module 1 regulations_0501

Impurities in Drug SubstancesImpurities in Drug Substances and Drug Products- A USP

A hApproachBehnam Davani, Domenick Vicchio,

Ravi Ravichandran and Sujatha Ramakrishna

DISCLAIMER:

Because USP text and publications may have legal implications in the U.S. and elsewhere, their language must stand on its own. The USP shall not provide an ffi i l t f t i t t ti t t th b l i th tiofficial ex post facto interpretation to one party, thereby placing other parties

without that interpretation at a possible disadvantage. The requirements shall be uniformly and equally available to all parties.

In addition, USP shall not provide an official opinion as to whether a particular article does or does not comply with compendial requirements, except as part of an established USP verification or other conformity assessment program that is conducted separately from and independent of USP's standard-setting activities.y g

3

Contents Module I

Introduction History

R ll Recalls Definitions Classification/Origin of ImpuritiesClassification/Origin of Impurities Investigation of impurities Setting limits for impurities

Regulatory aspects ICH Pharmacopeiasp FDA

Non drug related impurities Extractables and Leachables

4

Extractables and Leachables Impurities due to Adulteration Impurities in Water and Excipients

Pharmaceutical industry - Timeline

Merck(Germany)- 1668- originated as a pharmacy GlaxoSmithkline- 1715 First patented medicine in1842 Pfizer- 1849- provided medicines for Union war effort

Colonel Eli Lilly was serving in the army- 1876 setup his own business Edward Robinson Squibb 1858- Setup a laboratory- todays BMS

Naval doctor threw the low quality drugs he was supplied over the board

First two medicines- Isolated Insulin followed by penicillin from mould during world war IIworld war II

(beginning of purity concept) Nature of the Industry- unregulated during 18th century

5

Thalidomide Scandal

The Thalidomide scandal of 1961 prompted an increase in the regulation and testing of drugs before licensing

From a Pharma Forum articleFrom a Pharma Forum article

In the early 1950s the drug thalidomide was introduced as a sedative prescribed for nausea and insomnia in pregnant women.

Found to cause severe birth defects in children whose mothers had Found to cause severe birth defects in children whose mothers had taken it.

FDA instituted a recall of Thalidomide and banned its use. As a result the FDA utilized more stringent testing system is not As a result, the FDA utilized more stringent testing system is not

foolproof.

Now approved for treating leprosy.

6

Contents





7


Drug Recalls

The 10 Worst Drug Recalls In The History Of The g yFDA: 24/7 Wall Street First Posted: 02/11/11 05:12 AM ET Updated: 05/25/11 07:20 PM ET07:20 PM ET

Recent Tylenol recall from McNeal JNJ subsidiary

8

Tryptophan

Showa Denko had been producing tryptophan by fermentation for many years without any incident.

Decided to use genetic engineered bacteria to accelerate and increase the efficiency of tryptophan production. No additional safety testing.

More than 60 different impurities were identified in the L-tryptophan lots p yp passociated with the toxic effects.

EBT (1,1'-ethylidene-bis-L-tryptophan) and MTCA (1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid) were implicated as being toxic.y y ) p g

EBT- a dimerization product of tryptophan comprising less than 0.1% of tryptophan.

9

2010 USP Tryptophan Monograph

TryptophanTryptophan

Tryptophan Related Compound A = EBT

10

Tryptophan Monograph USP 31

Assay by titration with perchloric acid. Limits 98.5% -101 5%101.5%

Specific rotation -29.4o -32.8o

Purity tests: pH, LOD, Residue on ignition, Chloride, Sulfate, Arsenic, Iron, Heavy metals

No Organic impurities testNo Organic impurities test

11

Tryptophan Monograph USP 32

Included Organic Impurities Tests

Organic impurities, Procedure 1:Acceptance criteria

Total impurities 1: NMT 0.01% of the total impurities eluting prior to the tryptophan peak Total impurities 2: NMT 0.03% of the total impurities eluting after the tryptophan peak. [NoteExclude the peak for tryptophan related compound B ]B. ] Tryptophan related compound A: If a peak for tryptophan related compound A is observed in the Sample solution, then perform the test for Procedure 2: Limit of Tryptophan Related Compound A, below.Limit of Tryptophan Related Compound A, below.

Procedure 2: Limit of Tryptophan Related Compound A

12

yp p p

Acceptance criteria: NMT 10 ppm Tryptophan Related Compound A

Other Recalls

Leachables (July 8, 2010) McNeil Consumer Healthcare, Division of

McNEIL-PPC, Inc- recalled 21 lots of over-the-counter medicines because of consumer complaints of a musty or moldy odor.

Complaint linked to the presence of trace amounts of a Complaint linked to the presence of trace amounts of a chemical called 2,4,6-tribromoanisole (TBA).

