Pharmaceutical impurities: Regulatory perspective for

Advanced Drug Delivery Reviews 59 (2007) 64 – 72 www.elsevier.com/locate/addr

Pharmaceutical impurities: Regulatory perspective for Abbreviated New Drug Applications☆ , ☆☆ Arup K. Basak a,⁎, Andre S. Raw a , Ali H. Al Hakim b , Scott Furness a , Nashed I. Samaan a , Devinder S. Gill a , Hasmukh B. Patel b , Roslyn F. Powers a , Lawrence Yu a a

Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, USA Office of New Drug Quality Assessment, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA

b

Received 26 June 2006; accepted 25 October 2006 Available online 15 November 2006

Abstract Impurities in drug substances and drug products have been important regulatory issues in the Office of Generic Drugs by having significant impact on the approvability of Abbreviated New Drug Application (ANDAs). This review begins with a discussion of ANDAs and its similarity/ differences with NDAs, highlighting the importance of control of pharmaceutical impurities in generic drug product development and regulatory assessment. An overview of the FDA draft guidance documents “ANDAs: Impurities in Drug Substances” and “ANDAs: Impurities in Drug Products” are provided. This introduces the identification and qualification procedures for ANDAs and approaches to the establishment of acceptance criteria for both drug substance and drug product. Case studies included in this review illustrate the proposed pathway for determination of impurities and their acceptance criteria, based upon the general principles of these guidances. Published by Elsevier B.V. Keywords: Impurity; Drug substance; Drug product; Abbreviated New Drug Applications (ANDAs)

Contents 1. 2. 3. 4. 5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Generic drug application . . . . . . . . . . . . . . . . . . . . . . . Classification of impurities . . . . . . . . . . . . . . . . . . . . . . Analytical methods . . . . . . . . . . . . . . . . . . . . . . . . . . Control of impurities . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Drug substance . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Listing of impurities in drug substance specifications. 5.1.2. Setting acceptance criteria for impurities . . . . . . . 5.2. Drug product . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1. Listing of degradation products . . . . . . . . . . . . 5.2.2. Setting acceptance criteria for degradation products . Qualification of impurities. . . . . . . . . . . . . . . . . . . . . . .

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This review is part of the Advanced Drug Delivery Reviews theme issue on “Pharmaceutical Impurities: Analytical, Toxicological and Regulatory Perspectives". Opinions and comments expressed in this report are those of the presenter/writer only and do not necessarily reflect the views or policies of the FDA. ⁎ Corresponding author. Tel.: +1 301 827 5796; fax: +1 301 443 3839. E-mail address: [email protected] (A.K. Basak).

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0169-409X/$ - see front matter. Published by Elsevier B.V. doi:10.1016/j.addr.2006.10.010

A.K. Basak et al. / Advanced Drug Delivery Reviews 59 (2007) 64–72

6.1. 6.2.

Qualification thresholds . . . . . . . . . . . . . . . . . . . . . . Qualification procedures. . . . . . . . . . . . . . . . . . . . . . 6.2.1. i. Comparative analytical studies . . . . . . . . . . . . . 6.2.2. ii. Scientific literature and significant metabolites . . . . 6.2.3. iii. Toxicity studies . . . . . . . . . . . . . . . . . . . . 7. Case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Case study of a non-compendial drug substance and drug product 7.2. Case study of a compendial drug substance [10] . . . . . . . . . 8. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction An impurity in a drug substance as defined by the International Conference on Harmonisation (ICH) Guidelines [1] is any component of the drug substance that is not the chemical entity defined as the drug substance. Similarly, 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]. 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. ICH Q3A and Q3B address issues relevant to the regulation of impurities in the drug substance and drug product. While many of the concepts and principles outlined in these documents are applicable to Abbreviated New Drug Applications (ANDAs), certain additional or modified restraints need to be considered. When FDA receives an ANDA, a monograph defining certain key attributes of the drug substance and drug product is frequently available in the United States Pharmacopeia (USP). Sometimes, literature information on drug product impurities may also be available. These public standards and literature data play a significant role in the regulatory assessment process of an ANDA. This review is intended to provide a scientific perspective on drug substance and drug product impurities in ANDAs [3,4]. It provides recommendations for ANDAs on the identification and qualification of impurities for drug substances and drug products. It is also intended to assist in the establishment of impurity specifications for drug substances and drug products.

