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