Discusses CMC issues regarding Drug-eluting coronary stents (DES) & Oncology drugs.

1. March 2009 Vol 9 No 3 www.drugdeliverytech.com
IN THIS
ISSUE
INTERVIEW WITH
DEPOMED’S
PRESIDENT & CEO
CARL A. PELZEL
Combination
Devices 18
Abhijit Gokhale, PhD
Excipient
Sourcing 22
Alen Guy, PhD
Solid Dose
Injection 24
Charles Potter, PhD
Nanomedicine
Market 32
Bill Martineau, MBA
FEATURING
Analytical
The science & business of drug development in specialty pharma, biotechnology, and drug delivery
Testing Labs 62
Xiaochun Yu, Ms. Cindy H. Mr. Mike
PhD Dubin Mesa Cardiology &
From Battlefield to
A New Approach to Proteins & Peptides:
Backpack: Evolution
Oncology 68
Threshold Evaluation & Dependent On
Advances in Drug of the Auto-Injector Stuart L. Cantor, PhD
Quantitation of
Unknown Extractables Delivery?
& Leachables Using
HPLC/CAD

2. Therapeutic
Focus
Cardiology & Oncology Drug Development
& Regulation
By: Stuart L. Cantor, PhD, Senior Scientist, and Kadriye Ciftci, PhD, Senior Director Drug Delivery,
ICON Development Solutions
reach $80 billion by 2012, according to the development of highly potent,
Introduction IMS Health. hydrophobic compounds, and difficulty
Heart disease and cancer are still the
There are several reasons for this in ensuring their solubility as well as
two leading causes of mortality in the
increased sales growth, which include specificity to target the tumor site.
world. Recent data show that in the US,
extended lifespan, increases in obesity Because oncology drugs are cytotoxic,
the total direct and indirect costs
and hypertension in the US population, maintaining containment facilities during
associated with treating cardiovascular
an increasing number of patients on the developmental phase for these actives
diseases and stroke are estimated to be
chemotherapy in major markets, longer can become expensive. Furthermore,
$449 billion, by comparison, the
treatment periods for a growing number with both of these drug classes,
estimated costs for all types of cancer
of patients, and the
was $219 billion.1 Sales of drugs treating
greater availability
cardiovascular disorders, hypertension,
of more expensive
and cancer accounted for roughly 31% of
and modern
the $287 billion prescription
targeted therapies
pharmaceutical market in 2007; these
Vol 9 No 3
to treat these
drugs continue to be the largest therapy
diseases. However,
classes in the US (Figure 1).2 In the
hotly debated
cardiology sector, Pfizer’s Lipitor®
issues have risen
amassed sales revenues of $12.7 billion
MARCH 2009
over the long-term
in 2007, making it the best selling drug
safety of coronary
in pharmaceutical history. Not to be
drug-eluting stents
outdone, the biotech industry has
(DES), efficacy of
likewise developed a number of
beta-blockers in
successful blockbuster cancer therapies
SPECIALTY PHARMA
treating
as intravenous solutions or vaccines,
hypertension, and
including Herceptin® and Avastin®,
the long-term
monoclonal antibody-based therapies to
safety of statins. In
treat breast and colon cancer,
the oncology
respectively, and Gardasil®, a vaccine
sector, there has Figure 1.
against cervical cancer.3 Sales of cancer
been an increase in
drugs are projected to double and could
68

3. difficulties proving efficacy or organization
unexpected safety concerns, particularly (CRO) can assist a
during later-stage development amid company with
Phase III trials, can be particularly developing a
challenging. game plan for the
The increased number of extent of both
blockbuster drugs that are scheduled to preclinical animal
lose patent protection in the coming testing and future
years (Figure 2), coupled with the FDA’s clinical trials;
Amendments Act of 2007 granting such services can
sweeping new powers to the agency for be outsourced by
such tasks as requiring drug makers to start-up or virtual
do post-marketing clinical trials, are companies with
making the regulatory climate more limited in-house
expensive and time-consuming for the drug development
pharmaceutical industry. Furthermore, resources. The
because drug safety issues are CRO can also
paramount due to highly publicized help the company
cases like Vioxx®, the FDA is closely in its
scrutinizing safety data while improving correspondence
its management of safety signals. with the FDA and Table 2.
offer guidance
physicochemical stability and potential
Drug Development during the critical pre-IND meeting.
