Transcript Introduction to Generic Drug Product Development

Introduction to Generic Drug
Product Development
Hatim S. AlKhatib, PhD
University of Jordan
Definition
• A generic drug product, also referred to as a multisource
pharmaceutical product, is one that is considered to be
therapeutically equivalents (to an innovator product) and thus
suitable for substitution (interchangeable).
• To be defined as such a product has to be ‘‘essentially similar’’ to an
innovator (brand name) product:
• Pharmaceutically equivalent
• Bioequivalent
Definitions
• The FDA classifies as therapeutically equivalent those products that
meet the following general criteria:
I.
They are approved as safe and effective;
II. They are pharmaceutical equivalents in that they,
 Contain identical amounts of the same active drug ingredient in
the same dosage form and route of administration.
 Meet compendial or other applicable standards of strength,
quality, purity, and identity.
III. They are bioequivalent in that they,
 Do not present a known or potential bioequivalence problem,
and they meet an acceptable in vitro standard, or
 If they do present such a known or potential problem, they are
shown to meet an appropriate bioequivalence standard;
IV. They are adequately labeled.
V. They are manufactured in compliance with Current Good
Manufacturing Practice regulations.
Definitions
• FDA considers drug products to be therapeutically equivalent even
though they may differ in certain other characteristics such as:
•
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Shape
Scoring configuration
Release mechanisms
Packaging
Excipients (including colors, flavors, preservatives)
Expiration date/time
Minor aspects of labeling (e.g., the presence of specific pharmacokinetic information)
Storage conditions.
• When such differences are important in the care of a particular
patient, it may be appropriate for the prescribing physician to
require that a particular brand be dispensed as a medical
necessity. With this limitation, however, FDA believes that products
classified as therapeutically equivalent can be substituted with the
full expectation that the substituted product will produce the same
clinical effect and safety profile as the prescribed product.
Definitions
• Drugs are deemed bioequivalent if:
• "The rate and extent of absorption of the test drug do not show a
significant difference from the rate and extent of absorption of the
reference drug when administered at the same molar dose of the
therapeutic ingredient under similar experimental conditions in either a
single dose or multiple doses;"
Or
• "The extent of absorption of the test drug does not show a significant
difference from the extent of absorption of the reference drug when
administered at the same molar dose of the therapeutic ingredient
under similar experimental conditions in either a single dose or
multiple doses and the difference from the reference drug in the rate of
absorption of the drug:
• Is intentional
• Is reflected in its proposed labeling
• Is not essential to the attainment of effective body drug concentrations on chronic
use, and
• Is considered medically insignificant for the drug."
Definitions
• Where these above methods are not applicable (e.g., for drug
products that are not intended to be absorbed into the
bloodstream), other in vivo or in vitro test methods to demonstrate
bioequivalence may be appropriate.
• Bioequivalence may sometimes be demonstrated using an in vitro
bioequivalence standard, especially when such an in vitro test has
been correlated with human in vivo bioavailability data. In other
situations, bioequivalence may sometimes be demonstrated
through comparative clinical trials or pharmacodynamic studies.
Definitions
• Drug products are considered pharmaceutical alternatives if they
contain the same therapeutic moiety, but are different salts, esters,
or complexes of that moiety, or are different dosage forms or
strengths (e.g., tetracycline hydrochloride, 250mg capsules vs.
tetracycline phosphate complex, 250mg capsules; quinidine sulfate,
200mg tablets vs. quinidine sulfate, 200mg capsules).
• Data are generally not available for FDA to make the determination
of tablet to capsule bioequivalence. Different dosage forms and
strengths within a product line by a single manufacturer are thus
pharmaceutical alternatives, as are extended-release products when
compared with immediate-release or standard-release formulations
of the same active ingredient.
Generic Pharmaceutical Business
• The FDA states that(1): “Today, nearly 8 in 10 prescriptions filled in
the United States are for generic drugs. The use of generic drugs is
expected to grow over the next few years as a number of popular
drugs come off patent through 2015”.
• Generic drug products are typically sold at substantial discounts
from their brand name counterparts.
• A study(2) quoted by the FDA website(1) states that: “In 2010 alone,
the use of FDA-approved generics saved $158 billion, an average of
$3 billion every week”.
(1)
http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingGenericDrugs/ucm167991.htm
An Economic Analysis of Generic Drug Usage in the U.S., GPhA, September 2011, page 1.
(2) SAVINGS
Generic Pharmaceutical Business
(1)
(1) Leon
(2)
Shargel and Izzy Kanfer, Introduction to generic product development, in Generic Product Development: Solid Dosage Forms,
Marcel Dekker, New York, 2005.
(2) Shifts in the Generic-Drug Market: Trends and Causes, Somnath Pal, US Pharm., 2013;38(6)(Generic Drug Review suppl):6-10.
http://www.uspharmacist.com/content/s/253/c/41309/
Generic Pharmaceutical Business
Generics Outlook: Turning to Innovation After the Patent Cliff, Cara Latham, Pharmacy Times, Published Online: Tuesday, July 23,
2013.
http://www.pharmacytimes.com/publications/supplement/2013/Generic-Supplement-2013/Generics-Outlook-Turning-toInnovation-After-the-Patent-Cliff
Generic Pharmaceutical Business
• The manufacture of generic drug products must make provision for
market competition and lower prices for the consumer, thereby
making medicines more affordable and more accessible to the wider
population.
• Generic drug product availability almost certainly influences the
innovator drug product manufacturer to develop new drug products
that have improved efficacy and/or safety features.
Generic Pharmaceutical Business
Branded company
innovates
Generics are
distributed;
branded company
loses revenue
Branded company
rewarded with
monopoly position
Patent expiration
opens market to
generic competition
Cycle of innovation and competition
Generic Pharmaceutical Business
• Generic drug product development uses a different approach and
strategy compared to that used to develop a brand name drug
product containing a new chemical entity.
• Generic drug product manufacturers must formulate a drug product
that will have the same therapeutic efficacy, safety, and
performance characteristics as its brand name counterpart.
• In order to gain market approval, a generic drug product cannot be
‘‘superior’’ or ‘‘better’’ than the brand name drug product.
• The key factor is that the generic drug product should meet all the
necessary criteria to be pharmeutically equivalent and bioequivalent
to the brand name (reference) drug product.
Selection of A Generic Drug Product for
Manufacture
• The main driving force for the selection of generic drug products for
manufacture is the estimated sales volume for the branded product
and the potential market share that the firm expects to have once
the generic drug product is manufactured and approved for
marketing.
• The size of the market
• The percentage of the market is captured by the brand-name
drug
• The growth opportunities that are there in this category of drug
• The presence of generic competitors marketing the same drug
Selection of A Generic Drug Product for
Manufacture
• Patent and legal considerations are also very important.
