**THE IMPACT OF POLYMORPHISM ON DRUG DEVELOPMENT:**

**A REGULATOR\'S VIEWPOINT**

**Wilson H. DeCamp**

**Division of New Drug Chemistry III**

**Food and Drug Administration**

**Rockville, MD 20857, USA**

**Presented to**

**XVIIIth Congress of the International Union of Crystallography**

**Glasgow, Scotland**

**August 7, 1999**

**Abstract:**

A general overview will be presented of the typical interactions between
a drug company and the FDA during the development of a drug. The
physical chemistry of the solid state bulk drug, especially its
potential for crystallizing in multiple solid state forms, can
significantly influence the development of both the synthetic process
and the analytical chemistry of the drug. The drug is marketed and used
as a finished drug product, which must be controlled to assure
consistent quality. When the drug substance is known to be polymorphic,
it can present special analytical concerns for the product. These topics
will be discussed from two points of view: the type of information that
should be acquired during drug development and how this information
relates to issues of drug quality.

The fundamental responsibility of the U. S. Food and Drug Administration
is to assure the public at large that the drugs brought to market are
truly safe and effective. We share this goal with our regulatory
colleagues in many other countries. To do this, we have established a
variety of regulatory procedures. These range from guidance documents
that have been harmonized through the International Conference on
Harmonization, or ICH, to improve international consistency to our own
FDA guidances on other issues. Today I will discuss how polymorphism of
a drug can affect its development and how regulatory scientists at FDA
approach this problem. Our colleagues in other countries may have
different ideas of what information should be included in the
registration dossier. So, please take the diversity of our various
national laws and regulations into account as you listen to me today.

Since our concern is polymorphism, my thoughts are related to this issue
alone. There are, of course, many types of analytical investigations
undertaken as a drug is developed. There isn\'t enough time to discuss
all of them. I will mention only those types of chemical or physical
studies that are relevant to the potential problems related to
polymorphism. To provide the context of our review work, I may mention
general concerns of our reviewers in other disciplines, such as
clinical, pharmacology, or biopharmaceutics. Although our chemistry and
manufacturing review is intimately involved with each of these areas, my
comments are not intended as definitive statements about the policies of
these other disciplines.

Let me also clarify two terms. We refer to the active ingredient as the
\"drug substance\", and the finished dosage form as the \"drug
product\". If I use the word \"drug\" by itself, the context should make
it clear which is intended. Although drug substances usually include
both biotechnology products and botanicals, today I will be addressing
substances resulting from chemical synthesis only.

I believe that it is essential to comment on one general and overriding
issue at the outset. Our concern is assuring the safety and
effectiveness of the drug product. This does not, however, mean that
information about the solid-state forms of the drug substance is
unnecessary when the planned drug product is a solution. This is not
necessarily correct. Suppose, for example, that one solid state form is
much less soluble than another. Perhaps one differs in its morphology or
other physical properties. Either case may increase the difficulty of
handling it in the manufacturing process, regardless of the dosage form.
Even when the finished drug product is identical when made from either
solid state form, there may be a need for in-process controls on the
manufacturing process to assure this quality.

Bulk drug substances are often synthesized and tested at one location,
and then shipped to another site as a solid material. It is important
that appropriate tests be available to show that the crystalline form
has not changed. This also means that the information about the
solid-state forms of the drug substance should not be limited to
crystalline forms of the same empirical composition. The likelihood of
desolvation in transit should be considered, or even of a gain in water
from exposure to high-humidity conditions. For reasons like this,
polymorphism and solvation are closely related. I\'ll be talking about
them together today under the general term \"crystalline forms\".

Now, let\'s go on to examine how information about polymorphism acquired
during drug development relates to later issues of drug quality.

The first slide is a typical timeline for the development of a new drug
product. At each stage, I will identify the regulatory issues related to
polymorphism that are of greatest concern at that phase of drug
development. I will also suggest various laboratory studies that may be
useful in resolving such issues.

The earliest stage of development is called \"pre-clinical\". This phase
includes various animal studies, many of which are short-term. Longer
studies to establish oral toxicity may also be appropriate. These
studies are intended to accumulate the basic information needed to
evaluate the safety of the drug. Prior approval isn\'t required in the
U.S., although the results obtained are reviewed later. Obviously, the
drug has been synthesized at this time, even though the process and
specifications may not be as refined as they are later. Nevertheless,
this time is the first time that variations in the crystalline form of
the drug might reasonably be observed. Diffraction studies, among
others, may reasonably be considered to supportive of the identification
of the drug. They also suffice to establish awareness of the possibility
that other crystalline forms may occur.

