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in the alpha crystal form throughout the entire clinical study. The company got a
lucky break….pure and simple.
Potential polymorphic changes in both drugs and excipients need to be studied
and understood early in a research program and then monitored for changes
throughout development. It should be kept in mind that, once elevated to the development phase, the expectation will be that a product will be moved rapidly to clinical
studies and to market. Consequently, if polymorphism is overlooked in the research
phase, the mistake may not be caught during the rush to market; the formulator
should include a “check for polymorphs” in the stability study regimen.
1.3.2 The Chosen Route of Administration
Drugs have been delivered to the back of the eye by the oral, transdermal, topical
ocular, intravitreal, intraarterial, sub-Tenon’s, retrobulbar, suprachoroidal, intrascleral, transscleral, and subconjunctival routes of administration (Tzekov et al. 2009).
Some of these routes will be discussed in other chapters; this section will focus on
the advantages and disadvantages of each route of administration, provide examples
of drug delivery systems for each route, and highlight the tissues where drug delivery
formulations and devices would be most effective.
The oral route is advantageous in that it is easy for the patient to self-administer,
facilitating good compliance for daily dosing. This route is also relatively inexpensive because the cost of manufacturing an oral dosage form is low and because
medical intervention or supervision is relatively minor.
On the other hand, systemic exposure to the active drug and metabolites increases
the possibility for serious adverse effects. Moreover, systemic dilution and difficulty
in drug penetration of the blood-retinal barrier may result in a relatively low concentration at the active site with potentially little or no efficacy. Also, with oral dosing,
the “first-pass effect” in the liver may substantially metabolize the active. Drugs taken
by mouth may result in considerable patient-to-patient variability in drug blood
levels, side effects, and efficacy. Furthermore, a drug’s concentration in the blood is
subject to significant peaks and valleys, which might range between toxic and
subeffective levels.
Notwithstanding these hurdles, oral dosage forms have been administered to
treat – or attempt to treat – back of the eye diseases. For example, a clinical study
by the National Eye Institute (ARED Research Group 2001a, b) has demonstrated
that certain orally administered vitamins and minerals retard the progression of
ARMD. Both zinc and antioxidants significantly reduced the odds of developing
advanced ARMD in a high-risk group (e.g., Ocuvite®, ICAPS®).
There are several other examples of oral therapies for the eye. Aspirin tablets
(250–500 mg) appear to be more beneficial in the treatment of CRAO than intravenously administered heparin (Arnold et al. 2005). Oral administration of steroids has
been one approach to treating noninfectious uveitis. A new oral therapy, Luveniq,™
(voclosporin), an immunosuppressive agent, is claimed to have demonstrated
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“clinically meaningful efficacy and enabled preservation of vision in treated
patients” in uveitis patients (Lux 2010). Assuming this drug is approved by regulatory agencies, it may not only replace oral steroid for this use but also possibly
ocular injections, implants, and topical drops.
Oral dosing of memantine, a neuroprotectant, has been shown to enhance the survival of retinal ganglion cells in the inferior retina in primates (Hare et al. 2004a, b).
However, in a phase III clinical study evaluating its benefit in glaucoma patients,
memantine did not demonstrate efficacy different from a placebo (Osborne 2009).
Moreover, a relatively high incidence of adverse effects, such as
dizziness, headache,
constipation, and confusion, are associated with oral dosing of this drug. Likewise, a
clinical safety study evaluating oral eliprodil as an ocular neuroprotectant, demonstrated significant patient-to-patient variation in blood levels of the active; when one
patient, having a particularly high blood concentration of drug, experienced a lifethreatening prolongation of the QTc interval, the study was discontinued.
Although the transdermal route has not been used in man for treating posterior
ophthalmic diseases, it is a promising alternative to oral dosing; for example, a
transdermal patch of eliprodil, studied in minipigs, demonstrated zero order drug
delivery at purported effective drug levels; this route would likely minimize the
patient-to-patient variation in blood levels and toxicity, which was observed in
the oral-dosing clinical.
Similar to the transdermal route of administration, intravenous dosing avoids the
“first-pass effect” while providing a very consistent, usually well-controlled, blood
level of drug. This route is currently the path of choice for photodynamic therapy.
In ARMD, blood vessels behind the retina grow under and within the macula and
leak blood and fluid. A bolus intravenous infusion of a light-activated drug formulation allows the photosensitive pharmaceutical to seep into the tissue adjacent to the
leaky vessels. Shortly after initiating the infusion, a low-intensity laser beam is focused
through the cornea to posterior tissue, photoactivating the drug, which then destroys
the defective sight-impairing vessels. This is a marginally effective therapy.
