anvisa regulation draft on nitrosamines risk assessment

Anvisa Resolution-RDC on nitrosamines risk assessment and control of potentially

carcinogenic nitrosamines in APIs and drug products.

Public Consultation Nº. 1050, of May 31, 2021.

Guidance nº 50 version 1 .

Nayrton Flávio Moura Rocha

(COIFA)/GQMED/GGMED/ANVISA

Initial provisions and scope

This resolution establishes the rules for risk assessment,confirmatory testing and control of potentially carcinogenicnitrosamines in synthetic and semi-synthetic activepharmaceuticals ingredients (API) and in medicines for humanuse, as well as, in biological products, when applicable.

Chemically sinthesized fragmentsPackaging material (nitrocellulose )

Article 1º

The provisions of this resolution apply to regularized products as wellas new applications(petitions) for registration(market authorization)and post-approval of APIs and medicines.

The post-approval changes referred in this article are only those considered relevant to the formation of nitrosamines (§3º of Art.1º).

The non-compliance to any requirement in this resolution must be technically justified (Art.2º).

Registered(authorized),Notified or listed

It’s not expected a riskevaluation for non-related tonitrosamines post-approval

changes.

• Some of them are mutagenic, genotoxic and potentiallycarcinogenic compounds.

• Included in the group of high potency mutagenic carcinogens ICH M7 “cohort of concern” alongside with aflatoxin-like and alkyl-azoxy compounds.

• They are found in the water, grilled food, smoked food andvegetables.

• It is not expected to cause harm when ingested at low levels.

N-nitrosamines(or nitrosamines) are compounds characterized by a

nitroso group(-NO) bonded to an amine(>N-) group.

Andrew Thresher et al (2020), Regulatory Toxicology andPharmacology, Volume 116, 2020, 104749, ISSN 0273-2300,

Formation of nitrosamines

¹nitrous acid (HONO), reactive nitrogen oxide species (N2O3, N2O4, and ONOOH), species composed of an ON and strong nucleophilic moieties (ONCl,

ONBr, and ONSCN), and alkyl nitrites (RONO)

• Step 1 - Risk assessment (chapter II, section I)Investigation, identification and analysis of the risk arising from API route ofsynthesis, drug manufacturing process and the storage of the medicineregarding nitrosamines presence.

• Step 2 - Confirmatory testing (chapter II, section II)Only if the risk assessment suggests a risk of nitrosamines presence.

• Step 3 - Control of nitrosamine (chapter II, section III)Only if the presence of nitrosamine is confirmed in confirmatory tests.

GENERAL PROVISIONS (Chapter II)

Risk management (Section I)

Step 1 - Risk assessment

Article 4º of Public consultation nº 1050 de 31/05/2021

I- reagents and other materials;

II- recovery of materials;

III- degradation of materials;

IV- cross contamination between processes and

V- production process, including theoretical interaction between API, excipient and packing.

Article 4º §2º The investigation must include the evaluation of any potentially carcinogenic nitrosamine presence, according to precursors or conditions for its formation

Risk assessment must include:

The objective of the risk assessment is to answer the questionsbelow:

What is the risk of nitrosamine formation in the API route of synthesis, considering

the combination of reagents, solvents, catalysts, starting materials, intermediates,

impurities and degradation products?

What is the risk of contamination by nitrosamines (from recovered materials such

as solvents, reagents and catalysts, equipment, starting materials or

intermediates)?

What is the risk of nitrosamine formation during manufacture of the finished

product or during storage throughout its shelf life

objective

Possibilities to generate nitrosamines in API route of synthesis

Raw materials and impurities in raw materials

Raw material : Triethylamine - amine

+ NaNO2 - nitrosating agent

N-Nitrosodiethylamine - nitrosamine

Raw material : Isopropylamine – primary amine

+ NaNO2 - nitrosating agent

Impurity in raw material : diisopropylamine – secondary amine

N-Nitrosodiisopropylamine – nitrosamine

H

N

CH3

CH3

O

+ H2O

H+ ou OH

-

Δ

H OH

O

+ NH

CH3

CH3

N

N CH3

CH3

O

NaNO2 / HX

dimetilformamida - DMF

dimetilamina - DMA

dimetilnitrosamina - NDMA

Amines as degradation products from solvent.