FDA R ll M k t Withd l & S f t Al tFDA Recalls, Market Withdrawals, & Safety Alertshttp://www.fda.gov/Safety/Recalls/default.htm

13

Other Recalls

Contamination

West-Ward Pharmaceuticals Inc. recalled all lots of Ondansetron in 5% Dextrose Injection, supplied in 32mg/50mL Single-Use Plastic Bag Containers and Metronidazole Injection 500mg/100mL USP in Flexible IV Plastic Bag Containers.Plastic Bag Containers.

Floating matter and non-sterility of Ondansetron and M t id l b dMetronidazole observed.

14

Other Recalls

Adulteration

Serious adverse reactions and deaths observed in products containing Heparin Sodium USPHeparin Sodium USP.

FDA reported that some of the adverse reactions and deaths may be the result of a Heparin-like contaminants found in some of the recalled lots. p

15

Substandard Medicines

One-Third of Antimalarial Medicines Sampled in Three African Nations Found to be Substandard in Large Scale USP WHONations Found to be Substandard in Large-Scale USP-WHO Study

Substandard medicines are those that do not meet the quality specifications set for them, primarily because they do not contain the correct amount of the active ingredient(s), do not dissolve properly in the body, or include unacceptable levels of potentially harmful impurities.

The Standard, USP, Spring 2010

16

Contents





17


Definitions

Impurity Any component of a drug substance that is not the chemical entity

defined as the drug substance and in addition, for a drug product, any component that is not a formulation ingredient.

Degradation Product An impurity resulting from a chemical change in the drug substance p y g g g

brought about during manufacture and/or storage of the drug product by the effect of, for example, light, temperature, pH, water, or by reaction with an excipient and/or the immediate containerclosure system.

18

Impurities and Impurity Profile

Impurities are unwanted coexisting components in bulk pharmaceutical chemicals that arise during manufacture and/orpharmaceutical chemicals that arise during manufacture and/or subsequent storage.

International Conference on Harmonization (ICH) impurity is any component of a International Conference on Harmonization (ICH)- impurity is any component of a substance for pharmaceutical use that is not the chemical entity defined as the substance.

an account of impurities present in the product of interest. Impurity profile of a substance under investigation gives maximum possible p g g ptypes of impurities present and also estimates the actual amount of different kinds of impurities present in it.

19

Definitions

Concomitant Components:Not necessarily impurities

Geometric and optical isomers (or racemates) of theGeometric and optical isomers (or racemates) of the drug substances and antibiotics that are mixtures.

Examples : Atracurium Besylate, Doxepine Hydrochloride

20

Atracurium Besylate

Definition Atracurium Besylate contains NLT 96 0% and NMT 102 0% ofAtracurium Besylate contains NLT 96.0% and NMT 102.0% of

C65H82N2O18S2 , calculated on the anhydrous basis. It contains

NLT 5 0% and NMT 6 5% of the trans trans isomer NLT 34 5% andNLT 5.0% and NMT 6.5% of the trans-trans isomer, NLT 34.5% and NMT 38.5% of the cis-trans isomer, and NLT 55.0% and NMT 60.0% of the cis-cis isomer.

Organic Impurities g p

trans-trans isomer, cis-trans isomer, or cis-cis isomer are not listed as impurities

21

impurities

Definitions

Foreign Substances (Extraneous Contaminants)

Introduced by contamination or adulteration. Cannot be anticipated when monograph tests and assays are Cannot be anticipated when monograph tests and assays are

selected. Examples of foreign substances include ephedrine in Ipecac or a

pesticide in an oral liquid analgesicpesticide in an oral liquid analgesic. Allowance is made in USP for the detection of foreign

substances by other methods.

22

Contents





23


Types of Impurities

Process Impurities Organic

I i Inorganic

Degradation Impurities chemical chemical physical (aggregation polymorphs; change to another

polymorph)

Contaminants not drug related (herbicides and pesticides in botanicals). Most controlled by cGMPs.

24

Sources of Process Impurities

Organic Last step intermediates

R t ( i d t i iti ) Reagents (carried over as trace impurities) Side reactions (incomplete reaction, over-reaction, isomerization,

rearrangement)Impurities in starting materials (positional isomers) or their reaction Impurities in starting materials (positional isomers) or their reaction products

Impurities due to multiple synthetic routes Identity and amounts of impurities vary as a function of the synthetic routeIdentity and amounts of impurities vary as a function of the synthetic route Synthetic route might change during the development of a product Generic manufacturers might use different routes Eg: Paroxetine Hydrochloride synthesized by many different procedures and

l d b th LC danalyzed by more than one LC procedure.

25

Chromatograms of Products by Three of the Synthetic Routes

26

Sources of Impurities

Inorganic Reagents, ligands and catalysts Heavy metals or other residual metals Inorganic salts Other materials (e.g., filter aids, charcoal)

Residual Solvents Solvents are liquids used during the synthesis/purification of a drug q g y p g

substance.

