API have favorable properties, and test methods are representative of the process to detect API segregation and content uniformity issues. Close collaboration between the formulators and analytical/process chemists is important to develop strategies for continuous monitoring of dosage form performance to allow successful technology transfer.
In the case where a CR tablet or capsule is required, further API-excipient compatibility studies may be needed with matrix fillers and barrier membrane polymers, depending on the desired image, i.e., matrix or osmotic tablets, or multiparticulates filled into capsules. Technologies for these processes (described above) are evaluated at bench scale before producing larger batches. Coating processes may also become critical for optimization to ensure that the target release profile is met. The size and shape of tablets, granules, and pellets are important in ensuring a uniform coating. For matrix or osmotic tablets, the excipients used must have good compression characteristics to ensure drug release is not affected by small changes in compact porosity. Phase I pharmacokinetic data and modeling provide guidance on the type of profile required for drug delivery, i.e., zero order or ascending release. In addition to resolving short half-life issues, a CR formulation may be designed to reduce systemic adverse events, which may be detected in Phase I. This is achieved by lowering the C
Once the final IR or CR formulation has been selected, the Phase IIa prototype is tested for stability to generate data for the regulatory filing. For Phase IIa clinical trials, ~3 to 4 months of data are needed for filing to cover the length of the clinical study. However, the prototype DP may be monitored over 9 to 12 months. Traits such as potency, purity, and dissolution are monitored. For IR tablets containing soluble API (BCS 1), disintegration may be an alternative test to dissolution. The final Phase IIa batch is manufactured under GMP conditions and release data included in the regulatory filing. The retest date is often updated based on further stability data in case the clinical study requires an extension.
Development reaches “late stage” or “full development” when a compound progresses into Phase IIb or Phase III. If proof of concept studies and safety data are promising, programs can be accelerated into Phase III. It is important that the formulation and process approximate the commercial image of the drug product. Clinical studies conducted for Phase IIb involve a significantly greater numbers of patients than in Phase IIa. Phase III studies are more complex than Phase I or II, involving many geographically distinct test sites. Excipients selected at this stage should be globally acceptable. Significant changes to the formulation and process can be made in Phase IIb for use in Phase III. Once the dosage form is approved for Phase III it is difficult to make changes before commercialization, unless they fall within the Scale-up and Post-Approval Changes guidelines [Center for Drug Evaluation and Research (CDER) guidances, Nov 1995; Sept. 1997]. These documents describe criteria for development and post approval changes for both IR and CR dosage forms. If changes deviate from the requirements, a clinical bioequivalency or bridging study may be required. However, applications to waive late- stage bioequivalency studies can be conducted based on the FDA biowaiver guidance (CDER guidance, Aug. 2000) by considering the BCS class of the compound.
During late stage development, marketing will help define a target product profile of the dosage form, whether it is IR or CR, target population, number of dosage strengths, therapeutic indications, and information on shape, size, and color. A tablet may also be embossed for brand identity. Special tablet tooling may be needed in this case as sophisticated markings are routinely used to prevent counterfeiting. The formulator can plan in advance for late-stage options by conducting some experiments in parallel with formulation development. For capsule formulations, granulations or coated pellets may be filled in capsules of different colors and sizes, and studied for stability. Prototype tablets can be film coated with various color options and undergo accelerated stability studies. In addition to creating the image, the final formulation and process must be optimized. Pediatric dosage forms tend to be considered for certain indications after development for adults to ensure safety. However, many formulations are now developed in parallel for evaluation in both populations for Phase I/II. Taste-masking technologies are very important for pediatric DPs. These involve the use of sweeteners, coating materials, and other agents to delay API solubilization in the oral cavity.
Process and formulation optimization studies for DPs often yield useful and extensive data in a brief period of time. Design of experiments is an extremely useful tool for the simultaneous study of the effect of many variables and for reducing the number of experimental runs. Statistical models should be used to plan the design of experiments so that meaningful correlations are obtained. A combination of partial least squares regression and principle component analysis may be used for multivariate analysis to isolate variable main effects and multiple interactions. Design of experiments is not limited to late development, with most organizations demanding it be used earlier in the development process. However, it has become characteristic of late stage development to manage the process and formulation variables under constrained timelines. This approach is part of the ICH Q8 Quality by Design guidance (ICH Q8R2, Nov 2009) that has transformed the pharmaceutical industry to focus heavily on risk assessment and implementation of science and process control tools (Garcia-Munoz et al., 2010) to ensure consistent quality of the DP. An in-depth review of this philosophy and approach can be found in the ICH Q8 guidance report.
