Contamination control –

Product and Facility

point of view
Part II – Topic 1
Content

⚫ Contamination
⚫ Consequences of Contamination
⚫ Regulatory perspective
⚫ Overview- Possible ways of contamination and its preventions
⚫ Contamination through Airborne with examples
⚫ Contamination through Mechanical transfer with examples
⚫ Contamination through retention with examples
⚫ Contamination through Mix up with examples

2
Contamination & Cross-contamination

Contamination Cross-contamination

Undesired Introduction of any Undesired Introduction of any

Unwanted/foreign Physical, Chemical, Unwanted/foreign Physical, Chemical,
Biological material into the product Biological material into the product

Unlike above example, many times contamination / Cross

contaminations are not visible and not identified during visual
inspection as well as during consumption.
3
Consequences of Contamination/Cross-contamination

Risk to patient health:

⚫ Adverse drug reaction, health
complications leads to life
threatening.
⚫ Penicillin contamination may trigger
hypersensitive exaggerated allergic
immune response

Risk to Organization
⚫ GMP non-compliance

⚫ Recalls

⚫ Sales Loss

⚫ Company Regulation
4
Regulatory Perspective

EU GMP Chapter-3 21 CFR Part 211: ISPE’s risk map guide

(Premises and Subpart C: Buildings to managing Risks
equipment) and Facilities Associated with
Cross-Contamination
inline with Capter-3
EU GMP chapter-5 211.176 Penicillin and Chapter-5 of EU
(Production) Contamination GMP.

ICH Q9: Quality risk

management

5
Regulatory Perspective

1. Facility Desing 1. Facility Desing 1. Cleaning

• Containment • Personnel/Material
• Cleaning Methods – 1. Facility design flow
Auto/Manual • Unidirectional flow
movement • Cleaning validation
2. HVAC
2. Labelling Procedure:
• Pressure regimen 2. Gowning/Gloves 2. Equipment: • Labelling of product,
• Filtration • Decontamination • Equipment Design equipment etc.
• Maintenance

6
Airborne Transfer:

Airborne
Transfer

Facility
HVAC
Design

Filtration
Containment and Pressure
gradient

Transfer of powder aerosol via air movements and deposition

on exposed product surface of equipment surface 7
 Controls to prevent Airborne Transfer

Closed Transfer Containment Facility Design HVAC Micro

⚫ Close transfer of material

from one equipment to other

⚫ No manual interventions
during transferring and
unloading

8
 Controls to prevent Airborne Transfer cont’d

Closed Transfer Containment Facility Design HVAC Micro

⚫ Closed Charging, processing, sampling and discharging of powder / granules

⚫ Closed cleaning via. CIP/WIP
⚫ Decontamination before exposing the product contact area using wet sprinklers within equipment.

Isolator with Sifter Compression M/C with Containment FBE with Containment 9
 Controls to prevent Airborne Transfer cont’d

Closed Transfer Containment Facility Design HVAC Micro

⚫ Smooth surfaces of walls, floor and ceiling-wall and ceiling with modular partition or PU painted.
Flooring with epoxy coating. Curved corners.
⚫ Accessibility for cleaning – process area including mezzanine and service area with easy
accessibility for cleaning clean room fitting – light fixture, HEPA, Smoke sensors, grilles, etc. with
leak proof design
⚫ Clean & positively pressurized corridor / airlock against process area

10
 Controls to prevent Airborne Transfer cont’d

Closed Transfer Containment Facility Design HVAC Micro

⚫ Appropriate filtration level to maintain required

cleanliness gradation
⚫ Maintaining adequate differential pressure between
clean and process area
⚫ Maintaining Temperature / RH for working comfort of
personnel and product requirement.
⚫ Maintaining maximum ACPH and low level riser for
effective flushing of airborne particles air change per hour
⚫ The HVAC and dust collector ducts cleaning in fixed
frequency
⚫ NRV and interlocking with HVAC system to be
considered for dust collector. Easy to clean piping
system installation for dust collector. Non return value