27

Contents

Introduction History Recalls Recalls Definitions Classification/Origin of Impurities Investigation of impurities Setting limits for impurities

Regulatory aspects ICH Pharmacopeias FDA


28

Impurities due to Adulteration Impurities in Water and Excipients

Investigation of Impurities

U d t d th i i Understand the origin Understand mechanisms for minimization or removal

Structural characterization of impurities and of degradation products are an integral part of the pharmaceutical product development

Essential forProduction of a high-quality product shown to be safeg q y pOptimization of the production process of the drug substance

and of the drug productD l t f b tt f l tiDevelopment of better formulations

Development of suitable storage conditionsFulfilling requirements of regulatory agencies

29

g q g y g

Impurity Profiles

Determined at the time ofTh i iti l IND fili The initial IND filing

NDA filing

Post NDA approval Post NDA approval

ANDA Filing

Monitored on an ongoing basis Monitored on an ongoing basis Reconfirmed after changes in

S f Synthesis of the bulk drug substance

Drug product process or formulation

30

Impurity Profiling

Impurity profiling detection, identification/structure elucidation quantitative determinationelucidation, quantitative determination

Detection by chromatography or others (detection sensitivity essential)

Identification Matching mobility with authentic samples of potential impurities

(not less than two orthogonal systems)(not less than two orthogonal systems) Hyphenated techniques (HPLC, GC, etc) /

Spectroscopy (Diode-array UV has the UV spectrum h d? H ? NMR IR MS)changed? How? - NMR, IR, MS)

Isolation (Preparative chromatography) or synthesisDevelopment of method for quantitative determination

31

Development of method for quantitative determinationEvaluation of their toxicological properties

Sources of Degradation impurities: Drug Substances

Can occur at any stage: manufacturing, isolation, purification, drying, storage, transportation Reagents used from synthesis (Catalysts, Solvents, etc) Products from side reactions Intermediates Stereo isomers

Conditions inducing degradation: heat, humidity, solvent, pH, light, interactions with other materialsinteractions with other materials

Types of reaction causing degradation Hydrolysis

O id ti Oxidation Photolysis (e.g. cis/trans isomerization) Racemization (chiral centers)

32

Elimination

Sources of Degradation impurities- Drug products

Degradation of the final product Interactions with excipientsConditions inducing degradation: heat, humidity, solvent,

pH light interactions with other materialspH, light, interactions with other materialsTypes of reaction causing degradation

Hydrolysisy y Oxidation Photolysis (e.g. cis/trans isomerization) Racemization (chiral centers) Elimination

33

Control of Process Impurities

High-quality starting materials

High-quality reagentsTi h l f di iTight control of process conditions

Additional purification stepsp p Crystallization for synthetic drugs

Preparative chromatography for biotech drugs

34

Monitoring Degradation Products

Long term stability testing (252oC; 605% relative humidity)

Accelerated stability testing (402oC; 755%Accelerated stability testing (402oC; 755% relative humidity)

Stress testing (more severe than accelerated testing)g)

35

Contents





36


Setting Limits for Impurities

Limits are set for impurity levels or degradation products asLimits are set for impurity levels or degradation products as one of the steps in ensuring the identity, strength, quality, and chemical purity of drug substances or drug products.

37

Factors influencing Setting of Limits for Impurities

Toxicology of a drug substance containing typical levels of impurities and/or the toxicology of impurities relative to a drug substance; Route of administration, e.g., oral, topical, parenteral, or intrathecal; Route of administration, e.g., oral, topical, parenteral, or intrathecal; Daily dose, i.e., frequency and amount administered of a drug substance; Target population (age and disease state) e g neonates children Target population (age and disease state), e.g., neonates, children, or senior citizens; Toxicology of an impurity, when appropriate; Source of a drug substance, e.g., synthetic, natural product, or biotechnology; Duration of therapy, i.e., administration over a long period (treatment of chronic conditions) versus administration intended for a short duration (treatment of acute conditions); Capability of a manufacturer to produce consistently high-quality

38

final product.

Contents





40


ICH Guidelines

The ICH Topics are divided into four major categories and ICH T i C d i d di t th t iTopic Codes are assigned according to these categories.

Q Quality Topics

S Safety Topics

E Efficacy Topics

M Multidisciplinary Topics

41

ICH Q Guidelines

Q1 Stability

Q2 Analytical ValidationQ2 Analytical Validation

Q3 Impurities Q3A Impurities in New Drug SubstancesQ3B Impurities in New Drug ProductsQ3B Impurities in New Drug ProductsQ3C Impurities: Guideline for Residual Solvents

Q4 Pharmacopoeias

Q5 Quality of Biotechnological Products

Q6 Specifications

Q7 Good Manufacturing Practice

Q8 Pharmaceutical Development

42

Q9 Quality Risk Management

Q10 Pharmaceutical Quality System

ICH Guidelines Addressing Impurities

Q1A Stability testing of new drug substances and products

Q1B Photostability Testing of New Drug Substances and Products

Q2A Text on Validation of Analytical Procedures

Q3A Impurities in drug substances

Q3B Impurities in drug products

Q3C Impurities: residual solventsQ3C Impurities: residual solvents

Q6A Specifications: test procedures and acceptance criteria for new drug substances and new drug substances; chemical

43

new drug substances and new drug substances; chemical substances

Definitions in Q3A(R2) and Q3B(R2)

Identification (Reporting) Threshold: A limit above which an impurity (degradation product) should be identified (reported)

Qualification Threshold: A limit above which an impurity (degradation product) p y ( g p )should be qualified

Reporting Threshold: A limit above which an impurity or degradation productshould be reported.

