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g-Outsourcing_21-24:Jasper Art5.0 #11 4/28/08 12:37 PM Page 1 Published in Inhalation, APRIL 2008 devoted nearly two decades to the long and arduous Why companies are looking
journey through the transition from the use of CFCs for product development
to HFA as a propellant for MDI products. Devel -opment work focused mainly on what were essen- partners, how the process
tially line extensions of existing products. Now, withthe transition to HFA nearly complete, companies works, and what to look for in
are turning their attention to other treatment areas.
Although the development and production of severalinhaled insulin products has now been dropped, the Craig Davies-Cutting and Dean McKinney
approval of Pfizer and Nektar's Exubera in 2006 Catalent Pharma Solutions
demonstrated the potential for successful develop-ment of inhaled products in new areas. Clinical trials Until fairly recently, most large, fully integrated phar- are underway for inhalation and nasal products to maceutical and biotechnology companies liked to keep treat conditions as diverse as obesity, breakthrough all aspects of product development and manufacturing pain in cancer patients, and Alzheimer's disease.
in-house, under direct control of the company. Today, Despite the substantial interest in the use of inhala- however, we estimate that the industry spends nearly tion and nasal delivery platforms for a variety of one dollar out of every five on outsourced services, and drugs, few pharmaceutical and biotechnology compa- Big Pharma has joined smaller companies in turning to nies today have the in-house expertise or intellectual contract development. In some areas of development property necessary for timely and cost effective devel- and manufacturing, as much as two thirds of all of a com- opment. Whether they involve new chemical entities pany's expenditures on an inhaled product may go (NCEs) or existing drugs reformulated for delivery towards outsourcing. And with the substantial growth ofspecialty, emerging, and virtual pharmaceutical and with an inhaler or spray pump, these products gener- biotechnology companies, partnering for mission criti- ally present much more complicated development cal expertise and services has become the rule rather challenges than do solid dosage forms, injectables, than an exception.
and even the standard inhalables like salmetrol andfluticasone. Depending on the size of the pharmaceu- Why are more and more pharmaceutical companies tical company and its experience with inhaled prod- turning to outsourcing partners for inhalation devel- ucts, it may turn to a contract research organization opment and manufacturing? One reason has to do (CRO) for help with one aspect of development or with the diversification of the market for inhalation complete development all the way from feasibility products in recent years. Since its introduction, in - studies to commercialization (Figure 1). halation therapy has mostly focused on the topicaldelivery of drugs to the nasal and pulmonary airwaysfor the treatment of diseases such as asthma, chronicobstructive pulmonary disease (COPD) and sea- sonal/allergic rhinitis. By 2006, according to reports Typical outsourcing demographic
from Frost & Sullivan and Datamonitor, the value ofproduct sales in this market segment exceeded $25 Full development Selected phases Discrete services billion, and continued growth is forecasted.
Much of that continued growth is taking companies beyond their well-established expertise in drugs for the treatment of pulmonary diseases. After the 1987 Montreal Protocol, pharmaceutical companies g-Outsourcing_21-24:Jasper Art5.0 #11 4/28/08 12:37 PM Page 2 In addition to traditional development and manufac- CRO and efficient sharing of information and tech- turing considerations, inhaled products also require nology throughout the process, customers may come device characterization and selection. In many cases, to a CRO with projects at various stages of develop- an entirely new device must be designed, or an exist- ment and require the CRO to pick up their projects ing platform must be modified to work with a specific seamlessly and progress from there on out. As an formulation. Optimization of product and pro cess, example, customers may conduct early feasibility process scale-up and generation of a submission- studies internally or with providers that ultimately do ready regulatory package can also require skills and not offer the services necessary for continued devel- knowledge not available at traditional oral or in - opment. In these cases, the CRO must be sufficiently jectable product development organizations. With agile to respond rapidly to both individual customer development of inhalation products for NCEs taking and individual project needs. The first step for the about 5-6 years and costing millions of dollars, a customer, therefore, is to evaluate the offerings of pharmaceutical company's relationship with the various CRO providers to understand how their capa- CRO it works with is critical.
bilities align with the type of work being outsourced. By choosing the right outsourcing partner, compa- During the selection process, teleconferences and site nies can often gain access to valuable expertise and visits with the CRO are valuable in assessing capabili- experience across a broad range of inhaled dosage ties. These activities are typically managed through the forms, allowing parallel development or format opti- CRO's business development groups and involve mization for the target disease state and patient pop- establishing some form of a mutual confidentiality ulation. A drug delivery company looking to develop agreement to allow both parties freedom to exchange products around its technology in addition to out- the necessary information to build an effective rela- licensing its intellectual property to large pharma- tionship. Most often it is the business infrastructure ceutical companies may not be looking for a CRO to within the CRO and working relationship between the take the product or technology through full develop- customer and CRO that will determine the success or ment to regulatory submission, but may simply seek failure of a particular venture. That said, development a data package to demonstrate the technical and/or is development, and even with the best laid plans the clinical proof of concept to illustrate the value of unexpected can happen. In such instances, aside from their asset. For companies looking to commercialize technical expertise and the experience of having seen their own products, a CRO with the infrastructure such issues previously, the real value that the CRO can and expertise to take a development forwards bring to such situations is the ability to effectively part- beyond very simple studies, with experience in over- ner with the customer to work through any problems coming the high regulatory hurdles, having cGMP proactively, efficiently, and with open and honest com- capability, and possibly having the infrastructure for munications to a successful conclusion. commercial manufacturing is probably the best bet.