The intravenous route also may be a good choice for treating CRAO. Since the
flow of the blood in the central retinal artery is toward the eye, topical ocular, intravitreal, sub-Tenon’s, suprachoroidal, intrascleral, retrobulbar, and subconjunctival
routes of administration are unlikely to deliver an effective concentration of drug to
the site of blockage.
The intravitreal and sub-Tenon’s routes are currently targets for human implantation of drug delivery formulations and devices and are the most promising ways to
deliver drugs at effective and safe concentrations to the back of the eye. Drug delivery
devices have been explored in the intrascelaral, transscleral, subconjunctival, and
suprachoroidal spaces in animals but, to date, no advantage has been demonstrated
over intravitreal or sub-Tenon’s administration.
Intravitreal administration of a drug delivers it proximate to the site(s) of
action, where there are few physiological barriers to overcome. Suspensions may
form a depot for prolonged delivery. Both biodegradable and degradable drug
delivery devices can provide a continuous dose of a drug for months or years. An
important advantage of this route is that systemic exposure to the drug is limited
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and, consequently, systemic adverse effects minimized. However, this route of
administration comes with some risks. Common adverse effects include: conjunctival hemorrhage, eye pain, vitreous floaters, retinal hemorrhage, vitreous detachment,
and intraocular inflammation.
Endophthalmitis, retinal detachment, and traumatic cataract occur in proportion
to the number of times the vitreous is breached; although the incidence of these
adverse effects is low, the chance of occurrence is additive. Fear of this procedure
may cause some patients to avoid therapy.
More than any other method of administration targeting posterior diseases, the
intravitreal route predominates because the injection/implantation is relatively
straightforward and the chance of successful delivery to the target is facilitated by the
drug being delivered near target tissues. Commercial intravitreal pharmaceuticals,
for treating posterior diseases, include Ozurdex,™ Vitrasert,
®
Retisert,® Lucentis,®
Triesence,™ Posurdex,® Macugen,® and Trivaris.™ In addition, numerous formulations and drug delivery devices have been patented, some currently in preclinical and
clinical studies. The potential for adverse effects caused by penetrating into the vitreous makes long-acting products highly desirable because the number of intrusions
would be minimized.
It is important to note that, just because the drug is placed in the vitreous, does not
guarantee that the drug will reach the target tissue in a safe, effective dose because
many factors affect a drug’s permeation into the tissue. Intravitreal formulations and
devices will be discussed in greater detail in several upcoming chapters.
The sub-Tenon’s space – which is above the outer surface of the sclera and below
the Tenon’s capsule – is an excellent location to administer drug formulations and
devices for the treatment of posterior ocular diseases; it is less invasive than the intravitreal route and, with training, fairly easy and rapid to access. Using this route of
administration, the drug can be delivered near its site of action, where it is likely to
permeate the sclera and reach the choroid and retina. From this juxtascleral space,
there are three barriers which the drug must permeate in order to reach the neuroretina: the sclera, Bruch’s membrane-choroid, and RPE (Kim et al. 2007a, b). The sclera
is quite permeable; there is evidence that even large molecules (e.g., polypeptides
and proteins) may diffuse through this tissue (Olsen et al. 1995). The Bruch’s membrane may be disrupted in ARMD and DR, and therefore drugs may not encounter an
intact barrier (Chong et al. 2005; Peddada et al. 2002; Ljubimov et al. 1996). In order
to penetrate the RPE in effective concentrations, the drug will generally need to be in
substantial concentration, be unionized, and fairly hydrophobic. These conditions
are no different than a drug administered in the vitreous. Yet, sub-Tenon’s administration avoids penetrating the vitreous and therefore is a safer alternative.
This route, while promising, has its pitfalls. In rabbits, anecortave acetate readily
penetrates intact tissue barriers to provide a purported effective concentration in the
tissue; however, the drug only moves laterally in the choroid and retina about
1–2 mm; this may be due to this drug’s hydrophobic nature or perhaps some other
property unique to anecortave acetate. The point is that this observation suggests
that a drug, or drug delivery device, ideally should be placed, in the sub-Tenon’s
space, directly over the macula, for treatment of ARMD, while the same drug may
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need to be spread throughout the episcleral space, as much as possible, in order to
treat DR. Of course, other drugs with different physicochemical properties may
afford better distribution characteristics.
