Practical approach to meeting the new RDC nitrosamine

Practical approach to meeting the new RDC nitrosamine regulatory

guidelines

What is a nitrosamine?

FDA:

Nitrosamine impurities may increase the risk of cancer if people are exposed to them above

acceptable levels and over long periods of time, but a person taking a drug that contains

nitrosamines at, or below, the acceptable daily intake limits every day for 70 years is not

expected to have an increased risk of cancer.

Classical nitrosamines

X

Mutagenicity mechanism

• Carcinogenicity based on the fact that they can react with DNA base pairs after cytochrome P450-mediated

metabolic activation to form unstable α-hydroxymethyl-N-nitrosamines, which generate alkyl or aryl

diazonium ions as the final carcinogens.


The presence of O(6)-methylguanine in DNA

can be very harmful because methylation at

the O(6) position alters the hydrogen

bonding properties of guanine, thus inducing

G to A transition mutations. The (6) -MeG · T

is selected during replication instead of (or

preferentially) the O (6) -MeG · C pair.


EMA guideline

Sep/2019

Timeline

Valsartan

Recall

EMA, FDA

(NDMA) Jul/18

Apr/2019

ANVISA performed in loco

audits to evaluate

nitrosamines in products

which contain sartans

May/2019

Publication RDC 283

Investigation, control and

elimination of nitrosamines in

angiotensin II receptor

antagonists.

Aug/2018

Recall:

Valsartan,

Losartan e

Ibesartan

(NDEA)

Sep/2019

Recall of

ranitidine

Dec/2019

Contamination

of Metformine

(NDMA)

Ofício nº 3

Anvisa recommends

nitrosamine control by

drug manufacturers

Jan/2020

May/2019

pioglitazone

contamination

Feb/2020

Meeting between

Anvisa (GGFIS) and

regulated sector

• Official letter of entities

with evaluation proposal

and deadlineAnvisa

• Official Letter in response

to the entity Official Letter

- evaluation and

deadlines

• Mar/2020

Oct/2020

Starting ofworking

group

• Publication of the Draft for

contributions from entities

(15 days)

• extended term of RDC

283/19 - RDC 493/21

Apr/2021

Jun/2021

• Publication of Public

consultation 1050/21

Timeline

Jan/2021

Metformine call

Ofício nº 3

Anvisa recommends

nitrosamine control by

drug manufacturers

Jan/2020

• Started with EMA guidelines:

(ALL authorized human-use drugs that combine chemically synthesized APIs)

* Portfolio matrix

How Libbs deals with Nitrosamines?

2019 20202020 2021

Implementing

workflow

Step 1

• Risk assessment to identify products with a risk of N-nitrosamine formation or cross contamination.

Step 2• Confirmatory tests

Step 3• Control strategy

How to control nitrosamines?

Submitted: 27/03

12 369

Entities Request

Very high

High

Medium Low

Low

Very low

Very lowLow

Medium

Medium

Medium

High

HighVery high

Risk classification

Duration of Treatment

Max. Daily dose

Deadline for evaluation

MonthsCP 1050/2021

Dosagem Uso Crônico Pacientes tratados Risco Legenda

Baixo Não Baixo 0-Baixíssimo

Critério

Alto Médio Baixo

Baixo Sim Baixo 1- Muito Baixo Inferior Superior Inferior Superior Inferior Superior

Baixo Não Alto 1- Muito Baixo Dosagem >= 500 mg - - > 50 mg < 500 mg - - - <= 50 mg

Baixo Sim Alto 2- Baixo Utilização >= 120000 usuários - - - - - - - - - - - <= 119999 usuários

Médio Não Baixo 3- Pouco Moderado

Médio Sim Baixo 4- Moderado

Médio Não Alto 4- Moderado

Médio Sim Alto 5- Muito Moderado

Alto Não Baixo 5- Pouco Alto

Alto Sim Baixo 7- Alto

Alto Não Alto 7- Alto

Alto Sim Alto 8- Altíssimo

Entities Request

9 12 36

PRODUCTS

Months

Step 1





ICH M7(R1)

ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC)

IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL

CARCINOGENIC RISK

Risk Characterization

Exposure

Dose-response evaluation

Hazard Identification

DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery

Cross contamination Cleaning

validation

Packing material

Solvents DP Process

Cross contamination

Excipient

Excipient compatibility

Degradation

Degradation

Packing material


Exposure



Risk Assessment

WorkflowDMF

team

Analytical

Development

team

Packing

material

development

team

Multidisciplinary

team

Integrated risk analysis of

nitrosamine contamination

DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery


validation

Packing material

Solvents DP Process

Cross contamination

Excipient


Degradation

Degradation

Packing material


Exposure



Risk Assessment


Exposure



Risk Assessment

01

02Whichnitrosamine

can be formed?

ICH M7 Classification

Retrosynthesis

Nitrosating agent

How are nitrosamines formed?