Specified Impurity (Degradation Product): An impurity (degradation product) that is individually listed and limited with a specific acceptance criterion in the new drug substance specification. Can be either identified or unidentified.

Unspecified Impurity (Degradation Product): Unspecified Impurity An Unspecified Impurity (Degradation Product): Unspecified Impurity An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the existing drug substance specification.

Identified Impurity (Degradation Product): An impurity for which a structural characterization has been achieved.

Unidentified Impurity (Degradation Product): An impurity for which a

44

structural characterization has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time).

ICH Reporting and Control of ImpuritiesExpectation and Requirements (Q3A and Q3B)

Organic Impurities List of actual and potential impurities [total and individual

impurities, identified and unidentified for all batches (in variousimpurities, identified and unidentified for all batches (in various stages of the development)]

Scientific appraisal of synthetic pathways D d ti th d t ti l i iti t d Degradation pathways and potential impurities generated

during manufacture, storage, and stability studies Impurities associated with raw materials Studies conducted to detect and identify impurities (including

stress testing) Impurities arising from the interaction with excipients and/or Impurities arising from the interaction with excipients and/or

the immediate container closure system.

45

Thresholds for Impurities in Drug Substances (% of Drug Substance)

Maximum Daily Dose (g)

Reporting Threshold

Identification Threshold

Qualification ThresholdDaily Dose (g) Threshold Threshold Threshold

0.10% or 1.0 /

0.15% or 1.0 / 2 0.05% mg/day intake

(whichever is lower)

mg/day intake (whichever is lower)

> 2 0.03% 0.05 % 0.05 %

Illustration of Reporting, Identification, Qualification of Impurities

Example 1: 0.5 g Maximum Daily Dose Reporting threshold = 0.05% Identification threshold = 0.10% Qualification threshold = 0.15%

"Raw" Result (%)

Reported Result

Calculated Total Daily

Action Action

(%) Intake (TDI) (mg) of the

impurity

Identification Qualification

0.044 Not reported 0.2 None None0.0963 0.10 0.5 None None

0 12 0 121 0 6 Yes None0.12 0.121 0.6 Yes None0.1649 0.161 0.8 Yes Yes

47

1After identification check correctness of the response factor and determine need for qualification

Thresholds for Impurities and Degradation Products in Drug Products

Maximum Daily Dose

Reporting Threshold

Identification Threshold

Qualification Threshold

1g / > 1g 0.1% / 0.05%

< 1 mg 1 0% or 5 g Total Daily< 1 mg

1-10 mg.

>10 mg to 2 g

1.0% or 5 g Total Daily Intake (whichever is lower)0.5% or 20 ug Total Daily

Intake (whichever is lower) 0.2% or 2 mgTotal Daily

I t k ( hi h i l )

>2 g

Intake (whichever is lower)0.1%

< 10 mg 1.0% or 50 g Total Daily Intake (whichever is lower)

0 5% or 200 g Total Daily Intake10 100 mg

>100 mg to 2 g

> 2 g

0.5% or 200 g Total Daily Intake(whichever is lower)

0.2% or 3 mg Total Daily Intake

0.15% 2 g

Illustration of Reporting, Identification, Qualification of Degradation Products

Example 1: 50 mg Maximum Daily Dose Reporting threshold: 0.1% Identification threshold: 0.2% Qualification threshold: 200 g (TDI)

"Raw" Result (%)

Reported Result

Calculated Total Daily

Action Action(%) Result

(%) Total Daily

Intake (TDI) (g) of the impurity

Identification Qualification

0.04 Not reported 20 None None

0.2143 0.2 100 None None

0.349 0.31 150 Yes None

0.550 0.61 300 Yes Yes

49

1After identification check correctness of the response factor and determine need for qualification

ICH Reporting and Control of Impurities (Q3C)

Residual solvents Controlled as per ICH Q3C

50

Contents

Introduction History Recalls Definitions Classification/Origin of Impurities Classification/Origin of Impurities Investigation of impurities Setting limits for impurities

Regulatory aspects ICH PharmacopeiasPharmacopeias FDA

Non drug related impuritiesE tractables and Leachables

51


Impurities in Pharmacopeias

General NoticesG l Ch tGeneral Chapters

Requirements in Individual MonographsReference Standards are provided where required

The United States PharmacopeiaEuropean PharmacopeiaBritish Pharmacopeia and Japanese Pharmacopeia

52

General Notices

The specification in a monograph consists of tests,procedures, and acceptance criteria that helpensure the identity, strength, quality, and purity of th ti l the article.