To ensure quality, DP performance should be insensitive to factors such as minor changes in API and raw materials (such as impurities and particle size distribution) and equipment scale. Experiments can be statistically designed to explore these effects. For example, several API particle size grades and vendor lots of a matrix polymer may be used in a CR formulation to investigate effects on dissolution performance. For chemical stability, several lots of an excipient may be employed to study the effects of slight variations in metal or peroxide impurities on degradation rates. To optimize manufacturing, several parameters on a roller compactor or fluid bed granulator may be investigated at once to understand granule quality and tablet hardness/ disintegration. Examples of “quality by design” studies in powder blending, granulation, and coating can be found in Wu et al. (2007), Huang et al. (2009), and Prpich et al. (2010). Most companies designate “preferred” processes involving equipment already present at their commercial facilities. Capital investment in new equipment may occur if high volumes are predicted. Otherwise, a contract manufacturer may be retained for special requirements. Currently, trends to “offshore” or “outsource” manufacturing to countries with emerging economies (China, India, Brazil) are prevalent in the interest of cost. To make the “offshoring” model successful, sources of raw materials, equipment trains, and environmental conditions must be met to ensure DP quality.
During Phase III, the DP formulation and process is finalized and the commercial site of manufacture for the DP is identified. In preparation for an NDA submission, three validation batches must be manufactured either at 1/10 scale or full scale (if API quantities are available) at the desired site. The batches are studied for their performance under accelerated stability conditions. A minimum of twelve months of accelerated stability data at ICH conditions is required for the NDA submission. Microbial testing of the solid DP is usually required for late stage development to ensure contamination is absent from the commercial process.
Parenteral Development
The development of parenteral formulations may involve homogeneous solutions or dispersions. In the former, the compound is solubilized in aqueous or polar media containing buffers, co-solvents, or bulking agents, then sterile filtered, and placed into vials. Lyophilization (or freeze-drying) is performed if the solution or dispersion does not have adequate chemical or physical stability for the duration of the clinical study. For emulsions, the development and processing is more complex, as the compound must be solubilized in an oil phase and then finely dispersed in aqueous media. The final emulsion is filtered and placed into vials. Lyophilization is not usually conducted unless prolonged aqueous contact is unfavorable and the emulsion can be made to spontaneously re-disperse upon reconstitution. If filtration is found to be unsuitable for either solution or suspension products (API adsorption to filters and components, or emulsion instability), other sterilization techniques, such as heat or gamma irradiation, may be used, or the entire process can be conducted under aseptic conditions (Floyd, 1999).
In early development, most screening for solubilization and dispersion components occurs during the preformulation stage. Long-term stability is important for the clinical parenteral product. Typical problems include hydrolysis/oxidation, API precipitation from solution, or coalescence of emulsion droplets. Lyophilization can be a complex unit operation in producing a stable cake for reconstitution (preventing collapse), and ensuring the compound retains its desired physical form after this step. Excipient selection, temperature gradients, and evacuation rate controls should be optimized for obtaining good cake morphology and API stability. For extended use, microbial growth is also a concern. For this reason preservatives may be added to prolong the shelf life of the DP. For emulsions, efficient dispersion and homogenization is required during processing and scale-up. Maintaining aseptic conditions for all processing steps is desirable and tedious. The best approach is to filter the final formulation before the filling step instead of filtering each component individually (Floyd, 1999). Another challenge involves compatibility of the compound and formulation with processing equipment and packaging materials. As mentioned above, filtration incompatibility may decrease the potency of the formulation. Other components that may directly interact with the compound include process tubing, stoppers, and the glass vial. The formulator must be careful in selecting these materials, as the compound may irreversibly adsorb to these surfaces, reducing potency. Silicone-based plastic tubing is commonly used for transferring the parenteral liquid, and compatibility with solvents and co-solvents must be studied to prevent leaching of components and determine effects on tube performance (Krishna et al., 2001). Containers for the DP include USP Type I or II borosilicate glass vials or bottles. In some cases, siliconization of glass vials/bottles may improve the hydrophobicity of the surface to prevent growth of emulsion droplets (Floyd, 1999). Plastic containers are usually avoided to prevent leaching of plasticizers into the DP (Floyd, 1999). Polytetrafluoroethylene (PTFE) coating of rubber stoppers also adds a barrier to prevent API adsorption, emulsion instability, and permeation of oxygen (Floyd, 1999; Krishna et al. 2001).
