Contamination Control

Introduction to Contamination Control
Module MP6405-1 Ver 01

SeerPharma
Pty Ltd
This training program is copyright to SeerPharma Pty Ltd and may not be modified, reproduced, sold, loaned, hired or traded in any
form without the express written permission of SeerPharma Pty Limited, SeerPharma (Singapore) Pte Ltd or its subsidiaries.
Module Content
This module covers the
requirements for
contamination control in
non-sterile & sterile
manufacturing.
It identifies potential
sources of contamination
and issues regarding
effective control.
Module Outcome
On completion of this module, you will be able to:
Define Contamination Control and explain
why it is critical
List the major sources of physical, chemical and
microbiological contamination
State regulations pertaining to contamination
control
Explain the systems or procedures required
for control of each type of contamination
Principle
The holder of a manufacturing authorization
must manufacture medicinal products so as
to ensure that they are fit for their intended
use, comply with the requirements of the
marketing authorization and do not place
patients at risk due to inadequate safety,
quality or efficacy.
PIC/S Guide to GMP Chapter 1 Quality Management- Principle
Principle
It is manifestly impossible to include in each
monograph a test for every impurity,
contaminant, or adulterant that might be
present, including microbial contamination.
These may arise form a change in the source of
material or from a change in the processing, or
may be introduced from extraneous sources.
USP/NF General Notices, Foreign Substances and Impurities
CONTAMINATION CONTROL REQUIRED
What is Contamination?
Contamination is the act of contaminating or
polluting; including either intentionally or
accidentally unwanted and potentially
dangerous substances or factors
Contamination is also the state of being
contaminated
What is meant by the term

Contamination Control?
prevention of penetration of process ambient
by contaminants.
A set of systems and techniques that ensure
the minimisation or reduction of
contamination
Why is contamination control

critical to product quality?
To minimise risk to patient
To ensure product remains safe, pure and
effective
Because we cannot test for each contaminant
and impurity
To avoid costly recalls
Some Statistics
Drug Recall Data (a typical year)
35
Potency
30
Dissolution
25
Other
20
Contamination
15
Labelling
10
NDA Compliance
5
0
Manuf./Testing
Recalls in 2003
Examples of Pharma Contamination

1937 Elixir sulfanilamide incident: S. E. Massengill Company used
diethylene glycol as the solvent, it led to the 1938
Federal Food, Drug, and Cosmetic Act[1][2]
1982 Chicago Tylenol murders: Tylenol pain-relief capsules were laced
with potassium cyanide, leading to 7 deaths.[3]
2007 Panamanian Eduardo Arias discovered that toothpaste sold in his
country was labeled as containing diethylene glycol, the same
ingredient that had tainted cough syrup and killed 138 Panamanians in
2007 Toxic cough syrup in Panama: Pharmaceutical manufacturers
using diethylene glycol, which they believed to be glycerine, to make
cough syrup.[13]
2009, 84 Nigerian children were reported to have died after being given
"My Pikin", a teething syrup contaminated with diethylene glycol.[16]
2012: As of 2 November 2012 (2012-11-02)[update] in the
New England Compounding Center meningitis outbreak, 404 cases of
fungal infection occurred with 29 deaths due to contaminated injectable
medication.
10
Examples of Food Contamination

1986 - Adulteration of Italian wines with ethylene glycol killed more than
18 people[18]
2011 - Poor-quality illegal alcohol in West Bengal has resulted in an
estimated 126 deaths. The alcohol may have contained
ammonium nitrate and/or methanol
2013, March - A vegetable seller in western Germany, Rhine Main,
realized that the lettuce he had been selling throughout the day
contained rat poison. The poison appears as small blue kernels
2013, May - A Chinese crime ring was found to have passed off rat,
mink, and small mammal meat as mutton for more than 1 million USD
in Shanghai and Jiangsu province markets.[66]
2013, May - Halal Lamb Burgers contained samples of Pork DNA,
affected schools 19 schools in Leicester, UK
11
Reasons/Motives
Accidental:
One off
Systematic
Deliberate:
Criminal/Retaliation
Substitution
12
Types of Contamination
Physical, e.g.
Dust
Fibers
Metallic or plastic particles
Chemical, e.g.
Cross contamination
Microbiological, e.g.
Bacteria, endotoxins
Fungi & Yeast
Viruses
13
Group Activity
In groups of 3 to 6
Time allocation 25 minutes
Prepare response to question as dot points.
Try and identify some of the sources of
contamination for the contaminants
mentioned in the previous slide.
Any ideas on how to control those
contaminants?
14
Sources Of Contamination (1)

Buildings and Premises
cracks, holes: dust, filth, pests
Services and Utilities

Water cleanliness: Viable and non viable contamination
Environment (HVAC system)

Viable, non-viable contamination
Temperature: chemical degradation
Humidity: viable contamination in particular mould
Equipment
Material of construction
Cleanability
Personnel
Hygienic behaviour
Gowning practices
Inadequate training: GMP, procedures and on the job
15
Sources Of Contamination (2)
Visitors and Contractors

