Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators...

Evaluation of quality and interchangeability of medicinal productsTraining workshop for evaluators from National Medicines

Regulatory Authorities in East Africa Community

10-14 September 2007, Dar Es Salaam, Tanzania

Presented by

Rutendo Kuwana

Active pharmaceutical ingredients

Active Pharmaceutical Ingredients 2 |

What is an API?What is an API?

Active Pharmaceutical Ingredient (API)

A substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient)


Presentation approachPresentation approach

Collect and interpret available information on the APIs (pre dossier studies), such as:

Literature, all aspects (chemical/physical) Monographs in pharmacopoeia (example: ARVs)


Some definitionsSome definitions

Enantiomer

cpds with same molecular formula as substance but differ in spatial arrangement of atoms and are non-superimpossable mirror images

Polymorphism – occurrence of different crystalline forms of the same substance

Degradation product – molecule resulting from chemical change in substance due to e.g. light, temperature, pH, water, reaction with excipient, immediate container/closure


Some definitions (2)Some definitions (2)

Impurity – any component of the medicinal product which is not the chemical entity defined as the active substance or an excipient of the product

Identified Impurity – an impurity for which structural characterisation has been achieved

Unidentified degradation product – an impurity defined only by qualitative properties e.g. Rt


Available information on APIAvailable information on API

Applicants should collect and analyse available information of the API in a systematic approach

Some outcomes: Sound scientific understanding of the API, with respect to

properties, stability, specifications, etc. Assists in API manufacture and DMF compilation Sound choice of API manufacturer (source) Assists in dossier compilation Important for FPP pharmaceutical development Reduction of time / cost


Literature information on APILiterature information on API

Standard works / series / books – such as: (Analytical) Profiles of Drug Substances and Excipients [eds:

Florey / Brittain – 31 volumes] The Merck Index (for structures, properties) Pharmaceutical Codex (12th edition) (“old” APIs)

Journals through search facilities such as International Pharmaceutical Abstracts, Chemical Abstracts,

Analytical Abstracts & internet

Pharmacopoeial monographs (current)

Analysis of structure & stereochemistry


Information from literature and structures

Information from literature and structures

APIs which are organic compounds, have unique chemical structures & stereochemistry

These structures, together with the solid/liquid state conditions, are basically responsible for chemical and physical properties of the APIs


Information from literature & structure: Rifampicin

Information from literature & structure: Rifampicin

hydrolysis (to 25-desacetyl)

oxidation hydrolysis (to quinone) (to 3-

formyl)

Oxidation to N oxide

light sensitive


Information from literature & structure Rifampicin (discussion - 1)


Oxidation

Hydroquinone group Main degradation of API (to rifampicin quinone) Enhances solubility in alkaline medium

Tertiary amine Moderately prone towards oxidation (to N-oxide) Enhances solubility in acid medium

Oxidation enhanced by Metal ions Low pH




Hydrolysis

Hydrazone (imine) group Hydrolysis to 3-formyl rifamycin

25-acetyl (ester) group Hydrolysis to 25-desacetyl rifampicin (minor)

Light sensitive Due to conjugation in molecule (unsaturated)

Storage of bulk raw material (BP/Ph.Eur.): Store under nitrogen in an airtight container, protected from light at

temperature of ≤ 25ºC


Information from literature & structure Isoniazid

Information from literature & structure Isoniazid

Small molecule (quite stable) Basic amino functions Primary amine - reacts with aldehydes/lactose see presentation: FPPs – formulation problems? Can hydrolyze under stress conditions to e.g. isonicotinic acid & hydrazine Oxidize in presence of strong oxidants (e.g. permanganate), with metals as

catalyst


Information from literature & structure

Indinavir sulfate Information from literature & structure

Indinavir sulfate

Basic amino atoms (2)forms H2SO4 saltethanol in crystal

Unstable 2 main degradation products

– moisture and temp. sensitive– acid / base enhanced– Intra-molecular reaction

+

Kreutz, J. Pharm. Biomed. Anal., 19, 725-735 (1999) and Crixivan® EPAR


Literature supportLiterature support

Literature information used in the dossier should always be accompanied by

Full traceable reference citations, for instance: Devani, M.B., Shishoo, C.J., Doshi, K.J. & Patel, H.B. Kinetic

studies of the interaction between isoniazid and reducing sugars. Journal of Pharmaceutical Sciences, 74, 427-432 (1985)