As with oral DP studies, the final clinical manufacturing of parenterals takes place in a GMP facility, but with additional sterile or aseptic requirements. Once Phase I clinical pharmacokinetic and safety data are obtained, the formulation may be optimized for Phases II and III. Process and formulation optimization studies with excipients and primary containers (i.e., vials/stoppers) are important prior to commercialization. Solution or emulsion manufacturing methods should be consistent over the desired range of conditions (i.e., temperature, pH, ionic strength, shear). The “quality by design” approach is also important, and similar design of experiments may be conducted with homogenization or lyophilization parameters to ensure quality of the final DP, such as droplet stability or reconstitution of the cake. Validation batch studies at the final commercial site are required for the NDA filing. Commercial images for the drug product include attributes such as design of the vial and unique packaging/labeling colors. Parenteral formulations for immediate release are more frequently introduced into the market. However, depending upon the target product profile, extended release injectables, achieved with emulsion and liposome technologies, could be marketed as a second-generation formulation.
Transdermal Development
Transdermal DPs are typically introduced as an alternative to oral or parenteral routes. They are often considered as a second-generation concept, or even a lifecycle extension. The mechanism of delivery from a transdermal patch is much different from oral or parenteral and requires extensive formulation optimization and clinical evaluation to ensure viability. API loading is limited based on equilibrium solubility. However, higher content may be possible in dispersions or supersaturated systems. Although several options were mentioned in the Technologies section, development related to matrix systems is explained here.
For matrix patches, preformulation studies provide guidance on the combinations of adhesives, permeation enhancers, and solubilizers that are compatible with the API. In cases where the API is either solubilized or slightly supersaturated in the formulation, recrystallization or precipitation is undesirable. For solid dispersions of API in the matrix, complete dissolution over time or growth of particles by Ostwald ripening (dissolution of small particles and the solubilized components depositing over larger particles, facilitating their growth) is also undesirable. These phenomena may be probed with accelerated stability studies to enable selection of the best formulation. If the compound is suspected to have low transport through the skin, permeation enhancers, such as fatty acid derivatives and lipids, may be implemented.
Bench-scale studies are performed to understand the film-forming and adhesive properties of the polymer with various mixed components, and its interactions with solvents. The ingredients are dissolved in the desired solvent, mixed under low to moderate shear, and then cast onto plastic release liners. Once the films are dry, they are cut or punched to desired sizes for further testing. Testing of films is conducted to measure their adhesive strength and durability in ambient conditions and at higher temperatures and humidities. Samples are also made for in vitro flux studies to understand permeation of the compound from the patch to the skin. This testing is performed in a diffusion apparatus, typically a Franz cell, containing human cadaver skin or a synthetic membrane to mimic transdermal transport. The Franz cell is typically a glass container with a clamp and closure for inserting a membrane, dividing the cell into two chambers. The bottom chamber has a port for adding or aliquoting physiologically relevant buffers. In the top chamber, the test patch is attached to the membrane and buffer is added to the bottom chamber, filled to contact the membrane. The permeation of API from the patch is determined by measuring its concentration in the buffer solution collected from the bottom receptacle of the Franz cell. Membranes can be human cadaver skin (stratum corneum ~10- to 40-µm thick) or synthetic polymers. Studies should be performed to establish correlations between synthetic membranes and human skin. Ng et al. (2010) review the usage of various synthetic membranes, such as cellulose derivatives, siloxanes, and other microporous polymers, using ibuprofen as a test compound. They found that membranes varied widely in flux values, but could be categorized into two groups: high and low flux membranes. The most challenging step in formulation selection is relating in vitro flux values to pharmacokinetic data from clinical subjects. The variability of skin transport can be high within a subject (such as arm versus thigh), and between subjects. Factors such as age, ethnicity, and pathology can affect skin permeability. The regulatory agencies usually accept strong scientific arguments to justify use of a diffusion model. Franz cell studies are used for rank ordering and selection of the formulations with maximal API flux.