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product is pharmaceutically equivalent and bioequivalent, and therefore therapeutically equivalent to the RLD. In addition, the sponsor must also demonstrate that the proposed product is appropriately labeled and that it is manufactured in compliance with Good Manufacturing Practice (cGMP) guidelines [5]. If approved, an applicant may manufacture and market the generic drug product provided all issues related to patent protection and exclusivity have been resolved. Fig. 1 provides a comparison between the requirements of a New Drug Application (NDA) and an Abbreviated New Drug Application (ANDA) [6]. The primary difference between the requirements of a “full” and an “abbreviated” application is that the pre-clinical and clinical data in the NDA that establishes the safety and efficacy of the drug product do not need to be repeated for the ANDA. The requirements of an ANDA are based upon the premise that an active ingredient shown to be safe and effective and absorbed into the body to the same rate and extent as the innovator product, will be therapeutically equivalent. Apart from the differing requirements in the submission of clinical data, the remaining requirements including those for chemistry, manufacturing, controls, testing, and labeling are similar, regardless of whether the application is an ANDA or NDA. These ANDAs are submitted to the Office of Generic Drugs and are carefully scrutinized to assure that the standards of quality for generic products are the same as those for brand name products. In the context of the ANDA review, because the overall safety of a drug product is dependent not only on the toxicological properties of the drug substance, but also on the impurities that it contains, it becomes critical to ensure that the generic drug product is of comparable purity and quality to the RLD. Thus, the control of pharmaceutical impurities constitutes an important element of generic drug product regulatory assessment.

2. Generic drug application A generic drug product is one that is therapeutically equivalent to an innovator or first version of the drug product approved by the FDA, and designated as the reference listed drug (RLD). An ANDA is submitted to the Office of Generic Drugs and includes supporting data for the review and approval of a generic drug product. For approval, a sponsor of an ANDA must have information to show that the proposed generic

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Fig. 1. Comparison between NDA and ANDA requirements.

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3. Classification of impurities The safety and quality of the drug substance and drug product in a generic product can be impacted by the presence of impurities. The nature and the quantity of these 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, solvents, purification steps, excipients, drug product manufacturing processes, packaging, and storage of the end product. Based on ICH Q3A [1], drug substance 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 drug substance. They can be identified or unidentified, volatile or nonvolatile, and include: • • • • •

Starting materials By-products Intermediates Degradation products Reagents, ligands, and catalysts

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 (see ICH Q3C [7] on residual solvents). 4. Analytical methods The safety and quality of the generic drug product/drug substance can be impacted by the presence of impurities. The nature and quantity of these impurities is governed by a number of factors, including the synthetic route of drug substance, reaction conditions, quality of the starting material, reagents, solvents, purification steps, and storage of the end product. As the structure of impurities are sometimes unknown, several spectroscopic and micro-chemical techniques have been developed which require minute quantities of material and readily enable the structural elucidation of the impurity. Versatile analytical methods are also 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. The separation methods include thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), and capillary electrophoresis (CE). 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. Based upon these developments, it is now possible to replace all non-specific assay methods with highly specific and precise separation methods for assay and detection of impurities, thus greatly improving the value of the analytical determination in bulk drug materials. The spectroscopic methods include ultraviolet (UV), infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS). 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. Mass spectrometry which requires minute amounts of sample, provides excellent structural information based upon mass ion fragmentation patterns. Thus, UV, IR, NMR, and MS are excellent techniques for characterization and analysis of pharmaceutical compounds and impurities. 5. Control of impurities A specification 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 [8]. It establishes the set of criteria to which a drug substance or drug product should conform to be considered acceptable for its intended use. “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. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of approval. 5.1. Drug substance 5.1.1. Listing of impurities in drug substance specifications The specifications for a drug substance include a list of impurities. Stability studies, chemical development studies, routine batch analyses, and scientific appraisal of potential by-


products from synthetic steps and degradation pathways, can be used to predict those impurities likely to occur in the 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. 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. Identified specified impurities should be included in the list of impurities along with specified unidentified impurities that are estimated to be present at a level greater than the identification threshold given in Table 1. 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. 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). General acceptance criteria of not more than the identification threshold shown in Table 1 are generally set for any unidentified impurity. The drug substance specification includes, where applicable, a list of the following types of impurities: • Organic impurities ▪ Each identified specified impurity ▪ Each specified unidentified impurity ▪ Any unspecified impurity with an acceptance criterion of not more than (≤) in the identification threshold in Table 1 ▪ Total impurities • Residual solvents • Inorganic impurities 5.1.2. Setting acceptance criteria for impurities The acceptance criterion for impurities in the drug substance should be set no higher than the qualified level (see Section 6). In establishing impurity acceptance criteria, the first critical