At this time, only the most fundamental of laboratory studies are
usually done. Thermal studies such as DSC and TGA, along with microscopy
and powder diffraction, will likely provide sufficient information about
the identity and characteristics of the drug substance. If single
crystal data are available, this is a plus, since indexing the powder
pattern may be easier. Nevertheless, there is no expectation that such
data will be available at this early stage of development.

When studies of the drug in humans \-- clinical studies \-- are planned,
FDA requires that an IND, or Investigational New Drug application, be
submitted. Our initial regulatory concern is to assure the safety of the
human subjects during the \"Phase 1\" trials. In \"Phase 2,\" the usual
goals are to show that the principle upon which the drug is presumed to
act is sound, and to establish an appropriate dosage range and route of
administration. Again, our primary role is assuring the safety of the
human subjects through adequate identification of the drug substance.

Prudence at this stage suggests that, in addition, this may be the best
time to begin to search for polymorphs. Of course, this may have been
done earlier, or may be deferred until later in the development process.
Exactly when this work is done isn\'t as important as it being done
before the application is submitted. That\'s when our reviewers begin to
look at polymorphs in greater detail.

The next step in drug development will involve larger and more expensive
clinical trials. It seems appropriate to search for the physical or
chemical characteristics that should be controlled to derive the
greatest value from these studies. As regulatory scientists, we
generally expect that laboratory investigations will be sufficient to
show that the drug substance and drug product are consistent in quality.
Unanticipated variations in quality, such as discovering a new polymorph
or solvate, can be a setback in your development plans.

During the phases of clinical development, the drug substance is
commonly purified by the same method. This provides a certain degree of
assurance that the same crystalline form is studied. Does it, however,
challenge the manufacturing process in a way that will identify
potential problems? I don\'t think so, and will suggest how this might
be done.

First, let us look at the recrystallization process by which the bulk
drug is purified. Concerns such as the nature and amount of impurities
that need to be removed, as well as issues of cost and safety, will
likely influence the choice of this solvent. Unless other solvent
systems are studied as well, it may be easy to overlook the possibility
of the formation of other crystalline forms. This may be most easily
done at a laboratory scale of, at most, a few tens of grams. As product
development approaches completion, the beginning of larger-scale
clinical trials will usually require that the synthesis of the bulk drug
be scaled up, possibly by several orders of magnitude.

It\'s one thing to recrystallize a drug in small amounts, and something
quite different to do the same thing on a scale of several kilograms or
more. These scale-up procedures may require changes that were not
studied at the smaller laboratory scale. It may be necessary to use
solvents that cost less, are safer to handle, easier to recover, or less
damaging to the environment. At this point, the conclusions from the
laboratory studies should be re-examined to provide assurance that they
will be adequate to support the marketing application.

Attempts should be made to recrystallize the drug from various solvents.
Two obvious choices are water and the solvent used in the last
purification step for the bulk drug. Other choices should be solvents to
which the bulk drug is exposed in the course of manufacturing, including
liquid components of the drug product. Alternates that approximate the
polar and hydrophobic properties of these solvents may also be
appropriate. This is what is often referred to as a \"polymorph
screen\".

What happens next is clearly driven by the results of your studies. If
you have accumulated sufficient data to be reasonably certain that no
polymorphs or solvates are likely to be formed, then it may be time to
move on to the next project. If not, then additional studies of the
solid state are needed.

Second, the physical stability of the drug substance in the anticipated
dosage form should be studied. Although the exact composition of the
dosage form may not be finally determined, stability studies should be
carried out to examine the possibility of changes in the physical state
when the dosage form is subjected to various conditions. Extremes of
humidity, as well as heat, may alter the crystalline form of the drug
substance in the dosage form. For example, exposure of tablets of
anhydrous theophylline in tablets is known to form theophylline
monohydrate in a period of a few days. This can alter the hardness of
the tablet, as well as the dissolution behavior. If you are aware of
facts such as these, the design of clinical trials may be altered
appropriately.

Regulatory concerns about polymorphism are not limited to solid dosage
forms. Oral suspensions, as well as creams and ointments, may contain a
solid phase dispersed in a liquid phase. Changes in the solid phase over
time should be studied. Optical microscopy may be the least expensive
and most appropriate method for such initial studies, and may justify
later studies using other techniques.

Up to this time, the specifications for the drug substance may have been
poorly defined. The amount of knowledge about the drug substance has,
presumably, always been increasing. When \"Phase 3\" begins, the
developmental objective expands beyond safety. At this point, probably
seventy percent of candidate drugs have been rejected for a variety of
reasons. The remainder will be studied to prove their clinical
effectiveness. Furthermore, the manufacturing process should be
reasonably well-defined and essentially similar to how the drug
substance and drug product will be manufactured for marketing. By this
time, the potential of the drug to form polymorphs or solvates should be
known, with appropriate specifications established \-- if necessary.

