National Drug Quality Assurance

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 1

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) 2

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 3

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 4

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 5

Further on, we speak about full Drug Registration (Bee careful, the EU and WHO/USA English may differ!) I use registration = marketing authorisation 6

Why is it important? The pharmacist always should speak about medicines. It were a pity not to know how they are assessed and authorised... 7

Moreover... There are always inventors Natural products in fashion Physicians’ or pharmacists’ new combinations The patient heard something(Internet!) 8

Medicine (assessment for) registration = = very complex (and interesting!) in nature, it is better to know it! 9

Medicine registration = marketing authorisation (EU terminology) Medicine Act: only authorised medicines may be used Marketing authorisation: the most frequent one 10

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 11

Medicine registration Legal side (both the regulatory authority and the Firm are concerned) Pharmaceutical/medical (professional) side (assessment: suitable to be medicine or not?) 12

Registration? • Product categorisation is it medicine? • Professional side is it suitable to be medicine? • Legal side civil service step with consequences 13

Professional side Assessment of the documentation (sample) submitted • Quality (substances and preparation) • Relative safety • Efficacy (risk/benefit) 14

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 ? 15

Before detailing the drug registration: • Intellectual Property rights (IP): Patent protection • Data exclusivity 16

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!) 17

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… 18

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 19

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) 20

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! 21

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 22

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 23

Doha arrengement • e.g. Canada, European Union signed • Labelling that would hinder re-export • e.g. HIV/AIDS medicines concerned 24

The art of medicine registration and assessment Documentation Expert Reports 25

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

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

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” 28

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 29

Structure and terms Structure for all parts: • Introduction • Overview: short description • Overall summary:  written  tabulated • Original study/trial reports EXPERT REPORTS 30

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 31

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) 32

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) 33

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

Structure elicidation of new APIs paroxetin SO2NH 2 furosemid Cl HOOC NH-CH2 O

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

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

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) 38

„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

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

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

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

Corticosteroid-protein interaction CH2-OH C=O HC=O C=O H2N H2N ox. CH- arginin-reziduum of human proteins cortiko-steroid The new modified protein is taken as „foreign” by the human immune system and antibody formation starts

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?

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!

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!

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

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?

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) 49

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) 50

National Drug Quality Assurance