Pharmaceutical Sciences

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Theodora O’Connor’
6 years ago
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SRI International Biosciences From Idea to IND Research on Disease Mechanisms Drug Discovery Drug Metabolism, Pharmacokinetics, & Toxicology Services Pharmaceutical Sciences Preclinical Development

1 SRI International Biosciences From Idea to IND Research on Disease Mechanisms Drug Discovery Drug Metabolism, Pharmacokinetics, & Toxicology Services Pharmaceutical Sciences Preclinical Development Planning & Regulatory Services Clinical Analysis Laboratory Pharmaceutical Sciences SRI s approach to drug formulation is customized according to the needs of your program. Our drug formulation experience ranges from preparation of dose formulations for preclinical in vitro and in vivo safety studies to design of finished drug product dosage forms for clinical trials. We routinely integrate physicochemical property information, in vitro characterization, and pharmacokinetic data into the drug development process. Formulation scientists work closely with analytical chemists who develop and apply sensitive, selective, and robust methods for establishing the identity, strength, quality, purity, and stability of active ingredients and drug products. We have more than 30 years of experience solving challenging formulation, drug delivery, and characterization problems for small molecule drugs and biologics. Our extensive expertise can help you maximize the potential of drug candidates of poor solubility, low bioavailability, short half-life, or gastric intolerability. Our objective is to develop a product with the therapeutic amount of drug in the right form, and in a formulation that maintains the drug s chemical and biological integrity for delivery at or over the proper time and rate at the desired site. SRI s comprehensive services will help you achieve your goals from Idea to IND. Learn more Preformulation Studies page 2 Formulation Development page 3 Alternative Drug Delivery Systems page 4 Analytical Chemistry page 5 Dosage Form Manufacturing page 6 Stability Studies page 7

Preformulation Studies SRI specializes in developing problem compounds those with poor solubility, low bioavailability, short half-life, and/or gastric intolerability.

2 Preformulation Studies SRI specializes in developing problem compounds those with poor solubility, low bioavailability, short half-life, and/or gastric intolerability. We conduct preformulation studies to guide the formulation strategy for your drug candidate. Typical preformulation characterization studies offered include determination of: Physicochemical properties Aqueous and ph solubility, organic solvent solubility Dissociation constants Hygroscopicity and lipophilicity pka, partition coefficients, and tissue distribution coefficients Thermal properties Moisture content Polymorphism Particle size morphology Drug-excipient compatibility Our high-throughput solubility screening system is based on an SRI-developed database of solvent combinations based on compatibility and miscibility at FDAacceptable concentration levels. Drug candidates are screened against single, binary, and ternary solvent combinations to identify optimal solubilizing agents or cosolvents that will provide the best compatibility and solubility. SRI has developed an in vitro Ussing system that can estimate drug transport through different sections of the intestine. This information can guide targeted drug delivery approaches and functional excipient selection to develop a product with maximum absorption. While the Ussing system is primarily used to determine absorption through intestinal tissues and thus is useful for development of oral drug delivery formulations, it can be tailored to estimate absorption through other systems such as mucosal cells and skin. 2 Every drug formulation is customized to enhance the physicochemical properties of your drug candidate.

Our staff has extensive industry experience relating to all types of dosage forms and has worked with new chemical entities, OTC products, generic products, and line extensions.