Defining the project scope, including information such A CRO with complete development and manufactur- as the dosage form, the number of product strengths ing capability for metered dose inhalers, dry powder to be developed, the phases of product development inhalers, nasal spays, and solutions and suspensionsfor inhalation has the ability to partner with a com-pany at any point in the development process from feasibility to commercialization (Figure 2). Serviceswill include formulation and device screening along Interactivity of business and product
development processes in outsourcing
with the development of chemical and performance methods. Later in the process, the formulation andanalytical teams will work closely with the manufac- turing team to perform process scale-up and opti-mization, while the analytical team optimizes and validates methods and provides analytical process support. Once in production, raw materials, manu- facturing, materials handling and analytical teamswill work together to deliver clinical batches. Theanalytical and stability teams are then ready to per- form the supporting stability studies. Although outsourcing any or all stages of product development to one contract facility has many advantages, including having to manage only one g-Outsourcing_21-24:Jasper Art5.0 #11 4/28/08 12:38 PM Page 3 Stages of a typical product development project
Determine feasibility of developing formulation in the requested dosage form(s).
• Evaluate/screen formulation options
• Establish analytical methods
• Provide materials for early pre-clinical studies (if requested)
Product Proof of Concept
Establish product concept for pre-clinical and early clinical studies (Phase I and Phase IIa).
• Evaluate formulation compatibility with primary packaging options
• Qualify analytical methods for Phase IIa clinical studies and establish cleaning verification
• Provide materials for pre-clinical, Phase I and Phase IIa studies (as required) Product Optimization
Product optimization—all product strengths (API, formulation, packaging) for Clinical Phase IIb
• Refine formulation and primary packaging and/or device to achieve product development targets
• Additional analytical methods qualification for Phase IIb clinical studies (if required)
• Provide materials for Phase IIb studies (as required)
• Verify timing of Phase III readiness
Process Scale-up
Commercial-scale process defined for Clinical Phase III/registration batch production
• Validate analytical methods with final product(s)
• Optimize production process
• Scale-up manufacturing process to not less than 1/3 commercial batch size
• Validate cleaning methods for process equipment
• Provide materials for Clinical Phase III/registration studies
Product Registration Studies
Generate supporting data and write product dossier
• Conduct Registration stability studies
• Conduct Developmental Pharmaceutics studies
• Prepare Registration Dossier including stability package
• Validate Full-Scale Manufacturing Process-if required for EU
• Complete validation of cleaning methods for process equipment
• Provide materials for registration stability
Preparation for product launch
• Respond to regulatory deficiency questions and support PAI
• Process validation/Produce commercial launch supplies
g-Outsourcing_21-24:Jasper Art5.0 #11 4/28/08 12:38 PM Page 4 requiring support, the development strategy, and parties agree upon an effective development process timelines will help the CRO to identify the appropriate that encourages teamwork and a coordinated cross- technical experts needed for development of the con- functional development path for the program, while tract or quotation for the desired work. In some providing a forum for addressing and correcting any instances, the CRO can provide technical experts right issues within the program as early in the develop- from the beginning of the process to assist the cus- ment cycle as possible.
tomer in defining this scope. Once both parties have The objective of a well-designed product develop- agreed on a scope, the CRO will generally prepare a ment process is to facilitate good business decisions proposal for the work that details the key deliverables and timely management oversight throughout the and the costs associated with each deliverable.
program lifecycle; to provide the customer with To avoid delay in starting work with a CRO, it is im - assurance that required tasks, deliverables, and doc- portant to get a start on completing the necessary umentation will be completed prior to program documents early in the business development stage.
maturity; and to provide an essential gating mecha- With all work, standard terms and conditions will nism such that program budgets and resource alloca- require agreement and, in some cases, negotiation tion needs can be examined in a timely manner. By between the two parties. With outsourced projects relating functional responsibilities to key program where production of clinical supplies is involved, activities, horizontal integration of vertically orga- additional documents such as Clinical Supplies nized functions is encouraged, resulting in a unified and/or Quality Agreements may be required. For team approach to development. work involving cGMP studies or production of clinicalsupplies, it is also advisable, where possible, to per-form a Quality Assurance (QA) audit of the facility The authors would like to thank Robin Spivey and being evaluated to ensure that there are no regulatory David Wilcox, Senior Scientists in Research & concerns about placing work with the selected CRO.
Development; Sterile, Respiratory & AnalyticalServices. Once the quote is signed and all other necessary legalagreements in place, the CRO will assemble a projectteam and outline the key program objectives, deliver- Craig Davies-Cutting is Director of Research and ables, and milestones. They will then establish a pro- Development at Catalent Pharma Solutions, P.O. ject timeline in preparation for project initiation.
Box 13341, Research Triangle Park, NC 27709. Following a kick-off meeting with the customer to Tel: +1 919 465-8430. Craig.Davies-Cutting@ finalize agreements on the program objectives and Dean McKinney is Director, Business project timelines, the actual laboratory work can Development at Catalent. Tel: +1 919 465-8215. begin. In planning for success, it is key that both


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