Raw and Packaging Materials
Process Aids (tubes, filters, etc.)
Process and Production
Cleaning Agents
Sampling Procedures
16
GMP Requirements
Premises and equipment must be located,
designed, constructed, adapted and
maintained to suit the operations to be carried
out. Their layout and design must aim to
minimise the risk of errors and permit
effective cleaning and maintenance in
order to avoid contamination, build up of
dust or dirt and, in general, any adverse
effect on the quality of products.
PIC/S GMP Chapter 3- Principle
17
Buildings and Premises

Should be constructed with the following in mind to
protect from/ minimise contamination:
Environment
Maintenance and repair operations
Cleaning and sanitation
Lighting, temperature, humidity and ventilation
Protection from insects or other animals
Flow of materials and personnel
Storage Areas
Limited Access Areas
Visitors and Contractors
Dedicated and contained facilities where applicable
18
Facility Cleaning
Premises should be carefully maintained,
ensuring that repair and maintenance
operations do not present any hazard to the
quality of products.
They should be cleaned and, where
applicable, disinfected according to detailed
written procedures
PIC/S Code of GMP- Clause 3.2 (part)
19
Exercise
In groups of 3 to 6
Prepare response to question as
dot points.
Using EU GMP Chapter 5
What controls should be in place
place to prevent contamination from
the buildings / facility themselves?
20
10
Equipment
Equipment should be designed, located and
maintained to suit its intended purpose.
The following need to be considered to prevent
contamination:
Choice of material of construction & lubricants
Repair and maintenance operations
Ease and thoroughness of cleaning
Choice of washing and cleaning equipment
Time limitations between use and cleaning, and
cleaning and use
Storage of equipment post cleaning
21
Exercise
In groups of 3 to 6
Prepare response to question as dot
points.
What controls could be in place to

prevent contamination from the very
equipment used to product the
products?
22
11
Personnel
Detailed hygiene programs should be
established and adapted to the different
needs within the factory.
Hygiene programs should be promoted by
management and widely discussed during
training sessions
PIC/S GMP- Clause 2.13 (part)
23
Personal Hygiene
Medical examination upon recruitment
No infectious diseases or open lesions on exposed
surface of the body
Protective garments
No eating, drinking, chewing or smoking, or the storage of
food, drink, smoking materials or personal medication
In general, any unhygienic practice within the
manufacturing areas or in any other area where the
product might be adversely affected, should be
forbidden.
No direct contact with exposed product or equipment that
comes into contact with the products
Hand-washing facilities
PIC/S GMP- Clause 2.14 - 2.19 (part)
24
12
Starting and Packaging Materials

Quality of purchased starting and packaging
materials
Integrity and sealing of containers
Cleanliness of containers
Sampling operations
Storage and protection from contamination
FIFO principles
25
Exercise
In groups of 3 to 6
Prepare response to question as dot
points.
What controls could be in place to

prevent contamination from the
starting materials themselves?
26
13
Sampling Procedures
There should be written procedures for sampling,
which include:
the person(s) authorised to take samples,
the methods and equipment to be used,
the amounts to be taken, and
any precautions to be observed to avoid
contamination of the material or any deterioration
in its quality
PIC/S GMP- Sampling -Clause 4.22
27
Q&A Code of GMP (1)

How should contamination of starting materials be
prevented?
5.18 Contamination of a starting material or of a product by
another material or product should be prevented. This risk of
accidental cross-contamination resulting from the uncontrolled
release of dust, gases, vapours, aerosols, genetic material or
organisms from active substances, other starting materials, and
products in process, from residues on equipment, and from
operators clothing should be assessed. The significance of this
risk varies with the nature of the contaminant and that of the
product being contaminated. Products in which crosscontamination is likely to be most significant are those
administered by injection and those given over a long time.
However, contamination of all products poses a risk to patient
safety dependent on the nature and extent of contamination.
Ref EMA GMP Part 1 Chapter 5 rev Aug 2014
28
14
Q&A Code of GMP (2)

