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> serving the global supply chain API manufacturing Abstract Sponsor companies developing innovator therapeutics for today’s pharmaceutical markets are feeling intensified pressure to control costs and expedite time to market approval. While safety and efficacy ultimately dictate the success of a new drug, other factors such as the manufacturing strategy and execution can greatly impact the cost and timelines of a drug development How a CMO Can Help With Investigational New Drug Applications program or even derail it. For small-molecule drugs, many sponsor companies today outsource the development and manufacture of the active pharmaceutical ingredients (APIs) to contract manufacturing organizations (CMOs). This article speaks to the critical importance of identifying the right CMO partner and strategic approach to filing the chemistry, manufacturing, and control (CMC) section of an investigational new drug (IND) application. Introduction New drugs in the United States must receive a marketing authorization from the Food and Drug Administration (FDA) before they can be marketed to healthcare providers and patients on the open market.1 The clinical path to market approval begins with an investigational new drug permitting a compound to begin evaluation in clinical trials.1 An IND application provides the FDA with basic information about the drug substance, formulated drug, and clinical trial design.2 As the drug candidate progresses through further phases of clinical testing, additional CMC data are required.3 As a result of the changing dynamics in the pharmaceutical industry, including the shift of growth to emerging markets that prefer lower-cost drugs and away from blockbusters to therapies designed for smaller, more targeted patient populations, there is significant pressure on drug companies to bring innovative products to market more quickly than ever. To do so means getting potential candidates into clinical trials more rapidly. The decision to conduct clinical trials is a significant one. Early-phase clinical testing in humans can cost millions of dollars, while later-phase trials can cost a drug company tens to hundreds of millions of dollars. Because the amount of CMC information required for an initial IND is limited and largely related to ensuring the safety of trial participants, many pharmaceutical firms tend to focus their efforts on designing an ef- > BY Dr. Stephen A. Munk CEO Ash Stevens ficient and effective clinical trial protocol and develop the minimal amount of data required to support the Dr. Stephen Munk has been with Ash Stevens Inc. since 1997, serving as President since 1998 and CEO since 2001. He is experienced in drug discovery, development, and manufacturing both as a scientist and as a manager. Prior to joining Ash Stevens, Dr. Munk worked at Allergan, Inc. as a drug discovery scientist and subsequently as the co-team leader of the adrenergic drug discovery team. Under Dr. Munk’s stewardship, Ash Stevens has received ten regulatory approvals for the manufacture of novel drug substances to treat serious life-threatening conditions. These approvals include bortezomib, clofarabine, 5-azacitidine, amotosalen, and ponatinib. Dr. Munk is also an Adjunct Professor of Chemistry at Wayne State University and has served on the Board of Directors of MichBio. 10 American pharmaceutical review Supplement April 2015 safety of the drug substance and initial formulation. Such an approach can have significant consequences as the drug candidate moves through further phases of clinical study and hopefully into commercialization. Developing more extensive CMC data from the start often is a far more effective approach to minimizing both risk and overall project timelines. The forces at work in the pharmaceutical industry are also driving greater use of contract manufacturers throughout the entire drug development cycle, from the cal controls used to produce both the drug substance discovery stage through the commercial production, and product (both of which comprise the CMC section) and even for patent-life extension activities. When it is also required. Of course, detailed protocols for the comes to projects supporting IND applications, it is clinical study and information on the investigator that imperative that sponsor companies select a CMO that will be running the trial must also be provided. has a thorough understanding of the IND application The FDA has 30 days to review an IND application to process and recognizes the value in developing appro- determine whether the drug candidate is safe for use priate regulatory data. In addition, because communi- in the proposed clinical trial.1 This decision is in large cation with FDA is crucial to the successful acceptance part based on the results of animal toxicology and ef- of IND applications by the agency, a CMO that has a ficacy studies as well as the identity, strength, quality, strong, positive record of compliance and an effective and purity of the drug as presented in the application. system for communicating with all interested parties, If information is deemed lacking, the FDA may conduct including the sponsor organization, the regulatory bod- an inspection to further assess the risk, place a hold on ies, and the clinical trial team, is an ideal partner. the trial, or even terminate the IND application.4 The IND Application Clinical trials will only be planned for a drug candidate if the results of initial animal studies suggest that it efficient review of the ind Importance of Developing Appropriate CMC Information The quantity and type of information required in the has potential efficacy and the results of initial toxico- CMC section of an IND application varies with the logical evaluations suggest the compound is safe for phase of the clinical trial. Less information is required use in humans. Once the decision to conduct a Phase for Phase I trials because patient safety is the main I clinical trial has been made, data that establish that concern and is addressed by the pharmacology and the product will not expose humans to unreasonable toxicity data. Initially, only a limited number