Photocopies of publication or relevant pages


Properties of APIsProperties of APIs

Scenarios:

API not described in BP, Ph., JP, Ph.Eur., or USP (non - compendial)

API described in BP, Int.Ph., JP, Ph.Eur.,or USP (compendial)

Information from literature (important)


Properties: non-compendial APIsProperties: non-compendial APIs

Proof of structure/stereochemistry correctness– Single crystal X-ray structure (sufficient) or– Spectrometric data (IR, 1H & 13C NMR, MS, etc.): QA certified

copies of the spectra and tabulated data with• assignments against structure

or• correlation against API spectral data from peer reviewed literature,

preferable innovator publication (in tabulated form!!). Strongly recommended

Physico-chemical properties


Properties: Compendial APIsProperties: Compendial APIs

Physico-chemical and other relevant properties, e.g.– Solubility in water (effect of pH), other solvents such as ether,

ethanol, acetone and dichloromethane– pKa, partition coefficient– Existence/absence of polymorphs and pseudo-polymorphs e.g.

solvates (with XRPD, DSC, IR)• e.g. Rifampicin polymorphs I and II• See Nevirapine (later in this presentation)

– Hygroscopicity e.g. Ethambutol hydrochloride in FDC tablet– Particle size


Properties for Compendial APIsExample: solubility of TB APIs

Properties for Compendial APIsExample: solubility of TB APIs

API Water CHCl3* Ethanol

Rifampicin Water: Slightly 1,2

pH 7.5: 0.3% 2

pH 5.3: 0.4% 2

pH 2.0: 10% 2

Freely 1,2 Slightly 2

Ethambutol 2HCl 50% 2 0.1% 2 20% 2

Ethambutol base Sparingly 2 Very 2

Isoniazid 14% 1 0.1% 1 2% 1

Pyrazinamide 1.5% 1 0.7% 1 0.6% 2

1 Merck Index 13th ed 2 Pharmaceutical Codex 12th ed

* Dichloromethane has similar properties to chloroform as solvent, but preferred for safety reasons


Properties APIsExample: solubility protease inhibitors (mg/ml)

Properties APIsExample: solubility protease inhibitors (mg/ml)

GC Williams & PJ Sinko, Advanced Drug Delivery Reviews, 39, 211-238 (1999)

Medium Saquinavir

mesilate

Ritonavir Indinavir

sulfate

Nelfinavir

mesilate

Amprenavir

mesilate

Water 2.2 0.001 >100 4.5 0.19

pH 7.4 0.036 0.005 0.07 very low 0.06

pH 6.8 0.19

pH 6.5 0.073

pH 4.8 0.3

pH 4.0 0.007

pH 3.5 60 0.5

pH 2.6 4.5


Properties Compendial APIsPseudo-polymorphism nevirapine

Properties Compendial APIsPseudo-polymorphism nevirapine

Int. Ph. monograph Nevirapine (anhydrous & hemihydrate)

Identification test C

Carry out the examination as described under “Spectrophotometry in the infrared region”.– For the anhydrous substance, the infrared (IR) absorption spectrum

is concordant with the spectrum obtained from anhydrous nevirapine RS or with the reference spectrum of anhydrous nevirapine

– For the hemihydrate, the IR absorption spectrum shows a characteristic sharp absorbance at about 3503 cm−1; after heating the test substance for one hour at 140°C and cooling, the IR absorption spectrum is concordant with the spectrum obtained from anhydrous nevirapine RS or with the reference spectrum of anhydrous nevirapine


