Agencija za lekove i medicinska sredstva Srbije

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Vršac, 14-15 Novembar 2014

Agencija za lekove i medicinska sredstva Srbije

Agencija za lekove i medicinska sredstva Srbije

IMPORTANCE OF PHARMACOIMPORTANCE OF PHARMACO--TOXICOLOGICAL EVALUATION TOXICOLOGICAL EVALUATION

OF INCREASED DRUG IMPURITIES AND PRESERVING DRUG OF INCREASED DRUG IMPURITIES AND PRESERVING DRUG

QUALITQUALITYY AND PATIENTAND PATIENT’S SAFETY’S SAFETY

V.StanimirovicV.Stanimirovic

Agencija za lekove i medicinska sredstva Srbije

ZNAČAJ FARMAKOLOŠKOZNAČAJ FARMAKOLOŠKO--TOKSIKOLOŠKE PROCENE TOKSIKOLOŠKE PROCENE

POVEĆANIH NEČISTOĆA U LEKU I OČUVANJE POVEĆANIH NEČISTOĆA U LEKU I OČUVANJE

KVALITETA LEKA I BEZBEDNE PRIMENE KOD KVALITETA LEKA I BEZBEDNE PRIMENE KOD

PACIJENTAPACIJENTA

V. V. StanimirovicStanimirovic

INTRODUCTIONINTRODUCTION

IND/NCEIND/NCEChemical and physical changes of active pharmaceutical ingredients (API) and drug products /DP/in the drug development process can affect both the safety and efficacy of drugsAbility to rapidly predict and assess the potential for drug product performance changes for impuritychanges for impurityformation formation and the associated associated safety safety concerns concerns are important parts of speeding the development of innovativedrug therapies without compromising quality.

GenericsGenericsWhen developing a generic drug productgeneric drug product , current regulations allow for flexibility in the choice of inactiveingredients used to design the product.Rationale/explanation for establishing impurity acceptance cr iteria include safety considerationsQualification pathway includes:

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Qualification pathway includes:1. Comparison to the brand or reference-listed product (RLD) using the same validated, stability-indicating analytical procedure2. Demonstrating that the impurity in question is a significant (human) metabolite of the drug substance, assuming there are no

quality or efficacy concerns with the level of the m etabolite3. Using appropriate scientific literature to justify a level as safe4. Evaluation of the impurity using toxicity studies

OTCOTCRegulatory and scientific challenges of impurities for over-the-counter (OTC) drug products have no beenhave no beenestablished established Nor FDA nor EMA do not perform any prenot perform any pre--approvalapproval assessment assessment of OTC monograph products beforecommercialization, there is a concern that these products may not meet current impurity monitoring expectationsRef. Karen M. Alsante et al.”Recent Trends in Product Development and Regulatory Issues on Impurities in Active Pharmaceutical Ingredient

(API) and Drug Products. Part 2: Safety Considerations of Impurities in Pharmaceutical Products and Surveying

the Impurity Landscape, AAPS PharmSciTech (# 2013), DOI: 10.1208/s12249-013-0061-z 3

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aggregates subunits fragments truncated proteins deamidated, oxidised, phosphorylated, sulfated or N-terminally cyclised products.

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General Toxicity StudiesSingle and repeated dose toxicity

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Recommended High Dose Selection

The current ICH guidance on impurity evaluation (Q3A and Q3B) provides guidance on how to identify genotoxic impurities but give no guidance on acceptable levels.

•What are acceptable levels of genotoxic impurities during drug development?

•What are acceptable levels of genotoxic impurities for marketing?

•Should those impurities be regulated differently that are likely to have threshold effects?

•Should levels of genotoxic impurities be regulated using a Threshold of Toxicological Concern (TTC) approach?

•Structurally related genotoxic impurities are likely to have similar

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•Structurally related genotoxic impurities are likely to have similar mechanisms of action. Should these be summed in calculating a TTC?

•What process of qualification testing should be followed for impurities that are metabolites?

•What additional data are needed to support having no special restrictions, or a higher acceptable daily intake than the TTC, for a genotoxic impurity?

Drug Substance & Drug Product impurity assessment :What impurities need to be assessed?Hazard assessment:How to assess whether impurities are mutagenic?Risk characterisation:What are acceptable intakes for mutagenic impurities?Control:What are appropriate options for impurity control drug

What impurities need to be assessed?

Synthetic Impurities

• Actual impurities that have been identified in DS

• Potential impurities likely to be present in the final DS including starting materials (SM), reagents, intermediates

• Assess risk of carryover into the DS of identified impurities in SMs and

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• Assess risk of carryover into the DS of identified impurities in SMs and intermediates

• For SMs introduced late in the synthesis of the DS the final steps of the synthesis should be evaluated

• Actual & potential degradation products

• All above products where the structures are known should be evaluated for mutagenic potential

Hazard Assessment

How to evaluate whether impurity is mutagenic?

For all actual and potential impurities where the structures are known:

• Conduct database & literature searches for genotoxicity and carcinogenicity data

or (if data unavailable)

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• perform a computational toxicology assessment using (Q)SAR* methodologies that predict DNA reactivity/ mutageni c potential (i.e., outcome of «Ames test»)

To follow up on a structural alert a bacterial muta tion assay can be performed• Testing material: appointed impurity should be used

• A negative bacterial mutation assay would reject an y structure-based concern. These impurities should be considered non-mutagenic .

*Quantitative structure–activity relationship models

Impurities Classification with Respect to Mutagenic and Carcinogenic Potentia l

and Resulting Control Actions

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«… application not expected prior to 18 months after publication.» (M7 Step 4 published June 2014)

• Exceptions to 18 month timeline:

• Ames tests should be conducted according to M7 upon publication.No need to repeat tests conducted prior to publication.

