11

National Drug Quality Assurance

• Regulated introduction of new drugs

• National Drug QA laboratory

• Inspection of the drug supply chain (GMP)

• Organised recall if quality defects

22

Regulated introduction of new drugs

WHO: 3 levels•„Registration”: assessment of submitted dossier + certain own tests•„Authorisation” on the basis of foreign registration + WHO Certification Scheme•„Notification” (simple listing)

33

Notification

• In the less developed countries: only „to know, what is on the market”

• If drugs imorted in ahigher quantity or donated: their data (name, API, origin, etc.) must be notified (e.g. MoH)

• MoH has/issues the actual list

44

Authorisation

• Moderately developed countries: select countries the drug authorisation of which is recognised, publish it + WHO Certificate from these countries’ authorities needed

• No (or minimal) local assessment, data put into the Register

55

Registration

• Submission of formal dossiers (quality, safety, efficacy, both animal and human studies) requested

• (at least some parts of the) dossier assessed locally (e.g. quality, bioequivalence), some own tests (e.g. physico-chemical and chemical quality control, in vitro dissolution)

• Suitable also for registration of locally manufactured drugs

66

Further on, we speak about full Drug Registration

(Bee careful, the EU and WHO/USA English may differ!)

I use registration = marketing authorisation

77

Why is it important?

The pharmacist always should speak about medicines. It were a pity not to know how they are assessed and authorised...

88

Moreover...

There are always inventors

Natural products in fashion

Physicians’ or pharmacists’

new combinations The patient heard something (Internet!)

99

Medicine (assessment for) registration =

= very complex (and interesting!) in nature, it is better to know it!

1010

Medicine registration = marketing authorisation (EU

terminology)Medicine Act: only

authorised medicines may be used

Marketing authorisation: the most frequent one

1111

Other kinds of authorisation?

• Individual import or compassionate use (rare diseases, to a named patient or to a hospital)

• Donation (to hospital, pharmacist’s supervision advisable!)

• Clinical trial samples

1212

Medicine registrationMedicine registration

Legal side (both the

regulatory authority and

the Firm are concerned)

Pharmaceutical/medical (professional) side (assessment: suitable to be medicine or not?)

1313

Registration?

• Product categorisation is it medicine?

• Professional side is it suitable to be medicine?

• Legal side civil service step with consequences

1414

Professional side

Assessment of the documentation (sample) submitted

• Quality (substances and preparation)

• Relative safety• Efficacy(risk/benefit)

1515

Registration: professional sideRegistration: professional side

• Application — Assessment of• Quality and its guarantee (Manufacture and

process validation, Quality Specification and method validation, Pharmaceutical development)

• Safety (animal and clinical toxicology)

• Efficacy (experimental and clinical pharmacology)

• Authorisation with info material

?

1616

Before detailing the drug registration:

• Intellectual Property rights (IP): Patent protection

• Data exclusivity

1717

Patent protection

• After synthesis (etc.), new innovations (e.g. drug entities) may be patented

• As a rule, 20 years• („Bolar provision” permits the same

drug development, clinical trials, registration underpatent protection, but not marketing!)

1818

Data exclusivity, 1

• Generic route of registration: patent expired, other manufacturer may produce similar drug with the same API

• No animal experiments and human clinical trials performed, only the „equivalence” to the innovator product proven…

1919

Data exclusivity, 2

• …as if it said „I do not know what is in the innovator’s pre-clinical and clinical dossier submitted, however, for I Have proven the equivalence, take as I had submitted the same dossiers”

• =reference to the innovator’s data

2020

Data exclusivity, 3

• DE is to forbid the regulatory authorities to accept any reference to the innovator’s data for a specified period of time after the registration (10 years in the EU at present, from the first registration in any of the member states)

2121

PP and DE

• Patent: 20 years from filing the patent protection request (the drug still in early development phase)

• DE: 10 years from the first registration!

2222

Patent/DE issues during registration

• As a rule, DRAs are not empowered to clarify patent/DE issues when new drug applications are submitted (however, in Canada, the MA is on hold and issued only after patent issues are checked)

• Moreover, it would require enormous resources

• Advisable solution: Applicant’s declaration required that IP/DE rules were clarified and no violation found

2323

Doha declaration

• November 2001• Permits development and export of a

generic product, still under PP in the country of manufacture, to developing countries

• as a rule, the brand patent holder’s (BPH) consent needed

• BPH is given also royalty

2424

Doha arrengement

• e.g. Canada, European Union signed

• Labelling that would hinder re-export

• e.g. HIV/AIDS medicines concerned

2525

The art of medicine registration and assessment

Documentation

Expert Reports

26

In drug assessment

• Work interdisciplinary

• Everything must be evaluated from every angle!

