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Contamination & Cross Contamination in Pharmaceutical

Presentation · August 2020

DOI: 10.13140/RG.2.2.19291.80169

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 Contamination & Cross
Contamination in Pharmaceutical

A. B. M. Mahfuz ul Alam
Director, Quality Operations
ACI HealthCare Limited
Contaminant
Current Situation:

Prevention of 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
- Uncontrolled release of dust, gases, vapours, sprays or organisms from
materials and products in process,
- From residues on equipment,
- From operators’ clothing.
The significance of this risk varies with the type of contaminant and of product being
contaminated. Amongst the most hazardous contaminants are highly sensitising
materials, biological preparations containing living organisms, certain
hormones, cytotoxics, and other highly active materials. 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 time. (EU-GMP; Medicinal Products of human
and vetinaryuse; Ch 5)
 Physical and chemical Contaminations –

Invisible to naked eye below ~50um without special illumination

Ref: Clean rooms Magazine, 2000

Contamination Control and Its Relationships

• All sources of contamination and control are

interrelated
Personnel

Contamina
Surface Product
tion

Air
Physical and chemical Contaminations –

Three prevalent themes are central to the vast number of aseptic

processing contamination problems:

• poor personnel practice

• loss of environmental control
• flawed operational design
Physical and chemical Contaminations –

Manufacturers should assess all drugs handled in non-dedicated areas

and establish defined areas or controls necessary to prevent the risk of
product cross contamination. [Case by Case Basis]

All compounds are potent, some are more potent than others.
Step 1: Risk Identification

• Ask the question “What Might Go Wrong?”

• Evaluate each stage in the manufacturing process- be
sure to include in the assessment evaluation of the
manufacturing rooms, equipment and complete process
• Focus on Four Possible Failure Modes
• Mix-ups
• Retention
• Mechanical transfer
• Airborne transfer.

Remember:
Risk analysis should consider all potential routes of
cross-contamination Under all operational conditions
Cross Contamination Can Occur

Mix-up
Cross contamination is caused by human error (incorrect API, use of
contaminated equipment)

Retention
Material which is left from the previous process due to failure or inadequate
cleaning

Mechanical transfer or carry over

Transfer by mechanical means of contaminants from non-product contacts
part, transfer system etc.

Airborne precipitation
The risk of one product in airborne suspension contaminating another
product
Level of Risk
Risk Analysis: ADE Uncertainty Factor
Risk Analysis: Establishing Risk
Occurrence Rankings
Risk Analysis: Establishing RPN Value the

Risk = Severity x Occurrence x Detection

Severity =A measure of the possible consequences of the failure.

Based on evaluation of contamination in the next batch.

Occurrence =The likelihood that the failure event will happen.

Base on MDR, Breakdown maintenance, annual product review,
complaints, change controls and internal audits.

Detection = The ability to detect failure. Based on current controls

(Batches per Year) (API per Batch) Process Risk Value)

Risk = ----------------------------------------------------------------------------
ADE
Logic Diagram: Compound or Product being
Processed
People as Contamination

5 to 10 million cells per day

2300 micro-organisms per
square cm
Filter efficiency of clothing is
highly variable
. . . People and Process can
contaminate the Product
Effect of the Clean room User
Activity and Particle Generation

• User behavior has huge effect on

particle generation (from Ramstorp)
Activity and Contamination
(from Ramstorp)
Surfaces

Contamination caused by inappropriate

cleaning of equipment
• What is clean?
• What is “worst case”
• Inadequate cleaning procedures
• . The use of non-validated cleaning practices
• .He use of non-validated analytical test
methods
Vacuuming of Surfaces

• Dry and wet

– Dry has low (<25% ) efficiency for particles smaller
than 10 microns (about .0005 inches)
– wet uses liquids which result in greater force on the
particles and hence better cleaning
Wet wiping of Surfaces
• Can be very efficient
• Liquid breaks some bonds between surface and
particles and allows particles to float off
• Those adhering on surface can be rubbed off and
retained in wiper.
• Must be careful not to redeposit particles
• Efficiency varies
Contamination Measurement

