Full Day Workshop

1. Manufacturing of Sterile Products
Session 2
Real Time Invisible Issues

2. Sterile Aseptic Products
Pharmaceutical Products that must
be sterile at time of use include
Injectables Opthalmics
Medical
Devices

3. Presentation Focus
1. Clean vs. Sterile
2. Non-viable particles
3. Viable particles
4. Dynamic strategy

4. Particles when enter in blood stream
Sterilization does
not guarantee
that the product
is clean

5. Particles when enter in blood stream
Death
Septicemia
Infection
Viable
Non-viable
Vein irritation
& phlebitis
Pulmonary
granulomass
Anaphylac
tic shock
Death

6. Particles when enter in blood stream
Injecting a product containing
particulate matter may result in
blockages of blood vessels, which
can result in stroke, heart attack
or damage to other organs such
as the kidney or liver. There is
also the possibility of allergic
reactions, local irritation and
inflammation in tissues and
organs

7. Lets identify the source of particulate matter
Dust
Glass
Rubber
Cotton fiber
Insoluble materials
Precipitates

8. Lets identify the other origination
of particulate matter
Preparation of the product
for administration
Product packaging
Production process & its
variables
Solution itself or its
ingredient
Personnel
Environment
Equipment
Production process &
its variables

9. 1994-US-FDA
Calcium phosphate precipitation
in TPN took lives
Autopsy confirmed micro-
vascular pulmonary emboli
containing calcium phosphate

10. Size of Particles & Challenge
2 um diameter particles may be
associated micro thrombi
formation, whereas, smallest
capillary blood vessels have 7
um diameter.
The visibility of particles from
naked human eye is
approximately 40 um

11. Clean Room
in which the concentration of
airborne particles is maintained

12. Clean Room
Design to provide
control of
environmental
factors
For particles
Temperature &
Humidity
Air flow pattern
Air pressure
differential
Containment of
hazardous aerosols

13. Source of Contamination
• Wall, floor, ceiling, paint,
spill, leaks
Facilities
• Skin, flakes cosmetics,
perfumes, clothing,
debris, hair, spittle
People
• Friction & wear
particles, lubricants &
emission, vibrations,
brooms, mops, duster
Toolgenerated
• Particulates flowing in
air (bacteria, organics &
moisture), floor finishes,
cleaning chemicals,
water
Fluid
• Glass flakes, clean
room debris, aluminum
particles, silicone,
Productgenerated

14. Aseptic Manufacturing Practices
Proper facility design
Proper material & Personnel Flow
Contamination Control
Environmental monitoring
Validation of aseptic processing
(e.g. media fills)

15. Aseptic Area Environmental Control
1
• Rinsing
2
• Cleaning
3
• Sanitization
4
• Disinfection
5
• Sterilization
6
• Depyrogenation

16. Managing an Aseptic Processing Area (APA)
Drug
Product
Sterilization
Process
Sterile Drug
Containers
Sterilization
Process
Sterile
Container
Excipient
Sterilization
Process
Sterile
Excipient
Closures
Sterilization
Process
Sterile
Closures
Contact
Surface
Sterilization
Process
Sterile Contact
Surface
S
t
e
r
i
l
e
D
P
Managing of all these steps is a real challenge for personnel

17. Managing an Aseptic Processing Area (APA)
O
P
E
R
A
T
O
R
Have to work/intervention in the critical area
(where the product is exposed to the
environment) while keeping product sterile
Fact: 1
Covered in microbes
Fact: 2
Major contributors
of particles

18. Managing an Aseptic Processing Area (APA)
What you found
Where you found
Atleast3logreduction
Efficiencyisnotmore
than4hours
Sanitization

19. Entry and Gowning Practices

20. Clean room Garments
People shed one layer of epithelial cells
every 24 hours ; 109 cells per day
People disperse 3.3x105 particles/min > 5um
in clean street clothes vs. 3.7x104
particles/min in clean room garments
(Averages based on 55 people measured in study)

21. Working in Aseptic Processing Area
Personnel
Knowledge
Ability
Skill

22. Working in Aseptic Processing Area
Atypical
Job
Heavy
gowning
Physical
Exhaustion
Technical
understanding

23. Working in Aseptic Processing Area
Very
important
Educational
background
K, A, S
Personal
attributes

24. People that are more successful in APA
Introverted
people
Avoid
talking
Not taking
in critical
area
Aptitude

25. Related Regulatory Citations
Operator performing
inoculation was
observed reaching
outside the bio-safety
cabinet
Employee did not
remove his sleeve cover
Technique issue

26. Related Regulatory Citations
Operator reached over
open, unfilled vials to adjust
filling needle/ bracket
without immediately
defecting the affected vials
Behavior issue

27. Related Regulatory Citations
Personnel intervention
SOP does not clearly describe the criteria to determine which
interventions are considered “significant” to require discarding
of product and/or the pulling of sterility sample
Only one instance had been recorded in the batch record
Intervention was not recorded in the batch record

28. Aseptic Processing
Grade A
Grade B
Grade C
Grade D

29. Air Classifications
Grade
A
Class
100 or
ISO 5

30. Critical Primary Operations
Formulation Filling Lyophilization

31. Critical Support Operations
Tank Cleaning,
Assembly &
Sterilization
Equipment
Cleaning, Assembly
& Sterilization
Stopper Washing &
Sterilization
Inspection (visual)

32. Stopper Processing
Washed and
sterilized by the
supplier
OR
Washed after
purchase from
supplier?

33. Aseptic Processing
The final quality level of finished product that is
produced aseptically will be no better than the
lowest quality processing step
During aseptic processing, each critical procedure
must be carried out flawlessly, otherwise
contamination of the finished product can occur

34. Aseptic Processing
Process simulations
(Media Fills) which
typically employ 5000 to
9000 containers, can only
confirm a SAL of 10-3 (at
the 95% confidence level)

35. Wrap up
Process,
Facilities
&
Design
Personnel
with
appropria
te K,A,S
Training
(Knowledge
based &
performance)
Monitori
ng
perform
ance
Effective
CAPAs
Aseptic
Process

36. Propofol (02nd April 2014)
Embedded particulate in neck
of glass vial
Free floating metal particles
Labetalol (16th May 2014)
Embedded particulate in neck
of glass vial
Visible floating particles
Dobutamine (14th May 2014)
Discolored solution
Embedded particle
in neck of glass vial
Particulate matter

37. Visible particulate matter found in
reserve sample units (hair, cotton
thread, metal)
• Cefoxitin & Dextrose
• 0.9% Na Cl (50, 100 & 1000 ml)
• Cefazolin & Dextrose
• Ceftriaxone & Dextrose
• Cefipime & Dextrose
• Amino acid etc. etc.

38. 27th Dec 2013.
Particulate matter
• 5% Dextrose Injection, USP
• 0.9% Sodium Chloride Injection, USP 50, 100
ml