Concepts about purity change with time and developments inConcepts about purity change with time and developments in analytical chemistry

I f ti b t i iti ti l f th lit d f tInformation about impurities essential for the quality and safety of a drug product

53

General Notices

5.60. Impurities and Foreign Substances

Tests for the presence of impurities and foreign substances are provided to limit such substances to amounts that areare provided to limit such substances to amounts that are unobjectionable under conditions in which the article is customarily employed.

Non monograph tests and acceptance criteria suitable for Non-monograph tests and acceptance criteria suitable for detecting and controlling impurities that may result from a change in the processing methods or that may be introduced f t l h ld b l d i dditi t thfrom external sources should be employed in addition to the tests provided in the individual monograph, where the presence of the impurity is inconsistent with applicable good

f t i ti d h ti l ti

54

manufacturing practices or good pharmaceutical practice.

General Notices

5.60.10. Other Impurities in USP and NF Articles

If a USP or NF monograph includes an assay or organic impurity test based on chromatography, other than a test for residual g p y,solvents, and that monograph procedure does not detect an impurity present in the substance, the amount and identity of the impurity, where both are known, shall be stated in the p y, ,labeling (certificate of analysis) of the official substance, under the heading Other Impurity(ies).

A material produced by a different synthetic route than that used for the development and validation of the official monograph

t i diff t i iti

55

may contain different impurities

Other Impurities Under General Notices

The presence of any unlabeled other impurity in an officialThe presence of any unlabeled other impurity in an official substance is a variance from the standard if the content is 0.1% or greater. The sum of all Other Impurities combined with the monograph detected impurities maycombined with the monograph-detected impurities may not exceed 2.0% unless otherwise stated in the monograph.

Manufacturer must identify other impurities if they are >0.1% and declare them on the Certificate of Analysis.y

56

General Chapters

Ordinary Impurities

Impurities in Official Articles

Organic volatile Impurities Chapters for limits for inorganic impurities

57

Ordinary Impurities

Ordinary impurities are defined as those species in drug substances and/or drug products that have no significant, undesirable biological activity in the amounts present Theseundesirable biological activity in the amounts present. These impurities may arise out of the synthesis, preparation, or degradation of compendial articlesD f lt li it NMT 2 0% Default limit: NMT 2.0%

Methodology estimation by relative methods rather than by comparison to y y p

individual Reference Standards Typical evaluation methods by thin-layer chromatographic

(TLC) techniques(TLC) techniques About 100 USP monographs include this test.

58

Ordinary Impurities- Example

Estrone monograph (typical example)Ordinary impurities

Test solution: acetone. Standard solution: acetone. Eluent: a mixture of chloroform and acetone (9:1) in a non-Eluent: a mixture of chloroform and acetone (9:1), in a non

equilibrated chamber. Visualization: 5

59

Organic Impurities

Impurities in Official Articles

Informational Chapter

Definitions of various types of impuritiesDefinitions of various types of impurities

Rationale for setting limits for impurities (toxicology, route of administration, daily dose, etc)

60

Impurities in Drug Substances and Drug Products

Classification of impurities - as in ISO Q3A and Q3B Definitions

Identified Impurities and Identified Degradation ProductsImpurities or degradation products for which p g pstructural characterizations have been achieved.

Specified Impurities and Specified Degradation Products (Previously referred to as Signal Impurities)Products (Previously referred to as Signal Impurities) impurities or degradation products that are individually listed and limited with specific acceptance criteria in individual monographs as applicable Specified impurities or specifiedmonographs as applicable. Specified impurities or specified degradation products can be identified or unidentified.

61

Impurities in Drug Substances and Drug Products (cont.)

Toxic Impuritieshave significant undesirable biological activity, even as minor components, and require individual identification and quantification by specific tests.

Unidentified Impurities and Unidentified Degradation ProductsImpurities or degradation products for which structural characterizations have not been achieved and that are identified

l l b lit ti l ti l ti ( h t hisolely by qualitative analytical properties (e.g., chromatographic retention times).

Unspecified Impurities and Unspecified Degradation ProductsI iti d d ti d t th t li it d b lImpurities or degradation products that are limited by general acceptance criteria but not individually listed with their own specific acceptance criteria in individual monographs.

R l t d S b t t t ll l t d t d b tRelated Substances structurally related to a drug substance. may be (a) identified or unidentified impurities arising from synthesis manufacturing process such as intermediates or by-products and do not increase on storage or (b) identified or unidentified degradation

62

not increase on storage or (b) identified or unidentified degradation products that result from drug substance or drug product manufacturing processes or arise during storage of a material.