A prototype patch is manufactured with the best formulation options. Studies are typically conducted within a pilot plant. Patches can consist of a single layer or multiple layers, depending on the desired release profile. Each layer is typically cast separately and laminated together. A review of some scale-up parameters for transdermal patches can be found in Van Buskirk et al. (1997). Mixing of the components within the casting solvent must be thorough to ensure solubilization or suspension of the API for either type of matrix. The viscosity ranges of such mixtures tend to be between several hundreds to thousands of centiPoise, and may also fall in the non-Newtonian regime (where viscosity as a function of shear rate is not constant) depending upon the concentration of drug, polymer, and other excipients. Rheology studies (measuring flow behavior at different speeds and stresses) can be helpful to indicate the conditions at which optimal mixing and processing will occur. Solvent addition or adjusting the solids loading can lower the viscosity to improve processing of the matrix. The particle size of the API is controlled by micronizing (typically jet-milling) to optimize drug loading, dispersion, and film formation. Milling may also affect the dissolution properties of the API in the polymer mix. It is desirable to avoid supersaturation of the drug. Control of the mixing blade type, tip speed, and temperature can facilitate processing a range of solids concentrations.
After the mixing step, the solution/dispersion is then cast onto a release liner material using a line coater, where the liquid falls as a thin film and is carried on a conveyer containing the liner. The nascent cast film is then passed through various ovens to ensure drying of the solvent. Key parameters during this step include the feed rate, coating speed, temperature and residence time in the ovens, air velocity and distribution, and coating web tension. It is important that the coating thickness is uniform throughout the process, and that bubbles do not form during solvent evaporation. The dried cast film is wound on rollers and stored for further lamination. Either another active layer or a nonwoven skin-colored backing material is laminated onto the exposed surface of the film. Once all the layers have been attached, the material passes through a cutting and pouching process for sizing the patch and packaging/sealing the contents. In these steps, temperature and pressure control is important to ensure processing does not affect the chemical and physical stability of the API, and to ensure that undesirable diffusion is prevented between layers in a multi-laminate patch system.
In vitro paddle dissolution tests are used as a qualitative measure for patch compound content and release (Van Buskirk et al., 1997) since in vitro permeation experiments for a large set of patches may be tedious. Once the manufacturing of the prototype patch is optimized and it has demonstrated stability, the DP can be manufactured in a GMP facility for clinical trials. Phases I and II may be accelerated if this product is an extension of an approved oral or parenteral product. As mentioned in the oral and parenteral sections, data generated for the prototype DP and clinical batch is filed within the CMC sections of the regulatory document. Because patches, unlike oral or parenteral systems, are considered to be combination products, regulatory guidelines should be consulted prior to filing (Combination Products Guidance, Sept. 2006). As long as the patch (or device) is shown to be safe and effective in releasing the API consistently, the concept can proceed to late development. Statistical design of the clinical study is important to elucidate differences contributed by skin type versus the patch device. In Phase IIb/III development, the target product profile should be clearly defined as to the patch size or area, as this can affect compound loading and flux. Other important attributes include time for release, such as a single-day patch, or one that lasts for several days. Chronic pain and hormonal therapies may require long-term delivery DPs. Other commercial traits include shape, color of pouches, and style of secondary packaging. An NDA or ANDA (Abbreviated New Drug Application) may be filed depending upon the prior clinical use of the compound. If the compound has been previously approved for clinical use, an accelerated regulatory filing timeline may be achieved with the ANDA.
Analytical Methods
An important part of DP development is the existence of accurate analytical methods for characterizing performance of the API and the dosage form. This enables understanding of phenomena related to the API, formulation, and manufacturing process. Data generated for CoAs and regulatory submissions are obtained by validated analytical methods, which are proven to be consistent and statistically reproducible between laboratories and equipment. Analytical laboratories must conform to GMP conditions in order to support clinical and commercial batch manufacture of DP. It is beyond the scope of this unit to review all analytical methods in detail. However, a short summary of those most important to DP development is provided.