• In addition to the expiration date of the patent for the active
ingredient, the generic firm must consider any other patent claims
and exclusivities that the innovator firm has filed.
Selection Of A Generic Drug Product For
Manufacture
• The generic drug manufacturer needs to consider the lead time that
is needed to make the product and submission of an Abbreviated
New Drug Application (ANDA) to the U.S. Food and Drug
Administration (FDA) for approval.
• How long will it take to develop the drug?
• How long will it take to obtain FDA approval?
• The timing considerations are evaluated against market demand
forecasts, changing demographics and the forecast date that a
generic product can legally enter the market.
• Moreover, there is a financial incentive to being the first generic
drug product filed and approved by FDA: The Hatch-Waxman Act
provides a 180-day exclusivity, under certain conditions, for the
generic manufacturer who is first to file.
Selection Of A Generic Drug Product For
Manufacture
• The availability of technology and the cost of acquiring technology
to manufacture the product will also impact on the choice of generic
drug:
• If the technology requires a fluidized bed coater, roller compactor, or any
other special equipment, then the firm must consider whether this
equipment is available or must be acquired.
• Formulation considerations include the availability of raw materials,
chemical purity, polymorphic form, and particle size of the active
pharmaceutical ingredient and any patents that the innovator company
has ¢led, including patents for the synthesis of the active pharmaceutical
ingredient and composition of the dosage form.
• Experience with certain drug products will also affect the choice of
generic drug product development. Niche drug products, such as
transdermal drug products, may be difficult to make and also riskier, but
may have a greater financial reward due to less competition from other
generic drug firms.
Selection Of A Generic Drug Product For
Manufacture
Considerations in the Selection of a Generic Drug Product forManufacture
Sales and potential market share
Patent expiration and exclusivity issues
Availability of active pharmaceutical ingredient
Timing
Technology
Formulation
Experience
Research and Development
Securing API
Formulation
Testing,
Formulation,
Manufacturing
and Production
Approval
Bioequivalence,
Clinical trials
Legal Challenges
and Costs
Securing API
Formulation
Testing,
Formulation,
Manufacturing
and Production
Bioequivalence,
Clinical trials
Legal
Challenges and
Costs
 The active pharmaceutical ingredients (API) are sourced from international
suppliers or produced internally.
 The manufacturer conducts an assessment of any legal issues affecting the
availability and use of the API.
 The API must be tested for its quality and consistency prior to formulation.
 The supplier’s production facilities need to be assessed for their quality
control.
 The supplier’s ability to guarantee a stable supply of the API is critical to the
success of developing a generic drug.
 Time frame of 6 months to a year
Securing API
Formulation
Testing,
Formulation,
Manufacturing
and Production
Bioequivalence,
Clinical trials
Legal Challenges
and Costs
 The brand-name product is reverse engineered to determine the composition
of its active pharmaceutical ingredients and non-active ingredients.
 Data is collected and reviewed.
 The product monograph of the brand-name drug is analyzed.
 Development of various formulations of the active and the non-active
ingredients.
 Various formulations are laboratory tested against the brand-name drug.
 Development of a quality control matrix for formulation to be integrated into
the manufacturing process.
 Time frame of 6 months to a year
Securing API
Formulation
Testing,
Formulation,
Manufacturing
and Production
Bioequivalence,
Clinical trials
Legal
Challenges and
Costs
 The generic drug formulations are further tested in the manufacturing setting.
 Complexity of drug manufacturing process determined.
 Manufacturing equipment designed and/or purchased for a dedicated
production line.
 Production quality control matrix developed and tested in full manufacturing
setting prior to federal approval.
 Packaging production is designed and quality control matrix developed to
ensure consistency in product output.
 Time frame of 9 months to a year.
Securing API
Formulation
Testing,
Formulation,
Manufacturing
and Production
Bioequivalence,
Clinical trials
Legal Challenges
and Costs
 Standard bioequivalence studies undertaken to measure the rate and extent of
absorption of the generic drug. The results of the studies are compared to the
same characteristics in the brand-name drug.
 The manufacturer files a submission with the FDA, which contains data that
compares the generic drug to the brand-name product.
 Submissions must contain sufficient data to assess the effectiveness of the
generic drug to the brand-name drug.
 The submissions include the evidence of tests conducted to measure the
potency, purity and stability of the new drug.
 Regulatory agencies cannot approve a generic drug until any relevant legal
issues are addressed.
 Time frame of 3-6 months.
Legal Framework
• The U.S. Food and Drug Administration was established in 1906 by
the Federal Food, Drug, and Cosmetic Act (the ‘‘Wiley Act’’) to
prevent the manufacture, sale, or transportation of adulterated or
misbranded or poisonous or deleterious foods, drugs, medicines,
and liquors, and for regulating traffic therein, amongst others.
• In 1938, the Act was amended to require drug manufacturers to file
a New Drug Application (NDA) for each newly introduced drug and
to provide data to establish the safety of the drug product.
• In 1962, the Kefauver-Harris Amendments to the Act required all
drug manufacturers to establish that their products were effective
for their claimed indication(s), in addition to adhering to the safety
requirements.
Legal Framework
• The 1962 legislation provided an exemption from the NDA approval
process for drugs that had been marketed before 1938, based on the
assumption that they were generally recognized as safe and
effective, the so-called ‘‘grandfather’’ provision.
• Manufacturers continued to conduct clinical efficacy and safety
studies until 1978, when a dispensation was granted to
manufacturers whereby the citation of published reports of trials
documenting safety and efficacy would suffice
Legal Framework
• In 1984, the Drug Price Competition and Patent Term Restoration Act
(Waxman-Hatch Act) extended the ANDA process to generic versions of
drugs marketed after 1962.
• This act meant that generic drug manufacturers avoided duplicating
expensive, time-consuming clinical and nonclinical studies to
demonstrate safety and efficacy.
• Furthermore, this Act expedited the availability of generic drug products
provided that the generic drug manufacturer shows that no patent
infringement would occur.
• The Waxman-Hatch Act also compensated the innovator drug
manufacturer for perceived losses due to competition from the generic
drug products by extending the patent terms of some brand name drug
products for up to an additional 5 years to make up for time lost while
their products were going through FDA’s approval process.
Legal Framework
• The Hatch-Waxman bill brought the following changes:
• Generic drugs no longer needed to prove their safety and efficacy. Under
the bill, generic drug manufacturers need only submit an Abbreviated
New Drug Application (ANDA) to prove their product’s therapeutic
equivalence to the original branded drug. This is a cheaper process for
manufacturers.
• Generic drugs are granted a 180-day period of exclusivity. Either the first
drug to file an ANDA, or the first group of drugs, is granted this period.
• Manufacturers filing ANDAs can do so for drugs that have not been
patented.