• (A fulsih exampleon the next slide)

27

„Everything must be evaluated form every angle”!

Do you like this girl?

See it upside down. Do you still like her?

2828

Common Technical Document

• An ICH Guideline• International Conference on

Harmonisation of technical requirements for registration of pharmaceuticals for human use: EU, USA, Japan - DRA and Industry

• „Soft law”

2929

CTD

Regional administrative info

Nonclinical overview

Nonclinical summary

Clinical overview

Clinical summary

Quality

overall

summary

M3

Quality

M4

Nonclinical study reports

M5

Clinical study reports

M1Not part of CTD

CTDM2

3030

Structure and terms

Structure for all parts:

• Introduction

• Overview: short description

• Overall summary:

written

tabulated

• Original study/trial reports

EXPERT

REPORTS

3131

Expert reports

• EU phylosophy: an evaluated documentation should be submitted for authorisation

• DRA review: comparison of the review done by the Company expert with that done by the regulatory one

• Never „to try to find out” why something was (not) done

3232

Quality Overall Summary

40 pages + tables, figures

• Evaluates the quality module, emphasising critical key parameters, justifies when guidelines are not followed, reference to other modules (e.g. toxicological qualification of impurities)

3333

Quality module, 1

DRUG SUBSTANCE (API)• General info (nomenclature, structure,

general properties)

• Manufacture (flow diagram, catalysators, solvents, temp., yields, etc.)

• QC of starting materials (standards and justification of the grade)

• Critical steps (identification and control)

34

Structure elucidation of new APIs – see the 3D structure!

furosemidSO2NH 2

HOOC

Cl

NH-CH2 O

paroxetin

35

Structure elicidation of new APIs

furosemidSO2NH 2

HOOC

Cl

NH-CH2 O

paroxetin

36

3D structure • Elucidation (abs. and rel.) – but not enough!• Assessment: other structure also present

impurity characterisation• Racemate or one single? (issue, PK, PD)

corporate decision: reveal it – hide it until PP expires? citalopram – escitalopram

• Stereochem. stability – If rapid interconversion: in vivo also possible

metabolism– If slow interconversion: take it into consideration at

PD and PK for the other form may have different action or at the toxicity studies (3 months + peri- és postnatal, minimum in 1 dose), as well as at planning human clinical trials

37

Physical structure• Particle size (issue: dosage-form,

significance?)– Dissolution, bioavailability? (PK)– During the processing?– Stability?– Content Uniformity (API-content in dosage-

form units)?– appearance?

Coated tablets under electron-

microscope

3838

Quality module, 2DRUG SUBSTANCE• Process validation (plans, limits, operational

parameters, etc.)

• Manufacturing process development (description, discussion, changes)

• Characterisation (impurities, reference to their toxicity, specification, test methods and validation, batch analyses, reference standards)

39

„Impurity rule”, ICH

• Unknown impurity should be noted:max. daily dose 1 g: 0.1%; 1 g: 0.05%

• Impurity should be identified: max. daily dose 1 mg: 1%; 1-10 mg: 0,5%; 10 mg-

2 g: 0.2%; 2 g: 0.1%

• Impusity must be toxicologically characterised:

max. daily dose 1 mg: 1%; 1-100 mg: 0.5%; 100 mg-2 g: 0.2%; 2 g: 0.15%

genotox. (in vitro mutagen. + kromoszóma-aberráció), egyszeri dózis, ismételt dózis 1-3 hó

40

Quality evaluation

Drug analysis!

Toxic degradation products, 1)• Acetilsalicylic acid (everobody knows?)

• cefalosporins

• oxitetracyclin

• PAS

• Fat emulsions...

41

Tetracyclin and its one toxic degradation product

H3C OH N-CH3

CH3

HO O HO O O

CONH2

OH

CONH2

OH

H3C N-CH3

CH3

HO OH O O OH H

tetracyklinepi-anhidro-tetracyclin

Renal complaints, tubular necrosis, reverzible Fanconi-syndrome

42

Quality evaluation

2) Anaphylactoid reactions of degradation products

• corticosteroids

• penicillins The ampicillin story

Studies in a Swiss hospital pharmacy

43

Corticosteroid-protein interaction

CH2-OH

C=O

HC=O

C=O

H2N

H2NCH-

cortiko-steroid

ox.

arginin-reziduum of human proteins

The new modified protein is taken as „foreign” by the human immune system and

antibody formation starts

44

The ampicillin-story

• Hungary, the early 80’s. The Paediatric Clinic (Budapest) notifies the regulatory authority: after administration of the (Bulgarian) Ampicillin injection there was a temperature elevation in children. It never occurred formerly when British Ampicillin injection was used

• ?• HPLC-analyses, withdrawal from the market.