of healthy risks during early clinical testing must be developed volunteers are employed in Phase I safety studies to for inclusion in the IND application.1 limit risk (with the exception of oncology studies, where oncology patients participate in Phase I trials as There are two categories of IND applications: 1 commercial applications submitted by the pharmaceutical company intending to manufacture or market the drug, and 2 research applications, which are generally Understanding regulatory requirement the agents under investigation are often quite toxic to a healthy person). Such studies are short-term and conducted under very controlled conditions. Finally, only submitted by research institutions.4 Three other types limited drug substance and formulated product have of IND applications4 are: 1 Expanded access, some- been manufactured, so there is little data available, times called “compassionate use,” IND applications and the manufacturing and analytical processes will are for drug candidates that have the potential to be be improved as the drug progresses through further effective for the treatment of unmet medical needs. 2 development. Emergency IND applications allow for the use of a new It is very important to recognize, however, that addi- drug in a variety of situations where there is insuffi- tional data will be required if the candidate drug does cient time to pursue a conventional IND application. go on to Phase II and Phase III studies. Consequently, 3 Investigator-initiated IND applications are submitted by physicians who also perform the clinical study, often to test an existing drug for a new indication or in a new patient population. Assembly of good CMC Package in some cases obtaining more extensive data prior to submission of the initial IND application for a Phase I study can be more efficient and productive and help reduce project timelines. It is important to note that IND applications are In addition, while current good manufacturing prac- required not only for new drug substances, but also tice (cGMP) activities that are appropriate for Phase I for existing drugs that are being considered for oth- clinical trials must be followed during the production er uses, including new routes of administration or of the drug substance and drug product, the detailed different dose levels, for treatment of the same disease understanding of a manufacturing process required for but in a different set of patients, and for new therapeutic purposes.4 An IND must be filed prior to initiating human trials. Regardless of the category, type, or reason for an IND application, all submissions must include the results of animal pharmacology and toxicity studies (and any human data if the drug is an existing product) that demonstrate the drug is reasonably safe to use in humans. Information on the chemical structure and properties of the drug substance, the composition and properties of the formulated drug product, the manufacturer, and the manufacturing process and analyti- Obtaining more extensive data prior to submission of the initial IND application for a Phase I study can be more efficient and productive and help reduce project timelines. Americanpharmaceuticalreview.com 11 commercial use is not expected.5 While a deep under- > Company Profile standing of the manufacturing process from the beginning may initially require additional time and effort, the consequent additional control measures do help reduce the risk of failure to produce the API and drug product of appropriate quality required for the clinical study. That additional control is also appreciated by regulatory bodies. The choice of producing Phase I material according to the minimum requirements versus a more Ash Stevens is YOUR IND Expert Getting your drugs into clinical trials and to patients in need on time and on budget detailed study of the manufacturing process at an early stage is just one example of the decisions that sponsors must make regarding CMC data and information that can impact the overall project with respect to its budget, timeline, and quality, the latter two of which can directly impact the success of the clinical trial and potential patient safety. The clinical trial cannot proceed without available supply of the candidate drug in a form appropriate for the study design. Therefore, adequate time must be allowed in advance of the start of the clinical trial for development of a CMC package that will include information sufficient to convince regulatory agencies that the drug product is safe for use in the planned study. This information includes evidence for the structure and purity of the API, stability study results indicating that the drug product will be stable during the period of the clinical trial, and descriptions of both process and testing methodologies and quality control systems.1-4 With 9 regulatory approvals since 2000, including the latest in January 2015 for amotosalen, the active pharmaceutical ingredient (API) in Cerus Corporation’s INTERCEPT Blood System, Ash Stevens has a solid history of helping pharmaceutical companies get their treatments into clinical trials and on to patients. We have over 50 years of experience developing robust cGMP manufacturing processes, drug substance for clinical studies, and commercial APIs on aggressive timetables, including highly potent compounds and APIs with FDA Fast Track status. There are many reasons to use Ash Stevens as a CMO for your drug development project: + Over 53 years of experience in drug substance development and manufacture + State-of-the-art manufacturing facility located in Riverview, Michigan + Full-service CMO offering comprehensive small-molecule drug substance development and cGMP manufacturing services + Close proximity to the Detroit Metro Airport It is important to stress that development of data for both the API and the formulated product is required, and while it is expected that the manufacturing processes ultimately used for commercial production will likely be different from those in the Phase I IND application, sponsors should be careful postponing the development of the formulation intended for later clinical trials without adjusting