11
 Controls to prevent Airborne Transfer cont’d

Closed Transfer Containment Facility Design HVAC Micro

Ideal Drain
Traps
Cleaning
and
Sanitization

12
 Controls to prevent Airborne Transfer cont’d

Closed Transfer Containment Facility Design HVAC Micro

⚫ Tanks should be pressurized with filtered

compressed air which is controlled through PLC
after SIP.
⚫ PLC is tested and validated for intended control
logic.
⚫ Equipment consist of below safety for prevention
of contamination
• Barrier filter

• Non Return Valve (NRV)

• Slow cooling with Filtered compressed air

13
Mechanical transfer :

Mechanical
Transfer

Gowning Facility Desing

Personnel/Material
Decontamination
Movement

14
Mechanical transfer: Causes and controls

Dirty Gowning
Process
equipment and De-
flow
handling gowning

Procedure for
decontamination
and
Unidirectional covering/wrapping
process flow of equipment/parts
during transfer from
one area to other
area/wash area. Procedure for
de-gowning,
removal of
gloves and other
apparels before
leaving the area.

MAL and PAL Mist showers

15
Retention:

Retention

Cleaning Equipment

Cleaning Equipment
Cleaning
Methods – Design and
Validation
Auto/Manual Maintenance

16
Controls to prevent cross contamination due to Retention: Automatic
Equipment and duct cleaning system

17
Controls to prevent cross contamination due to Retention: Automatic
Equipment and duct cleaning system (cont’d)

⚫ Fine dust particles escape the filters and get deposited in exhaust duct
⚫ Continuous deposition leads to accumulation and hardening of materials.

18
Retention : Equipment design and selection

Sanitary Piping Design Surface Finish and

Design MOC

⚫ Dent free surfaces ⚫ No/Minimum ⚫ MOC – Stainless

dead leg (less steel (SS304, SS316,
⚫ Accessible for SS316L), FDA
inspection and than 2D)
approved plastics
maintenance ⚫ Slopes for drain and rubber
⚫ Hermetically ability ⚫ Non-reactive, Non-
sealed hollow ⚫ Leak free valves porous, corrosion
areas and accessories resistance, smooth,
non-absorbent,
⚫ Difficult to clean ⚫ Inert gas and non-releasing and
locations shall be orbital welding cleanable surface
minimum followed by
borescope

19
Retention : Equipment Maintenance

Periodic replacement of Periodic inspection of Life cycle evaluation of

gaskets equipment equipment
• Gaskets of tri-clove • Equipment surfaces • Equipment shall be
joints, view glasses, shall be checked for evaluated periodically
Lids, filters shall be scratches, dents, frequent breakdown,
checked and replaced cracks and finished damages in
periodically • Periodic maintenance equipment should be
of equipment. considered for life
Scheduling, execution cycle evaluation
and recording
through electronic
ERP means like SAP
• Data trending and
review

20
Retention : Material (residue) evaluation

Criteria for Residues with great

risk to the next product
• High Toxicity
• High potency
• Sensitivity/Allergic reaction

Criteria for worst case product

selection
• Solubility
• Clean ability
• Toxicity

21
Mix-Up : Prevention of Cross-contamination

Mix up is the contamination of one product with another product by human error or
inadequate process or plant design.