Another potential problem occurs when an injection of drug suspension or solution is administered into the tight sub-Tenon’s space; a large portion of the dose may
reflux due to backpressure. This can be prevented by first expanding the space with
a probe prior to administration of the formulation. Alternatively, a counterpressure
device may prevent or minimize reflux (Kiehlbauch et al. 2008).
An additional common pitfall is that the practitioner may accidently inject into
the Tenon’s capsule, rather than into the space below it; this error would cause the
bulk of the drug to eliminate rather than reach the target tissue. It should also be
noted that there is an increased risk of scleral perforation in myoptic patients
(Canavan et
al. 2003).
Even with all these potential complications, the sub-Tenon’s space is still a viable
spot to place drug delivery formulations and devices. For example, in rabbits, juxtascleral devices were surgically implanted directly over the macula and were demonstrated to produce a sustained near-zero order delivery of anecortave acetate at
targeted concentrations for a period of 2 years (Yaacobi et al. 2003). When the study
was terminated, 40% of the drug remained in the devices, suggesting that the device
might have continued delivering the steroid for a substantially longer period.
Similar devices have been designed specifically for human use (Yaacobi 2002–2006);
these have been evaluated in a phase I safety study and were successfully implanted
over the human macula.
Although many practitioners prefer retrobulbar administration of local anesthetics, sub-Tenon’s administration may be a safer site because the former route allows
much of the drug to be quickly eliminated systemically, where the spike in systemic
drug concentration may cause serious adverse effects (Buys and Trope 1993; Tokuda
et al. 2000). Retrobulbar administration is not a likely route for long-term delivery
of drugs for treatment of posterior diseases except, perhaps, for delivering a neuroprotectant to the optic nerve (Zhong et al. 2008).
Studies in rabbits and horses suggest that administration of drug formulations
and devices into the intrascleral space is a feasible location for delivery of drugs to
the posterior segment of the eye (Einmahl et al. 2002; Okabe et al. 2003; Kim et al.
2007a, b). For example, a betamethasone nondegradable implant has been
demonstrated to yield zero order release for a period of 4 weeks in rabbits at or
above anti-inflammatory effective concentration. However, while a drug delivery
system may be placed closer to the site of action by this route, there is no evidence
that it would deliver drug more effectively than from the sub-Tenon’s route. Indeed,
the sclera is quite permeable to drugs, so the advantage of placing a device closer to
choroid may be insignificant, while the surgery to create a pocket in the sclera is
somewhat more complicated than in the sub-Tenon’s space.
As a site for drug delivery to posterior tissue, the subconjunctival route has produced mixed results in animal studies (Kompella et al. 2003; Amrite and Kompella
2005; Cardillo et al. 2010). The suprachoroidal space appears to be superior to the
subconjunctival route in serving as a reservoir for sustained-release pharmaceuticals
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(Kim et al. 2007a, b). But, device implantation in this latter site can be more difficult
than in the sub-Tenon’s space. Moreover, it has not yet been demonstrated that it can
be used for long-duration systems.
1.3.3 Location of the Target Tissue
In most cases of posterior ocular disease, the target tissue is in the retina and/or
choroid. Drug delivery to these tissues has been demonstrated in animals from a
number of sites of administration, as discussed earlier but, the most productive and
successful site for administering a drug delivery system, from a commercial point of
view, is the vitreous.
The vitreous, being chamber of significant volume (ca 3 mL in man), is superior
to other ophthalmic tissues in its flexibility to hold drug delivery systems of different
designs, sizes, and shapes; these devices may be either degradable or nondegradable.
But, as mentioned earlier, there is a small, but significant, chance of detaching the
retina or causing endophthalmitis by this route. In addition, care must be taken to
avoid blocking the field of vision, which begins roughly 5 mm in from the pars
plana, toward the central line of vision. Also, if the device or suspension of drug or
microspheres touches the lens – even briefly – a contact cataract may occur.
It should be kept in mind when designing a drug delivery device, that although the
vitreous will support relatively large devices (e.g., 5 × 3.5 × 5 mm sutured to the sclera),
the incision or injection should be as small as possible, in order to limit leakage of vitreous and to minimize the chance of retinal separation and/or infection. The incision is
made through the pars plana region because this entry point is devoid of retinal tissue.
The vitreous may not be the best place to locate a drug targeting the optic nerve
(e.g., a neuroprotective). For this target, the retrobulbar and sub-Tenon’s routes
should be compared to intravitreal dosing by PK evaluation. If either of the latter
locations deliver sufficient drug to the target, they should be preferred over puncturing
the vitreous.