3 Formulation Development At SRI, we have the experience and expertise to solve challenging formulation and drug delivery problems. We address the cost parameters and regulatory requirements for formulating new drugs, and we look for simple, economical solutions to dosage design challenges. Our staff has extensive industry experience relating to all types of dosage forms and has worked with new chemical entities, OTC products, generic products, and line extensions. Protection of proprietary information is routinely incorporated into our procedures. Safety and efficacy are the two most critical factors in drug development. The formulator must design a product that maintains a drug s chemical and biological integrity for delivery at or over the proper time at the proper rate in the desired location. We start with an understanding of the bulk drug s physical and chemical properties then screen the compound to determine its permeability characteristics and susceptibility to metabolizing enzymes. Once the pharmaceutical profile of the drug has been determined, the appropriate route of administration can be identified and designed. Excipients are selected to overcome potential problems in manufacturing and stability, and to address factors impacting delivery issues such as solubility and absorption. Bench studies are performed on pilot batches to establish excipient compatibility and dosage form specifications. The final formulation design is optimized to take into account the pharmacokinetic properties of absorption, distribution, metabolism, and excretion. Dosage forms include solutions, capsules, tablets, emulsions, suspensions, and semisolids. We have developed spray-dried, microencapsulated, and microfluidized formulations. We have also developed specialized alternative drug delivery systems such as bioadhesive nasal gels, biodegradable implants, enteric-coated capsules and tablets, topical gels, and multiparticulate systems. Formulated drug products are more effective than their individual components used singly. 3

Alternative Drug Delivery Systems Drug delivery technologies can modify drug release, absorption, distribution, and elimination profiles to improve product efficacy and safety, as well as patient

4 Alternative Drug Delivery Systems Drug delivery technologies can modify drug release, absorption, distribution, and elimination profiles to improve product efficacy and safety, as well as patient convenience and compliance. Oral and parenteral are the most common routes of drug delivery, but alternative routes of administration are preferred in many situations. SRI has expertise in the development of these specialized drug delivery systems: Nasal formulations Vaginal formulations Polymeric films and microspheres Biodegradable implants Transdermal delivery Transmucosal bioadhesive delivery Gels Ointments Creams SRI has been working on formulation and delivery approaches to enable currently approved drugs to be delivered in a more economical and practical manner in an approach sometimes referred to as IV to PO. We have had great success in reformulating IV drug products into oral dosage forms. 4 Drug delivery systems can improve efficacy and safety as well as patient convenience and compliance.

Analytical Chemistry SRI has state-of-the-art technology and experienced scientists offering a broad range of analytical method development and validation, and quality control analyses of small

5 Analytical Chemistry SRI has state-of-the-art technology and experienced scientists offering a broad range of analytical method development and validation, and quality control analyses of small molecules and biologics. We work closely with drug development scientists in medicinal chemistry, formulations, pharmacokinetics, toxicology, and manufacturing to identify, quantify, and characterize materials to meet R&D needs and be in full compliance with FDA GLP and cgmp requirements. Our analytical team contributes the following: Pharmaceutical analysis ``Reference standard characterization and Certificate of Analysis ``Bulk pharmaceutical ingredients ``Excipient testing according to official monographs ``Structure elucidation of intermediates, impurities, and degradants Methods development and validation ``In-house use `` Method transfer in and out ``Validation levels tailored to phase of development Analytical support for preformulation and formulation development ``Efficient immediate feedback to formulators ``Short-term stability studies ``Planning for final product methods Dose verification for in vivo and in vitro GLP studies ``Dose concentrations and homogeneity in vehicle media or device ``Short-term dose stability under conditions of use ``Test article characterization and stability Quality control activities and cgmp clinical trial materials ``Quarantine, testing, and release or rejection of materials and products ``In-process testing ``Cleaning validation ``Stability studies per ICH guidelines for drug substances and products We have decades of experience working with hundreds of drugs. 5

Dosage Form Manufacturing: R&D, GLP, and cgmp SRI s dosage form manufacturing facilities are designed to provide you with a single, high-quality resource for the manufacture and packaging of oral,

