This document discusses an investigation into adverse drug reactions caused by two different drug manufacturers using the same active pharmaceutical ingredient (API). The investigation found fundamental failures in good manufacturing practices at both the API manufacturer and drug product manufacturers. Specifically, the API manufacturer did not adequately validate and control their manufacturing process or water systems. This likely led to endotoxin contamination during the final washing steps. Samples from the API batches were found to contain pyrogenic and endotoxin levels above acceptable limits. Around 200 adverse drug events were reported after administration of the contaminated drugs. The manufacturers faced recalls, market withdrawals, and import detentions until major changes were made to comply with good manufacturing practices.

1. Regulatory Science of
Sterile Manufacturing Process
Obaid Ali
August 2018
Case Study - 02

2. Parenteral Grade Drug Substance
Pyrogenicity
Ref: Richard. L. Friedman,
US-FDAApril 2005 (PDA)

3. Pyrogenic
Shock
One API used by two different
manufacturers for their own drug
products
Both caused numerous adverse
drug reactions including pyrogenic
reactions

4. API
Used to manufacture both
injectable and oral dosage forms
All tests prescribed in USP are
routinely followed & compliant

5. API
Produced by a multistep process
Fermentation, Purification
& Isolation

6. API Deionized Water used for
Equipment cleaning
Dissolution step
Washing solvent

7. Unsuitable water in final
processing step
Validation was not done upon scale up & multiple
significant changes implemented

8. The equipment usage log for spray dryer was
not maintained
Same person signed as operator & checker for a
batch step in many instances

9. Record was rewritten without
explanation
Possible contributor of endotoxin had
not been evaluated

10. Potential capability of the process to destroy
or remove endotoxin had not been evaluated
Opportunity for endotoxin reduction in
the process did not exist

11. Composite testing was used to keep
endotoxin in acceptance limit
Laboratory failed to perform endotoxin control
required by the USP - BET

12. Water used for purification step & final rinse
was not tested for total microbial count
No procedure exist to characterize
the microorganisms

13. Impurity tests of the finished API were
not validated
Interestingly, HPLC system suitability test was
performed monthly

14. Complaint of ADR was not
adequately scrutinized
Strength of root cause analysis & CAPA
was questionable

15. Multiple quality system elements of
API manufacturer were objectionable
Manufacturer’s material system
became questionable by default
Inadequate raw material is often named as
root cause of product quality failure

16. The origin of product
problemRaw Material
Variability
Defects, product loss,
rejection or recall

17. The material system should
provide on going assurance
of acceptable
Compliant
Quality System
Raw Material Quality

19. Fundamental failure of GMP at API site &
Material System at FG Manufacturer site
Same manufacturing approach adopted by the
API manufacturer for parenteral & oral dosage
forms
1
2

20. Written assurance of process or laboratory
control
Unacceptable water system & standards
3
4

21. Greatest amount of endotoxin was contributed
during the final wash of crude active
Additional contribution of endotoxin might
have occurred during other steps
5
6

22. Rinse water with
significant endotoxin
load was used to wash
(clean) product contact
surface

23. Pyrogenic test &
endotoxin test found
positive by the FDA in
some samples picked
from discrete part of
drums

24. Some samples found
non-pyrogenic &
significant potential of
intrabatch variation
due to lack of process
control

25. About 200 ADE were
reported by the
medical practitioner
upon administration of
the contaminated drugs

26. Recalls & market
withdrawal of API and
Finished product

27. Import detention for
multiple years unless
reaches minimal
compliance with GMP

28. New owners,
assistance of
consultants & major
changes brought back
the company & it took
not days but years &
end up with change of
management