• Ph 2b/3 clinical trials started prior to publicatio n can be completed

Implementation of M7 Guideline

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• Ph 2b/3 clinical trials started prior to publicatio n can be completedup to and including marketing application submission and approval

• No need to complete with request for two (Q)SAR assessments, scope ofproduct impurity assessment and documentation recommendations

• For development of a commercial manufacturing process (that do not include Phase 2b/3 clinical trials), application of the above aspects would not be expected until 36 months after M7 publication.

HED /Human Equivalent Dose/

Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)July 2005 Pharmacology and Toxicology / ref.www.fda.gov/cder/guidance/index.htm /

provide common conversion factors for deriving a human equivalent dose (HED)

In a limited number of cases, animal pharmacokinetic data can be useful in determining initial clinical doses, but there are a number of unknowns regarding animal toxicity and comparability of human and anim al pharmacokinetics and metabolism:

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1. human bioavailability and metabolism may differ significantly from that of animals

2. mechanisms of toxicity may not be known (e.g., toxic accumulation in a peripheral compartment)

3. toxicity may be due to an unidentified metabolite, not the parent drug

4. animal data are not available in sufficient detail to construct a scientifically valid, pharmacokinetic model whose aim is to accurately project an MRSD /maximum recommended starting dose /.

Preclinical Safety Evaluation /pharmaco-toxicological evaluation /

No observed adverse effect levels (NOAELs) in the tested animal species has to be converted to HED /Human EquivalentDose /, on the basis of selection of the most appropriate animal species, and application of a safety factor

The algorithm is intended to be used for systemically administered therapeutics. Topical, intranasal, intratissue, and compartmental administration routes and depot formulations can have additional considerations, but similar principles should apply.

The process of calculating should begin after the toxicity data have been analyzed /ICH Topic Q3 (A). Other data (exposure/toxicity relationships, pharmacologic data, or prior clinical

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Other data (exposure/toxicity relationships, pharmacologic data, or prior clinical experience with related drugs) can affect the choice of most appropriate species, scaling, and safety factors.

The extrapolation of the animal dose to human dose should be done in one step by dividing the NOAEL in each of the animal species studied by the appropriate body surface area conversion factor (BSA-CF). This conversion factor is a unitless number that converts mg/kg dose for each animal species to the mg/kg dose in humans, which is equivalent to the animal’s NOAEL on a mg/m2 basis. The resulting figure is called a human equivalent d ose (HED). The species that generates the lowest HED is called the most sensitive species

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HUMAN EQUIVALENT DOSE

HED CALCULATION

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Factors that could influence the choice of the most appropriate species rather than the default to the most sensitive species include: (1) differences in the absorption, distribution, metabolism, and excretion (ADME)

of the therapeutic between the species, and (2) class experience that may indicate a particular animal model is more predictive

of human toxicity.

Factors such as whether an animal species expresses relevant receptors or epitopes may affect species selection (refer to ICH guidance for industry S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals)

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HED = animal NOAEL x (W animal/W human)(1-b)

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Figure 1. Formula for dose translation based on BSA .

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Reagan-Shaw S et al. FASEB J 2008;22:659-661

Copyright Federation of American Societies for Experimental Biology (FASEB). Please see the journal's copyright policies at www.fasebj.org to obtain permission to use this image.

Agencija za lekove i medicinska sredstva Srbije

PERSONAL EXPERIENCESPERSONAL EXPERIENCES

Agencija za lekove i medicinska sredstva Srbije

ALIMS

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Recombinant activated coagulation factor VII

Eptacog alfa (activated)

Ticagrelor Immunoglobuline (IgG-7S)

Fluconazole Piperacillin-tazobactam

Clavulanic acid Dihydroergotoxine

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Olanzapine Clopidogrel bisulphate

Vernakalant hydrochloride Bendamustine

Mycophenolic Acid Amlodipine besylate

Lidocaine hydrochloride

CONCLUSION As human bioavailability and metabolism may differ significantly from that of animals, drug toxicity may arise from exaggerated pharmacologic effects.

Mechanisms of toxicity may not be known and toxicity may be due to an identified or unidentified impurity/ies, not the parent drug / nevertheless if it is innovative or generic drug/.

Safety factor determined by animal toxicity studies and applied to the HED /Human Equvivalent Dose/ from the most appropriate species, could contribute selection of a pharmacologically active dose and maximum recommended therapeutic human dose

ZAKLJUČAK

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ZAKLJUČAK

Kako se bioraspoloživost i metabolizam kod ljudi značajno razlikuju u odnosu na životinjski, toksi čnost lekova može biti izraženija zbog naglašenih farmakoloških efekata u iv vivo ispitivanjima.

Mehanizam toksi čnosti ne mora biti poznat i može nastati zbog identifikovane ili neidentifikovane ne čisto će, bez obzira da li je to inovativni ili generi čki lek.

Faktor bezbednosti /Km/, odre ñen u animalnim toksikološkim studijama na najprikladnijem specijes u i inkorporiran u humanu ekvivalentnu dozu/HED/ doprinosi odre ñivanju farmakološki aktivne doze i maksimalno preporu čene terapijske doze kod ljudi.

ARE WE WORKING WITHIN THE BOUNDARIES?ARE WE WORKING WITHIN THE BOUNDARIES?

CRFAEs

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Protection of Company/Site ResourcesProtection of Company/Site Resources

AEsProtocol

Informed ConsentGCPs/SOPs

Regulatory DocumentsSource Document Verification

Internal Auditing

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THANK YOU

violeta.stanimiorvic @alims.gov.rs

Medicines and Medical Devcies Agency of Serbia -ALIMS