Table 1 Drug substance impurities thresholds a Maximum Reporting daily dose a threshold b ≤2 g/day

0.05%

>2 g/day

0.03%

a b c

Identification threshold c Qualification threshold c c

0.10% or 1.0 mg/day 0.15% or 1.0 mg/day intake (whichever is less) intake (whichever is less) 0.05% 0.05%

The amount of drug substance administered per day. Higher reporting threshold should be scientifically justified. Lower threshold can be appropriate if the impurities are unusually toxic.

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consideration is whether an impurity is specified in the United States Pharmacopeia (USP). 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. 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 FDAapproved 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. For example, if the level of the metabolite impurity is too high, other quality attributes such as potency could be seriously affected; and in this case, the impurity acceptance criterion should be set lower than the qualified level. 5.2. Drug product 5.2.1. Listing of degradation products The specification for a drug product should include a list of degradation products. Stability studies, chemical development studies, and routine batch analyses can be used to predict the degradation profile for the commercial product. As with the case of the drug substance, the inclusion or exclusion of degradation products in the drug product specification should be rationalized. The rationale may include a discussion of potential degradation pathways, interactions with excipients, forced degradation studies, as well as the observed degradation profile of the batch(es) manufactured during development and by the proposed commercial process. 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 given in Table 2. 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. 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). General acceptance criteria of not more than the identification threshold should be included for any

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Table 2 Thresholds for degradation products in drug products Maximum daily dose a

Reporting threshold b

≤1 g >1 g

0.1% 0.05%

Maximum daily dose a

Identification threshold b

10 mg–2 g >2 g

1.0% or 5 μg TDI, whichever is lower 0.5% or 20 μg TDI, whichever is lower 0.2% or 2 mg TDI, whichever is lower 0.10%

degradation product acceptance criterion be set lower than the qualified level. It should be noted that drug manufacturers should develop robust formulations and manufacturing processes that are based on sound state-of-the-art scientific and engineering principles and knowledge. Although routine manufacturing variations are expected, significant variation in batch-to-batch impurity levels or an unusually high level of impurity may indicate that the manufacturing process of the drug product is not adequately controlled or designed.

Maximum daily dose a

Qualification threshold b

6. Qualification of impurities

100 mg–2 g >2 g

1.0% or 50 μg TDI, whichever is lower 0.5% or 200 μg TDI, whichever is lower 0.2% or 3 mg TDI, whichever is lower 0.15%

c

c

c

a

The amount of drug substance administered per day. Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is unusually toxic. c Higher thresholds should be scientifically justified. b

unspecified degradation product and acceptance criteria for total degradation products. 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 in Table 2 • Total degradation products 5.2.2. Setting acceptance criteria for degradation products The acceptance criterion for impurities in the drug product should be set no higher than the qualified level (see Section 6). 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, we 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, we recommend qualification. Then, if appropriate qualification has been achieved, an applicant may wish to petition the USP for revision of the degradation product's acceptance criterion. 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 FDAapproved 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. For example, if the level of the metabolite impurity is too high, other quality attributes, like potency, could be seriously affected. In this case, we would recommend that the

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, we 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 FDAapproved 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. 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. 6.1. Qualification thresholds Recommended qualification thresholds based on the maximum daily dose as described in Table 1 for drug substance and Table 2 for drug product, are provided in ICH Q3A [1] and ICH Q3B [2]. 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.


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Fig. 2. Identification and qualification of impurities in drug substance and drug product. aLower thresholds can be appropriate if the impurity is unusually toxic. bFor example, do known safety data for this impurity or its structural class preclude human exposure at the observed level? cIn this context, an FDA-approved human drug product generally refers to the reference listed drug. It may also include a different drug product with the same route of administration and similar characteristics such as tablet versus capsule. dAn impurity is considered qualified for ANDAs when one or more of the following conditions are met: •. When the observed level and proposed acceptance criterion for the impurity do not exceed the level justified by an FDAapproved 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.eIf appropriate, a minimum screen (e.g., genotoxic potential) should be conducted. A study to detect point mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum screen. fIf general toxicity studies are appropriate, one or more studies should be designed to allow comparison of unqualified to qualified material. The study duration should be based on available relevant information and performed in the species most likely to maximize the potential for detecting the toxicity of an impurity. On a case-by-case basis, single dose studies can be appropriate, especially for single dose drugs. In general, a minimum duration of 14 days and a maximum duration of 90 days would be considered appropriate.

