CCK Discussion Forum on "Recall Affairs & NDMA Emergence"

1. Nitrosamines
Impurities
Failure, Challenge & Threat
CCK- Forum
Sunday, Oct 6th Karachi
Lecture
2

3. It reflects the views and understanding of presenter
& may not be construed to represent the views or
policies of organization or association to which
speaker has ties
Documents of US-FDA & Review Scientific
Articles are used to construct presentation
Disclaimer
Reference

4. Systems … Tissues
… Cell … Genetic
information
Human body
Harmonized,
Collaborated and
well integrated
Integrated
Respond to keep
life moving on with
its best
Immunity

5. Uncontrolled
growth of abnormal
cell in the body
Cancer
Substance that
promote Cancer
(Carcinogensis)
Carcinogen
Chemical agent
harms Genetic
information
Genotoxic

6. All genotoxic are not mutagen
But
All Mutagens are genotoxic

7. Mutation can cause cancer
But
Not always necessary so ..

8. Carcinogen can promote
Carcinogenesis
It is indeed formation of Cancer

9. As many mutation can cause cancer
therefore
Also likely to be carcinogen

10. A genotoxic agent damages
cellular DNA, resulting in
mutations or cancer.
Genotoxic are known to be
potentially mutagenic or
carcinogenic when inhaled,
ingested or penetrate the skin.
Genomics

11. AFLATOXIN
Most carcinogenic substance

13. APITransformation
Starting
material

14. Transformation Multiple Reactions
Reagent
Intermediate
Catalyst
Solvents

15. Reagent
Intermediate
Catalyst
Solvents
ImpurityByproducts

16. Impurity
Genotoxic
Carcinogenic
May be

17. N D M A
N-NitrosoDiMethylAmine
Zhejiang Huahi
Pharmaceuticals, China
Valsartan
A Global Recall due to an
unexpected impurity NDMA

18. Valsartan NDMA

19. NDMA
• Toxic known carcinogenic in lab
animal
• Used as poison
• The most recent food poisoning
case was of 2013 – 15

20. NDMA
• September 12, 2019
• Use of excessive heat generating
method to test the sample
• High level of NDMA reported
• An unannounced emergency launched
• Recalls & stop manufacturing
• Method validation challenged
• Recalls continued

21. What it is
? Yellow Odorless liquid
It was used to make rocket fuel
Unintentionally formed in air,
water, soil during various
manufacturing reactions
involving alkyl amines
Alkyl Amine
Widely distributed throughout
the environment

22. What it is
?
NDMA
Does not persist in the environment, break
down in sunlight in minutes

23. it enters in the human bodyHow
Breathe ContactEat Drink
Enters Blood & goes to many body organs in
minutes
Metabolize in Liver and leave the body within
24 hours through Lungs & Urine
?
?

24. March 2018
Risk assessment for any genotoxic
impurity
Helps in laying out the risk assessment
Agreed document issued; M7 (R1)
Control of DNA Reactive Impurities

25. June 2018
NDMA identified in one valsartan API
producer
Shaken all regulatory authorities & ICH
standards
Voluntary reporting

26. 13 July 2018
Zhejiang Huahai Pharmaceuticals,
Linhai, China
Manufacturing of API stopped &
investigation started
Voluntary recalls of products announced

27. 18 July 2018
Teva, Princeton, Actavis (Teva)
Stop distribution & change the medicine
NDMA impurity - Huge recall

28. 24 July 2018
Recalls expanded , panic elevated
List of valsartan products not impacted
is issued
Valsartan tested for NDMA

29. 27 July 2018
96 ng NDMA is considered reasonably
safe, < 1 in 100,000 may suffer
Panic tried to manage with scientific
evidences described in M7 (R1)
8000 people take highest valsartan dose
(320 mg/day) for 4 years …

30. 02 Aug 2018
Evaluation of process for unsafe
impurities continued
Review of manufacturing process &
change to those processes
Joint working focused to avoid NDMA in
future

31. 09 Aug 2018
Recall expanded, new list issued, Camber
Pharmaceuticals joined
Investigation expanded to other batches
Hetero Labs & Zhejiang are on the same
line, level higher in Hetero

32. 22 Aug 2018
Recall & Unrecall both lists issued
Method required validation on site
GCMS head space method released by
FDA to detect & quantify NDMA in
Valsartan

33. 30 Aug 2018
FDA, EDQM, EMA , HC, Japan
collaborated
Manufacturing process was challenged to see the
route of genotoxic impurity as by product
From where did the impurity comes in?