• Particulate contamination typically measured with laser

particle counter
• Microbial contamination can be measured in several
ways
– Centrifugal sampler
– Settle plate method
– Contact plate method
– Swabbing
 Common Protocol Violations
• Not wearing Safety Glasses
• Improper gowning
– zippers, snaps, masks
• Non-cleanroom materials in cleanroom
– paper, cardboard, personnel items
• Not cleaning up after you are finished
• General conduct
– Fast motions, incorrect carrying of materials
– Remember laminar flow; minimize turbulence
 General Clean room User Requirements I

• Minimize sources of contaminants

– No smoking
– No cosmetics
– Avoid high particulate clothing, such as wool
sweaters
– Cover up! Uncovered skin can lead to more
contamination
Protocols to Improve Contamination Control

• Follow gowning procedures and restrict materials used in

clean room
• An educated worker is essential to proper job
performance; workers should be well versed in the how
and why of their job
 You as the User I
• Very important to think about each and
every action you take:
– How does this affect cleanliness?
– Why do we do this the way we do?
– Is there a better way to do it?
– What will happen if I do not follow proper
protocols?
– You should know the answers to all of these
questions!
You as the User II
• Cleanroom environment is very fragile!
– Your actions have impact on other users
• Important to follow procedures EVERY TIME
– Make sure fellow workers follow procedures as well;
nothing wrong with pointing out mistakes
– Be an active participant: keep an eye out for areas
that can be improved
Facility Design
1. A model for identifying cross-contamination risks

2. Cross-contamination due to poorly designed facilities

(surfaces, cracks and other sources)

3. Contamination and cross-contamination due to equipment

and their maintenance

4. Inadequate segregation of processes involving sensitising

products from other products
Environmental Control – HVAC

1. Airborne contamination and airborne cross-

contamination
2. Capture of contaminants where dust is generated
3. Air handling and prevention of dust dissemination
4. Failures in HVAC design (filtration, airflow pattern,
pressure differentials)
5. Failures in HVAC operation (e.g. energy saving,
unbalanced pressure differentials)
 Minimalism is Good
• Bring only required materials into
cleanroom; if it is not necessary to perform
the task, it should not be there
• Personnel: only required personnel should
be in the clean space
• Reduce clutter—do not store materials in
clean areas unless they have to be there!
Repetition is Good

• Follow exact procedures every time

• Wipe down surfaces with cleanroom wipes before and
after every usage
• Remember: this can seem tedious and unnecessary, but
is essential to keeping the cleanroom maintained at its
highest levels
Outline
• Introduction—Cleanroom definitions
• Facility design & layout principles
• Air flow
• Contamination & Measurement
• Cleaning & Materials Selection
• The user!!
• Protocols to improve control
Conclusions

• Contamination control is a continuous battle

• User behavior has a critical impact on
contamination
• Proper procedures must be followed at all times
• Think about your actions! Be an active
participant
 Particulate Contaminants

Causes
Several causes of particulate contaminations of IV fluids are
known. This is because drugs are available in various containers (for example
vials, ampoules, pre-filled containers and premixed solutions) and their usage and
manipulations are highly diversified.
Consequently, many types of particle contamination can
occur:
- Glass
- Plastic
- Rubber
- Undissolved particles/drugs
Consequences
Consequences

1
Preventions
Metal Impurities Regulations

ATSDR—Agency for Toxic Substances and Disease

Registry of the US Department of Health and Human
Services
•EMEA—Guideline on Specification Limits for Residues of
Metal Catalysts or Metal Reagents
•IRIS—Integrated Risk Information System of the US
Environmental Protection Agency
•IPCS—International Program on Chemical Safety of the
World Health Organization
•JECFA—Joint Expert Committee on Food Additives of the
World Health Organization and the Food and Agriculture
Organization
Metal Impurities
Metal Impurities
Metal Impurities
Preventions of Metal Impurities

ATSDR—Agency for Toxic Substances and Disease

Registry of the US Department of Health and Human
Services
•EMEA—Guideline on Specification Limits for Residues of
Metal Catalysts or Metal Reagents
•IRIS—Integrated Risk Information System of the US
Environmental Protection Agency
•IPCS—International Program on Chemical Safety of the
World Health Organization
•JECFA—Joint Expert Committee on Food Additives of the
World Health Organization and the Food and Agriculture
Organization
Preventions
Preventions
Compressed Air
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