• ANDAs can be filed when a branded drug’s patent has expired.
• Generic drugs cannot go on to the market until the branded patent has
expired.
• Because branded drugs lose so much of their revenue when generic
drugs are introduced, the Act provides them with patent extensions
options, which now average about three years.
Securing API
Formulation
Testing,
Formulation,
Manufacturing
and Production
Bioequivalence,
Clinical trials
Legal Challenges
and Costs
 Generic Manufacturers are required notify the patent holder of the
submission of the ANDA.
 As part of the ANDA, the sponsor must consider the pertinent patents and
provide the results to the FDA.
 The ANDA sponsor must provide a certification that, in the opinion of the
sponsor and to the best of the sponsor’s knowledge with respect to each
patent that claims the listed drug, some or all of the following certification
may be submitted:
 Paragraph I: that such patent information has not been filed;
 Paragraph II: that such patent has expired;
 Paragraph III: of the date on which such patent will expire, or
 Paragraph IV: that such patent is invalid or will not be infringed by the
manufacture, use, or sale of the new drug for which the application is
submitted.
Securing API
Formulation
Testing,
Formulation,
Manufacturing
and Production
Bioequivalence,
Clinical trials
Legal Challenges
and Costs
 Since the patent holder can immediately sue the first generic sponsor
company who submits an ANDA with a Paragraph IV statement, a 180-day
period of market exclusivity is provided to that generic applicant.
 This special dispensation is considered as a reward to the generic
manufacturer who took a risk in challenging the patent.
 If the patent holder files an infringement suit against the generic applicant
within 45 days of the ANDA notification, FDA approval to market the generic
drug is automatically postponed for 30 months, unless, before that time, the
patent expires or is judged to be invalid or not infringed.
 Only an application containing a Paragraph IV certification may be eligible for
exclusivity, and to earn the period of exclusivity, the ANDA applicant must be
sued and successfully defend the suit.
“Through this 180-day provision,
Hatch-Waxman provides an
incentive for companies to
challenge patent validity and to
‘design around’ patents to find
alternative, non-infringing forms
of patented drugs. The 180-day
marketing exclusivity provision
was intended to increase the
economic incentives for a generic
company to be the first to file an
ANDA containing a paragraph IV
certification and get to market.”
•
•
Barr Labs. launches generic Prozac® (fluoxetine) in
August 2001
After the 180-day exclusivity ends, 4 generic
applicants enter the market
Effect on Barr Labs.:
• During the 180-day exclusivity, Barr earns a return
on investment following its successful patent
litigation and development of a new drug product
• Barr invalidated the patent on Prozac®  Generic
came to market 3 years early (Commissioner
Leibowitz, FTC)
Determine if application is acceptable
Bioequivalence Review
Application
submitted
to Office of
Generic
Drugs
Plant Inspection
Chemistry/Micro Review
FDA reviews
and decides if
product is
approved or
not approvable
Labeling Review
Generic manufacturers do not need to
complete the three phases of clinical trials
Active Pharmaceutical Ingredients
Terminology
• Active Pharmaceutical Ingredients are also known as:
• Drug Substances
• Bulk Pharmaceutical Compound (BPC)
• Bulk Actives
• Active ingredient
• New chemical entities (NCE), also termed new molecular entities
(NME) refer to drug substances that are first to enter the drug
regulatory arena under the banner of a New Drug Application (NDA).
• The term ‘‘official substance’’ is defined in the USP as an active or
inactive ingredient (frequently termed an excipient), a nutrient, a
dietary supplement ingredient, and/or a pharmaceutical ingredient,
or a component of an official device.
Terminology
• Official substances are the subject of formal monographs in the USP
or NF.
• Drug substance (API) monographs are the specialty of the USP
exclusively.
• The end use of the API is to produce a drug product, which is the
final form of the drug substance administered to patients. Drug
products are the subjects of companion monographs in the USP.
• The ultimate safety and efficacy of the finally administered drug
product are dependent on the assurance of the consistency of the
physical and chemical properties of the API.
Terminology
• Establishing specifications for critical quality attributes of the API
will assure that the generic drug product, employing the API
material, will have consistent in vitro/in vivo characteristics, batch
after batch.
Sources of Active Pharmaceutical Ingredients
• The three most commonly recognized categories of APIs are:
• Synthetic APIs are obtained directly by chemical conversion of
intermediates.
• Semi-synthetic APIs: indicates that a starting ‘‘intermediate’’ for the
preparation of the API was derived from natural sources. The
‘‘isolated’’ intermediate is then converted synthetically to the final
API.
• Natural: refers to the source of the API as being derived directly or
extracted from natural sources.
• It is not uncommon to see the market introduction of an API pioneer
compound as a natural product, which is subsequently produced by a
semi-synthetic procedure (paclitaxel).
• There is no requirement that the specific synthetic pathway be
identified for the API
Sources of Active Pharmaceutical Ingredients
• the USP has classified a category of drug substances as ‘‘complex
actives’’.This grouping of compounds includes biological and
biotechnological drug substances, complex natural source drug
substances.
• A Non Biological Complex Drug is defined as a medicinal product,
not being a biological medicine, where the active substance is not a
homo-molecular structure, but consists of different (closely related)
structures that can't be fully quantitated, characterized and/or
described by physico-chemical analytical tools. The composition and
quality of NBCD are dependent on the manufacturing process and
controls.
• The traditional APIs are referred to as ‘‘Non-Complex Actives’’
Patent Restrictions and Exclusivity Granted
to an NDA Sponsor
• The filing of an NDA with the FDA for a drug product made with a
NCE results in the listing of ‘‘relevant’’ patents and periods of
‘‘Exclusivity’’ for the approved drug product (frequently identified as
the ‘‘listed drug’’).
• This listing occurs in the FDA ‘‘Approved Drug Products with
Therapeutic Equivalence Evaluations’’, and is referred to as the
‘‘Orange Book’’.
• The FDA now provides all of this information online at their website:
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm
Patent Restrictions and Exclusivity Granted
to an NDA Sponsor
• For an API supplier, the listed patents in the electronic Orange Book
normally provides only those patents, which protect the NCE
(compound and method of use) as well as formulation patents
(presumably those relevant to the filed drug product).
• Process patents for the manufacture of the API or critical
intermediates for the API, beyond the original patent(s) governing
the NCE itself are not listed in the Orange Book.
• This point is covered by a section of the Food Drug and Cosmetic
Act, which authorizes an API supplier or an authorized party/agent
for the API supplier to write to an NDA sponsor and request a listing
of all relevant process patents which cover the filed NCE.This is a fee
for service request, with a maximum allowed charge of $500 for the
service.
Patent Restrictions and Exclusivity Granted
to an NDA Sponsor
• With this list of process patents, the API supplier must now review
all patents cited, as well as to conduct independent patent searches
for all patents relevant to the NCE, which were issued or applied for
in and outside the United States.
