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

I.

II.

• III.

IV.

V.

The FDA classifies as therapeutically equivalent those products that meet the following general criteria: They are approved as safe and effective;  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.  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; They are adequately labeled.

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 : • 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

(2) SAVINGS An Economic Analysis of Generic Drug Usage in the U.S., GPhA, September 2011, page 1.

Generic Pharmaceutical Business

(1) (2) (1) Marcel Dekker, New York, 2005.

(2) Leon Shargel and Izzy Kanfer, Introduction to generic product development, in Generic Product Development: Solid Dosage Forms, 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-to Innovation-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

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 Approval

Securing API Formulation Testing, Formulation, Manufacturing and Production 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

atoms or molecules in a three dimensional array.

of constituent •

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 (ΔT m ) between polymorphs is a measure of the metastable polymorph stability.

• A ΔT m  1 o C indicates that neither crystalline forms is more stable and either may be obtained upon conventional crstallization.

• If ΔT m is 25-50 o C, then the lower melting point species will be difficult to crystallize and will rapidly revert.

• The closer the two melting points (ΔT unstable form(s) can be obtained before a solid-solid transformation occurs.

m 1-25 o C), then the

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, n pentanol, 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

co crystals

. • 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

Crystalline Freeze dried Freeze dried Spray dried

0 12 46 53 % stable drug after storage at 31% RH 50 o C 100 100 85 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 manufacturability.

processability and drug product • 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 cholesterol-absorption potential of the compact surfaces for the crystalline and amorphous forms of the drug substance )a inhibitor treatment hypercholesterolemia) fracture for the of 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 solid state 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

Microscopy Fusion Methods (hot stage microscopy) Differential Scanning Calorimetry (DSC) Infrared Spectroscopy X-ray Diffraction Scanning Electron Microscopy Thermogravimetric Analysis Dissolution / Solubility Analysis

Material Requested Per Sample

1 mg 1 mg 2-5 mg 2-20 mg 500 mg 2 mg 10 mg 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 substance 1 .

• 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 product 2 .

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 identification criteria threshold should of not more be included than the 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.