The manufacturing process for the drug substance is now likely to be
ready to be scaled up. Therefore, variations in the process, especially
the final steps, should be anticipated. The solvent or solvents to be
used in a crystallization step should be selected with full knowledge of
their impact on the crystalline form. If a mixed solvent is to be used,
then the impact of variability in the composition should be studied.
Knowledge that the same crystalline form is obtained from each of the
pure solvents in the mixture may reduce later concerns about the
validation of the bulk manufacturing process.

The temperature at which the drug is dried may have an impact on the
crystalline form that is obtained. This is a critical in-process control
that is commonly implemented. The rationale for the choice of
temperature is rarely included. For example, chlorpheniramine maleate is
commonly dried for analytical uses at 105°C. Its optical isomer,
dexchlorpheniramine maleate, is dried at 65°C. From the submissions
available to us for review, it is difficult to establish whether this
results from differences in the solid state properties of the drug
substances. For larger scale manufacturing, similar differences may also
reflect the simple fact of availability of a particular type of drying
equipment, or preferences based on economic concerns.

Another common step in bulk drug manufacture is milling. This step is
intended to break up lumps of the dried drug substance. The material is
usually subjected to pressure between rollers, as well as screening.
However, the pressure may be sufficient to induce a change in
crystalline form. In one case, milling of ampicillin trihydrate was
sufficient to induce a loss of water, forming the anhydrous material, as
well as clogging the rollers because of the moisture. The driving force
behind this change was apparently the density difference between the
trihydrate (D~x~ = 1.366) and the anhydrate (D~x~ = 1.386).

During the manufacturing of the drug product, the drug substance can be
exposed to a variety of physical stresses. In addition to pressure, the
environment needs to be considered. Drug substances that are known to be
hygroscopic may require special controls to assure that the state of
solvation is not changed. A granulation step before a tablet is
compacted may include a liquid that is removed in drying, but
nevertheless may alter the crystalline form of the active. Awareness of
the physical conditions of each step in manufacturing provides a
rationale to support the selection of in-process or release controls,
such as hardness and dissolution.

As the drug product moves on into drug development, our regulatory
concerns expand. We seek assurance that issues such as I have mentioned
have been addressed, and that their results will be sufficiently
complete that they will be able to be reviewed later. As appropriate,
studies of the kinetics of any phase changes that may be possible should
be studied to determine if they may adversely impact the quality of the
product. If a phase change takes place over a period of days to months,
appropriate controls during manufacturing and packaging or label
statements of storage conditions may be adequate to assure consistent
quality. Extremely slow phase changes may have no impact on the product.
Extremely rapid changes may present questions of which controls may be
appropriate at the time of release, with storage concerns being minimal.
The important thing is that the laboratory studies should support the
controls and storage statements that are proposed.

For solid oral dosage forms, the solubility of the active ingredient is
a significant factor in our level of regulatory concern. Qualitative
solubility studies have likely been completed at a much earlier phase of
development. Quantitative solubility information, especially as a
function of pH, may determine the extent of our regulatory concern about
polymorphism. Highly soluble drugs, even if they have multiple
polymorphs, are less likely to vary in their properties *in vivo*. In
this case, the laboratory studies may justify a minimal concern in the
finished product.

For drugs where polymorphism is observed, the fact is that phase changes
are often very slow at room temperature. If a control is necessary to
assure that the correct crystalline form is used in the product, you
have probably found this out already. Nevertheless, these are the first
long term studies, so it may be useful to monitor the crystalline form
of the drug in the product, if possible. This may not require a lot of
analytical effort \-- perhaps only monitoring a few major peaks in the
diffraction pattern. This effort is likely to be more of a precaution.
Few dosage forms have ever required that polymorphism be monitored in
the drug product.

For less soluble drug substances, a determination of the intrinsic
dissolution rate may support the specifications and methods for
measuring dissolution. If different polymorphs are known, our
biopharmaceutics review will consider whether the specifications are
adequate to assure that the drug product always contains the same
crystalline form. If you believe that the various known crystalline
forms are biologically equivalent, this review may assess the need for a
study to demonstrate this, either through determination of systemic
levels of the active or through a clinical trial comparing the
polymorphic forms.

Following the completion of the Phase 3 studies, the New Drug
Application, or NDA, in the U.S., will be submitted. This should include
complete details about the drug substance, including information about
the various solid-state forms of the drug substance. Clearly, prudence
in the development process calls for a comprehensive awareness of the
potential for polymorphism at all these stages \-- pre-clinical through
NDA submission.

A crucial part of the content of the marketing application is the
information about the various solid-state forms of the drug substance.
This report should be sufficient to identify possible problems \-- or
the lack of them \-- in bulk drug manufacture, and to suggest
appropriate analytical tests when necessary. This is why it\'s not
enough to show that no other forms have been found. For example, if a
second crystalline form is possible, then we need to know if the forms
can be distinguished by simpler tests than the powder diffraction
pattern. If, knowing this, it can be shown that conversion to the
different polymorph is unlikely in the manufacture and storage of the
drug product, controls at these stages may not be necessary.