• This search should include not just the NDA sponsor but also any
issued patent concerning the drug substance or any pivotal
intermediate involved in the synthesis of the final drug substance.
• Specific aspects of the NCE that may be covered by process patents,
and other non-listed patents in the Orange Book include:
• Particle size/surface area
• Morphic forms (polymorphs, hydrates, solvates)
• Impurity/purity characteristics.
Patent Restrictions and Exclusivity Granted
to an NDA Sponsor
• The objective of the patent search is to determine what synthetic
route to exploit for the manufacture of the target API, which will be:
• Noninfringing
• Cost effective
• Yielding finished API of appropriate quality and physical attributes
suitable for formulation of the material into the targeted drug
product for filing an ANDA.
Patent Restrictions and Exclusivity Granted
to an NDA Sponsor
• Finally, with respect to ‘‘Exclusivity’’ for the filing of an NDA,
incorporating an NCE, the current regulations allow for a 5-year
period of exclusivity before an ANDA can be filed incorporating the
same API as the NCE.
• A different period of exclusivity is provided for the filing of formal
supplements to NDAs, which is based on providing clinical data as
part of the supplement.
Comparison with Innovator API
• The challenge that the API supplier/manufacturer faces in entering
the market place is to assure the user of the material that the API
will be comparable to the innovator or pioneer drug substance,
which is employed in an approved NDA drug product.
• Current FDA requirements regarding the filing of an ANDA for a
single component listed drug product is that the API must be the
same chemical entity, which is contained, in the listed drug.
• The critical aspects of sameness or comparability for the ‘‘generic’’
API vs. the innovator API include three critical aspects:
• Chemical Structure
• Impurity Profile
• Physical Form
Physical Form
• Many organic and inorganic compounds can exist in different solid
forms. They can be in the amorphous, i.e., disordered, or in the
crystalline, i.e., ordered, state.
• Crystals are characterized by repititous spacings of constituent
atoms or molecules in a three dimensional array.
• Amorphous forms have atoms or molecules randomly placed as in a
liquid (supercooled liquids).
Physical Form
• The amorphous form of a solid is typically prepared by rapid
precipitation, lyophilization or rapid cooling of liquid melts.
• A crystalline form, on the other hand, can be obtained by a
controlled-rate version of the above processes.
Physical Form
• According to McCrone’s definition, [Phys. Chem. Org. Solid State, 2
(1965) 725–767], “The polymorphism of any element or compound
is its ability to crystallize as more than one distinct crystal species”.
• Usually, different crystal arrangements of the same chemical
composition are called polymorphs. However, the term “polymorph”
has been used more broadly, including both the amorphous state
and solvates.
Physical Form
Physical Form
• It is convention to number the polymorphs in order of stability at
room temperature, starting with form I using Roman numerals.
• Form I usually has the highest melting point and lowest solubility.
Physical Form
• The difference of the melting point (ΔTm) between polymorphs is a
measure of the metastable polymorph stability.
• A ΔTm  1oC indicates that neither crystalline forms is more stable
and either may be obtained upon conventional crstallization.
• If ΔTm is 25-50 oC, then the lower melting point species will be
difficult to crystallize and will rapidly revert.
• The closer the two melting points (ΔTm 1-25 oC), then the
unstable form(s) can be obtained before a solid-solid
transformation occurs.
Physical Form
After Aulton, Pharmaceutics: The Science of Dosage Form Design, 2002
Physical Form
• By looking at the packing arrangements in the previous figure it can
be seen that:
• The molecules in (a) are more spaced out than those in (b), which
means that the two crystal forms would have different densities.
• It looks as though it would be easier to physically pull a molecule
off structure (a) than off (b), as the molecules in (b) are more
interwoven into the structure. If this were the case then (a) would
have a lower melting point than (b) and might dissolve more
easily.
• If an attempt were made to mill the two crystals, it appears that
(a) would break easily, as there are natural break lines (either
vertically or horizontally), whereas (b) does not seem to have an
obvious weak line to allow easy breakage. This could mean that
the milling and compaction properties of the two forms will differ.
• In summary, a change in the packing arrangement of the same
molecule, giving two different crystal forms, could result in significant
changes in the properties of the solid.
Physical Form
• Also of practical importance are solvates, sometimes called
pseudopolymorphs, where solvent molecules are incorporated in the
crystal lattice in a stoichiometric or non-stoichiometric way.
• Typical polymorphic change-inducing solvents are water, methanol,
ethanol, acetone, chloroform, n-propanol, isopropanol, n-butanol, npentanol, toluene and benzene.
• Hydrates, where the solvent is water, are of particular interest.
Physical Form
• If non-volatile molecules play the same role, the solids are called cocrystals.
• Solvates and co-crystals can also exist as different polymorphs, of
course.
Physical Form
• When a compound is acidic or basic, it is often possible
to create a salt with a suitable base or acid, and such a
salt can in turn often be crystallized.
• Such crystalline salts may also exist as various
polymorphs or solvates.
Physical Form
After, Polymorphism: in the Pharmaceutical Industry. Edited by Rolf
Hilfiker
Physical Form
Organic Molecular
Solid
Amorphous
Crystalline
Polymorphs
Solvates / Hydrates
Pseudopolymorphs
Monotropic
Reversible
Enantiotropic
Nonreversible
Physical Form
• Another term that should be introduced here is that of a
habit.
• A crystal habit is a description of an outer appearance of
a crystal. A single internal (molecular) structure of a
compound can have different habits depending on
crystallization solvent and method.
• The difference in crystal habits of the same crystalline
structure is essentially a function of the rate at which
different faces grow.
Physical Form
• Crystal habits are usually described by their shapes
under a microscope :
•
•
•
•
•
Tabular: moderate expansion of two parallel faces
Platy: plates
Prismatic: columns
Acicular: needle-like
Bladed: flat acicular.
• The crystal habit can have a profound impact on
important processing parameters such as filterability,
flowability and bulk density.
Physical Form
After Aulton, Pharmaceutics: The Science of Dosage Form Design, 2002
Regulatory Consideration in Abbreviated New Drug
Application
An ANDA contains data to show that the drug product is
pharmaceutically equivalent to the RLD. Pharmaceutical
equivalence requires that the drug product contain the “same”
active ingredient(s) as the RLD, that it be identical in strength,
dosage form, route of administration, and that it meet compendial
or other applicable standards of strength, quality, purity, and
identity
Regulatory Consideration in Abbreviated New Drug
Application
• In this context, the sponsor of an ANDA must provide chemistry,
manufacturing, and controls documentation for the proposed
generic drug product.