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Table 3 Setting impurity specifications for a non-compendial drug substance Name

Origin

Observed: drug substance (generic) lot

Observed RLD at expiry

Drug substance limits

Justification

Impurity A Impurity B Impurity C Impurity D Impurity E Impurity F (RRT 2.55) b Any unknown impurity Total impurities

Degradant (hydrolysis) Process impurity Process impurity Process impurity Degradant (oxidation) Process impurity

0.20% 0.10% 0.09% 0.11% 0.30% 0.30% ≤0.07% 1.4%

1.5% 0.01% 0.07% ≤0.02% 1.0% 0.50% ≤0.05% 3.7%

NMT 0.5% NMT 0.15% NMT 0.15% NMT 0.15% NMT 1.0% NMT 0.50% NMT 0.10% NMT 2.0%

Metabolite ICH Q3A qualification threshold a ICH Q3A qualification threshold a ICH Q3A qualification threshold a Qualified based on RLD Qualified based on RLD ICH Q3A identification threshold a Proposed acceptance criterion are below the levels present in RLD

a

The maximum daily dose of RLD is 64 mg/day. Therefore the corresponding recommended drug substance identification and qualification thresholds are 0.10% and 0.15%, respectively. b Impurity F is also present is the reference listed drug. This is based on both products exhibiting a peak with the same retention time on the HPLC, identical UV spectra (PDA), and similar mass spectra (MS-electrospray).

6.2. Qualification procedures The decision tree in Fig. 2 describes considerations for the qualification of an impurity when the usual qualification threshold is exceeded. 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. The following are descriptions of methods for qualifying impurities. 6.2.1. i. 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). However, 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, or in the case of an ANDA submitted pursuant to a suitability petition. Moreover, in the case of qualifying degradation impurities,

samples of comparable age should be considered 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. 6.2.2. ii. 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. 6.2.3. iii. 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. 7. Case studies The previous sections have dealt with the implication of pharmaceutical impurities in the context of the ANDA

Table 4 Setting impurity specifications for a non-compendial drug product Name

Observed: drug product (generic) lot

RLD at expiry

Drug product limits

Justification

Impurity A Impurity E Any unknown impurity Total impurities

≤2.0% ≤0.4% ≤0.09% ≤2.8%

1.5% 1.0% ≤0.05% 3.7%

NMT 2.5% NMT 1.0% NMT 0.20% NMT 3.5%

Metabolite Qualified based on RLD ICH Q3B identification threshold a Proposed acceptance criterion are below the levels present in RLD

a

The maximum daily dose of RLD is 64 mg/day. Therefore the corresponding recommended drug product identification threshold is 0.20%.


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Table 5 Setting impurity specifications for a non-compendial drug substance Name

Origin

Observed: drug substance (generic) lot

USP monograph limit

Drug substance limits

Justification

Impurity RC1 Impurity RC2 Impurity RC3 Any unknown impurity Total impurities

Process impurity Process impurity/degradant (light) Process impurity/degradant (light)

≤0.05% ≤0.05% 0.10% ≤0.05% 0.30%

Not Applicable 0.25% 0.25% ≤0.1% 0.75%

NMT 0.15% NMT 0.25% NMT 0.25% NMT 0.10% NMT 0.75%

ICH Q3A qualification threshold USP limit USP limit ICH Q3A identification threshold USP limit