Examples of Impurities in Drug SubstanceCapecitabine - Impurity Table

Name

Relative Retention Time

Relative Response Factor

Acceptance Criteria, NMT (%)

Capecitabine related compound A 0 18 1 05 0 3

Capecitabine Impurity Table

Capecitabine related compound A 0.18 1.05 0.3

Capecitabine related compound B 0.19 0.81 0.3

2,3-Di-O-acetyl-5-deoxy-5-fluorocytidine 0.36 0.89 0.1

5-Deoxy-5-fluoro-N4-(2-methyl-1-butyloxycarbonyl)cytidine + 5-Deoxy-5-fluoro-N4-(3-methyl-1-butyloxycarbonyl)cytidine

0.95 1.01 0.5methyl 1 butyloxycarbonyl)cytidine

Capecitabine 1.00 1.00 [1-[5-Deoxy-3-O-(5-deoxy--d-ribofuranosyl)--d-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester

1.06 1.00 0.3

[1-[5-Deoxy-2-O-(5-deoxy--d-ribofuranosyl)--d-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester

1.09 1.00 0.2

Capecitabine related compound C 1.11 0.91 0.3

[1-[5-Deoxy-3-O-(5-deoxy--d-ribofuranosyl)--d-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester

1.20 1.00 0.3

63

2,3-Di-O-acetyl-5-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine 1.37 0.85 0.1

Individual unspecified impurity

Total impurities

1.00 0.1

1.5

Examples of Impurities in Drug Product

Capecitabine TabletsName RRT RRF NMT%Capecitabine related compound A 0.18 1.05 1.0

Capecitabine Tablets

Capecitabine related compound B 0.19 0.81 1.0

2,3-Di-O-acetyl-5-deoxy-5-fluorocytidine* 0.6 0.89 -

5-Deoxy-5-fluoro-N4-(2-methyl-1-butyloxycarbonyl)cytidine + 5-Deoxy-5-fluoro N4 (3 methyl 1 butyloxycarbonyl)cytidine*

0.95 1.01 -fluoro-N4-(3-methyl-1-butyloxycarbonyl)cytidine*

Capecitabine 1 1 -

1-[5-Deoxy-3-O-(5-deoxy--D-ribofuranosyl)--D-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester*

1.06 1 -

1-[5-Deoxy-2-O-(5-deoxy--D-ribofuranosyl)--D-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester*

1.09 1 -

Capecitabine related compound C 1.11 0.91 0.50

1 [5 D 3 O (5 d D ib f l) D ib f l] 5 fl 2 1 20 11-[5-Deoxy-3-O-(5-deoxy--D-ribofuranosyl)--D-ribofuranosyl]-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]-carbamic acid pentyl ester*

1.20 1 -

2,3-Di-O-acetyl-5-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine* 1.37 0.85 -

64

[The impurities marked with * are process impurities and not included in the degradation products]

Total degradation products 2.0%

Other Examples: Multiple Procedures

Clavulanate Potassium Impurities (HPLC and GC)

Organic Impurities :(HPLC) L1, gradient elution methanol and

Clavulanate Potassium Impurities (HPLC and GC)

g p ( ) , gpH 4 phosphate buffer, 230 nm, Total impurities: NMT 2%

Li it f Cl 2 C b l t P t i (HPLC) L1 H 4Limit of Clavam-2-Carboxylate Potassium (HPLC) L1, pH 4 phosphate buffer, 210 nm: NMT 0.01%

Limit of Aliphatic Amines (GC); Column: 0.53-mm 50-m capillary fused silica column with a 5-m film coating of stationary phase G41 NMT 0.2%stationary phase G41 NMT 0.2%

Limit of 2-Ethylhexanoic Acid (GC) Column: 0.53-mm 25-m ill f d ili 1 fil ti f t ti h

65

capillary fused silica; 1-m film coating of stationary phase G35; NMT 0.8%

Other General Chapters Related to Impurities

Residue on Ignition determines unidentified inorganic impurities

Loss on Drying determines unidentified volatiles Metal Particles in Ophthalmic Ointments determines the

number and size of discrete metal particles Melting Range or Temperature purity and identityg g p p y y Refractive Index Particulate Matter in Injections Completeness and Clarity of Solution Dacarbazine for Completeness and Clarity of Solution Dacarbazine for

Injection When dissolved as directed in the labeling, it yields a clear, pale yellow to yellow solution

Oxidizable substances (persistance of the pink color of a Oxidizable substances (persistance of the pink color of a permanganate solution) Monographs: Acetone, Lanolin et al

Nitrogen Determination - Eg: Dextrin -NMT1.0% protein

66

Inorganic Impurities

General for many elements: Heavy Metalsy Residue on Ignition Plasma Spectrochemistry

Valacyclovir Hydrochloride Limit of palladium - NMT 10 ppmMagnesium Hydroxide Limit of lead NMT1.5 ppmg y

Other suitable procedures: Thioacetamide precipitationRopinirole Hydrochloride - Limit of palladium - NMT 10 ppm

67

Inorganic Impurities

More specific for individual impurities: Aluminum - atomic absorption spectrophotometry. NMT 0.2