Potency and content uniformity: The API content in a drug product must conform to the corresponding monograph (USP, EP, JP) and fall within ICH guidelines. The minimum potency criteria for most DPs is within 90% to 110% of the target dose. However, more stringent “in-house” criteria, such as 95% to 105%, are usually set by most pharmaceutical firms. There are unique cases where the FDA has also requested tighter specifications on certain products, e.g., levothyroxine (used for thyroid indications) to prevent potency losses during the shelf life of the product (http://www.fda.gov). Potency losses could occur during manufacturing if the API were to segregate or adhere to process equipment, especially for low-dose DPs. Other factors include chemical degradation of the API in the DP, or complexation of the API with excipients. Analytical approaches typically used to measure compound content in tablets, capsules, liquids, and other dosage forms include high-performance liquid chromatographic (HPLC) or spectroscopic [ultraviolet or near-infrared (NIR)] methods. The HPLC methods to measure the potency of the DP are normally developed from the API method. The concentration of API obtained relative to a reference standard of the target dose determines the potency of the API. Other terminology includes “label claim,” which is the amount of compound recovered based on the theoretical total weight of the DP.
Techniques to extract the API from the dosage form or device are optimized by adding solvents, stirring/shear, and disintegration. Method development in this area can be cumbersome, as incomplete extraction of the compound can occur based on interactions with excipients. Collaboration between the formulation and analytical scientists is helpful in designing the most useful methods. Factors such as granule/tablet hardness or unique complex formations between API and excipients may be identified to overcome challenges. Recently, intensive efforts have been made to develop technologies to characterize the performance of DPs and intermediates during manufacturing. Online and in situ monitoring of critical variables lead to consistent process control if changes can be made to improve the quality of the product. Many of these studies are categorized under Process Analytical Technology (PAT), for which the FDA established a guidance document in 2004 (CDER et al., guidance, Sept. 2004). This is now also part of the “quality by design” philosophy (ICH Q8R2, Nov. 2009). NIR measurements have been used to detect the uniformity of API during blending processes and correlate them to final API tablet content and segregation (Sekulic et al., 1998; Li et al., 2009). An NIR probe can be inserted into a rotating blender or high shear granulator to measure API dynamics over time, as well as water content, respectively. The time for blending and granulation processes can be optimized for many formulations. Chemical imaging can also be performed on final dosage forms for spatial mapping of API and other excipients (Wu et al., 2007; Li et al., 2009). Alternative methods, such as Raman spectroscopy and laser-induced fluorescence, can be used if the API exerts a strong signal.
Stability: Analytical techniques are developed to provide good separation and quantification of degradation species in DPs. These are referred to as “stability-indicating methods.” In some cases, the same HPLC method is used for both potency and purity analysis. However, a separate purity method may have to be developed in case a longer run time is needed or other combinations of mobile phases or detection wavelengths are required to identify species. Depending on the stage of development, the levels of degradants and impurities must be controlled to levels based on the ICH guidelines (ICH Q3A guidance, Jun 2008). Exposure limits are related to the maximum daily dose and length of a clinical study. Alternative methods (usually termed orthogonal in the pharmaceutical literature) are explored for understanding the reaction kinetics at very early stages when accelerated data may not be available. Liquid chromatography-mass spectrometry (LC-MS) methods are used to quantify new impurities or degradant species that occur based on changes to the API process or formulation. Bakshi and Singh (2002) provide a good review of various stability-indicating methodologies. Other spectroscopic methods, such as nuclear magnetic resonance (NMR), can be implemented to understand both physical and chemical stability within the DP, such as amorphous transitions and crystal defects that can lead to regions of chemical instability.