• This consists of information on:
• The drug substance, including characterization, method of manufacture, and controls
• The drug product, including composition, controls, method of manufacture, packaging,
and stability.
Regulatory Consideration in Abbreviated New Drug
Application
• The sponsor of an ANDA must demonstrate that the proposed
generic drug product contains the “same” active ingredient as the
innovator brand.
• Although the active ingredient may be shown to be the “same” in
both generic and innovator drug products, it may also exist in
several crystalline forms and hence, exhibit polymorphism.
• Polymorphism may result in differences in the physico-chemical
properties of the active ingredient and variations in these properties
may result in a drug product not exhibiting bioequivalence, and
hence in a product that is not therapeutically equivalent to the
innovator brand.
Regulatory Consideration in Abbreviated New Drug
Application
• Therefore, in the context of the ANDA review, careful attention is
paid to the effect that polymorphism may have on generic drug
product equivalency to the innovator product.
Consequences and Pharmaceutical Relevance
• Polymorphism is very common in connection with drug
substances, which are mostly (about 90%) small organic
molecules with molecular weights below 600 g.mol–1.
• Literature values concerning the prevalence of true
polymorphs range from 32% * to 51% ** of small organic
molecules. According to the same references, 56 and 87%,
respectively, have more than one solid form if solvates are
included.
* Henck, J.-O., Griesser, U. J., Burger, A., Pharm. Ind., 59 (1997) 165–169.
** Stahly, G. P., at the American Chemical Society ProSpectives Polymorphism in Crystals: Fundamentals,
Predictions and Industrial Practice, Tampa, FL, Feb 23–26 (2003).
Consequences and Pharmaceutical Relevance
• Other research conducted by Professor Ulrich Griesser at the
University of Innsbruck shows a lower incidence of multiple solid
forms in organic molecules: polymorphism (36%), hydrates (28%),
and solvates (10%). *
• 63% of barbiturates, 67% of steroids, and 40% of sulfonamides
exhibit polymorphism. * *
* Van Arnum, Advancing Approaches in Detecting Polymorphism, PharmTech, Oct 4, 2007
** Aulton, Pharmaceutics: The Science of Dosage Form Design, 2002
Consequences and Pharmaceutical Relevance
After Van Arnum, Advancing Approaches in Detecting Polymorphism,
PharmTech, Oct 4, 2007
Consequences and Pharmaceutical Relevance
• Different inter- and intramolecular interactions such as van der
Waals interactions and hydrogen bonds will be present in different
crystal structures.
• As a consequence, different polymorphs will have different free
energies
and
therefore
different
pharmaceutical
and
biopharmaceutical properties:
• Solubility, dissolution rate and bioavailability
• Chemical and physical stability
• Processability (hygroscopicity, bulk, mechanical and rheological
properties, ease of isolation, filtration and drying and degree of
purification).
Consequences and Pharmaceutical Relevance
• The polymorphs (or pseudopolymorphs) of some drugs have been
shown to exhibit different chemical stability.
• Examples are carbamezepine, paroxetine maleate, indomethacin,
methyprednisolone, furosemide, and enalapril maleate.
• For example, the photodecay of form II of carbamezepine was 5- and
1.5-fold faster than forms I and III, respectively.
Consequences and Pharmaceutical Relevance
• In addition to a change in the rate of decay, polymorphism may also
affect the mechanism of decay, as observed in the reactivity of
different polymorphs of cinnamic acid derivatives.
• In comparison to crystalline polymorphs, the amorphous form of a
drug is generally expected to be less chemically stable due to the
lack of a three dimensional crystalline lattice, higher free volume
and greater molecular mobility.
Consequences and Pharmaceutical Relevance
Typical plots of decomposition of (a) crystalline and (b) amorphous cefoxitin sodium at various temperatures ∆40°C,
□60°C and ○80°C [Oberholtzer and Brenner, J. Pharm. Sci. 68, 863–866 (1979)].
Consequences and Pharmaceutical Relevance
Rates of degradation of crystalline and amorphous spirapril hydrochloride at 75°C [Xu,
Investigation of solid-state stability of selected bioactive compounds. Ph.D. Thesis,
Purdue University, 1997].
Consequences and Pharmaceutical Relevance
The chemical stability of cephalothin Na related to the amorphous
content of the sample (Pikal et al., J. Pharm. Sci., 67, 6, 767-773,1978)
Sample
% Amorphous
% stable drug after
storage at 31% RH
50oC
Crystalline
0
100
Freeze dried
12
100
Freeze dried
46
85
Spray dried
53
44
Consequences and Pharmaceutical Relevance
• Polymorphic forms may also exhibit different physical and
mechanical properties, including hygroscopicity, particle shape,
density, flowability, and compactability, which in turn, may the
mechanical properties of drug particles, and thus may impact the
affect drug substance processability and drug product
manufacturability.
• For example, polymorphs of metoprolol tartrate, paracetamol,
sulfamerazine, phenobarbitone, carbamazepine, phenylbutazone
and other drugs have been shown to exhibit different mechanical
properties.
Consequences and Pharmaceutical Relevance
After Joiris et al., Compression Behavior of Orthorhombic Paracetamol, Pharm. Res., 15, 7, 1998
Consequences and Pharmaceutical Relevance
Photographs of the compact fracture
surfaces for the crystalline and amorphous
forms of the drug substance
)a
cholesterol-absorption inhibitor for the
potential
treatment
of
hypercholesterolemia)
Hancock et al., Comparison of the mechanical properties of the
crystalline and amorphous forms of a drug substance, Int. J.
Pharm., 241, 1, 73-85, 2002
Consequences and Pharmaceutical Relevance
• A common effect of polymorphism is alteration of powder flow due
to the difference in particle morphology of two polymorphs.
• Polymorphs with needle- or rod-shaped particles may have poor
flow compared to polymorphs with low aspect ratio, e.g. cubic habit
or irregular spheres. The effect of polymorphism on other
mechanical properties, such as hardness, yield pressure, elasticity,
compressibility and bonding strength is more complex.
Consequences and Pharmaceutical Relevance
• The impact of polymorphism on manufacturability and physical
attributes of tablets is dependent on:
• The extent of the difference in the mechanical properties of two
polymorphs
• The drug loading
• The robustness of each manufacturing step
• The absolute value of the mechanical property undergoing
change
Consequences and Pharmaceutical Relevance
• Nonetheless, the effect of polymorphism on pharmaceutical
processing is also dependent on the formulation and on the
manufacturing process.
• For a drug product manufactured by direct compression, the solidstate properties of the pharmaceutical solid will likely be critical to
drug product manufacturability, particularly when the solid
constitutes the bulk of the tablet mass.