International debate (won!), etc.• What happened?

45

Amino-penicillin decomposition product as eliciting antigen

• Beta-lactam of one penisicllin molecule reacts the amino group on the side chain of an other penicillin molecule, the beta-lactam of which reacts another side chain amino group, etc.

• oligomers (n = 4-8) formed this way)• (With which bonds)• These are still small molecules for antibody

formation, however, may react with existing penicillin antibodies giving rise to clinical manifestation of an anaphylactoid reaction (no clinical manifestation would occur in case of intect penicillin!)

• One of the symptom of the anaphlactoid reaction is: fever!

-CO-NH-, i.e. peptide!

46

Swiss hospital pharmacy study

• Comparison of penicillin infusion treatment

• Two groups– Penicillin injection into a large volume (1 litre)

infusion solution („inject the patient only once”), preparation the day before, stored in refrigerator

– Penicillin injection as bolus or in rapid infusion

• Significantly more hyeprsensitivity reactions in the first group!

47

Solvent residues, ICH

3 solvent classes:

1. To be avoided! benzene, chloro-ethanes…

2. To be limited chloro-methanes, methanol, ethylene glycol, acetonitrile…

3. Less toxic• Limits everywhere, depending on the single

and daily dose, but there are also absolute limits such as for acetonitrile 410 ppm

48

Solvent residues, examples

• Benzene (class 1!) e.g. may be side-product of a Grignard-reaction (Ph-Mg-halogenide, hydrolysis of its excess)

• The API is mesylate and the dosage-form has ethanol residues: ethyl mesylate is formed later (mutagenic)! (Methanesulfonate = mesulyte)

• In an application: loss on drying of an API”: 99.2% ethanol, 0.1% water. What can be the remaining part? Wasis absolute ethanol, the benzene is possible?

4949

Quality module, 3DRUG SUBSTANCE• Container and closure system (choice

of primary packaging, quality, dimensions, description of secondary)

• Stability (pre-approval forced degradation: types of studies, their justification; post-approval study plans, data and evaluation)

5050

Quality module, 4DRUG PRODUCT• Description and composition (all

constituents, their functions and qualities)

• Pharmaceutical development (compatibility of API with excipients, rationale, formulation development, manufacturing process development, container and closure, microbiological attributes, if appropriate)

5151

Just a word: are the excipients „inactive” regarding therapy,

and safe?

The CJD story

5252

Terms• Creutzfeld-Jacob Disease = CJD = fatal

neurodegenerative condition. Patients develop a rapidly progressive dementia associated with multifocal neurologic signs

• Sporadic CJD = sCJD, 1-2 cases per million people per year. Its cause is unknown.

(continued)

5353

Terms (continued)

• Variant CJD = vCJD = caused by prion (see BSE!) or iatrogenic way by contaminated human pituitary-derived growth hormone, gonadotropin, corneal transplants, etc.

• The casual link between vCJD and BSE is based on epidemiological, biochemical and transmission (animal) studies

(continued)

5454

Terms (continued)

• Bovine Spongiform Encephalopathy = BSE. Identified first in British cattle. Attacks the brain of the animal. The disease originated from the use of feed supplements contained meat contaminated with a TSE agent (mammalian derived protein)

• TSE = Transmissible Spongiform Encephalopathy = BSE, scrapie (in sheeps, goats)

(continued)

5555

Risk

• Human blood products

exclusion criteria for donation:

- CJD

- transfusion

- pituitary gland hormon therapy

• Vaccines produced in animals • Bovine, etc. derived materials used in

drug production

5656

Measures to minimise risk to humans from vaccines produced

in animals

• Selection of source countries: GBR Geographic BSE Risk (World Organization for Animal Health)

• Use of well-monitored herds

5757

Measures to minimise risk to humans from excipients from

animal sources

• Lactose from milk – appeared to be less/non infectious

• Gelatin (!) from bovine bone, skin…

(Animal, human) Tissue infecticity categories

5858

High-infectivity tissuesHigh-infectivity tissues

brain, spinal cord, retina, pituitary gland…

Lower-infectivity tissues

lymph nodes, large intestine, lung, perhaps blood

Tissues with no detected infectivity

placenta fluids, bone, skin, milk

5959

Gelatin• Skin gelatin: less dangerous than bone

gelatin• Bone gelatin: brain, spinal cord must be

excluded from source bone!• Alkaline hydrolysis better than acidic

treatment alone• Also: source country and non-infected

herd selection, certification (gelatin deliveries should be followed back to the source)