Dissolution
Changes in API dissolution from a dosage form can affect bioavailability. Analytical methods are developed and standardized to mimic dissolution of the drug in vivo, as well as to check the quality of the DP. The former is referred to as a bio-relevant method and the latter, a quality control method. The USP has standardized several dissolution apparatuses for assessing the performance of various dosage forms. These typically involve a stirred glass vessel or other containers with methods for inducing shear, such as a rotating or reciprocating basket. Modified methods are also being developed to improve dispersion and mixing dynamics. However, these usually require approval by the USP to use data for support of regulatory filings. The EP also has methods that complement the USP. Azarmi et al. (2007) provide a review of equipment adapted for conventional and novel dosage forms. Shown on Table 7.3.7 is a list of the various USP standard methods and applications to drug products. The first four methods relate to oral dosage forms, such as tablets and capsules. These may be adapted for IR or CR, and tailoring the residence time within release media, such as simulated gastric or intestinal fluids. The USP 5, 6, and 7 methods are typically used for characterizing transdermal systems. However, data from these approaches are often compared to skin or membrane permeation data from Franz cells to support regulatory filings. Although the equipment is standardized, extensive method development must be conducted to select the best system for a particular dosage form, based on its desired release characteristics. Poorly soluble API, or sustained release profiles, add complexities to the methods. Attributes such as pH, buffers, solubilizers, fed/fasted conditions, and residence time in the media are extremely important. For oral dosage forms, shear effects in the gastrointestinal tract must be considered when selecting the paddle or basket speed/frequency within the apparatus. Jantratid et al. (2009) review strategies to create bio-relevant methods. Early clinical data can be used to establish an in-vitro-in-vivo correlation with a bio-relevant method. In the absence of complete pharmacokinetic data, dissolution tests can act as discriminating quality control methods. Although dissolution methods are fairly standardized, it is important to minimize the variability that can occur between laboratories during test development and execution. Factors that can affect variability in compound release include tablet hydrodynamics and the coalescence or settling of solids in the dissolution vessel (often called coning). In the former, the tablets may float or stick to surfaces within the vessel. Sinkers or baskets may be used to aid tablet dispersion. Paddle speed and depth may also be optimized to improve mixing and prevent dead zones where “coning” of solids can occur.
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Primary Packaging
The selection of proper packaging components is essential to the shelf life and stability of DPs. Materials that are in direct contact with the DP are termed primary packaging, and should provide an adequate barrier for impurities and reactive species and, in addition, have tamper- and child-resistant features. Ward et al. (2010) discusses decision criteria for safe packaging based on patient feedback and practicality of containers. The packaging components should not compromise the product by introducing new impurities (i.e., leaching of plasticizers or other additives) or microbial contaminants. Most vendors supply pharmaceutical packaging materials that are compliant with ICH guidelines and USP/EP/JP monographs. During formulation development, packaging materials are screened and the prototype DP is placed on stability in the desired container. Factors such as moisture, oxygen, and light may need to be mitigated depending upon the reactivity of the API. In early development, packaging materials are simple and chosen for accommodating the clinical study design. The commercial packaging material is finalized during late stage development. For solid oral dosage forms, high-density polyethylene (HDPE) bottles with screw closures (and heat induction seals) are used for bulk packaging. However, in later stages of development, blisters (heat-sealed pockets of foil and/or plastic) may be used to allow convenience for dosing and blinding. Bottles with black liners or full aluminum foil blisters may be used to prevent light transmission. Desiccants can be added in bottles to control moisture. Although blisters are sound in preventing diffusion into the DP, they can also entrap moisture within the product and cause undesired effects. Waterman and MacDonald (2010) review packaging strategies for moisture control for solid dosage forms. For liquid products, bottles and vials are usually used with either stoppers or screw closures. Amber bottles can be used to mitigate light transmission. For parenteral or injectable products, it is important for packaging materials to be sterile and not interact with the solution. Glass vials (Type I, borosilicate) are typically used along with various rubber stoppers. Solomun et al. (2008) reviews criteria for selecting parenteral packaging materials, where the type of rubber stoppers or glass materials can cause pH drifts of the reconstituted liquid formulation. Other packaging configurations involve sealed pouches made of foil, paper, or plastic materials for containing transdermal patches. Similarly to blisters, these pouches can be heat sealed and made to resist moisture and oxygen diffusion.
Acknowledgements
The author acknowledges helpful discussions with Christopher Galli of Cabot Corporation and Karl Jacob, True Rogers, and Paul Sheskey of The Dow Chemical Company.