manufacturing of sterile products session 2 of 3-oa-13 may 2015
TRANSCRIPT
Manufacturing of Sterile Products
Session 2
Real Time Invisible Issues
Sterile Aseptic Products
Pharmaceutical Products that must be sterile at time of use include
Injectables OpthalmicsMedical Devices
Presentation Focus
1. Clean vs. Sterile
2. Non-viable particles
3. Viable particles
4. Dynamic strategy
Particles when enter in blood stream
Sterilization does not guarantee
that the product is clean
Particles when enter in blood stream
Death
Septicemia
Infection
Viable
Non-viable
Vein irritation & phlebitis
Pulmonary granulomass
Anaphylactic shock
Death
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
Lets identify the source of particulate matter
Dust
Glass
Rubber
Cotton fiber
Insoluble materials
Precipitates
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
1994-US-FDA
Calcium phosphate precipitation in TPN took lives
Autopsy confirmed micro-vascular pulmonary emboli
containing calcium phosphate
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
Clean Room
in which the concentration of airborne particles is maintained
Clean Room
Design to provide control of
environmental factors
For particles
Temperature & Humidity
Air flow pattern
Air pressure differential
Containment of hazardous aerosols
Source of Contamination
• Wall, floor, ceiling, paint, spill, leaks
Faci
litie
s
• Skin, flakes cosmetics, perfumes, clothing, debris, hair, spittlePe
op
le
• Friction & wear particles, lubricants & emission, vibrations, brooms, mops, duster
Too
l gen
erat
ed
• Particulates flowing in air (bacteria, organics & moisture), floor finishes, cleaning chemicals, water
Flu
id
• Glass flakes, clean room debris, aluminum particles, silicone,
Pro
du
ct g
ener
ated
Aseptic Manufacturing Practices
Proper facility design
Proper material & Personnel Flow
Contamination Control
Environmental monitoring
Validation of aseptic processing (e.g. media fills)
Aseptic Area Environmental Control
1• Rinsing
2• Cleaning
3• Sanitization
4• Disinfection
5• Sterilization
6• Depyrogenation
Managing an Aseptic Processing Area (APA)
Drug Product
Sterilization Process
Sterile Drug
ContainersSterilization
ProcessSterile
Container
ExcipientSterilization
ProcessSterile
Excipient
ClosuresSterilization
ProcessSterile
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
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: 2Major contributors
of particles
Managing an Aseptic Processing Area (APA)
What you found
Where you foundAt
leas
t 3
log
red
uct
ion
Effi
cien
cy is
no
t m
ore
th
an 4
ho
urs
Sanitization
Entry and Gowning Practices
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)
Working in Aseptic Processing Area
Personnel
Knowledge
Ability
Skill
Working in Aseptic Processing Area
Atypical Job
Heavy gowning
Physical Exhaustion
Technical understanding
Working in Aseptic Processing Area
Very important
Educational background
K, A, S
Personal attributes
People that are more successful in APA
Introverted people
Avoid talking
Not taking in critical
area
Aptitude
Related Regulatory Citations
Operator performing inoculation was
observed reaching outside the bio-safety
cabinet
Employee did not remove his sleeve cover
Technique issue
Related Regulatory Citations
Operator reached over open, unfilled vials to adjust
filling needle/ bracket without immediately
defecting the affected vials
Behavior issue
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
Aseptic Processing
Grade A
Grade B
Grade C
Grade D
Air Classifications
Grade A
Class 100 or ISO 5
Critical Primary Operations
Formulation Filling Lyophilization
Critical Support Operations
Tank Cleaning, Assembly & Sterilization
Equipment Cleaning, Assembly
& Sterilization
Stopper Washing & Sterilization
Inspection (visual)
Stopper Processing
Washed and
sterilized by the
supplier
OR
Washed after
purchase from
supplier?
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
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)
Wrap up
Process, Facilities
& Design
Personnel with
appropriate K,A,S
Training (Knowledge
based & performance)
Monitoring
performance
Effective CAPAs
Aseptic Process
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 solutionEmbedded particle in neck of glass vial
Particulate matter
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.
27th Dec 2013.
Particulate matter
• 5% Dextrose Injection, USP
• 0.9% Sodium Chloride Injection, USP 50, 100 ml