• On the other hand, during wet granulation, the original properties
of the pharmaceutical solid are to a great extent modified, and
hence, the solid-state properties of the pharmaceutical solid are
less likely to affect drug product manufacturability
Consequences and Pharmaceutical Relevance
• Different transformations can happen to a solid form during
processing which necessitates a close monitoring of the formulas’
physical and chemical stability:
• Dehydration of a hydrated crystal
• Conversion of an ansolvate form to a solvate form
• Conversion of the stable form to a metastable form
• Conversion of a metastable form to the stable form
• Polymorphic transformation during wet granulation
• Phase changes during freeze drying
Consequences and Pharmaceutical Relevance
• The principle regulatory concern with regard to drug substance
polymorphism is based upon the potential effect that it may have
upon drug product bioavailability/bioequivalence (BA/BE).
• As the solid-state properties of a drug substance are known to
potentially exert a significant influence on the solubilization of
drugs, and as polymorphic forms differ in internal solid-state
structure, polymorphs of a drug substance may have different
apparent aqueous solubilities and dissolution rates.
Consequences and Pharmaceutical Relevance
• When the differences in the solubilities of the various polymorphs
are sufficiently large, this may have an effect upon drug product
bioavailability.
Consequences and Pharmaceutical Relevance
The relationship between in vitro and in vivo release from fluprednisolone implants. After Aulton, Pharmaceutics: The
Science of Dosage Form Design, 2002
Consequences and Pharmaceutical Relevance
The relationship between melting point and solubility for three polymorphs of riboflavine. After Aulton, Pharmaceutics:
The Science of Dosage Form Design, 2002
Consequences and Pharmaceutical Relevance
• Chloramphenicol palmitate exists in three polymorphic forms (A, B
and C) and an amorphous form.
• Aguiar and co-workers (J. Pharm. Sci., 56:847, 1967) investigated the
relative absorption of polymorphic forms A and B from an oral
suspension administered to human subjects.
• Their results show that the peak serum level increased substantially
as a function of the percentage of the form B polymorph.
Consequences and Pharmaceutical Relevance
Correlation of the peak blood serum levels (after 2 hours) of chloramphenicol vs percentage of
concentration of polymorph B (Aguiar et al., J. Pharm. Sci., 56:847, 1967)
Consequences and Pharmaceutical Relevance
Serum levels obtained after oral administration of a suspension containing 250 mg ampicillin as the
anhydrate (○) and the trihydrate )∆) [Poole et al., Curr. Ther. Res., 10, 292, 1968]
Consequences and Pharmaceutical Relevance
• For a drug whose rate and extent of absorption is limited by its
dissolution, large differences in the solubilities of the various
polymorphic forms are likely to affect BA/BE.
• On the other hand, for a drug whose rate and extent of absorption is
only limited by its intestinal permeability, differences in the
solubilities of the various polymorphs are less likely to affect BA/BE.
• Furthermore, when the solubilities of the polymorphic forms are
sufficiently high and drug dissolution is rapid in relation to gastric
emptying, differences in the solubilities of the various solid-state
forms are unlikely to affect BA/BE.
Consequences and Pharmaceutical Relevance
• Once the sponsor of the ANDA has demonstrated in vivo
bioequivalence between the generic drug product and the RLD, in
vitro dissolution testing is subsequently used to assess the lot-to-lot
quality of the drug product.
• Drug product dissolution testing frequently provides a suitable
means to identify and control the quality of the product from a
BA/BE perspective.
• In particular, inadvertent changes to polymorphic form that may
occur, and which may impact drug product bioavailability, are often
detected by drug product dissolution testing.
Characterization of Polymorphism
Method
Material Requested Per Sample
Microscopy
1 mg
Fusion Methods (hot stage
microscopy)
1 mg
Differential Scanning Calorimetry
(DSC)
2-5 mg
Infrared Spectroscopy
2-20 mg
X-ray Diffraction
500 mg
Scanning Electron Microscopy
2 mg
Thermogravimetric Analysis
10 mg
Dissolution / Solubility Analysis
mg-g
Characterization of Polymorphism
• Powder X-ray diffractometry (PXRD)
• Gold standard for phase ID
• Limited by the presence of preferred orientation, interference from
crystalline excipients
• Single crystal XRD
• Ultimate phase ID with in depth understanding of the structure
• Difficulty associated with preparing single crystals
• DSC/MDSC
• Provides information on phase transitions and interaction with excipients
• Disadvantage of being a “black box” with no information on the nature of
transition
• Susceptible to interference from both crystalline and amorphous
excipients
After Tong, Crystalline Solids, Integrated Drug Product Development Process, 2006
Characterization of Polymorphism
• TGA
• Provides information on the stoichiometry of solvates/hydrates
• Interference from water-containing excipients
• IR
•
•
•
•
Complimentary phase ID method
Able to differentiate between the different states of water
Susceptible to interference by moisture and excipients
Difference between forms may not be clear and distinct
After Tong, Crystalline Solids, Integrated Drug Product Development Process, 2006
Characterization of Polymorphism
• A preformulation program should be able to answer the following
questions:
• How many polymorphs exist?
• How stable are the metastable forms?
• Is there an amorphous glass?
• Can the metastable forms be stabilized?
• What is the solubility of each form?
• Will the more soluble form survive processing and storage?
ICH Guidance Q6A
• Process for evaluating when and how polymorphs of drug substances
in ANDAs should be monitored and controlled is based on the ICH
Guidance Q6A decision trees on polymorphism.
• According to ICH Guidance Q6A, Various decision trees can give
following acceptance criteria for polymorphism.
Investigating the need to set acceptance criteria for polymorphs in drug substances and drug products for solid dosage forms or
liquids containing undissolved drug substances.
What might be considered when setting acceptance criteria for polymorphs in drug substances for solid dosage forms
or liquids containing undissolved drug substance.
Investigating the need to set acceptance criteria for polymorphs in drug products for solid dosage forms or
liquids containing undissolved drug substance.
Impurity Profile
• Significance
• The safety of a drug product is dependent not only on the
toxicological properties of the active drug substance itself, but
also on the impurities that it contains.
• Therefore, identification, quantification, and control of impurities
in the drug substance and drug product, are an important part of
drug development and regulatory assessment.
Impurity Profile
• An impurity in a drug substance is defined as any component of the
drug substance that is not the chemical entity defined as the drug
substance1.
• An impurity in a drug product is any component of the drug product
that is not the chemical entity defined as the drug substance or an
excipient in the drug product2.
1 Guidance
for Industry, Q3A, Impurities in New Drug Substances.
2 Guidance for Industry, Q3B, Impurities in New Drug Products.
Classification of Impurities
• The nature and the quantity of impurities is governed by a number
of different factors, including:
• Synthetic route of the drug substance
• Reaction conditions
• Quality of the starting material of the drug substance, reagents
and solvents.
• Purification steps
• Excipients
• Drug product manufacturing processes, packaging, and storage of
the end product.