/ i S di A t tg/g in Sodium Acetate Arsenic colorimetry. NMT 2 g/g in Choline Bitartrate. Chloride and Sulfate turbidity (visual) with silver nitrate and y ( )

barium chloride, respectively. 0.018% - 0.025% in Dextrose Iron L d l i t i NMT 5 / i L t Lead colorimetric. NMT 5 g/g in Lactase Mercury titration or AAS. NMT 0.5 g/g in Calcium

carbonate Selenium UV spectroscopy. NMT 0.003 % in

Hydrochlorothiazide

68

Example: Aspirin Monograph

Residue on Ignition : NMT 0.05%

Chloride : NMT 0.014%

S lf t NMT 0 04% Sulfate: NMT 0.04%

Heavy Metals : NMT 10 ppm

69

Residual Solvents

Organic volatile Impurities 467 Organic volatile Impurities

70

Monitoring Water

General Chapters for determining water contentTitration

Water DeterminationGravimetric

Loss on Drying (determines water and other volatiles) Thermal Analysis (Thermogravimetric Analysis)

71

Example: Azithromycin

Water : not more than 2.0% where it is labeled as anhydrous; between 4.0% and 5.0% where it is labeled as theanhydrous; between 4.0% and 5.0% where it is labeled as the dihydrate; between 1.8% and 4.0% where it is labeled as the monohydrate, except that it may be between 4.0% and 6.5% when the requirements of the Loss on drying test are metwhen the requirements of the Loss on drying test are met.

Loss on drying (where it is labeled as Azithromycin monohydrate and has a Water content of between 4.0% and 6.5%) (seeThermal Analysis )) ( y )

72

USP and EP

USP EPImpurities and foreign substances

General NoticesSection 5 6

General Notices Sections 1 0 5 1substances Section 5.6 Sections 1.0, 5.1

Impurities in official General Chapters1086

General Chapters2034p

articlesOrdinary impuritiesOther impurities

466231, 232 and 467

N/A2.4.8, 5.4

73

Contents





74


FDA Guidance for IndustryNDAs: Impurities in Drug Substances and Drug Products

Refers to ICH Q3A, Q3B and Q3C

75

FDA Guidance for Industry: ANDAs

Organic impurities

Expected list of impurities

g p Each specified identified impurity Each specified unidentified impurity Any unspecified impurity with an acceptance criterion of not

more than the identification threshold in Attachment 1, Q3A(R)Q3A(R)

Total impurities Residual solvents Residual solvents Inorganic impurities

76

Setting Acceptance Criteria for Impurities

If there is a monograph in the USP that includes a limit for a specified impurity, we recommend that the acceptance

it i b t hi h th th ffi i l di l li itcriterion be set no higher than the official compendial limit. If the level of a specified impurity is above the level specified in

the USP, we recommend qualification. Then, if appropriate qualification has been achieved, an applicant can petition the USP for revision of the acceptance criterion.

If a limit for a specified impurity does not exist in the USP, we If a limit for a specified impurity does not exist in the USP, we recommend that you qualify the impurity by comparing it to the observed amounts of the impurity in the reference listed drug product (RLD) Your acceptance criterion should be similar toproduct (RLD). Your acceptance criterion should be similar to the level observed in the RLD. Alternatively, the acceptance criterion may be set based on a qualified level that is justified by scientific literature metabolite data or toxicity studies

77

by scientific literature, metabolite data, or toxicity studies.

Setting Acceptance Criteria for Impurities (cont.)

An impurity is considered qualified for an ANDA when one or more of the following conditions are met:

The observed level and proposed acceptance criterion for the impurity do not exceed the level justified by the reference listed drug product. g p

The impurity is a significant metabolite of the drug substance. The observed level and the proposed acceptance criterion for the

impurity are adequately justified by the scientific literature. The observed level and proposed acceptance criterion for the

impurity do not exceed the level that has been adequatelyimpurity do not exceed the level that has been adequately evaluated in toxicity studies.

78

FDA Guidance for Industry IMPURITIES IN NEW VETERINARY DRUG SUBSTANCES

Same classification and sources as in human drugsSimilar approaches and reporting requirements

(specifications and analytical procedures)Specifications to include list of impurities (organic,

inorganic residual solvents)inorganic, residual solvents)

79


80


81

Contents





83


Extractables and Leachables

Leachables are chemical entities, either organic or inorganic, that migrate from pharmaceutical container closure system components into a drug product formulation. Can migrate from glass (metal oxides), rubber stoppers, plastic containers

Extractables (potential leachables) are compounds that are forced out of container closure system materials and components under laboratory

i t l ditiexperimental conditions. Information available from the component supplier, is often incomplete. Non-drug related impurities

21 CFR parts 210 and 211. Subpart D-211.65CDER Guidance Document: Container closure systems for packaging human drugs and biologics,

1999IPAC-RS Leachables and Extractables Testing: Points to Consider; March 2001K. Nicholas, Extractables and leachables determination: a systematic approach to select and qualify a

container closure system for a pharmaceutical product American Pharm. Review, 9(3) 21 (2006)P. Kushwaha and A. K. Madan Extractables and Leachables: An Overview of Emerging Challenges

Ph ti l T h l 32(8) 2008

84

Pharmaceutical Technology, 32(8), 2008D. Norwood et al., Pharmaceutical Research, Vol. 25, No. 4, April 2008S. Northup, Pharmaceutical Containers. Safety qualification of extractables/leachables, Amer. Pharm.

