Download how a Cmo Can help wIth InvestIgatIonal new drug applICatIons

> 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