Properties Compendial APIsPseudo-polymorphism nevirapine (2)

Properties Compendial APIsPseudo-polymorphism nevirapine (2)

Interpretation of this IR identification test:

Nevirapine anhydrous (one test)– IR spectrum against nevirapine anhydrous RS

Nevirapine hemihydrate (two tests, conform to both)1. IR spectrum shows signal at 3503 cm-1 (water) and2. Heat converts the hemihydrate to the anhydrous form

• IR spectrum against nevirapine anhydrous RS

- ½H20

Nevirapine, ½H20 ————> Nevirapine

heat

The reaction is not reversible at room temperature


IR-spectraIR-spectra

Nevirapine ½H20

3503 cm-1

O-H signal (water)

Spectra not concordant

(do not match)

Nevirapine anhydrous

no crystal water

no O-H signal

434.5

0

464.4

3

500.0

3

548.2

3

588.5

8619.5

1

652.2

3

698.4

071

1.8

6

767.1

1780.8

279

4.2

6

819.4

583

0.5

684

4.9

2894.6

8

939.8

995

9.8

497

9.3

699

8.5

110

27.0

010

50.9

610

71.5

71092

.50

1107

.16

1117

.27

1144

.79

1168

.40

1221

.94

1244

.441272

.70

1295

.94

1351

.84

1381

.78

1411

.84

1459

.55

1491

.86

1582

.33

1600

.74

1654

.00

1913

.05

1945

.48

1961

.46

1983

.68

2070

.73

2218

.44

2515

.27

2599

.59

2861

.41

2916

.77

3007

.45

3062

.78

3193

.26

3502

.85

3893

.86

40

45

50

55

60

65

70

75

80

85

90

95

%T

rans

mitta

nc

e

500 1000 1000 2000 3000 4000

Wavenumbers (cm-1)

436.3

2

462.3

9

499.6

5

523.6

754

0.2

655

1.8

8

576.0

6

621.4

9

655.8

8

697.5

671

0.8

7

761.6

6

789.1

280

3.6

2

829.4

4

885.0

3

941.7

595

6.6

396

5.3

397

5.1

3

999.2

410

25.4

01048

.30

1074

.82

1091

.16

1107

.27

1153

.13

1167

.32

1210

.77

1243

.06

1258

.94

1289

.19

1354

.95

1384

.34

1415

.3214

65.3

514

87.8

6

1568

.92

1586

.57

1647

.72

1927

.40

1950

.21

2065

.49

2088

.38

2320

.66

2456

.46

2505

.28

2583

.59

2698

.58

2861

.26

2914

.76

3011

.59

3062

.45

3124

.51

3189

.89

3294

.95

10

20

30

40

50

60

70

80

90

100

110

%T

rans

mitta

nc

e

500 1000 1000 2000 3000 4000

Wavenumbers (cm-1)


Route(s) of synthesisRoute(s) of synthesis

Scenarios:

API not described in BP, Int.Ph., JP,Ph.Eur., or USP (non-compendial APIs)

Specifications of raw materials and intermediates used in the synthesis of non-compendial APIs

API described in BP, Int.Ph., JP, Ph.Eur., or USP (compendial APIs)


Route(s) of synthesis (cont.)Route(s) of synthesis (cont.)

Requirements: The synthesis should– lead to the correct structure, stereochemistry and crystal

form & size (if relevant)– be well controlled and validated (GMP)– produce an API which meets acceptable standards of

quality, including limits of impurities (organic, inorganic, residual solvents)


The information required for the synthesis of the API may depend onThe information required for the synthesis of the API may depend on

Is a valid CEP is available? - no synthesis information required. CEP must however have all appendices and applicant to submit other info not covered by CEP

Is the quality of the API controlled by a monograph in an acknowledged pharmacopoeia?