Occlusions of the CRVO may be treatable from a number of sites of administration
including oral aspirin, oral or intravenously administered anticoagulants and fibrolytic
agents, oral and intravenously administered anti-inflammatory agents, and intravitreal
administration of a steroid, tissue plasminogen activator, or bevacizumab. It is a common practice to use topically or intravenously administered glaucoma agents to treat
CRAO. However, the success of decreasing ocular pressure for this purpose is unclear
(Arnold et al. 2005; Hazin et al. 2009). Better therapies are needed. The traditional
CRAO therapy is to use intravenous acetazolamide to reduce intraocular pressure,
along with anterior chamber paracentesis. More recently, it has been observed that the
use of fibrinolytics appears to be more useful; if treated in the first few hours of onset
of the occlusion, intravenous-administered fibrinolytic, such as tissue plasminogen
activator, can be effective. Alternatively, urokinase has been administered through a
microcatheter placed in the proximal segment of the ophthalmic artery (Schumacher
et al. 1993; Koerner et al. 2004; Arnold et al. 2005; Hattenbach et al. 2008).
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1.3.4 Potency of the Drug
The potency of a drug is another factor that impacts the design of a drug delivery
system. If a drug is highly potent, then it can be delivered for months or years from
a miniscule device. In contrast, if a high concentration of a drug is required at the
receptor for efficacy, then there will need to be a trade-off between the size of the
device and the duration of delivery. For example, the intravitreal device, Vitrasert®
delivers ganciclovir from a coated tablet-core containing about 4.5 mg of ganciclovir
and delivers an effective dose for a period of 5–8 months (Dhillon et al. 1998).
The device dimensions are approximately 5 × 3.5 × 5 mm, after the surgeon manually
adjusts the size. In contrast, Retisert™ contains 0.59 mg of fluocinolone acetonide – a
medium to high potency corticosteroid – which delivers 0.3–0.6 mg/day for about
30 months and dimensions of this device are 3 × 2 × 5 mm (Hudson 2005; Miller
et al. 2007).
A much smaller intravitreal device, Iluvien,® has completed clinical studies
for the treatment of diabetic macula edema (DME) and an NDA has been submitted. Fluocinolone acetonide has been loaded into a tiny tubular device, which is
injected through the pars plana and into the vitreous using a 25-gauge inserter;
the device –a mere 3.5 × 0.37 mm cylinder – delivers drug for up to 3 years
(Ashton 2009).
Potent drugs or, drugs which are not particularly potent, may be delivered by a
novel phase-transition injector, which can deliver a substantially larger payload
through a 27–30-gauge needle (Marsh et al. 2006). Inside a rapid-heating chamber,
a drug delivery formulation is melted and injected into the vitreous where it “balloons” and rapidly solidifies to form a long-duration system. Preliminary toxicology
studies have shown this system to be safe.
1.3.5 Need for Continuous or Pulsatile Delivery
It is well known that some receptors in the body are subject to tachyphylaxis – a
decrease in the response to a drug after closely repeated doses. For example,
decongestants (e.g., phenylephrine hydrochloride) will induce this response, when
used continuously to treat nasal congestion; indeed, the rebound congestion may
be quite severe.
There is evidence that some ophthalmic receptors may demonstrate tachyphylaxis
(Chan et al. 2006; Forooghian et al. 2009). However, all of the commercial drug deliv-
ery systems are designed to deliver continuously. These systems are effective to some
degree or they would not have had successful clinical trials or have been approved by
regulatory bodies. Could these systems be more effective if they delivered drug in
pulses? And, if so, how might a system be designed to deliver a pulsed dose?
One very innovative and interesting pulse-delivery system has been designed to
release drug from gold-coated holes in a microchip via radio signal (Santini et al. 1998).
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Another novel system is an implantable MEMS-activated miniature pump with a
refillable drug reservoir, which is currently being commercially explored for ocular
use; this device might be used to deliver either a continuous or pulsatile dose of a
soluble or suspended drug on demand (Ronalee et al. 2009).
Drugs such as Lucentis and Macugen are currently delivered by intravitreal
injection once every 4–6 weeks, despite the fact that their half-lives are far shorter
than this periodic administration. Surely, the reason for selecting this dosing regimen is related to a balance between a need to minimize adverse effects of penetration
into the vitreous while maintaining significant efficacy. But, is this choice of dosing
interval the serendipitous equivalent of pulsatile delivery? Time will tell whether the
continuous delivery of a Lucentis, in the effective range, will be found to be superior
or inferior in efficacy, when compared to the current 4–6 weekly regimen.