Review, March/April 2008

USP Extractables and Leachable Standards

Biological Reactivity Tests, In Vitro Biological Reactivity Tests, In Vivog y Elastomeric Closures for Injections Containers Glass Containers Plastic Containers Plastic Containers Performance Testing Repackaging into Single-Unit Containers The Biocompatability of Materials Used in Drug Containers,

Medical Devices and Implants

USP Positive Bioreaction RSUSP High-Density Polyethylene RS (negative control)

85

Extractables and Leachables Official Documents

Equipment shall be constructed so that surfaces that contact components, in-process materials or drug products shall not be reactive additive or absorptiveprocess materials or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product . . .

Code of Federal Regulations, Foods and Drugs Title 12, Part 211.65. U S G t P i ti Offi W hi t DC R i d A i1 2006U.S. Government Printing Office, Washington, DC. Revised Apri1, 2006

Production equipment should not present any hazards to the product. The parts of the production that come into contact with the product must not beparts of the production that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.

EUDRALEX Volume 4: Good Manufacturing Practices, Medical Products for Human and Veterinary Use. European Commission: Brussels, Belgium, 1998.

86

Contents





87


Adulteration

Over the years, many countries around the world, i l di th U it d St t h b h ll d bincluding the United States have been challenged by economically motivated adulteration. Examples include melamine in pet food and infant formula, oversulfated pchondroitin sulfate in heparin, and diethylene glycol in glycerin. Such instances involve the deliberate substitution of a less costly substance for a moresubstitution of a less costly substance for a more expensive one, resulting in patient harm and even death.

88

Heparin Adulteration

In 2007-2008, serious injuries and deaths have been associated with the use of heparin.

In February 2008, Baxter Healthcare Corporation recalled multi-dose and single-dose vials of heparin sodium for injection

FDA scientists identified a contaminant oversulfated chondroitin sulfate (OSCS) i th h i ( l ti ill(OSCS) in the heparin (nuclear magnetic resonance, capillary electrophoresis, enzymatic kinetics, and bioassay).

OSCS mimics the biological activity of heparin; OSCS mimics the biological activity of heparin;

Source identified to be API manufactured in China.

USP revised monographs for heparin sodium and heparin calcium, to quantitatively measure OSCS.

89

Diethyleneglycol and Ethylene Glycol in Glycerin and Related Excipients

Fatal Poisoning reported among Young Children due to contaminated Acetaminophen oral syrups --- Nigeria, 20082009

Glycerin used as a sweetener in oral syrup formulations DEG (and ethylene glycol and propylene glycol) - contaminated

glycerin was used in the oral syrup preparations g y y p p p Diethyleneglycol (DEG), is a nephrotoxin and hepatotoxin and is

used in industrial solvents and antifreeze USP monograph revised to include USP monograph revised to include.

A GC Limit of diethylene glycol and ethylene glycol added to the Glycerin, Propylene Glycol and Sorbitol solution monographs

Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, 45, 649 (1996)C. M. Gryniewicz et al, Amer. Pharm. Review 10 (7) 24 (2007)

W. Bogdanich and J. Hooker, From China to Panama, a Trail of Poisoned Medicine, The New York Times, May 18, 2007

90

Melamine Adulteration

Granular melamine was found (2008) to have been intentionally added to product formulations, including infant formula, in order to pass protein tests by indicating a higher level of protein than actually existed in the products.

EXAMPLES OF AT-RISK PHARMACEUTICAL COMPONENTS (e.g. Urea)

Guidance for Industry Pharmaceutical Components at Risk for Melamine Contamination F d d D Ad i i t ti C t f D E l ti d R h (CDER) C t fFood and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for

Veterinary Medicine (CVM) August 2009

91

Melamine Adulteration

Protein Content by Nitrogen Determination, Method II 461

Oxytocin

Melamine

92

Contents





93


Impurities in Water and Excipients

Water Cl, SO4, NO3, Hypochlorite, Organic impurities Phenols Endotoxins

Excipients: Heavy metals- As Inorganic salts Ca, Mg, Al Organic impurities

94

Impurities and Quality

A key component of the overall quality of a pharmaceutical product is control of impurities as their presence even in small amounts maycontrol of impurities, as their presence, even in small amounts, may affect drug safety and efficacy.

Analysis of Drug ImpuritiesAnalysis of Drug ImpuritiesRichard J. Smith (Editor), Michael L. Webb (Editor)

May 2007, Wiley-Blackwell

95