Dimethylformamide(DMF)

N-Methyl-2-pyrrolidone (NMP)

Solvent: Dimethylformamide (DMF) - amideH

N

CH3

CH3

O

+ H2O

H+ ou OH

-

Δ

H OH

O

+ NH

CH3

CH3

N

N CH3

CH3

O

NaNO2 / HX


dimetilamina - DMA


dimethylamine (DMA)

Hydrolysis

H

N

CH3

CH3

O

+ H2O

H+ ou OH

-

Δ

H OH

O

+ NH

CH3

CH3

N

N CH3

CH3

O

NaNO2 / HX


dimetilamina - DMA


N-nitrosodimethylamine(NDMA)

H

N

CH3

CH3

O

+ H2O

H+ ou OH

-

Δ

H OH

O

+ NH

CH3

CH3

N

N CH3

CH3

O

NaNO2 / HX


dimetilamina - DMA


Nitrosating agent

N

O

H+ ou OH-

Δ, H2OHO

N

O

H

HO

N

O

N

O

NaNO2 / HX

metilpirrolidona - NMP

ácido N-metil-4-aminobutanóico

carboxipropilmetilnitrosamina - NMBA

N

O

H+ ou OH-

Δ, H2OHO

N

O

H

HO

N

O

N

O

NaNO2 / HX




Hydrolysis

N

O

H+ ou OH-

Δ, H2OHO

N

O

H

HO

N

O

N

O

NaNO2 / HX




4-methylaminobutyric acid(MBA)

N

O

H+ ou OH-

Δ, H2OHO

N

O

H

HO

N

O

N

O

NaNO2 / HX



carboxipropilmetilnitrosamina - NMBAN-nitrosomethylamino butyric acid

(NMBA)

Nitrosating agent

Nitrosamine formed from catalyst


Calalyst: tetrabutylammonium bromide (TBAB)

Possible presence:Tributylamine(TBA) Dibutylamine(DBA)

Nitrosating agent

N-nitrosodibutylamine (NDBA).

NOx

Nitrosamine as degradation product


API: Ranitidine

N-nitrosodimethylamine (NDMA)

H

N

CH3

CH3

O

+ H2O

H+ ou OH

-

Δ

H OH

O

+ NH

CH3

CH3

N

N CH3

CH3

O

NaNO2 / HX


dimetilamina - DMA


Degradation

• Poor quality solvents

• Limited controls or unappropriated defined specification limits for recycled solvents

• Water (presence of nitrosating agents)

Where is the solvent recovered from ?

Same manufacturing plant ?Same API ?Same step ?

Is the proposed specification justified ?

Possibilities of contamination with nitrosamines in API route of synthesis

Purge of nitrosamines

Similar to ICH M7 option 4 approach.

Possibility of overestimated purge factor in certain cases

Analytical data may or may not be necessary in view of resultsobtained.

Burns, M. J., et al. (2019). "New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities." Organic Process Research & Development 23(11): 2470-2481.

Teasdale, A., et al. (2013). Organic Process Research & Development 17(2): 221-230.

What is the risk of nitrosamine formation in the manufacture of the

finished drug product or during its storage throughout shelf life ?

Yongmei Wu et al (2011); Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility AAPS PharmSciTech. 2011 Dec; 12(4): 1248–1263doi: 10.1208/s12249-011-9677-z

Presence of nitrites in excipients

Degradation of API

Packaging materialLiberation of nitrogen oxides from nitrocellulose and subsequent

nitrosating of amines in the printing drug ink.

Confirmatory testing

If there is a possibility of nitrosamines presence, companies must carry out confirmatory tests in order to confirm or refute the presence of

nitrosamines in the API or finished product.