Under current regulations, a sponsor is immunologic issues need to be closely
Oncology drugs in development are monitored and controlled to ensure a
permitted to start their clinical trials 30
generally highly potent as well as drug product’s beneficial effects.
days after filing its IND with the FDA
cytotoxic; some may even have narrow “In contrast to most drugs that are
unless notified earlier that there are
therapeutic windows. It is important to chemically synthesized and with a
issues with the application.
assess the safety of these compounds known structure, most biologics are
Recent reports from the
early on to determine that they are complex mixtures that are not easily
Pharmaceutical Research and
effective in treating the disease process identified or characterized. Biological
Manufacturers of America (PhRMA)
while not damaging healthy tissue. products, including those manufactured
noted that 750 new medicines are being
According to the M3 Guidance for by biotechnology, tend to be heat
tested in the fight against cancer, and
Industry, single-dose acute toxicity
Vol 9 No 3
256 new medicines are in development sensitive and susceptible to microbial
studies are required to be performed for contamination,” says Paul Richards,
to treat cardiovascular diseases.5,6 While
pharmaceuticals and should be FDA Spokesperson at CBER.
there have been a number of successful
evaluated in two small mammalian “Therefore, it is necessary to use aseptic
anti-neoplastic small molecules
model species before the first human principles from initial manufacturing
MARCH 2009
launched over the years, such as 5-
exposure.4 steps in order to ensure sterility of the
fluorouracil, paclitaxel, and
The ratio of time for animal to finished products, which is also in
doxorubicin, the focus has shifted away
human testing is 1:1, meaning that the contrast to most conventional drugs.”
from broad-acting cytotoxic drugs
FDA will allow a company to conduct Furthermore, vaccine clinical
toward the development of new
SPECIALTY PHARMA
human clinical trials for only the same development follows the same general
therapies directed against specific
time period in which animal data has pathway as for drugs and other
molecular targets. Although biologics
been supplied. Sometimes, the agency biologics. However, due to the complex
and vaccines derived from larger protein
can also request that safety and/or nature of many vaccines, each lot must
molecules offer promise in these
toxicity data in a non-human primate be thoroughly tested for safety, sterility,
therapeutic areas due to their high
also be supplied before an and potency by the manufacturer. These
disease specificity and activity at
Investigational New Drug (IND) can be tests, as well as many others that
relatively low concentrations as
approved. A contract research manufacturers must perform, are 69
compared with small molecules,

4. specified in their biologic license NDAs (ANDAs) from the US and approved drug product, and such filings
applications (BLAs). If the product is required for European and Japanese can be used to support new and
subject to official release by the FDA’s submissions. Canadian INDs must also innovative drug delivery forms. Data
Center for Biologics Evaluation and be in CTD format; however, these are from published studies can even be
Research (CBER), the manufacturer referred to as CTAs or Clinical Trial submitted to the FDA. However, the
must submit samples of each production Applications for Phases I-III. The CTD company would need to provide
lot to the Agency together with a release contains several modules with Modules 2 additional clinical data necessary to
protocol showing a summary of the lot and 3 containing critical Chemistry, demonstrate any safety and efficacy
manufacturing history and the results of Manufacturing, and Control (CMC) differences between the original drug
all the manufacturer’s tests performed on information. and the 505(b)(2) drug. Some of the
that lot, says Mr. Richards. While Module 2 deals with both different types of applications covered by
“The most challenging aspects to non-clinical and clinical overviews and the section 505(b)(2) are:
developing these biologic drugs is the summaries, the quality section or
design of efficient and robust Module 3 deals only with CMC issues • change in an active ingredient (ie,
fermentation and purification processes and provides information on the different salt, ester, complex,
and the production of a stable physicochemical properties and control chelate, clathrate, racemate, or
formulation,” says Peter Ihnat, PhD, Sr. of the drug substance as well as the enantiomer) for a listed drug
Principal Scientist, Protein Therapeutics, development, manufacture, and control containing the same active
Bristol-Myers Squibb. of the finished drug product. Modules 4 moiety;
Protein formulations can be and 5 address non-clinical and clinical
developed using either lyophilized study reports, respectively. Updates to • change in dosage form, strength,
powders or liquid parenterals; however, the IND data following Phase I-II trials formulation, dosing regimen, or
freeze-drying is not as popular an option can be provided in information route of administration; and/or
nowadays due to the increased cost and amendments and annual reports; • change from a prescription
longer development time required to however, the emphasis should be on indication to an over-the-counter
produce a successful formulation. reporting significant changes that can indication.