the overall project schedule, as they may find it difficult to meet the supply requirements for those trials. Process changes should not introduce new impurities as bridging studies will be required to prove that those new impurities are not toxic to patients. + Privately held, financially stable company + Committed to safety, quality, on schedule and on budget delivery, and customer satisfaction + Project managers are experienced process chemists with extensive knowledge of early-stage drug development through registration and commercial manufacturing + Recipient of a 2014 Eli Lilly Global Supplier of the Year Award + All projects and clients, large or small, are treated equally + Four FDA Fast-Track API manufacturing approvals + Dedicated core team stays with the project throughout the development lifecycle + Expert regulatory and analytical support services for all phases of drug development + Highly experienced staff with low employee turnover + Engineering and containment controls for the safe handling and cGMP manufacture of small- and large-scale highly potent APIs with OELs ≤0.1 µg/m3 + Twelve FDA approvals for innovator small-molecule APIs The Role of the CMO Information on the manufacturer of any pharmaceutical intermediates, the API, and the formulated drug must be provided as part of the CMC section of an IND application. That includes CMOs. The CMO is also typically involved in discussions with FDA about the CMC package and is responsible for at least identifying the need to make any amendments to the initial IND. Amendments are required if changes in the CMC information may have an effect on patient safety, such as the use of a different process route, the + Global regulatory record of successful inspections that include the United States, Japan, Korea, European Union (QPs), Australia, and Mexico + Experienced in Quality by Design (QbD) principles including regulatory filings + Award-winning EHS&S program certified by SOCMA’s ChemStewards® + Multi-million dollar, multi-year, ongoing investment in infrastructure appearance of a new impurity after switching to a At Ash Stevens we translate our clients’ scientific discoveries into medicinal products new synthetic method or a new raw material supplier, that improve the quality of patients’ lives. We support sponsor clients of all sizes, or a problem with a container closure resulting in a from virtual biotech to large pharma, providing a safe and high-quality work product, product quality issue.1-3 while meeting delivery obligations on time and on budget. 12 American pharmaceutical review Supplement April 2015 12 FDA Approvals for small-molecule APIs 4 FDA fast-track API manufacturing Approvals The basic requirements for a CMO include extensive the first pre-IND meeting with FDA to discuss the expertise and state-of-the art technologies for API syn- CMC and determine any specific agency requirements thesis and/or drug product formulation, an effective related to the particular API or drug product to the quality program, a history of regulatory compliance, a End of Phase I (EOPI) (and EOPII) meeting,6 the CMO strong track record of on-time or accelerated delivery, plays a major role in ensuring that the agency’s CMC and available capacity, appropriate lead times, and rea- requirements are met on a continual basis and that sonable project pricing. FDA regulators remain satisfied that the drug product These qualities are insufficient, however, if the spon- is safe for use in the clinical study. sor intends to rely heavily on the CMO for management CMOs should also have effective communication of an IND project. Extensive experience in carefully and project management strategies in place for inter- balancing the financial, project timeline, and regula- acting with the sponsor company and the group per- tory requirements of an IND project is crucial. The abil- forming the clinical study. In order to make the most ity of a CMO to make rapid decisions based on all three appropriate decisions regarding project timing, the considerations will have a direct impact on the success extent and type of development work, a CMO must of an IND project. stay apprised of the goals of the sponsor. In addi- A deep understanding of regulatory requirements tion, while CMOs are not involved in the actual clini- is a key attribute that a CMO must have in order to cal study, they must be aware of the timeline for successfully complete IND projects. An understand- the trial and the goals of the study to ensure that ing of the requirements and assembly of a good CMC the appropriate materials are produced when they package will afford an efficient review of the IND. From are needed. A > references 1. Code of Federal Regulations, Title 21, Part 312. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRsearch.cfm?CFRPart=312. Accessed 2/1/2015. 2. FDA Guidance for Industry. Content and format of Investigational New Drug applications (inds) for phase 1 studies of drugs, including well-characterized, therapeutic, biotechnology-derived products. November 1995. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM074980.pdf. Accessed 2/1/2015. 3. FDA Guidance for Industry. INDs for phase 2 and phase 3 studies–chemistry, manufacturing, and controls information. May 2003. http://www.fda.gov/downloads/ Drugs/.../Guidances/ucm070567.pdf. Accessed 2/1/2015. 4. FDA Website. Investigational New Drug (IND) application. http://www.fda.gov/drugs/developmentapprovalprocess/ howdrugsaredevelopedandapproved/approvalapplications/ investigationalnewdrugindapplication/default.htm. Accessed 2/1/2015. 5. FDA Guidance for Industry. CGMP for phase 1 investigational drugs. July 2008. http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM070273.pdf. Accessed 2/1/2015. 6. IND Meetings for Human Drugs and Biologics– Chemistry, Manufacturing, and controls information. May 2001. http://www.fda.gov/downloads/drugs/guidance complianceregulatoryinformation/guidances/ucm070568.pdf. Accessed 2/1/2015; FDA Guidance for Industry. Formal meetings between the fda and sponsors or applicants. May 2009. http://www.fda.gov/downloads/Drugs/Guidances/ ucm153222.pdf. Accessed 2/1/2015. Americanpharmaceuticalreview.com 13