Section III, Chapter II

Confirmatory testing

Validated methods in line with RDC nº166/2017 or ICH Q2 should be adopted

Only applicable if the risk assessment suggests the possibility of nitrosamines presence

The confirmatory testing must be carried out as soon as possible after the risk assessment verifies the risk of nitrosamines

If there is a possibility of nitrosamines presence, companies must carry out confirmatory tests in order to confirm or refute the presence of

nitrosamines in the API or finished product.

Confirmatory testing - batches to be tested

For already marketed products, a minimum of 10% of annual batches, or 3 batches per year, whichever is greater, must be

properly sampled and tested.


If less than 3 batches are manufactured in the year, all manufactured batches must be tested.

For already marketed products, a minimum of 10% of annual batches, or 3 batches per year, whichever is greater, must be

properly sampled and tested.

If more than one manufacturer, manufacturing process and/or sources of major risk-related materials used, more batches should be tested in order to cover all risk factors.

When the possible nitrosamines are degradation impurities, at least 3 representative batches of product’s shelf life should be tested.

Other technically justified approaches may be accepted


However, for petitions that require less than three batches, the implementation will beconditioned on the company's commitment to test the implementation batches also later, inorder to complete the 3 required batches.

These data must be available for presentation to Anvisa, when requested or during inspection.

For new registration or post-approval petition(application), the number of batches to be tested must be consistent with the

quantity required by the current legislation.

Confirmatory testing - Results

It’s admitted the absence of nitrosamines when it is below 10% of the acceptable intake(AI) limit*.

Validated methods with suitable sensitivity to confirm or refute the nitrosamine presence must be used.

Limit of detection(LOD) or limit of quantification(LOQ): ≤ 10% do limit of AI.

If the results are above of 10% of AI the nitrosamine control must be included.

Other approaches can be justified, not exceeding the 30% limit.

Control of nitrosaminesIf the presence of nitrosamines is confirmed, and if it is within the acceptable limits, a control strategy must bedefined and the registration holders (product market authorization holders) must, when applicable, includecontrol of nitrosamine in the API or drug product, according to specific petitions to be publicized.

- I - Inclusion of critical control test for nitrosamines in the finished product;

Section III, chapter II

- II- Inclusion of the nitrosamine control test in the API with CADIFA;

- III- Inclusion of the nitrosamine control test in the API without CADIFA

Additional post-approval changes may be necessary due to the actions demanded for risk mitigation and will be treated according to the regular procedures.

If more than one nitrosamine needs to be controlled in the specification of the API or the finished product, the limits must be adjusted in order to ensure the maintenance of negligible risk.

Control of nitrosaminesIf the presence of nitrosamines is confirmed, and it is above the established acceptable intake, the companies mustimmediately suspend manufacturing, distribution, marketing, use and the manipulation of the drugs or APIsinvolved, and:

- I - segregate the stock in the company;

Section III, chapter II

- II - recall the batches of medicines and the API;

- III- notify Anvisa within 48 (forty-eight) hours .

If the company chooses to maintain the product in the market, it must protocol the relevant post-approval changes to make the product suitable for human use.

Limits for single known nitrosamines

Abbreviation Nitrosamine CAS Acceptable intake (ng/dia)NDMA* N-Nitrosodimethylamine 62-75-9 96,0

NDEA* N-Nitrosodiethylamine 55-18-5 26,5

EIPNA** Ethylisopropyl-N-nitrosoamine 16339-04-1 26,5

DIPNA** N,N-diisopropylethyl-N-ethylamine 601-77-4 26,5

NMBA** N-Nitrosomethylaminobutyric Acid 61445-55-4 96,0

MeNP** 1-Methyl-4-nitrosopiperazine 16339-07-4 26,5

NDBA** N-Nitroso-di-n-butylamine 924-16-3 26,5

NMPA* N-Nitrosomethylphenylamine 614-00-6 34,3

*Limit calculated on the basis of harmonic mean TD50 derived from carcinogenic potency database (CPDB) **Limit derived using structure-activity-relationship (SAR) /read-across approach

Determination of acceptable limits or AI (Acceptable Intake) of the nitrosamines listed above was based on the specificcalculation guidance for each compound provided in ICH Guide M7(R1) and harmonized with limits already accepted byother regulatory authorities (EMA 2020, FDA 2020).