What environment is required for sampling primary
packaging materials? Can they be sampled in the
warehouse?
Clause 3.9 also describes the physical requirements
for the area being used to sample primary packaging
materials. The standard of air quality is optional and
HVAC is not expected. However sampling in an open
warehouse would not be allowed.
29
Cross-Contamination in Production
Contamination of a starting material or of a product by
another material or product must be avoided. This risk of
accidental cross contamination arises from the
uncontrolled release of dust, gases, vapours, sprays
or organisms from materials and products in process,
from residues on equipment, and from operators
clothing.
The significance of this risk varies with the type of
contaminant and the product being contaminated..
Products in which contamination is likely to be most
significant are those administered by injection, those
given in large doses and/or over a long period of time.
PIC/S GMP- Prevention of cross-contamination in production -Clause 5.18
30
15
Controlling Cross-Contamination
Production in segregated areas or by
campaign followed by appropriate cleaning
Appropriate air locks and air extraction
Minimizing risk of contamination caused by
recirculation or re-entry of untreated or
insufficiently treated air
Keeping protective clothing inside areas
where products with special risk of cross
contamination are processed
31
Processing Operations
The following should be in place:
Line clearance prior to start
In-process and environmental controls
Acceptable ranges for expected yields and
review of actual yields
Time limits on manufacturing
Maintenance handover procedures
Chronologically completed log books and
records
32
16
Packaging Operations
When setting up a program for the packaging
operations, particular attention should be
given to minimizing the risk of crosscontamination, mix-ups or substitutions.
Different products should not be packaged in
close proximity unless there is physical
segregation.
PIC/S GMP- Packaging Operations -Clause 5.44
33
Systems to minimise/reduce
contamination
Written Programs have to be in place to
ensure that steps towards minimizing /
reducing contamination and that they are
being followed:
Plans
Procedures
Records
34
17
Quality System
file://localhost/Users/
raymondcollyer/Desktop/Module 3
MP6405 Cross Contamination/
MP6405 Contamination Control/
MP6405-1 Introduction/Not for
printing/10 IER Ben Venue Nov
2011.pdf
Quality should be built into the product and testing

alone cannot be relied on to ensure product quality
FDA - Guidance for Industry- Quality Systems approach to Pharmaceutical
cGMP Regulations - Sep 2004
35
General Concepts
Quality of the Product
Achieving characteristics of the product that are designed
to ensure the required levels of safety and effectiveness
Quality by Design and Product Development
Designing and developing manufacturing processes to
consistently ensure the predefined quality at the end of the
manufacturing process
Risk Management and Risk Assessment
Which contaminants are of concern?
Corrective and Preventive Action (CAPA)
Change Control
How will a change in process, a solvent, a cleaning agent,
impact the performance of a product?
The Quality Unit and Internal Audits
36
18
A Contamination Control Approach

Determine all sources and types of physical, chemical and
biological contaminant introduction in the process
Use technically and scientifically sound risk-based methods
(e.g. HACCP or FMEA) to determine the impact of these
contaminants on the final product. Establish:
Probability of occurrence
Severity or impact
Levels of detection for each source
Determine the risk of occurrence
Identify key contaminant sources for contaminants of concern
Identify methods of assuring their controls
Conduct studies to show that contaminants can be controlled to
desired levels
37
What needs Qualifying

At a minimum, consider qualification of the following:
Air handling system
Employee health, hygiene and sanitation
Cleaning and sanitation
Control of residues on process equipment
Suppliers of starting materials
Critical services including water systems used in the
manufacturing process and cleaning
Manufacturing process and possible degradation
Hold and Storage times
Microbiological bioburden of environment, starting
materials and processes
Lubricants and process aids used in manufacturing (tubes,
filters etc.)
Computerised systems in manufacturing
Pest control program
38
19
Ongoing Monitoring
Monitoring Programs
for all the above. Also:

Training Programs
Visitors and Contractors Programs
Internal Auditing Programs
Use quality systems (CAPA, Change Control, Risk

Management, etc) to control on an ongoing basis and
should any deviation, OOT etc. occur
Use key quality indicators from other systems to
evaluate any impact on contamination control
(Complaints, ADEs, Product Quality Reviews,
Standards, etc.)
39
Some additional and specific

Requirements
Personnel working in areas where
contamination is a hazard, e.g. clean area or
areas where highly active, toxic, infectious or
sensitising materials are handled, should be
given specific training.
PIC/S GMP Chapter 2- Personnel- Training
40
20
Glossary
Containment The action of confining a biological
agent or other entity within a defined space.
Contained area An area constructed and operated in
such a manner (and equipped with appropriate air
handling and filtration) so as to prevent
contamination of the external environment by
biological agents from within the area.
Cross-contamination Contamination of a starting
material or of a product with another material or
product.
41
References
The PIC/S Guide to Good Manufacturing Practice for
Medicinal Products.
USP/NF: General Notices chapter
FDA Guidance for Industry: Quality Systems
Approach to Pharmaceutical CGMP Regulations
The Gold Sheet: Vol. 38, No.3, March 2004- Drug
Recall Data
42
21
Regulatory Agency and

Industry Web Sites
PIC/S - www.picscheme.org
EMA www.ema.europa.eu
FDA - www.fda.gov
Product Recalls - http://www.recalls.gov.au
Medicines Australia
- www.medicinesaustralia.com.au
Australian Self-Medication Industry - www.asmi.com.au

Medicines & Healthcare products Regulatory Agency http://www.mhra.gov.uk
Malaysian National Pharmaceutical Control Board (NPCB)
www.bpfk.gov.my
Contamination Control for Life Sciences and Microelectronics

www.a2c2.com
43
22

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Introduction to Contamination Control

Module MP6405-1 Ver 01

Module MP6405-1 Ver 01

Module MP6405-1 Ver 01