MIX Ups

Procedure and
Facility Design
controls

Unidirectional flow
of Man & Labelling and
Material/Electronic SOPs
Process controls

22
Mix-Up : Causes & Controls to prevent Cross-contamination

Facility &
Technical Administrative
Procedural
Engineering Controls Dedicated Facility SOP

• Linear Layout Design • Dedicated facility of high • Labeling and identification

• Electronic verification of potent molecules procedure
materials through Bar • Dedicated Suites for • Man and material
coding manufacturing of specific movement procedure and
• Electronic verification products layout
through Camera systems • Dedicated storage areas for • Procedures for segregation
• Access control for Dispensed, in-process of equipment/material
authorized entry material, clean and Dirty during storage and process
• Access control System equipment • Room status labelling
• Dust collectors –Swan neck • Physical separation of high
at point of use and risk products
interlocking with AHU

23
Consequences of Cross-contamination

⚫ Penicillin can be a sensitizing agent that triggers a hypersensitive exaggerated

allergic immune response in some people. Differences in the 6-aminopenicillanic
acid side chain can generate allergic reactions ranging from skin rashes to life-
threatening anaphylaxis.

⚫ All penicillin finished pharmaceutical manufacturers, including re-packers, are

required by the CGMP regulations to establish a comprehensive control strategy
designed to prevent cross-contamination of other drugs with penicillin.

⚫ These requirements include:

21 CFR 211.42(d) : Separation of facility and equipment
21 CFR 211.46 (d) : Separate air handling systems (HVAC)
21 CFR 211.176: Test for traces of penicillin where possible exposure exists

Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination,

2022

24
QRM for prevention of cross contamination

⚫ Product profile review of products manufactured in shared

facility
• High risk products
• High vulnerability products
• Potent products

⚫ Current containment approach review

• Process flows
• Equipment / room matrix
• HVAC evaluation (AHU matrix)

⚫ Required Primary/minimum Controls (FMEA)

• Challenging controls for 4 probable pathways of cross contamination
25
QRM for prevention of cross contamination cont’d

26
QRM for prevention of cross contamination cont’d

Review the risk profile:

⚫ Change / Modification in the Facility & HVAC design.
⚫ Change / Modification in equipment or utilities catering the process
area
⚫ Change / Modification in Limit for pressure differential in process area
⚫ Change in procedure
⚫ Introduction of new Equipment / HVAC / New manufacturing process
⚫ Corrective action effectiveness check

27
28
 CCS:
A Path for Quality & Safety
Part II – Topic 2
Introduction

⚫ Controllingcontamination of sterile drug products has been a

challenge for years.

⚫ Product contamination and the failure to establish and

maintain a state of control for microbial and particulate
contamination is a major cause of recalls and regulatory
actions.
⚫ This
continues to be the case despite the accumulated
knowledge of sterile drug manufacturing processes, available
technology and improved testing that has taken place in the
industry.

2
Annex 1 : A path to Improved Contamination Control

⚫ In 2015, EMA and PIC/S published a concept paper

announcing the intention to revise Annex 1: Manufacture
of Sterile Products.

⚫A goal of the revision is to improve how companies

address the contamination control for sterile products and
to reinforce the use of modern quality risk management
(QRM) systems to “…. establish and maintain a state of
control…. facilitate continual improvement”

3
Annex 1 : A Path to Improved Contamination Control cont’d

⚫ Processes,equipment, facilities and manufacturing activities

should be managed in accordance with QRM principles to
provide a proactive means of identifying, scientifically
evaluating and controlling potential risks to quality.

⚫ ….should be implemented across the facility in order to

define all critical control points and assess the effectiveness
of all the controls (design, procedural, technical and
organizational) and monitoring measures employed to
manage risks associated with contamination.

4
Proposed CCS Concept vs. Current Practice

⚫ The industry has always been sensitive to the need for controlling
contamination but has tended to focus on evaluation of individual
sources and the means to control it.
⚫ This approach has not always been proactive, and it has not always
addressed the interaction of all critical control points and controls

⚫ The CCS tends to accomplish this intent by help of a more emphatic

and reinforced QRM program and overall pharmaceutical quality
system (PQS).

⚫ The CCS concept is aimed at encouraging companies to consider

and evaluate the risk and impact of multiple sources of
contamination to product quality and patient safety.
5
Proposed CCS Concept vs. Current Practice cont’d

⚫ It suggests looking at this problem more holistically and

dealing with it in a structured way to evaluate the effectiveness
and interdependencies of measures to control these risks.