Limits for single known nitrosamines

maximum daily dose (mg)

acceptable intake(ng)Limit (ppm) =

500 mg

26,5 ngLimit (ppm) = = 0,053 (ppm)

New nitrosamines

Determination of specific limit based on carcinogenicity studies, when available.

For TD50-based limit determination of carcinogenicity studies, these studies should meet quality androbustness criteria as described in ICH Guide M7(R1), for example, studies with multiple doses (atleast 3 groups) and 50 animals per dose by sex.

In cases where carcinogenicity studies are not available, it is recommended to derive a limit based onstructure-activity relationship (SAR) approach considering the known nitrosamines

Apply a specific TTC for the class of nitrosamines of 18 ng/day

Calculation of limit when more than one nitrosamine is identified

Option 1 – The total amount of all N-nitrosamines in the product should not exceed the limit of the mostpotent nitrosamine identified in the product.

For example, the sum of NDMA and NDEA can be controlled at maximum intake of 26,5 ng/day

Option 2 – The individuals limits of each nitrosamine are adjusted to ensure that total risk of exposure does not exceed the negligible risk.

Calculation of limit when more than one nitrosamine is identified

Option 2 – example:

7,95 ng/day(30% NDEA AI)+

67,2 ng/day(70% NDMA AI)

Less Than Lifetime Approach

Duration of treatment < 1 month 1 - 12 months 1 - 10 years > 10 yearsFator to be applied 80 13,3 6,7 1,0

Acceptable Daily Intake(ng/day)

Duration of treatment fator

Maximum daily dose (mg/day)

Acceptable limit (ppm)

Bercu, J., et al. (2021). “Use of less-than-lifetime (LTL) durational limits for nitrosamines: Case study of N-Nitrosodiethylamine (NDEA)” Regulatory Toxicology and Pharmacology 123: 104926.

N-nitrosodiethylnitrosamineAcceptable intake

Less Than Lifetime Approach

Duration of treatment < 1 month 1 - 12 months 1 - 10 years > 10 years

Factor to be applied 80 13,3 6,7 1,0

2000 mg

26,5 ngLimit (ppm) = = 0,01325 ppm x 80 = 1,06 ppm

Maximum Daily DoseFactor

< 1 month

Limit

Acceptable Daily Intake(ng/day)

Duration of treatment fator

Maximum daily dose (mg/day)

Acceptable limit (ppm)

The sequence of risk assessment to be carried out by companiesshould be stablished based in a risk matrix in order to categorize theproducts as "very high", "high", "medium", “low” and “very low” risk.

Treatment duration

Maximum daily dose > 1 year 1 a 12 months ≤ 1 month

>1000mg very high high medium

100mg to 1000mg Alto medium low

<100mg medium low very low

Consulta Pública nº 1050 de 31/05/2021

Public consultation nº 1050 de 31/05/2021

(Art.4º§3º)

Art. 12. Companies must comply with the requirements set forth in this resolution from the entry into its force, and within:

I - nine (9) months for risk assessment of products classified as “very high” risk;

II - 12 (twelve) months for risk assessment of products classified as "high” risk;

III - 36 (thirty-six) months for risk assessment of all other products; and,

IV - 3 (three) years from the conclusion of the risk assessment, to carry out the confirmatory tests and protocol for post-approval change petitions necessary.

Art.13 ANVISA may request the risk assessment of a any nitrosamine in a period prior to that described in this Resolution, if there is evidence of toxicity.

This Resolution enters into force 30(thirty) days after the date of its publication

Deadlines

Section IV

Thank you

[email protected]

anvisa regulation draft on nitrosamines risk assessment

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