No official monograph is available for quality control

- Detailed information required e.g. Open Part of DMF (from API manufacturer)

- Also signed declaration from API manuf that synthesis and purification are as described in the dossier


Synthesis non-compendial APIsSynthesis non-compendial APIs

A flow diagram of the synthesis process including structures & stereochemistry of starting materials & intermediates;

reagents; catalysts; solvents

A full description of each step / process, including: Reaction conditions (temp., time, moisture control, etc.) Quantities of reagents/solvents Size of production scale Purification of intermediates Final API purification method / crystallisation / solvent(s) Reprocessing (has to be justified, validated) Process controls Validation of critical steps, e.g. aseptic processes Discussion of (possible) process impurities

Organic, residual solvents and catalysts/inorganic


Specifications of raw materials and intermediates used in synthesisSpecifications of raw materials and intermediates used in synthesis

Provide specifications for starting materials and intermediates (if isolated) reagents, solvents & catalysts

Class 1 solvents should not be used (ICH Q3C) Benzene, Carbon tetrachloride, 1,2-Dichloroethane,

1,1-Dichloroethene & 1,1,1-Trichloroethane

Provide a declaration on the use/non-use of material of animal or human origin (TSE) Risk of Transmitting Animal Spongiform Encephalopathy Agents

(WHO TRS 908, Annex 1 or EMEA/410/01 Rev.2)

To limit impurities in the API (Safety reasons)


WHAT IS A STARTING MATERIAL?WHAT IS A STARTING MATERIAL?

Contributes an important structural part of the API

Available in free trade

Compound well defined in chemical literature (name, chemical structure, chemical and physical properties, and impurity profile)

Synthesized by commonly known process


RE-DEFINITION OF STARTING MATERIALRE-DEFINITION OF STARTING MATERIAL

MARKS THE START OF THE MANUFACTURING PROCESS DESCRIBED IN AN APPLICATION Manufacturing steps before are not described Manufacturing steps before need not be performed in accordance

with GMP Changes in manufacturing steps before need not be reported to

Agency

EACH BRANCH OF A SYNTHESIS WILL BEGIN WITH ONE OR MORE STARTING MATERIALS


INDINAVIRINDINAVIR


CHEMICAL SYNTHESISCHEMICAL SYNTHESIS

• Indinavir is a chiral molecule with 5 stereogenic centers

• Only stereoisomer observed in the API is the 4-(R)-epimer.

• It is stereoselectively prepared in six steps.

• The enantiomeric purity of the API and other ingredients is ensured by the route of manufacture and quality control on intermediate products (starting materials and intermediate indinavir free base) rather than a test for specific rotation.


CHEMICAL EQUIVALENCE (1)CHEMICAL EQUIVALENCE (1)

The stereochemistry is well under control during the synthesis

Racemization after the synthesis is extremely unlikely

Formation of epimers cannot be excluded but should be detectable by the purity tests applied.

Potential impurities from synthesis, stereoisomeric impurities and degradants have been identified. Minimised or removed by control on the reaction parameters and in-process controls

High humidity, which leads to formation of degradants, is avoided.


CHEMICAL EQUIVALENCE (2)CHEMICAL EQUIVALENCE (2)

The API is very pure

The limit for any single impurity is not more than 0.1 %

limit for the sum of all impurities is not more than 0.5 %

Due to the high doses to be given in clinical use (> 2 g/day), the qualification threshold as defined in the ICH guideline on impurities, is 0.05 %.


PHYSICOCHEMICAL EQUIVALENCEPHYSICOCHEMICAL EQUIVALENCE

Indinavir Sulfate Ethanolate

Freely Soluble In Aqueous Solutions

PARTICLE SIZE Not Critical

No POLYMORPHISM

POOR FLOWABILITY

Relatively Loose Bulk Density


API STABILITY TESTSAPI STABILITY TESTS

Indinavir is highly hygroscopic at relative humidity above 60 %

In the presence of moisture and/or elevated temperatures, the API undergoes conversion to an amorphous material or to a hydrate crystal form and to the formation of degradation products i.e. lactone and several unidentified impurities occur