Classification of Impurities
• Impurities can be classified into the following categories:
• Organic impurities (process- and drug-related)
• Inorganic impurities
• Residual solvents
• Organic impurities can arise during the manufacturing process
and/or storage of the new drug substance. They can be identified or
unidentified, volatile or nonvolatile, and include:
• Starting materials
• By-products
• Intermediates
• Degradation products
• Reagents, ligands, and catalysts
Classification of Impurities
• Inorganic impurities can result from the manufacturing process.
They are normally known and identified and include:
• Reagents, ligands and catalysts
• Heavy metals or other residual metals
• Inorganic salts
• Other materials (e.g., filter aids, charcoal)
• Solvents are inorganic or organic liquids used as vehicles for the
preparation of solutions or suspensions in the synthesis of the drug
substance or the manufacture of the drug product. Since these are
generally of known toxicity, the selection of appropriate limits for
these solvents is easily accomplished (ICH Q3C, residual solvents).
Analytical methods
• Versatile analytical methods are available for the detection and
monitoring of impurities in drug substances and drug products.
• The primary criterion of analytical methodology is the ability to
differentiate the compounds of interests.
• The commonly used methods are separation (isolation) and
detection and quantification (spectroscopic) in tandem.
Analytical methods
• The separation methods include:
• Thin layer chromatography (TLC)
• High performance liquid chromatography (HPLC)
• Gas chromatography (GC)
• Capillary electrophoresis (CE).
• The spectroscopic methods include:
• Ultraviolet (UV) spectrometry
• Infrared (IR) spectrometry
• Nuclear magnetic resonance (NMR) spectrometry
• Mass spectrometry (MS)
Analytical methods
• HPLC is the most commonly used method for impurity monitoring in
an inexpensive way.
• TLC can be used to separate a broad range of compounds. The
primary difficulties related to the TLC method are limited resolution,
detection, and ease of quantitation.
• Gas chromatography can provide the desired resolution, selectivity,
and quantitation, unless the sample is not volatile.
• Capillary electrophoresis is a useful technique when very low
quantities of samples are available and high resolution is required.
Analytical methods
• Ultraviolet spectroscopy at a single wavelength provides minimal
selectivity of analysis while the availability of diode array detectors
offers much more information at various wavelengths to ensure greater
selectivity.
• Infrared spectroscopy provides specific information on some functional
groups that may allow quantitation and selectivity.
• Nuclear magnetic resonance spectroscopy offers fairly detailed
structural information on molecules and is a very useful method for
characterization of desired product and associated impurities.
Analytical methods
• Mass spectrometry which requires minute amounts of sample, provides
excellent structural information based upon mass ion fragmentation
patterns.
Control of impurities
• A specification, in the context of pharmaceutical product
development, is defined as a list of tests, references to analytical
procedures, and appropriate acceptance criteria that are numerical
limits, ranges, or other criteria for the tests described.
• It establishes the set of criteria to which a drug substance or drug
product should conform to be considered acceptable for its intended
use.
• Specifications are critical quality standards that are proposed and
justified by the manufacturer and approved by regulatory
authorities as conditions of approval.
Control of impurities
• “Conformance to specifications” means that the drug substance
and/or drug product, when tested according to the listed analytical
procedures, will meet the listed acceptance criteria.
Control of impurities:
Drug substance
• The specifications for a drug substance include a list of impurities.
• The impurities likely to occur in the drug substance may be
predicted from:
• Stability studies
• Chemical development studies
• Routine batch analyses
• Scientific appraisal of potential by-products from synthetic steps
and degradation pathways.
Control of impurities
Drug substance
• The inclusion or exclusion of impurities in the drug substance
specification should be discussed and rationalized.
• The rationale may include:
• A discussion of the impurity profiles observed in the batch(es)
during the development process
together with
• A consideration of the impurity profile of the batch (es)
manufactured by the proposed commercial process.
Control of impurities
Drug substance
• Individual impurities with a specific acceptance criterion that are
included in the specification for a drug substance are referred to as
specified impurities.
• Specified impurities can be identified or unidentified.
• For unidentified impurities to be listed in the drug substance
specification, the procedure used and assumptions made in
establishing the level of the impurity should be clearly stated.
• It is important that specified unidentified impurities be referred to
by an appropriate qualitative analytical descriptive label (e.g.,
unidentified A, unidentified with relative retention of 0.9).
Control of impurities
Drug substance
Control of impurities
Drug substance
• A critical cut-off point for the organic impurities appears to be
a level of 0.1%.
• The API manufacturer is encouraged to try and reduce the
level of detected, individual impurities to levels of less than
0.1%.
• Maintaining individual impurities below 0.1% and assuring
that the total of all specified and unspecified, identified and
unidentified impurities at a level of 1% is likely to satisfy FDA
concerns about the impurity profile for an API
Control of impurities
Drug substance
• Qualification is the process of acquiring and evaluating data that
establishes the biological safety of an individual degradation product or
a given degradation profile at the level(s) specified.
•
• If the impurity limit is greater than the ICH qualification threshold then
it should be qualified:
• Through toxicological trials.
• By comparison to a limit specified in the Ph. Int., Ph. Eur., or USP for
a specific impurity. It could even be in a monograph for another
substance. A statement in a monograph of "any other impurity NMT
0.5%" can not be used as justification for an impurity limit, as it is
not specific.
• By comparison to levels found in an innovator or prequalified
finished product.
• By comparison to a limit previously approved in a prequalified
finished product.
Control of impurities
Drug substance
• For impurities known to be unusually potent or to produce toxic or
unexpected pharmacological effects, the quantitation and/or
detection limit of the analytical procedures should correspond to
the level at which the impurities are expected to be controlled.
Control of impurities
Drug substance
• The drug substance specification includes, where applicable, a list of
the following types of impurities:
• Organic impurities
• Each identified specified impurity
• Each unidentified specified impurity
• Any unspecified impurity with an acceptance criterion of not
more than (≤) in the identification threshold.
• Total impurities
• Residual solvents
• Inorganic impurities
Control of impurities
Drug substance
• The acceptance criterion for impurities in the drug substance should
be set no higher than the qualified level.
• If there is a monograph in the USP that includes a limit for an
identified specified impurity, it is recommended that the acceptance
criterion be set no higher than the official compendial limit.
• However, if the level of the impurity is above the level specified in
the USP, qualification would be recommended. Then, if appropriate
qualification has been achieved, an applicant may wish to petition
the USP for revision of the impurity's acceptance criterion.
Control of impurities
Drug substance
• If the acceptance criterion for a drug substance impurity does not
exist in the USP and this impurity can be qualified by comparison
with an FDA approved human drug product, it is important that the
acceptance criterion be consistent with the level observed in the
approved human drug product.