“Typically, the target level for have a safety-related impact. CMC
protein impurities for liquid formulations development will continue in parallel
is < 5%, and these are usually due to with the clinical development during The important benefits of using the
oligomers or aggregates; however, due to Phase III studies.9,10 505(b)(2) filing route are a faster
the immunogenic potential of these If the CMC section will be written pathway toward regulatory approval
compounds, impurity levels are for an already approved drug but a new without giving the sponsor the burden of
evaluated on a case-by-case basis. dosage form, the Drug Master File supplying duplicate safety and efficacy
Moreover, long-term protein stability is (DMF) number, if available, can be data on an already existing compound.
Vol 9 No 3
monitored using at least two to three referenced for some of the pertinent However, the FDA does still require that
orthogonal methods in addition to an in manufacturing information for the drug a sponsor provide additional clinical
vitro bioassay to assess biological substance. For all scientific data, the data, termed bridging studies, which are
activity,” says Mr. Ihnat. FDA is particularly concerned that the necessary to support any changes or
MARCH 2009
experimental study design and statistical modifications from the listed drug(s) to
analysis be sound and free from flaws, the 505(b)(2) drug(s), and these studies
Regulatory and requires a rationale and justification will allow extrapolation of the efficacy
Submissions used for final specifications selected as and safety data. Furthermore, a
SPECIALTY PHARMA
The CTD or Common Technical well as the use of novel excipients and 505(b)(2) applicant may qualify for 3 or
Document was developed to be used for any unusual tests performed. 5 years of Hatch-Waxman marketing
regulatory submissions and finalized as Two other regulatory submission exclusivity.11
the M4 Guidance for Industry in 2004.7,8 pathways available are the 505(b)(2) and The other non-traditional route for
This table of contents format is highly combination product options. The regulatory approval deals with
recommended for INDs, New Drug 505(b)(2) route offers companies the combination products, such as coronary
Applications (NDAs), and Abbreviated advantage of not having to supply the DES, which are considered a drug-
70 safety and efficacy data on an already device combination product under the

5. Code of Federal Regulations (CFR) 21 such as near-infrared (NIR) or Raman clinical endpoint such as survival or
CFR 3.2(e)(1). The Office of spectroscopy, to provide real-time process morbidity, and which is reasonably likely
Combination Products (OCP) at the FDA data. PAT finds wide applicability in the to predict clinical benefit. Examples of
assigns such products to a lead agency pharmaceutical industry and can be used tumor assessment endpoints are response
center, based upon the product’s primary to assess blend and content uniformity, rate to drug therapy or time to tumor
mode of action. OCP ensures timely, prediction of dissolution time, and can progression, measured using anatomic
consistent pre-market review and determine the end-point of a coating or imaging techniques. Once accelerated
appropriate post-market regulation of drying operation. Not only can end- approval has been granted, continued
combination products by facilitating the product testing be reduced, which can marketing of the product will be
review process involving more than one save a company money, but the FDA can contingent on the sponsor’s providing
agency center. In this case, the also provide some regulatory flexibility timely and conclusive evidence from
investigational device exemption (IDE) for any process changes that could occur validation trials that establishes that the
application would be sent to the FDA’s in the future, provided that they are experimental drug is safe and provides
Center for Devices and Radiological accompanied by scientific justification.13 tangible clinical benefit. The product
Health (CDRH) with significant “The Agency considers PAT to be a approval can be withdrawn if
consultation by the Office of New Drug tool for designing, analyzing, and confirmatory studies fail to show clinical
Quality Assessment (ONDQA)/Division controlling manufacturing through timely benefits, or if the drug sponsor fails to
of Cardiovascular and Renal Products. measurements (ie, during processing) of conduct the confirmatory studies.