HVAC SYSTEM SHOULD MAINTAIN A RELATIVE HUMIDITY OF ≤ 33% AT 25OC

NEVIRAPINE


CHEMICAL STRUCTURECHEMICAL STRUCTURE

N

N

O

N

H3C

N

H


CHEMICAL STRUCTURECHEMICAL STRUCTURE

Nevirapine does not contain an assymetric carbon atom (a chiral centre)

The nitrogen in position 11 shows weekly basic properties

Other functional groups are not very reactive under everyday manufacturing environmental conditions


CHEMICAL INFORMATIONCHEMICAL INFORMATION

C15H14N4O (anhydrate for tablets) 266.30

C15H14N4O·1/2 H2O (hemihydrate

for oral suspension) 275.35

CAS number: 129618-40-2

NEVIRAPINE is lipophilic (partition coefficient 83) and is essentially nonionized at physiologic pH. As a weak base (pKa 2.8), NEVIRAPINE is known to be soluble at acidic pH

values.


PHYSICO-CHEMICAL INFORMATIONPHYSICO-CHEMICAL INFORMATION

Aqueous solubility (anhydrate) (90 μg/ml at 25°C).

NEVIRAPINE anhydrous is a white to off-white crystalline powder.

No potential toxicity was found in intermediates found in the synthesis of NEVIRAPINE

NEVIRAPINE is milled in order to obtain an acceptable particle size distribution.


SPECIFICATION, STABILITYSPECIFICATION, STABILITY

Innovator results showed that Nevirapine is highly stable even under stressed conditions over a 24 month study period

No degradants were detected and all the results remained within the specifications.


DESK CONCLUSIONDESK CONCLUSION

Critical API parameters:

Particle size of the micronized drug substance


API specificationsAPI specifications

API not described in BP, Int.Ph., JP, Ph.Eur., or USP (non-compendial APIs)

API described in BP, Int.Ph., JP, Ph.Eur., or USP (compendial APIs)

General note

An API has only one set of specifications applicable at release and throughout the re-test period– an FPP may have two sets of specifications – release and shelf-life


Specifications: Non-Compendial APIsSpecifications: Non-Compendial APIs

ICH Q6A (new APIs and products) – for instance:

Requires justification for proposed specifications

Impurities to be characterised and limits set synthesis and degradation according to ICH Q3A(R) residual solvents according to ICH Q3C

Analytical methods with validation

Preparation and potency determination/specification of primary and secondary (working) standards, with CoAs

Valid CoAs for at least 2 batches


Non-compendial APIsTypical set of specifications

Non-compendial APIsTypical set of specifications

Appearance/description

Identification (at least one specific, e.g. IR spectrum)

Moisture content (or LOD: moisture + residual solvents)

Impurities - Related organic substances (synthesis or degradation)

specified unspecified and total organic impurities

- Inorganic impurities, including catalysts - Residual solvent(s)

Assay

Additional parameters important for specific API such as particle size, polymorphic form, microbial limits


Specs: Compendial APIsSpecs: Compendial APIs

The current monograph always applicable

Additional critical specifications that are not included in monograph e.g.– particle size & polymorphic form– synthesis related impurities resulting from specific process which

may be additional to monograph– residual solvents (specific to process)

Valid CoAs for at least 2 batches required

CEP normally states tests additional to the monograph – e.g. residual solvents & impurities


IMPURITIESIMPURITIES

Extraneous contaminant (foreign substances)

Toxic impurities

Concomitant components

Signal impurities


Classes of ImpuritiesClasses of Impurities

Organic

Inorganic

Residual solvents


Organic ImpuritiesOrganic Impurities

May arise during manufacturing process and storage

Starting materials

By products

Intermediates

Degradation products

Reagents, ligands and catalysts


Inorganic ImpuritiesInorganic Impurities

May be from manufacturing process and are normally known and identified:

Reagents, ligands and catalysts

Heavy metals

Inorganic salts

other materials (e.g. filter aids, charcoal etc.)