Primary, secondary or

tertiary amine and

carbonyl derivatives

Condition

From secondary amines:

Classical mechanism

Gaur, P., & Banerjee, S. (2019). Oxone-sodium nitrite mediated N-

nitrosamines formation under mild conditions from secondary amines.

Synthetic Communications, 1–10. doi:10.1080/00397911.2019.1622733

2020 Webinar: Controlling a cohort - Understanding the risk of

nitrosamines within drug substance synthesis

The common feature of these methods seems to reside in the oxidative release of the known nitrosing agents HNO2 / NO + and subsequent

formation of N-nitrosamine by reaction with secondary or tertiary amines

Other mechanisms


Exposure



Risk Assessment

01

02Whichnitrosamine

can be formed?



Exposure



Risk Assessment

01

02

Whichnitrosamine

can be formed?


Mutagenicidade – Teste de Ames

Teste in vitro - em bactérias

Predição in silico

Carcinogenicidade

Teste in vivo

ICH M7 (R1), 2017

Classe

1

2

3

4

5


Exposure




Based on a slide of Fernanda Waechter. Lhasa

DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery


validation

Packing material

Solvents DP Process

Cross contamination

Excipient


Degradation

Degradation

Packing material


Exposure



Risk Assessment

DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery


validation

Packing material

Solvents DP Process

Cross contamination

Excipient


Degradation

Degradation

Packing material


Exposure



Risk Assessment

Classe

1

2

3

4

5

Carcinogenic impurities

Potentially mutagenic impurities

ICH Q3A e

ICH Q3B

Nitrosamines = 18 ng/day (cronic use) ou SAR



Exposure



DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery


validation

Packing material

Solvents DP Process

Cross contamination

Excipient


Degradation

Degradation

Packing material


Exposure



Risk Assessment

DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery


validation

Packing material

Solvents DP Process

Cross contamination

Excipient


Degradation

Degradation

Packing material


Exposure



Risk Assessment

Purge factor

Analytical results

Drying

Wash

Filtration

Centrifugation

Extraction

Reactivity

Can it be

washed?

Is it volatile?

Is it reactive?

API Impurity

Impurity level in the API or drug

2 Options


Exposure



Based on a slide of Fernanda Waechter. Lhasa

Exposure evaluation

Slide from Fernanda Waechter. Lhasa

Purge factor calculation

Initial concentration

Safe limit

Required

purge

Predicted level

Overall

predicted

purge


Acceptable intake

API dose


Safe limit

Purge Ratio

Overall predicted purge

Required purge

Purge ratio

https://www.youtube.com/watch?v=OnclED3e4jc&t=299s

Exposure evaluation

Purge factor 4.wmv

https://www.youtube.com/watch?v=OnclED3e4jc&t=299s

DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery


validation

Packing material

Solvents DP Process

Cross contamination

Excipient


Degradation

Degradation

Packing material


Exposure



Risk Assessment

DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery


validation

Packing material

Solvents DP Process

Cross contamination

Excipient


Degradation

Degradation

Packing material


Exposure



Risk Assessment

Acceptable

Limit

Impurity level in the API or drug

Control strategy


Exposure



* Startingmaterial

* Intermediate * API

Mutagenic impurity

• API specification control Option 1

• Intermediate specification control Option 2

• Intermediate specification control (Higher limit + purge factor)Option 3

• Purge factorOption 4

Control strategy

DS DP

Route of Synthesis

Water

IntermediateKSM

Reagents

Solvents

Materials recovery


validation

Packing material

Solvents DP Process

Cross contamination

Excipient


Degradation

Degradation

Packing material


Exposure



Risk Assessment

Risk Assessment of nitrosamines

Step 1





• Actions for confirmatory testing (Step 2) begin immediately after identifying therisk in Step 1.

36 months to carry out Step 2 and 3 (when applicable)

Validation according to RDC 166/17 or ICH Q2

The number of batches tested must to be stablished according to risk assessment

• High sensibility of methods:

Analytical partner deadline : 90 days for results

Prospecting for more partners

Step 2- Confirmatory test

According to CP 1050/2021

Step 1





• 2 Scenarios:

• Presence within limits

• Presence above limits

RECALL

Carry out corrective measures

E.g.: Process changes, replacement of API, excipient or packaging material

suppliers.

- Test inclusion in Drug Product or API control

Step 3 - Control

- benefit risk assessment should be considered before recall

According to CP 1050/2021

WorkflowDMF

team

Analytical

Development

team

Packing

material

development

team

Multidisciplinary

team

Quality

Monitoring

Team

Pharmacotechnical

Team

Lessons learnt

Lessons learnt

3 months to become effective

Absence / Presence of risk


Exposure



To investigate the risk, first you must to

understand the ROOT CAUSE, rather than

running random tests. The root cause can be

understood only through the scientific

knowledge behind each process.

Lessons learnt

-

Paulo Eliandro

e-mail: [email protected]

WhatsApp: 16-994493113

Thank you!

Questions?

mailto:[email protected]

Documents

Practical approach to meeting the new RDC nitrosamine