Many scientific and regulatory issues critical quality and performance attributes A fast-track status is granted by the
will arise due to the complex nature of a of raw and in-process materials and Agency for those drugs also developed to
coronary DES. Some important concerns processes, with the goal of ensuring final treat life-threatening diseases and that
that would need to be evaluated and product quality. The goal of PAT is to demonstrate the potential to address an
discussed in a submission include acute enhance understanding and control of the unmet medical need. In this instance, a
and chronic stent biocompatibility, manufacturing process and to facilitate rolling NDA can be approved that allows
polymeric coating characterization (ie, innovation in development, for completed sections of the NDA to be
thickness, uniformity, integrity, adhesion manufacturing, and quality assurance by submitted to the FDA on an ongoing
to stent), and drug release profile. The focusing on process understanding. These basis. The FDA strongly recommends
predominant percentage composition of a concepts are applicable to all several meetings, including a pre-IND
combination product does not dictate the manufacturing situations,” says Jon E. consultation, meetings following Phases
Agency center(s) where it is regulated, Clark, MS, Associate Director for the I-II, and a pre-NDA meeting to expedite
rather, it is the primary mode of action or Office of Pharmaceutical Science (OPS) the approval process. The other
the “most important therapeutic action of Policy Development at the FDA CDER. designation, priority review, is for drugs
a combination product” that determines Due to the serious nature of the showing a significant therapeutic benefit
where a combination product will be diseases they treat, both cardiology and compared to the standard of care. In this
Vol 9 No 3
regulated. For example, DES submissions oncology drugs qualify under the fast- case, the FDA would review a NDA
are assigned to CDRH because the track drug development program within 6 months as opposed to the
device’s role in physically maintaining classification. The three designations standard review completion timeline of
vessel lumen patency provides the most given by the FDA are accelerated 10 months.
MARCH 2009
important therapeutic action of the approval, fast-track, and priority
combination product. The drug plays only review.14,15 In 1992, accelerated approval
a secondary role in reducing restenosis or for oncology drugs was codified into law
Outsourcing Key
re-narrowing of the coronary arteries, a under Subpart H (21 CFR part 314.530) Capabilities
SPECIALTY PHARMA
phenomenon which is caused by the and added to the new drug application In addition to hearing the term CRO
body’s formation of scar tissue in regulations. Accelerated approvals are as a common buzzword these days, the
response to stent implantation.12 granted for the treatment of serious or fact is that both small and large
While the agency currently does not life-threatening conditions and a benefit pharmaceutical companies can benefit
require the use of Process Analytical over available therapy exists. from utilizing the added services and
Technologies (PAT) for their submissions, This designation requires using a expertise of a global CRO while focusing
the use of PAT for CMC documentation surrogate endpoint for efficacy, ie, an on their core competencies. The CRO
is looked upon favorably. PAT uses tools, evaluation intended to substitute for a 71

6. market size is currently estimated at about $15 billion in revenue per year and is
growing at a healthy annual rate of 14.8%. By 2010, the market is forecast to be in
Stuart Cantor,
the vicinity of $22.9 billion, according to Frost & Sullivan. A CRO should be chosen PhD
carefully at the outset of a project after considering the budget, timelines, the range Senior Scientist
of services provided, and the resources offered. A CRO can assist with the review and ICON Development
Solutions
editing of the regulatory submissions and can either represent the company as their
sole agent or accompany their client in meetings with the FDA. For smaller
companies with limited resources, limited regulatory expertise, and tight timelines,
meetings with the FDA early in the development process can alert the company if
they are going down the wrong pathway.
Meetings with the FDA can be arranged at both the pre-IND stage, where the Dr. Stuart Cantor graduated from the University of
company can ask questions to see if they have done enough work to prove a drug’s Maryland Pharmacy School and is a Senior Scientist
safety, and also before going through the time and expense for Phase III clinical trials for ICON. Dr. Cantor currently assists global clients
(an after Phase II meeting). These meetings are invaluable in identifying additional with their CMC sections of regulatory documents for
safety, toxicity, or efficacy issues pertinent to cardiology and oncology IND/NDA solid dosage forms and biologics, and also handles
filings. More frequent interaction with the FDA would be recommended (ie, end of clinical supply chain management issues. He has 7
Phase I meeting) if the drug would be marketed to a small patient population with a pharmaceutical publications online/in-process, and
rare disease or condition, ie, orphan drug classification for a disease affecting less has published a book chapter on wet granulation.