SolventsSolvents

Organic or inorganic liquids used during the manufacturing process

Toxicity generally known, therefore controls achievable

Limits to be based on pharmacopoeial standards or known safety data


IMPURITIESIMPURITIES

Identified impurity

Unidentified impurity

Specified impurity

Unspecified impurity


IMPURITY THRESHOLDSIMPURITY THRESHOLDS

Maximum daily dose

Reporting

threshold

Identification threshold

Qualification threshold

<= 2g/day 0.05%

0.10% or 1mg/day

intake

0.15% or 1mg/day

intake

>= 2g/day 0.03% 0.05% 0.05%


IMPURITY EQUIVALENCEIMPURITY EQUIVALENCE

No new impurity is observed in the intermediate above 0.1%

No new impurity is observed in api above the qualification threshold

Each existing impurity is within its stated limit

Total impurities are within the stated limit



Each existing residual solvent is within its stated limit

New residual solvents, in either an intermediate or the api, are at or below the levels recommended in the ich guide



Ideally, impurities should be evaluated in isolated intermediates immediately following the process step in which they are produced

The impurity search can be extended to the next downstream intermediate and the evaluation process repeated until the final intermediate, even to the api


Stability testingStability testing

Stress testing of API (forced degradation) helps to identify the likely degradation products and pathways to establish stability of the molecule To verify specificity of stability assay method

Diode array detection for API peak purity !

Stability testing (regulatory) to provide evidence on how the quality of an API varies with time

under the influence of a variety of environmental factors such as temperature, humidity, and light; and

to establish a re-test period for the API and to recommended storage conditions


Stress testing (forced degradation) Typical conditions

Stress testing (forced degradation) Typical conditions

The conditions should

partially (e.g. 10-30%) decompose the API to primary degradation products

Conditions can be changed to get required degree of degradation

** Temperature should not come closer than 10°C from melting point

Stress factor Conditions (e.g.)

Humidity ≥ 75% RH (solid)

Heat ** ≥ 60°C (solid)

Heat water

Acid 0.1 M HCl

Base 0.1 M NaOH

Oxidative 3% H2O2

Photolytic ICH Q1B

Metal ions (optional)

0.05 M Fe2+ or Cu2+


Stress testing (forced degradation)Literature

Stress testing (forced degradation)Literature

Literature information and/or CEP– in support of and/or– to replace experimental data

Examples of literature information1. Rifampicin (earlier slides)

Oxidation, hydrolysis, light sensitivity2. Indinavir sulfate (earlier slide)

Intra-molecular reaction – heat, moisture, acid, base3. Efavirenz (see next slides)

Hydrolysis – pH dependent


Stress testing (forced degradation)Efavirenz (1)


Non-hygroscopic 4 Polymorphs

• Form 1 pharmaceutical(EPAR Sustiva®)

Hydrolysis main degradation– pH dependent

– Maximum stability at pH 4

– 2 Degradants isolated• structures elucidated

– Pathways postulated

Maurin, Pharm. Res. 19, 517 (2002)




The data (generated at 60°C) shows that

– Efavirenz is quite stable

– Maximum stability at pH 4 (Suspension possible?)

– Carbon dioxide formation

(30 mg/ml solution, 100 ml bottle:

1% decomposition ≈ 2 ml CO2


Efavirenz main route of degradation

Maurin (2002)

Efavirenz main route of degradation

Maurin (2002)

2nd route

1

2 + CO2 (g)


Important ElementsImportant Elements

The API must be of required structure & stereochemistry

The physical properties must be well understood, e.g.– hygroscopicity, crystal properties and solubility

The synthesis process must be according to GMP to– consistently produce an API of required chemical and physical

quality– limit impurities according to defined standards


Important Elements (2)Important Elements (2)

The set of specifications should be based on validated analytical methods with appropriate acceptance criteria to which an API should conform to be considered acceptable

for its intended use throughout the retest period in the proposed packaging

Evaluation of quality and interchangeability of medicinal products Training workshop for evaluators...

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