34. 13 Sep 2018
Investigation continued & expanded
Started looking for NDEA too
How impurity came in & how it may
affect patient health around the globe?

35. 28 Sep 2018
FDA inspection concluded
Reminded that it is manufacturer’s responsibility
too to develop & use method to detect impurities
Zhejiang Huahai – Import Alert issued
All APIs of the company stopped

36. 05 Oct 2018
Analytical report of different products &
materials issued by FDA
Expanded further
Number of products received attention

37. 11 Oct 2018
New method of GCMS issued
Research is committed for efforts to develop
direct detection method for NDMA & NDEA
detection
Method relatively more reliable for the
product

38. 16 Oct 2018
Commitment honored
Validation is always required
GC-MS/MS method issued

39. 30 Oct 2018
NDEA identified in Irbesartan in
FDA laboratory
SciGen for Westminister Pharmaceuticals
recalled their product
Aurobindo recalled all unexpired lots of
Irbesartan

40. 09 Nov 2018
Sandoz came in net of recall
Ringing bell was in full swing
Zhejiang Huahai API was used in
Losartan containing product

41. 21 Nov 2018
Mylan found door closed
Public question answers shared by FDA
NDMA & NDEA found in their valsartan
containing products

42. 06 Dec 2018
Recalls getting momentum
Updating of list for both groups
continued
Mylan, Teva expanded their recall

43. 11 Dec 2018
Warning letter issued to Zhejiang
Investigation & extensive testing
continued
Nitrosamine impurity was focused

44. 12 Dec 2018
Updated testing method
Method scope for API & product both &
for other ARBs
LOD was added

45. 19 Dec 2018
Interim limits for NDMA & NDEA were
issued for ARBs
26.5 ng/day was max. daily acceptable
intake of NDEA
96 ng/day was max. daily acceptable
intake of NDMA

46. 25 Jan 2019
A lot of recalls emerged & experienced
From where impurities came in remains a
question?
FDA conclusions does not diminish
concerns

47. 28 Feb 2019
NMBA interim limit established for all
96 ng/day, it is 2.4 ppm in Olmesartan
(40 mg/day daily max. dose)
96 ng/day, it is 0.3 ppm in case of
valsartan, (320 mg/day daily max. dose)

48. 01 March 2019
Another impurity NMBA comes in
Huge recalls again
Challenge elevated

49. 20 March 2019
NMBA 0.96 ppm to 9/.82 ppm
Drug shortage become a challenge
0.96 ppm ? This maintained supply

50. March 2019
Inspected Lantech, India
Failed to control associated risk with its
reuse … Import Alert imposed June 2019
Recovery of NDEA was investigated

51. 04 Apr 2019
40 ARB qualified without contamination
of Nitrosamines
Challenges grown & expanded all across
the world
FDA assessed and reported

52. 12 Jun 2019
Teva Pharmaceuticals, huge recall,
Hetero Labs, NMBA
No panic, FDA remind to contact
pharmacists & don’t stop taking drug
Losartan potassium

53. 26 Jun 2019
Macleods Pharmaceuticals, huge recall
No panic, FDA remind to contact
pharmacists & don’t stop taking drug
Losartan potassium & with HCTZ

54. 28 Aug 2019
Actual risk is likely much lower
than previously estimated
Exact number or real time cases not
yet established
320 mg daily for 4 years by 8000
people – 1 may get cancer

55. 28 Aug 2019
ICH not for managing changes &
revision
Expanding investigation foe similar
manufacturing processes of other drugs
etc.
ICH Q3A, 3C, 3D, Q7, Q11 & M7

56. 28 Aug 2019
Evaluate proposed process changes
Evaluate compliant & investigate the
issue that arise
Facility inspection, testing of samples

57. Thank You