regulatory review process and its relevance to pharmaceutical quality. What follows are two case studies from OGD's Model Quality Overall Summaries for both immediate and extended release drug products [9,10]. These case examples serve to illustrate the types of information on impurities that would be expected in a regulatory submission, as well as the conceptual regulatory framework regarding impurities as it relates to pharmaceutical quality. 7.1. Case study of a non-compendial drug substance and drug product [9] In the case of a non-compendial drug product, sponsors of ANDA submissions are expected to provide a summary of potential impurities, including structure (if known) with an explanation as to whether the origin is degradation and/or process related. As illustrated in Tables 3 and 4, applicants are encouraged to provide applicable data and a rationale supporting the justification for the proposed levels of these impurities. This generally encompasses 1) batch analysis of the proposed generic product, 2) qualification data based upon analysis of the RLD and/or literature information, and 3) applicable identification and qualification thresholds based upon the maximum daily dose, and 4) and in the case of the drug product, whether the impurities are degradants. This example depicts several important points that should be considered by applicants in their submissions in the context of the implication of impurity specifications to pharmaceutical quality. A fundamental point is that impurity specification limits in a generic product can often be adequately justified based upon a demonstration that the proposed limits are equivalent or more stringent, to the actual levels of the impurity observed in the RLD. As further illustrated in this example, this reasoning may also be extended to cases where there is a specified impurity of unknown structure (e.g. Impurity F at RRT 2.55), provided the unknown impurity is present in the RLD and sufficient evidence of comparability of structure is provided in the submission (e.g., via similar retention times, mass spectra, UV spectra). Noteworthy, is the fact that in some circumstances, a proposed limit of the known impurity exceeding the observed levels in the innovator may be deemed acceptable, particularly where there is adequate qualification data, such as in the instance of an impurity being an active metabolite (e.g. Impurity A). However, in the absence of adequate qualification data being provided, proposed limits should in general not exceed qualification thresholds. Finally, the example serves to illustrate

that, in the case of the drug product, it is only the potential degradation impurities, as opposed to process impurities, that require monitoring. 7.2. Case study of a compendial drug substance [10] In the case of a compendial drug substance, sponsors are expected to provide a summary of potential impurities including structure (if known) and origin, just as in the case of a noncompendial drug substance. However, in contrast to noncompendial drugs, the rationale supporting the justification for the proposed limits on impurities become quite simpler and straightforward. For example, where there are specified impurities identified by the USP monograph (e.g. RC2, RC3), proposed limits may be based solely upon the USP limits without further analysis of the RLD. However, an important point to stress in this regard is that if there are some specified impurities (e.g. RC1) not explicitly identified by the USP monograph, their limits must be justified by some other means, such as in analogy to a non-compendial drug as illustrated in Table 5. A final point that deserves discussion, relates to the fact that sponsors of ANDAs are required to demonstrate that the analytical methodology for impurity monitoring are both validated and suitable for their intended use. In this context, in the case of a compendial drug, although applicants can often invoke the USP methodology to monitor impurities, the mere existence of a USP monograph method does not assure its suitability. This is illustrated in the case example from the Model Quality Overall Summary for the IR product, where despite the existence of a USP method for related compounds in the drug substance, its suitability was deemed unacceptable because the monograph test methodology was unable resolve process impurity RC1 from RC2. Hence, this serves to point out that despite the existence of USP compendial analytical methods for monitoring impurities, applicants should demonstrate their suitability. In those situations where the test methodology has not been shown to be suitable (e.g. lacks specificity), ANDA sponsors are expected to develop in-house alternate analytical procedures that are acceptable for monitoring impurities in the drug substance and drug product. 8. Conclusions This review provides a perspective on impurities in drug substance and drug product for ANDAs. The review provides

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an overview of the FDA draft guidance document “ANDAs: Impurities in Drug Substances” and “ANDAs: Impurities in Drug Products” published in 2005. Case studies included in this review illustrate the proposed pathway for determination of impurities and their acceptance criteria, based upon the general principles of these guidances. Acknowledgement We would like to thank Gary Buehler, Frank Holcombe Jr., Rashmikant Patel, Florence Fang, Vilayat Sayeed, Paul Schwartz, and Richard Adams for their valuable suggestions. References [1] U.S. Food and Drug Administration. Guidance for Industry, Q3A Impurities in New Drug Substances. February 2003. [2] U.S. Food and Drug Administration. Guidance for Industry, Q3B Impurities in New Drug Products. July 2006.

[3] U.S. Food and Drug Administration. Draft Guidance for Industry, ANDAs: Impurities in Drug Substances. January 2005. [4] U.S. Food and Drug Administration. Draft Guidance for Industry, ANDAs: Impurities in Drug Products. August 2005. [5] Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) 23rd ed., 2003, pp. v–xxii. [6] S. Raw, M.S. Furness, D.S. Gill, R.C. Adams, F.O. Holcombe Jr., L.X. Yu, Regulatory considerations of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs), Adv. Drug Deliv. Rev. 56 (2004) 397–414. [7] U.S. Food and Drug Administration. Guidance for Industry, Q3C Impurities: Residual Solvents. December 1997. [8] U.S. Food and Drug Administration. Guidance for Industry, Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. October, 1999. [9] Model Quality Overall Summary for ER Product (http://www.fda.gov/ cder/ogd). [10] Model Quality Overall Summary for IR Product (http://www.fda.gov/cder/ ogd).