Next, let\'s briefly consider how extensive the information about solid
state forms of the drug substance should be in the marketing
application. Should we stop at just searching for polymorphs and
solvates? Although many applications stop here, there are cases where a
more extensive search may be justified by the nature of the composition
of the drug product. Your decision on this question should be based on
your knowledge of the manufacturing process, as well as the changes that
you think may be likely after the drug product is approved.

Bulk drugs that are claimed to be amorphous are particular sources of
concern. An amorphous drug is often manufactured to improve dissolution
properties. Such materials can be prepared by freeze-drying or
spray-drying. The fact that a drug can be manufactured in this way,
however, does not mean that a crystalline form is impossible. Even
worse, materials that are visually, or even microscopically, amorphous
can be sufficiently ordered at the sub-micron scale to have a
diffraction pattern. This suggests that, on compression, even an
amorphous form may transform to a crystalline phase.

Although most investigations of polymorphism are based on powder X-ray
diffraction, the structure proof that derives from a single crystal
study may provide useful additional background. To be sure, FDA does not
require that the molecular structure of a drug be proved by a crystal
structure. If such studies are done, they may also prove relevant to
questions of polymorphism. For example, the inability to index a powder
pattern on the single crystal unit cell is sufficient to show that the
powder is a different crystalline form.

The perceptive crystallographer will, of course, have accumulated a
variety of physical measurements of the possible polymorphs. Such
properties as density and melting point are more than just \"nice to
know\". Along with estimates of the lattice energy, they support
hypotheses about the relative stability of the polymorphs. We all know
that the basic thermodynamic principles of phase transitions require
that spontaneous processes go from a less physically stable form to a
more stable form. Since a more stable polymorph is also less soluble, an
early indicator of problems with solid dosage forms is often aberrant or
unexpected dissolution behavior.

Let\'s talk about that property for a moment. For example, if a solid
drug has a specification for dissolution, it will be expressed as a
figure such as \"not less than 80% in 15 minutes\" in a medium such as
0.1N hydrochloric acid, which approximates the conditions found in the
stomach. To the drug developer, rapid dissolution in the stomach is
often critical, so there may be good reasons to prefer to manufacture
tablets or capsules from crystalline forms which are less stable, and
thus more soluble. Unfortunately, this may increase the possibility of
undesirable phase changes.

Even so, please remember that the solubility differences between
polymorphs are seldom large. I\'m not aware of any comprehensive study
that would suffice to estimate the maximum probable solubility change,
nor does such a study appear to have a regulatory application. It likely
to be sufficient to be aware of the possibility when interpreting
dissolution data.

Regulatory concerns about the crystalline form of the drug substance do
not necessarily end when the product is approved. Frequently the
manufacturing process is changed. We look for evidence that there has
been no effect on the quality of the drug product, usually through
dissolution studies. As in the pre-approval stages, aberrant results may
suggest a re-examination of your conclusions about the consequences of
polymorphism, or lack of them.

When a new manufacturer of the drug substance is identified,
consideration of the crystalline form is important. If your
specifications require a specific crystalline form, you will surely be
aware of a change. If not, caution suggests that the question be asked,
just to be sure that your conclusion that such a specification is not
essential remains sound.

The last area of our regulatory concern is the development of published
standards for drug substances and drug products, including generic
drugs. The various national pharmacopeias fulfill this role, with FDA
and other regulatory agencies providing technical support in evaluating
monograph proposals. Few of these monographs include controls on the
crystalline form. This may be a reflection that there are few cases of
serious problems with polymorphs. It may suggest that bioequivalence
surrogates, such as dissolution, provide adequate control. It may,
though, suggest that we, as crystallographers, need to be more aware of
the impact that our work can have on all aspects of product development.

Having promised you a general overview of polymorphism as it impacts on
your development of a drug and our review of your application, I hope I
have clarified what our concerns are. In the earliest \-- pre-clinical
\-- stages, there is little concern beyond identity. In the early
investigational stages, we begin to examine the consequences of scale-up
in bulk drug manufacture. In the late investigational stages, we ask
questions about whether the polymorphs that have been found are
bioequivalent. For marketing, we consider whether polymorphism can
impact upon the quality of the product. And finally, we blend all of
these concerns into the development of published standards.

At all of these stages, though, it is essential that the questions
appropriate to that stage be regognized. They should be asked by the
prudent industry researcher. The thorough regulatory scientists will
look for answers in their review. Both join in setting a high scientific
standard. The public health is not well served by deviating from this
standard, either by asking too much or by asking too little.

Thank you very much for your attention.