6060

Quality module, 5DRUG PRODUCT• Manufacture (each steps, batch formula,

process and IPC description, critical steps and their control, process validation, excipient control and its validation)

• Product control (specifications, justification, test methods, validation batch analyses, reference standards)

• Container and closure system

61

Importance of dosage-form characteristics (such as

dissolution)• …and the presentation of the

dosage-form development in the application dossier

• The nitroglycerol sublingual tablet story in Hungary

62

Nitroglycerol 0.5 mg sublingual tablets

• Angina pectoris attack– treatment– prevention (according to the personal

experience, to be used before/starting the provocation of the attack)

• Adjuvant therapy of acute asthma cardiale in urgent cases

• In acute myocardial infarct…

63

angina pectoris and nitroglycerol…

64

Nitroglycerol 0.5 mg sublingual tablets

• Hungary, early 80’s: the nitroglycerol API production temporarily blocked

• The Ministry of Health, to avoid shortages, imported „similar” tablets without prior checks or registration (that time it was possible)

• They appeared to be not „similar”!

65

The NG story

• The most of the complaints received to the „Soviet” tablet. There were two kinds of complaints– No therapeutic action– Too rapid and strong action

• The API content was in order• The regulatory authority developed a

special dissolution test (small volume dissolution media + HPLC)

66

NG 0.5 mg sublingual tablets0 1 2 3 4 5

Soviet

Roman0

20

40

60

80

100

Soviet

Polish

Hungarian

Roman

time (min)

Dis-solv-ed %

Well, which of the is „good”?

67

The question was wrong!

• Any of them can be „good”!• But you can toke take any according to

the another’s instructions!• Hungarian tablets: „when you feel the

attack is coming, place one tablet under your tongue. When the signs of the attack are over, take the remaining part of the tablet out of your mouth”

68

NG 0.5 mg sublingual tablets• The Soviet one was a „pastille”, it

disintegrated completely at once in the mouth by releasing all the NG. Then– If the patient swallowed it: the absorption

from the stomach is slower = „no action”– If not, all the active principle absorbed from

under the tongue at once: „too strong action”

• Remember to one of the former class hours: „Drug = product + information”!

6969

Quality module, 6DRUG PRODUCT• Stability (pre-approval forced degradation:

types of studies, their justification; post-approval study plans, data and evaluation)

• Literature references

7070

Nonclinical overview

30 pages. Critical evaluation. Comments on GLP status. Association with quality module (impurity pharmacology and toxicology)

• The structure follows that of the nonclinical written summaries

7171

Nonclinical written summary, 1

GENERAL GUIDANCE• Age- and gender-related effects should be

discussed• Animal exposure discussed in relation to that

in humans

• Species sequence (mouse-rat-hamster-rabbit-dog-primates-other)

• Route of administration sequence oral-iv-im-ip-sc-inhal-topical)

7272

Nonclinical written summary, 2

PHARMACOLOGY• Primary pharmacodynamics• Secondary pharmacodinamics• Safety pharmacology• Pharmacodynamic drug interactions• Discussion, conclusions• Tables, Figures

73

Pharmacology evaluation

Experimental pharmacology on

animals• What is the action? the pain test story

74

Hot plate test

• Hot-plate test: rat placed on a plate, itis warmed, the time (or temperature) when the rat licks its legs or jumps (indicating the warmth of the plate has been recognised) is recorded

• The better is the pain-killing effect the later (at a higher temperature) is the record

75

The hot plate test story

• Hungarian inventor: new substance, with a morphine-like pain-killing result

• Authority assessor: dose too close to LD50

• Assessment: the rat became sick with the high dose, if so: recognised the warmth later, but it is not a pain-killing effect!

76

The hot plate test story

• Pharmacology results can not be evaluated without taking the toxicology data into account!

• In general: all different data needed for the final evaluation!

7777

Nonclinical written summary, 3

PHARMACOKINETICS• Methods of analysis• Absorption• Distribution• Metabolism• Excretion• Pharmacokinetic drug interactions• Discussion, Tables, Figures

7878

Nonclinical written summary, 4

TOXICOLOGY• Rationale for the programme• Single-dose tox., Repeat-dose tox. (various

from 1 to 9 months), Genotox., Carcinogenecity, Reproductive tox., Studies in juvenile animals, others (e.g. dependence).