1.3.6 Duration of Drug Delivery Necessary to Induce
and Maintain Efficacy
A drug should only be administered as long as needed to treat the underlying
disease state. So, for treatment of endophthalmitis, occlusions, or nonrecurring
inflammation, a relatively short-duration drug delivery system may be sufficient.
Since treatment of these maladies is likely to be for several days or perhaps a few
weeks, the system should be biodegradable (or bioerodible) rather than nondegradable; ideally, the excipients should disappear entirely within a few days after
the drug is gone.
For treatment of most other blinding diseases, a continuous or pulsed dose over
long periods (months or years) may be necessary. Biodegradable or bioerodible
systems are preferred for treatment periods of less than a year. In the future, it
might also be possible to use biodegradable or bioerodible systems for treatment
periods of 1 year or longer.
In contrast to biodegradable systems, the justification for use of a nondegradable
system becomes greater as the required duration becomes longer; generally nondegradable devices offer better control of drug release over longer periods. It also may
be easier to produce a more stable formulation in a nondegradable system because
some biodegradable systems accelerate the degradation of the incorporated drug.
1.3.7 Type of Drug Delivery System Selected
The choice of biodegradable/bioerodible systems vs. nondegradable systems has
been discussed but the nondegradable systems need to be further explored as
either nonrefillable or refillable. All of the current intravitreal devices are nonrefillable. But a refillable device might answer the conundrum of how to bring a device
to market that is designed to deliver for 20 years with a single surgery; if a fillable
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device can be used and refilled once a year or so, it may be useful for the rest of
the patient’s life.
Clinical studies of a refillable device might be limited to a year or two, which
would make it much more economically feasible than a nonrefillable device.
Furthermore, with a refillable device, if a better drug is later approved, that drug
may replace the original without further surgery.
The “Achilles heal” of refillable devices is the potential for infection; such a
device and its surgical implantation must be designed to protect the port against
infiltration of pathogens at all times.
Two often-touted types of drug delivery systems are iontophoretic devices and
drug-loaded contact lenses. These devices have significant hurdles to become
commercially viable. Iontophoretic devices use a low current to drive drug through
biological barriers to the back of the eye, from a topically applied pad. There is
little evidence that large molecules can be consistently delivered safely at effective
doses. There is, however, some data suggesting that such devices might be proven
both safe and effective for small molecules. However, to date, iontophoretic
devices have been designed to be used at the practitioner’s office, rather than be
self-administered by the patient. Since drugs (ca 300
Da) have a short halflife in the vitreous, to be effective the doses would likely have to be repeated
quite frequently. Is the patient going to visit the doctor several times a week for
such a treatment? How about once weekly? Would once weekly be effective?
Iontophoresis will be discussed more thoroughly in a later chapter. To the back
of the eye there are numerous patents and patent applications for drug-loaded
contact lenses. Some might even prove to deliver drug to the posterior segment.
However, there are many questions left unanswered with such systems. The great
bulk of patients with blinding diseases are over age 50. But, less than 5%, in that
age range, actually wear contact lenses. How many of these wearers would be
willing to give up their brand’s polymer for the drug delivery device polymer?
How many noncontact lens wearers would be willing to wear lenses to treat their
blinding disease? Will the drug-loaded device affect vision? Will the oxygen permeability of the lens be impaired by the drug and excipients? If impaired, would
the cornea be damaged by anoxia? If the drug needs to be delivered in pulses
rather than continuous, can a drug-loaded lens deliver in that manner?
Would the contact lens device be daily wear or continuous wear? If daily wear,
how would soaking the device in disinfectant affect the device? Would the drug
leach into the disinfecting solution during soaking? Would the lens adsorb the disinfectant and become toxic? Alternatively, if the device is continuous wear would
protein uptake block the release of the drug or cause ocular irritation?
Would the polymer for the device have a sufficiently low modulus for good fit,
yet be sufficiently high to provide strength? Would drug delivery lenses be provided
to treat patients with astigmatism or presbyopia? Would the device be available in
all diopters and diameters? Would there be devices with several base curves?
Since the combination of all diopters, diameters, and base curves, if provided, would
amount to hundreds of different devices, would all these deliver drug at the same rate?
If not, how could a clinical trial be conducted with hundreds of potential arms?