He interned at Wyeth and Bristol Myers Squibb
than 200,000 people in the US. Orphan drugs would also be granted accelerated
(BMS) and studied different granulation processes
approval status, and NDAs are given a priority review timeline of 6 months.
and their mechanical properties. His research
A CRO can act as a regulatory resource for a company to guide them as to what
covered preformulation, formulation, analytical
the minimum agency requirements are to prove safety and efficacy and which tests
method validation, blend segregation, and chemical
would be superfluous. Another key advantage of using a CRO is that they have the
imaging. His expertise is in extrusion-
capability to offer their clients a strategic viewpoint on risk assessment and
spheronization, wet granulation, and NIR
management, and can additionally shoulder some of that risk in interactions with the spectroscopy. Dr. Cantor previously developed the
FDA. The Agency will take a global view of the scientific data to assess the risk- sugarless fiber chews for diabetics launched by
benefit ratio, ie, the benefits of the drug substance and final drug product must far BMS under the Choice® DM brand.
outweigh any complications or potential risks to human health. The Agency also
examines what therapeutic advantages the new product has over therapies currently in
Kadriye Ciftci,
the market. Sometimes there is no information available on comparator products as PhD
the regulatory submission is for a first-in-class therapy. In such instances, a CRO can
Senior Director Drug
provide key information as it can draw from a wide knowledge base from past client Delivery
experiences with a variety of dosage forms. N ICON Development
Solutions
Vol 9 No 3
References
1. Rosamond W, et al. Heart Disease and Stroke Statistics 2008 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics
Subcommittee. Circulation. [Available at: http://circ.ahajournals.org/cgi/content/full/117/4/e25 (DOI: 10.1161/circulationaha.107.187998); Accessed August 6, 2008].
MARCH 2009
2. Buono D. IMS study finds decline in prescription drug market growth. Drug Store News. (April 21, 2008) [Available at:
http://findarticles.com/p/articles/mi_m3374/is_5_30/ai_n25407255; Accessed July 30, 2008]. Dr. Kadriye Çiftci is Senior Director of Drug
3. Lawrence S. Billion dollar babies-biotech drugs as blockbusters. Nature Biotechnol. 2007;25(4):380-382. [Available at: http://www.nature.com/naturebiotechnology ;
Accessed August 6, 2008]. Delivery/Formulations at ICON Development
4. FDA Guidance for Industry M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals. Center for Drug Evaluation and Research
(CDER) & Center for Biologics Evaluation and Research (CBER), (July 1997).
Solutions. She has more than 15 years of
5. 2008 Report: Medicines in Development for Cancer. [Available at: http://www.phrma.org/files/meds_in_dev/Cancer2008.pdf; Accessed July 27, 2008]. experience in academia and pharmaceutical R&D.
6. 2007 Report: Medicines in Development for Heart Disease and Stroke. [Available at: http://www.phrma.org/files/Heart2007.pdf; Accessed July 27, 2008]
Dr. Ciftci completed her training at the University of
SPECIALTY PHARMA
7. FDA Guidance for Industry M4: The CTD- Quality Questions and Answers/Location Issues. CDER & CBER, (June 2004).
8. FDA Guidance for Industry M4: The CTD- General Questions and Answers. CDER & CBER, (December 2004).
9. FDA Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized,
Illinois at Chicago and the University of Michigan
Therapeutic, Biotechnology-derived Products. CDER & CBER, (November 1995). Medical School. She previously worked as a Tenure-
10. FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies. Chemistry, Manufacturing, and Controls Information. CDER, (May 2003).
11. FDA Guidance for Industry: Applications covered by Section 505(b)(2). CDER (October 1999). track Assistant Professor at Temple University and a
12. FDA Guidance for Industry: Coronary Drug-eluting stents- Nonclinical and clinical studies. Center for Devices and Radiological Health (CDRH) and CDER (March
2008).
Research Fellow at the Schering Plough Research
13. FDA Guidance for Industry: Q8 Pharmaceutical Development. CDER & CBER (May 2006). Institute. Her special interests include cancer
14. FDA Guidance for Industry: Fast Track Development Programs- Designation, Development, and Application Review. CDER & CBER (January 2006).
15. Dagher R, Johnson J, Williams G, Keegan P, Pazdur R. Accelerated Approval of Oncology Products: A Decade of Experience. J Natl Cancer Inst. 2004;96(20):1500- research, gene therapy, and the development of
1509.
novel drug delivery systems, particularly biotech
72 products and vaccines.