⚫ It allows for better use of product and process risk knowledge

and contamination control expertise within the organization.

⚫ Even if companies are currently assessing, controlling and

monitoring contamination sources individually, the Annex-1
revision proposes they look at their collective effectiveness.

6
Proposed CCS Concept vs. Current Practice cont’d

⚫ The benefits of this holistic approach are :

⚫ Comprehensive program that ensures proportional attention to all

critical control points
⚫ Holistic program that builds awareness of various contamination
sources, how they are interconnected and their combined impact
on product and patient risks.
⚫ Reduction of ineffective control efforts and individual subjectivities,
allowing for better allocation of resources, optimal benefit and
continuous improvement.

7
The Pillars of Success

⚫ Asillustrated in Figure 1, a holistic CCS for a sterile

pharmaceutical dosage form has three inter-related pillars
for success.
1. Prevention
2. Remediation
3. Monitoring & Continuous Improvement (CI)

8
The Pillars of Success cont’d

9
The Pillars of Success : Prevention

⚫ Prevention – Prevention is the most effective means to control contamination.

⚫ Prevention of contaminants reaching the critical processing areas should be the

goal of CCS.

⚫ Complete prevention may not always be practical or feasible; however, it

should remain a target of continuous improvement in every site.

⚫ The prevention strategy should include the establishment of a well-defined,

organized program starting with a sound understanding of the sterile product
manufacturing process, objective risk assessments focusing on process
variables and sources of contamination, setting achievable acceptance criteria
and metrics, means to monitor performance and a plan to adjust the strategy
as needed.
10
The Pillars of Success : Prevention cont’d

⚫ The prevention strategy should apply to all possible sources of risk and
variability, including variables associated with humans (personnel),
machines (technology/equipment), materials (components/supplies),
methods (process/procedures) and the manufacturing facility
(cleanroom/environment).

⚫ All of these should be managed with an in-depth knowledge, qualified

as to their purpose, with and understanding of the interdependency or
over-all effect of all prevention steps taken together.

⚫ For example, consider the interaction of three important elements of an

aspect process CCS. (personnel, technology, materials)
11
Personnel

⚫ People are a primary source of microbiological contamination in aseptic

processing.

⚫ A well-designed program selection, training, capability enhancement and

qualification of cleanroom personnel is an indispensable part of the CCS.

⚫ Prevention also involves equipment, systems, processes and procedures

designed to prevent and minimize the impact of people-related contamination.

⚫ Personnel interventions that pose a risk to product sterility should be avoided

or designed to be performed with a minimal level of contamination risk.

⚫ Use of automation and barrier technology, adherence to first-air principles and

good aseptic technique/behavior are key part of a prevention strategy.
12
Technology

⚫ The role of technology in preventing contamination cannot be

overemphasized.
⚫ The current Annex 1 goes beyond other regulatory guidance to emphasize the
importance of using advanced aseptic technologies to prevent particulate and
microbiological contamination.
⚫ Keeping people and sources of contamination from the critical space of the
processing line as much as possible is the key focus of these advance
technologies.
⚫ The technology should be designed to match the needs of the process and
manufacturing requirements and address specific sources and risks of
contamination.
⚫ Where people are involved, steps should be taken to ergonomically design the
technology to meet personnel and process needs. 13
Materials

⚫ The quality of materials that enter the cleanroom or otherwise

impact the critical area environment or aseptic process must be
well controlled.

⚫ A sound vendor management program can play a crucial role in

setting the standard for each input material, consumable and
outsourced process.

⚫ The program should track the variability of the quality of supplies

and raise early-warning alarms that may increase the risk of
contamination from these supplies.
14
Materials (cont’d)

⚫ Nothing meant for cleanroom use can be considered trivial with

respect to a source of contamination.

