National Drug Quality Assurance

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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

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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)

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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

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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

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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

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Further on, we speak about full Drug Registration

• (Bee careful, the EU and WHO/USA English may
  differ!)
• I use registration marketing authorisation

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Why is it important?

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

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Moreover...

• There are always inventors
• Natural products in fashion
• Physicians or pharmacists
• new combinations
• The patient heard something (Internet!)

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Medicine (assessment for) registration

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

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Medicine registration marketing authorisation
(EU terminology)

• Medicine Act only authorised medicines may be
  used
• Marketing authorisation the most frequent one

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Other kinds of authorisation?

• Individual import or compassionate use (rare
  diseases, to a named patient or to a hospital)
• Donation (to hospital, pharmacists supervision
  advisable!)
• Clinical trial samples

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Medicine registration

• Legal side (both the
• regulatory authority and
• the Firm are concerned)
• Pharmaceutical/medical (professional) side
  (assessment suitable to be medicine or not?)

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Registration?

• Product categorisation is it medicine?
• Professional side is it suitable to be medicine?
• Legal side civil service step with consequences

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Professional side

• Assessment of the documentation (sample)
  submitted
• Quality (substances and preparation)
• Relative safety
• Efficacy
• (risk/benefit)

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Registration 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

?

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Before detailing the drug registration

• Intellectual Property rights (IP) Patent
  protection
• Data exclusivity

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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!)

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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

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Data exclusivity, 2

• as if it said I do not know what is in the
  innovators pre-clinical and clinical dossier
  submitted, however, for I Have proven the
  equivalence, take as I had submitted the same
  dossiers
• reference to the innovators data

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Data exclusivity, 3

• DE is to forbid the regulatory authorities to
  accept any reference to the innovators 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)

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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!

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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 Applicants declaration
  required that IP/DE rules were clarified and no
  violation found

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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 holders (BPH)
  consent needed
• BPH is given also royalty

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Doha arrengement

• e.g. Canada, European Union signed
• Labelling that would hinder re-export
• e.g. HIV/AIDS medicines concerned

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The art of medicine registration and assessment

• Documentation
• Expert Reports

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In drug assessment

• Work interdisciplinary
• Everything must be evaluated from every angle!
• (A fulsih exampleon the next slide)

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Everything must be evaluated form every angle!
Do you like this girl?
See it upside down. Do you still like her?
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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

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CTD
Not part of CTD
M1
Regional administrative info
Nonclinical overview
Clinical overview
Quality overall summary
M2
Nonclinical summary
Clinical summary
CTD
M3 Quality
M4 Nonclinical study reports
M5 Clinical study reports
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Structure and terms

• Structure for all parts
• Introduction
• Overview short description
• Overall summary
• ? written
• ? tabulated
• Original study/trial reports

EXPERT
REPORTS
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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

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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)

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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)

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Structure elucidation of new APIs see the 3D
structure!
paroxetin
SO2NH 2
furosemid
Cl
HOOC
NH-CH2
O
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Structure elicidation of new APIs
paroxetin
SO2NH 2
furosemid
Cl
HOOC
NH-CH2
O
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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

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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
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Quality module, 2

• DRUG 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)

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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
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Quality evaluation

• Drug analysis!
• Toxic degradation products, 1)
• Acetilsalicylic acid (everobody knows?)
• cefalosporins
• oxitetracyclin
• PAS
• Fat emulsions...

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Tetracyclin and its one toxic degradation product
CH3
CH3
H3C OH N-CH3
H3C N-CH3
OH
OH
CONH2
CONH2
HO O HO O O

HO OH O O O
H
H
epi-anhidro-tetracyclin Renal complaints, tubular
necrosis, reverzible Fanconi-syndrome
tetracyklin
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Quality evaluation

• 2) Anaphylactoid reactions of degradation
  products
• corticosteroids
• penicillins
• The ampicillin story
• Studies in a Swiss hospital pharmacy

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Corticosteroid-protein interaction
CH2-OH CO
HCO CO
H2N H2N
CH-
ox.
arginin-reziduum of human proteins
cortiko-steroid
The new modified protein is taken as foreign by
the human immune system and antibody formation
starts
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The ampicillin-story

• Hungary, the early 80s. 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?

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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!
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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!

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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

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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?

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Quality module, 3

• DRUG 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)

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Quality module, 4

• DRUG 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)

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Just a word are the excipients inactive
regarding therapy, and safe?The CJD story
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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)

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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)

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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)

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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

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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

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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

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High-infectivity tissues

• High-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

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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)

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Quality module, 5

• DRUG 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

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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

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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

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angina pectoris and nitroglycerol
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Nitroglycerol 0.5 mg sublingual tablets

• Hungary, early 80s 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!

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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)

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NG 0.5 mg sublingual tablets
Dis-solv-ed
Well, which of the is good?
time (min)
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The question was wrong!

• Any of them can be good!
• But you can toke take any according to the
  anothers 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

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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!

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Quality module, 6

• DRUG PRODUCT
• Stability (pre-approval forced degradation types
  of studies, their justification post-approval
  study plans, data and evaluation)
• Literature references

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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

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

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Nonclinical written summary, 2

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

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Pharmacology evaluation

• Experimental pharmacology on animals
• What is the action?
• the pain test story

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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

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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!

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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!

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Nonclinical written summary, 3

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

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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

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Other nonclinical part

• Nonclinical tabulated summaries
• Nonclinical study reports

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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

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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)

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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)

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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.)

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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

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Clinical written summary, 5

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

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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

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Levels of proof

• I. Meta-analysis of randomised, controlled
  clinical trials
• Ib. At least one randomised, controlled clinical
  trial
• IIa. At least one controlled, non/randomised
  clinical trial
• IIb. At least one open clinical trial
• III. Documented data on individual treatments,
  evaluated by scientific methods
• IV. Expert/regulatory Committees published
  standpoint on the basis of evaluated literature
  data

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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

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Complete application (new medicine)

• (ten)thousands of pages
• hundredMios of USD

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Application types

• Not only completely new
• Registered in another country
• Line-extension
• Generic

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Line extension

• New strength, dosage-form...
• It is advisable to use the template of the
  complete application and explain what is missing
  and why

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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

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Generics

• PP and DE expired
• Equivalence proven instead of pharmaco-toxicology
  and CTs bio-, farmacodynamic, clinical,
  evidence, in vitro
• cheaper!

C
time
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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?

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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

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Pharmacodinamic equivalence

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

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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

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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

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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)

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Medicine assessment

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

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