• In other circumstances, the acceptance criterion may need to be set
lower than the qualified level to ensure drug substance quality.
Control of impurities
Drug product
• In terms of the listing of impurities, the same conditions for drug
substances apply for drug products.
• The rationale for inclusion and exclusion of impurities may include a
discussion of:
• Potential degradation pathways
• Interactions with excipients
• Forced degradation studies
• The observed degradation profile of the batch(es) manufactured
during development and by the proposed commercial process.
Control of impurities
Drug product
• Individual degradation products with specific acceptance criteria that
are included in the specification for the drug product are referred to as
“specified degradation products”.
• Specified degradation products can be identified or unidentified.
• Specified identified degradation products should be included in the list
of degradation products along with specified unidentified degradation
products that are estimated to be present at a level greater than the
identification threshold.
• Where degradation products are known to be unusually potent or to
produce toxic or unexpected pharmacological effects, the quantitation
and/or detection limit of the analytical procedures should correspond to
the level at which the degradation products are expected to be
controlled.
Control of impurities
Drug product
Control of impurities
Drug product
• For unidentified degradation products to be listed in the drug product
specification, the procedure used and assumptions made should be
clearly stated in establishing the level of the degradation product.
• Specified unidentified degradation products can be referred to by an
appropriate qualitative analytical descriptive label (e.g., unidentified A,
unidentified with relative retention of 0.9).
Control of impurities
Drug product
• General acceptance criteria of not more than the
identification threshold should be included for any
unspecified degradation product and acceptance criteria for
total degradation products.
Control of impurities
Drug product
• The drug product specification includes, where applicable, a list of the
following types of degradation products:
• Each specified identified degradation product
• Each specified unidentified degradation product
• Any unspecified degradation product with an acceptance criterion of
not more than (≤) the identification threshold
• Total degradation products
Control of impurities
Drug product
• The acceptance criterion for impurities in the drug product should be
set no higher than the qualified level.
• In establishing degradation product acceptance criteria, the first critical
consideration is whether a degradation product is specified in the
United States Pharmacopeia (USP).
• If there is a monograph in the USP that includes a limit for a specified
identified degradation product, it is recommend that the acceptance
criterion be set no higher than the official compendial limit.
• If the level of the degradation product is above the level specified in the
USP, qualification is recommend.
• Then, if appropriate qualification has been achieved, an applicant may
wish to petition the USP for revision of the degradation product's
acceptance criterion.
Control of impurities
Drug product
• If the acceptance criterion for a specified degradation product does not
exist in the USP and this degradation product can be qualified by
comparison to an FDA approved human drug product, the acceptance
criterion should be consistent with the level observed in the approved
human drug product.
• In other circumstances, the acceptance criterion may need to be set
lower than the qualified level to ensure drug product quality.
Qualification of impurities
• Qualification is the process of acquiring and evaluating data that
establishes the biological safety of an individual impurity or a given
impurity profile at the level(s) being considered.
• When appropriate, it is recommend that applicants provide a rationale
for establishing impurity acceptance criteria that includes safety
considerations.
• An impurity is considered qualified when it meets one or more of the
following conditions:
• When the observed level and proposed acceptance criterion for the impurity do not
exceed the level observed in an FDA approved human drug product.
• When the impurity is a significant metabolite of the drug substance.
• When the observed level and the proposed acceptance criterion for the impurity are
adequately justified by the scientific literature.
• When the observed level and proposed acceptance criterion for the impurity do not
exceed the level that has been adequately evaluated in comparative in vitro
genotoxicity studies.
Qualification of impurities
• Although Quantitative Structure Activity Relationships (QSAR) programs
may be used for prediction of toxicity of an individual impurity or a
given impurity profile, the results are not generally considered
conclusive for qualification purposes.
Qualification of impurities
• When these qualification thresholds are exceeded, impurity levels
should be qualified. In some cases, it may be appropriate to increase or
decrease the threshold for qualifying impurities.
• For example, when there is evidence that an impurity in certain drug
classes or therapeutic classes has previously been associated with
adverse reactions in patients, it may be important to establish a lower
qualification threshold.
• Conversely, when the concern for safety is low, a higher threshold for
qualifying impurities may be appropriate.
• Thus, the issues such as patient population, drug class effects, and
historical safety data will be taken into account when establishing
alternative qualification thresholds.
Qualification of impurities
• When these qualification thresholds are exceeded, impurity levels
should be qualified. In some cases, it may be appropriate to increase or
decrease the threshold for qualifying impurities.
• For example, when there is evidence that an impurity in certain drug
classes or therapeutic classes has previously been associated with
adverse reactions in patients, it may be important to establish a lower
qualification threshold.
• Conversely, when the concern for safety is low, a higher threshold for
qualifying impurities may be appropriate.
• Thus, the issues such as patient population, drug class effects, and
historical safety data will be taken into account when establishing
alternative qualification thresholds.
Qualification of impurities
• In some cases, decreasing the level of the impurity below the threshold
rather than providing additional data can be the simplest course of
action.
• Alternatively, adequate data could be available in the scientific literature
to qualify the impurity.
• The studies considered appropriate to qualify the impurity will depend
on a number of factors, including the patient population, daily dose,
route, and duration of drug administration.
• Such studies can be conducted on the drug substance containing the
impurities to be controlled, although studies using isolated impurities
can sometimes be appropriate.
Qualification of impurities
• Comparative analytical studies:
• An impurity present in a drug substance covered by an ANDA can be
qualified by comparing the analytical profiles of the drug substance
with those in an approved human drug product using the same
validated, stability-indicating analytical procedure (e.g. comparative
HPLC studies).
• This approved human drug product is generally the reference-listed
drug (RLD). The impurity profile of a different drug product, having the
same drug substance, with the same route of administration and
similar characteristics (e.g., tablet versus capsule) may also be used if
samples of the reference listed drug are unavailable.
• Samples used should be of comparable age in order to get a meaningful
comparison of degradation impurity levels.
• Using this comparative analytical approach, an impurity present in the
ANDA drug substance is considered qualified if the amount of identified
impurity in the ANDA drug substance reflects the levels observed in the
corresponding approved human drug product.
Qualification of impurities
• Scientific literature and significant metabolites:
• If the level of the identified specified impurity is adequately justified
by the scientific literature, no further qualification is considered
necessary.
• In addition, an impurity that is also a significant metabolite of the
drug substance is generally considered qualified.
Qualification of impurities
• Toxicity studies:
• Toxicity tests are the least preferred method to qualify impurities.
• The test is used only when impurities cannot be qualified by either of
the above procedures.
• The tests are designed to detect compounds that induce general
toxic or genotoxic effects in experimental systems.
• If performed, such studies should be conducted on the drug product
or drug substance containing the impurities to be controlled,
although studies using isolated impurities may also be used.