6 Dosage Form Manufacturing: R&D, GLP, and cgmp SRI s dosage form manufacturing facilities are designed to provide you with a single, high-quality resource for the manufacture and packaging of oral, topical, and parenteral products for nonclinical and clinical studies. These activities are supported by our Quality Control and Quality Assurance Units which inspect, test, and release the products in full compliance with the FDA GLP and cgmp regulations and international regulatory agencies. Our R&D, GLP, and cgmp facilities and equipment are designed to support early phase development. The low volume batches needed for safety evaluations and early clinical trials present unique challenges, and we are ready to work with you to overcome limited bulk drug supplies and tight turnaround times. Our extensive collection of manufacturing equipment provides the capabilities needed to produce R&D, pilot, and clinical-scale batch sizes including: Mixing and Blending Planetary mixers V-Blenders Emulsifiers Solid Dosage Forms Capsule filling, sizes 00 to 4 and DB Capsule bander Capsule polisher Capsule sorter Tablet press Extruder Milling Low speed mills High speed mills Granulation Roller compactor Granulator/oscillator Spheronization Coating Pan coater Spray coater Packaging Liquid and semisolid fillers Blister pack sealer Heat sealer Laminated tube sealer Vial capper Sterilization Autoclave Depyrogenation Sterile filtration 6 We can customize our manufacturing capabilities to produce the dosage form and batch size you need.

7 Stability Studies SRI offers stability storage and testing that adheres to ICH guidelines. Our standard storage conditions include frozen (ultracold and -20 C), refrigerated (5 C), ambient (25 C/60% RH), intermediate (30 C/65% RH), and accelerated (40 C/75% RH). Custom storage conditions and specialized climatic zone considerations can also be accommodated upon request. In addition to long-term drug substance and drug product stability studies to support ongoing clinical trials, we routinely incorporate short-term stability studies in the evaluation of candidate formulations. We also perform photostability and temperature cycle studies. Our stability study evaluations are preceded by forced degradation studies to develop sensitive and specific analytical methods so that impurities and degradation products can be tracked and quantified. Our in-house analytical and synthetic chemists can identify impurities through various structure elucidation techniques and synthesize reference standards of the active ingredient and degradation products to support ongoing stability assessments. To ensure the quality and security of your drug substance and drug products, our stability storage program features: Storage units with validated conditions of temperature, humidity, and light (visible and UV) Validated computerized system for continuous monitoring of temperature, humidity, and light, with cumulative reports Emergency power back-up for chambers and computer monitoring systems Local audible alarms and an automatic notification system to 24/7 on-site security personnel with protocols for notifying facility engineers and technical staff A double-lock system to access chambers Stability study failures can be prevented or controlled by formulation development. 7

8 About SRI International Biosciences SRI Biosciences carries out basic research, drug discovery and drug development, and provides contract services. SRI has all of the resources necessary to take R&D from Idea to IND from initial discovery to the start of human clinical trials and specializes in cancer, immunology and inflammation, infectious disease, and neuroscience. SRI s product pipeline has yielded marketed drugs, therapeutics currently in clinical trials, and additional programs in earlier stages. In its CRO business, SRI has helped government and other clients and partners advance well over 100 drugs into patient testing. SRI is also working to create the next generation of technologies in areas such as diagnostics, drug delivery, medical devices, and systems biology. Contact Us SRI Biosciences 333 Ravenswood Avenue Menlo Park, CA Center for Advanced Drug Research SRI Shenandoah Valley 140 Research Drive Harrisonburg, VA Toll-Free: biosciences@sri.com About SRI International Silicon Valley-based SRI International is one of the world s leading independent research and technology development organizations. SRI, which was founded by Stanford University as Stanford Research Institute in 1946 and became independent in 1970, has been meeting the strategic needs of clients and partners for more than 60 years. Perhaps best known for its invention of the computer mouse and interactive computing, SRI has also been responsible for major advances in drug discovery and development, networking and communications, robotics, advanced materials, atmospheric research, education research, economic development, national security, and more. The nonprofit institute performs client-sponsored research and development for government agencies, businesses, and foundations. SRI also licenses its technologies, forms strategic alliances, and creates spin-off companies. Menlo Park Headquarters SRI International 333 Ravenswood Avenue Menlo Park, CA Washington, D.C. SRI International 1100 Wilson Blvd., Suite 2800 Arlington, VA SRI International and Idea to IND are registered trademarks of SRI International. All other trademarks are the property of their respective owners. Copyright 2011 SRI International. All rights reserved. 02/11

GUIDELINE FOR THE STABILITY TESTING

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 GUIDELINE FOR THE STABILITY TESTING OF NON-PRESCRIPTION (OTC)