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1.3.8 Pharmacokinetic (PK) Properties of the Drug
Obviously, when designing a drug delivery system, it is critical that PK studies be
conducted to help determine the optimal route of administration. What is not so
obvious is that it is important that the animal test eyes be analyzed in quadrants, so that
the true distribution of the drug can be revealed. If the target is the macula, then a
“punch-out” around the target will provide far more information than simple quadrant analysis.
For example, a drug formulation may analyze at “effective” concentrations, after
topical application, if the whole retina is analyzed. However, since there may be a
tenfold difference between concentrations in the anterior portion of the retina and
concentrations at the macula, the actual target may be getting a subeffective dose.
1.3.9 Local and Systemic Toxicity of the Drug and its Metabolites
As discussed earlier, the design of a drug delivery system should take into account
the toxicity of the drug and/or its metabolites at the proposed site of administration;
for a variety of reasons, a drug might appear to be toxic in the sub-Tenon’s region
while not in the vitreous or vice versa. The researcher needs to be cautious about
applying toxicology results from one dosage form to another. For example, a drug
solution injected into the vitreous might be quite toxic while a drug delivery device
delivering the same total amount of drug may not be because it controls the peaks
and valleys of the drug’s vitreal concentration.
1.3.10 Previous Ocular Use of Excipients
When designing a drug delivery system, it is always best to use excipients that
have already been used at the site of administration, preferably at the concentration previously used. For example, 0.25% magnesium stearate is used in the
preparation of the solid dosage form in Vitrasert and has a proven safety track
record. It would be unwise to use a different tablet lubricant without reasonable
justification for abandoning magnesium stearate.
However, the number of excipients safely used for dosage forms in the vitreous, sub-Tenon’s space, or other sites of ophthalmic administration is severely
limited. Consequently, the next best strategy is to use excipients shown safe for
injection. If previously identified injectable excipients do not meet the formulator’s need, then excipients previously used topically in the eye may be the next
best choice. The surface of the eye is quite sensitive, so a chemical that is safe for
topical administration has a fair chance of being suitable for in-eye purposes.
Excipients, which have GRAS status (i.e., Generally Recognized As Safe),
should be tried next; regulatory agencies generally will look kindly on the use of
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GRAS excipients. However, the burden of proof of safety is still higher than
those excipients already proven to be safe in the eye or by injection. Indeed,
GRAS materials, used in ophthalmic tissues, are not always as safe as the name
implies. The researcher should particularly watch out for materials which may
form peroxides or formaldehyde on standing.
All of the above are superior choices to using a totally new excipient; regulatory agencies will likely require a new excipient to be studied as if it was a drug;
a drug delivery system which includes such a chemical might be considered to be
delivering two drugs instead of one…..and, the requirements of a dual drug system
can be expensive in both time and money.
1.3.11 Development and Strategic Team Input
Even though it is quite common for a single researcher to publish on a “new”
ophthalmic drug delivery system, most of such “inventions” are not commercially
viable. As a rule, to be commercially viable, drug delivery systems require the
contributions of specialists in many different fields.
While the capabilities of a novel drug delivery system are being explored by the
researcher, it is prudent to get feedback from other functions. R&D planning
involving multiple functions is essential to designing a successful drug delivery
formulation or device. The typical R&D team should include a representative from
the pharmaceutics, regulatory, process development, chemistry, microbiology,
packaging, legal, safety, toxicology, clinical and quality assurance functions. If the
system is a device, an engineer may be needed on the team.
Drug delivery devices will be considered both a drug and a device by the FDA
and possibly, other regulatory agencies. As a consequence, the device will need to
meet both device and drug laws. Aside, from its main function of developing a plan
with action steps and timelines, the development team will help make key decisions related to the drug delivery system. Are the drug and excipients safe? How is
the drug distributed to various tissues from the site of administration and what
are the kinetics involved? What is the rate of elimination of the drug and its metabolites? How will the product be sterilized? What is the long-term stability of the
product? Are there endotoxins in the product? What type of packaging should
be used? What standards must the new device meet? What raw material assays are
necessary? What are the release and final product assays? What are the risks associated with the proposed product (risk assessment)?
The team will shape a development plan, which will include a detailed clinical
study proposal. The regulatory function will take the plan to regulatory agencies for
review and feedback. The plan and possibly the system itself may be modified based
upon the regulatory response.
In addition to a development team, a strategic team is quite useful in designing a
drug delivery system. While the development team deals with a current drug delivery
system, the strategic team deals with future products. This team generally has a
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