• Discussion, Tables, Figures

7979

Other nonclinical part

• Nonclinical tabulated summaries

• Nonclinical study reports

8080

Clinical overview

30 pages. Critical evaluation. Comments on GCP status. Association with safety module (toxic symptoms, interactions)

• The structure follows that of the nonclinical written summaries

8181

Clinical written summary, 1

• 50 to 400 pages

BIOPHARMACEUTIC studies• Development, in vitro-in vivo, dissolution

to develop bioavailability, anal. methods• Summary of individual studies,

comparison accross studies (possible effect of food…)

8282

Clinical written summary, 2

CLINICAL PHARMACOLOGY• Human PK, PD, in vitro studies on

human cells (dose-response, metabolism, dosage-ranging, single and repeated-dose PK, population PK)

• Immunogenecity (for proteins, e.g. vaccines)

• Clinical microbiology (if relevant)

8383

Clinical written summary, 3

CLINICAL EFFICACY

• The programme of controlled (and any other) studies, design, comparative efficacy, long-term efficacy

• Individual studies, comparison of results across studies (population, baseline characteristics, drop-outs, etc.)

8484

Clinical written summary, 4

CLINICAL SAFETY• Extent of exposure to the drug (population,

concomitant illness, etc.)

• Adverse events (common, serious, deaths, by organ and syndrome)

• Clinical Lab evaluations• Special groups and situations (ethnic,

alcohol-food, pregnancy and lactation, overdose, abuse, withdrawal, driving

8585

Clinical written summary, 5

CLINICAL SAFETY

• Post-marketing data (ADR reporting if it does exist in the country. Spontaneous or mandatory reporting)

86

Proof for safe use of a drug

• I.e. acceptable therapeutic effect/health risk ratio

• How it was established: we speak about different „levels of proof”

87

Levels of proof:I. Meta-analysis of randomised, controlled

clinical trialsIb. At least one randomised, controlled clinical

trialIIa. At least one controlled, non/randomised

clinical trialIIb. At least one open clinical trial III. Documented data on individual treatments,

evaluated by scientific methodsIV. Expert/regulatory Committees published

standpoint on the basis of evaluated literature data

88

Terms used

• Meta-analysis: statistical method to „pool” data generated in different clinical trials

• „Randomised”, „controlled”, „open”: see the lecture on clinical trials

• Level I. gives the highest, level IV. the lowest acceptable proof

• As a rule, minimum level Ib. is needed for the registration of a new drug in the Developed World. Herbal drugs: see later

8989

Complete application (new medicine)

• (ten)thousands of pages

• hundredMios of USD

9090

Application types

Not only „completely new”:

• Registered in another country

• Line-extension• Generic

9191

Line extension

• New strength, dosage-form...

• It is advisable to use the template of the complete application and explain what is missing and why

9292

Generics

“it shall not be required to provide results of toxicological and pharmacological tests and/or clinical trials if it is demonstrated that the product is essentially similar to a medicinal product authorised in the Member State concerned…”

9393

Generics

• PP and DE expired• Equivalence proven instead of pharmaco-

toxicology and CTs: bio-, farmacodynamic, clinical, evidence, in vitro

• cheaper!

time

C

9494

„Pharmaceutical equivalence”

• identical API

• comparable (administration) dosage-form

• strength?

only the same strength

two 50 mg tablets = one 100 mg tablet

½ 100 mg tablet = one 50 mg tablet?

95

Bioequivalence

• Equivalence established by pharmacokinetic (PK) method

• After administration of two (pharmaceutically equivalent) drug products: comparison of blood level – time curves

• Area under curve (AUC), the maximum concentration (cmax)and the time belonging to cmax (tmax) are compared, the maximu permitted differences specified

96

Pharmacodinamic equivalence

• Not only blood level could be measured for comparison in some cases, but e.g. blood pressure, body temperature…

• Rarely used

97

Equivalence by comparative clinical trials

• When no blood level or pharmacodynamic data could be measured

• E.g. comparing the two pharmaceutically equivalent drugs by treating 100-100 patients

98

Equivalence based on „evidence”

• E.g. two aqueous i.v. injections are, by definition, bioequivalent (shot into the vein: the drug is there!)

• Also, as a rule, oral aqueous solutions

99

Equivalence established by in vitro data

• Limited value! (Can the LADME be modelled by L exclusively?)

• Can be used e.g. for oral immediate release dosage-forms with an API that is highly soluble and permeable (see the Biopharmaceutical Classification System, BCS)

100100

Medicine assessment

• surely multidisciplinary business

• experts writing the summaries must emphasise the logics of the product development, preclinical study and CT strategy