The document discusses four case studies related to excipient safety assessments: 1) Bridging higher amounts of a polymer excipient based on existing toxicity data for other grades. 2) A case where chronic toxicity data was lacking for an excipient in a chronically used tablet. 3) A case where the proposed grade and amount of a polymer excipient in an oral suspension lacked safety data for the specific grade and pediatric population. 4) A case assessing the safety of several excipients, including flavors and preservatives, in a buccal film formulation based on existing data for other routes of administration.

1. E X C I P I E N T S
Criticality & Vitality in
Drug Product Performance & Claim
Obaid Ali & Roohi B. Obaid
104-CCK Forum at Regent Plaza, Karachi, 16 Feb 2020

3. Regent Plaza, Karachi, Sunday the 16 Feb 2020
CCK Forum

4. Acknowledgement
Robert T. Dorsam, OGD, FDA
PDA & IPEC Documents - 2020

5. Is bottle an excipient
?

6. Is water an excipient
?

8. Formulation
Drug ExcipientsExcipients

9. Active Pharmaceutical
Ingredients
Ingredients used in
Pharmaceuticals

10. Active Pharmaceutical
Ingredients
Ingredients used in
Pharmaceuticals
GMP - DMF - Oversight ? ?

11. Generic Drug Considerations

12. Available non clinical safety
information
Excipient grade & route of
administration
Maximum intake levels
Excipient Safety
Review

13. Route, dose, duration of use, existing
safety information, patient population,
drug toxicity & disease
Excipient Safety
Assessment

14. Key Question

15. Key Question
Will the excipient change the safety profile
of the proposed drug when compared
to the Reference (Innovator) ?

16. Pre IND

17. Pre IND

18. Pre IND IND

19. Pre IND IND
Clinical – Pharmacology – Toxicology – Chemistry,
Manufacturing Controls – Clinical Pharmacology

20. Pre IND IND
Clinical – Pharmacology – Toxicology – Chemistry,
Manufacturing Controls – Clinical Pharmacology
IND

21. Pre IND IND
Clinical – Pharmacology – Toxicology – Chemistry,
Manufacturing Controls – Clinical Pharmacology
IND

22. Pre IND IND
Clinical – Pharmacology – Toxicology – Chemistry,
Manufacturing Controls – Clinical Pharmacology
IND 1

23. Pre IND IND
Clinical – Pharmacology – Toxicology – Chemistry,
Manufacturing Controls – Clinical Pharmacology
IND 1 2

24. Pre IND IND
Clinical – Pharmacology – Toxicology – Chemistry,
Manufacturing Controls – Clinical Pharmacology
IND 1 2 3

25. Pre IND IND
Clinical – Pharmacology – Toxicology – Chemistry,
Manufacturing Controls – Clinical Pharmacology
IND 1 2 3 NDA

26. Bioequivalence
Reliance on Prior findings of Safety
& Efficacy
Less qualifying data is required
ANDA

27. Argument to support safety &
efficacy data of innovator studies for
your generic
Bridging

28. Acute toxicology, ADME, Genetic
toxicology, etc. (14 days or less)
Repeat dose toxicology in two
species (14 to 90 days)
6 month general toxicology on
rodents & 9 month on non-rodents, 2
year carcinogenic study on two
species (90 days or recurrent)
Route, Dose &
Duration

29. Large polymers that differ from previously
characterized excipients only in molecular
weight (chain length) can be adequately
characterized in an abbreviated manner using
less safety data, provided that the new excipient
and the previously studied excipient are
sufficiently similar with regard to physical state,
pharmacokinetics, and levels of unreacted
monomers and other impurities.

30. Large polymers that differ from previously
characterized excipients only in molecular
weight (chain length) can be adequately
characterized in an abbreviated manner using
less safety data, provided that the new excipient
and the previously studied excipient are
sufficiently similar with regard to physical state,
pharmacokinetics, and levels of unreacted
monomers and other impurities.
Case by Case Basis

31. Reduce animal usage
On the other hand, safety to target
organs, tolerability & signals
Why Bridging
Justification

32. What safety data exist and what is
being bridged?
Clear statement of physical/chemical
properties
Differences from other excipients if
intending to bridge
Data

33. Is it relevant to
the proposed product?
Route of
Administration

34. How are doses in studies relevant to
your proposed product?
Dose Relation

35. Justify the studies of innovator
product will not adversely impact to
patient with your product?
One more
Patient population & context of use is
also important
Chronicity

36. Case 1
Bridging
Excipient Grade & Amount

37. CNS stimulant: chronic oral product for
children to adults
Safety of 80 mg copolymer grade X/day
Physical/chemical properties of copolymer,
available supportive data, included in IIG
Higher amount
of Polymers
1 2 3

38. Poorly absorbed and well tolerated in general
toxicology study up to 6 months in rodents
alone
Negative across several genetic toxicology
studies
No safety signal in developmental &
reproductive toxicological data
Higher amount
of Polymers
1 2 3

39. 37.5 mg of polymer grade X is approved in
another product for chronic oral use
The RLD had different grades of same
polymer at higher amounts
Pharmacology/Toxicology data for polymer
grade X lacked 2-species chronic tox but had
considerable safety information
Higher amount
of Polymers
1 2 3

40. The proposed amount 80 mg was acceptable based on
totality of information as well as
Pharm/tox information, prior use, similarity with other
grades at higher levels

41. Case 2 Data Gap for Chronic Toxicity

42. An excipient is not included in IIG
Non-clinical safety justification based on
published literature
Minimal information exist on specific
compound
Genetic & acute general toxicology on
compounds with different molecular size &
variable substitution of same class
Chronically
used Tablet
(Adult)
1 2 3

43. Compound is an approved for topical product
Toxicology & carcinogenicity was creating
gap
Post marketing requirement was an option
Published data was inadequate for chronic
toxicity assessment
Chronically
used Tablet
(Adult)
1 2 3

44. Meetings, commitments offered
Chronically
used Tablet
(Adult)
1 2 3

45. Insufficient to bridge
May remove excipient from formulation or qualify
toxicity and carcinogenicity concerns

46. Case 3 Grade & Patient Population

47. Oral suspension for chronic use
Two year and above
Non-clinical toxicological summary consisted
of data from various excipients in class
ranging in molecular weight
900 mg
Excipient/day
1 2 3

48. Polymer was negative for genotoxicity, low
absorption
NOAELs available in rodent studies for
various grades
53 mg excipient approved in another dosage
form
900 mg
Excipient/day
1 2 3

49. Molecular weight is lower of the excipient
than evaluated in available information
Absorption of this grade is not characterized
900 mg
Excipient/day
1 2 3

50. Safety information is deficient
Proposed level is 18 folds higher than approved level for
this route. Safety in peadriatics is not addressed

51. Case 4
Bridge for
Route of Administration

52. Proposed formulation is a film
Requires assessment of safety for both local
and potential for systemic toxicity
9 excipients were consulted including flavors
& preservatives that are used in the buccal
film.
Buccal Route in
adult population
1 2 3

53. Physical description of excipient and
published safety information was provided
Evidence of systemic exposure & local safety
in clinical and non-clinical information were
reviewed
Genetic toxicology was assessed
Buccal Route in
adult population
1 2 3

54. Several excipients were resent in similar
approved products
Similar use in other flavors were reviewed
Low probability of absorption
Buccal Route in
adult population
1 2 3

55. All excipients in buccal film were acceptable based on
evidence of local & systemic safety
Each case is unique but similar principle applies

56. Some excipients could interfere with
analytical methods used for the control of the Active
Pharmaceutical Ingredients (API)

57. Thanks