⚫ Materials and technology should be designed, configured and

packaged to allow for decontamination, transfer, handling and use
in the critical area.

⚫ The extent of screening and qualification before acceptance of the

materials should be defined in the CCS based on the QRM
standards of the company.

15
The Pillars of Success : Remediation

⚫ The second important pillar for successful CCS is remediation.

⚫ Remediation is the reaction to contamination events due to the lack of or

limitations of preventive steps.

⚫ Remediation includes evaluating or investigating the source of

contamination and taking the specific actions (i.e., CAPAs) required to
maintain or return the process to a state of control.

⚫ Decontamination steps might include combinations of cleaning,

disinfection, sterilization, purification, filtration and other means to
identify and eliminate contamination.

16
The Pillars of Success : Remediation (cont’d)

⚫ If the contamination is intrinsic to the process, as might be the case

with particulate contamination generated from machinery (e.g.,
blow-fill-seal extruder or fill-line conveyors), the remediation may
involve scheduled cleaning of the affected areas.

⚫ If the contamination is extrinsic, such as particulate or

microbiological contamination from people working in or materials
entering the cleanroom environment, the remediation might
include actions to eliminate the contamination and
decontamination of the compromised surfaces.

17
The Pillars of Success : Remediation (cont’d)

⚫ Precision of execution is as important as the sound design of the

program- remediation.

⚫ Many facilities struggle with contamination/cross-contamination-related

issues due to gaps in program design coupled with poor execution.

⚫ The CCS should reflect plans for remediation and the means to ensure
its effectiveness.

⚫ Steps should be taken, including process modification or use of

technology, to ensure that errors and lapses in execution are addressed.

18
The Pillars of Success : Remediation (cont’d)

⚫ Personnel-related remediation steps must be accurately reflected in

SOPs or protocols and should be monitored and controlled effectively.

⚫ Where technology is added or modified to address contamination, the

use of the technology should be carefully designed and qualified to
meet the specific decontamination objective and the manufacturing
process requirements.

⚫ A scientifically sound and risk-based design of the decontamination

program, along with follow-through and consistent execution on the
shop floor, is the key for its success.

19
The Pillars of Success : Monitoring and Continuous Improvement (CI)

⚫ Understanding the effectiveness of prevention and remediation strategies is

equally important for contamination control and process improvement.

⚫ Critical contamination control parameters should be monitored and evaluated

to a level that allows for evaluation of the effectiveness of the controls.

⚫ For more critical parameters, such as differential pressure and total particulates
in cleanrooms, this may require monitoring on a continuous basis.

⚫ Controls should be established and systems should be qualified to detect

contamination event.

⚫ Meaningful data should be captured and trend should be analyzed.

20
The Pillars of Success : Monitoring and Continuous Improvement (CI)
(cont’d)

⚫ Often, monitoring and test results are lagging indicators of process

control.

⚫ However, evaluating trends helps capture the early warning

indicators and learn from past mistakes, which may prevent future
out-of-specification results.

⚫ This can change monitoring from strictly a reactive tool to a more

effective proactive means to control the risk of contamination.

21
The Pillars of Success : Monitoring and Continuous Improvement (CI)
(cont’d)

⚫ Alarm, action and trending levels should be set, and actions should be
determined for each type of event and, where possible, the sources of
contaminant.

⚫ Plans should be in place for the timely investigation, identification and

correction for the root cause and remediation of the results of the
contamination event.

⚫ Actions or process changes that result from the investigation should be

carefully designed and qualified to meet the contamination control
objective, taking into account any unintended consequences or effects
on other aspects of the process.
22
Conclusion

⚫ Implementation of CCS is not about reaching the destination one time.

⚫ It is the means to achieve a state of control that is required to ensure

product quality and patient safety.

⚫ It not only reflects the current state of control, but also brings awareness
about the need for new technology or methods that can bridge any gap.

⚫ It follows a lifecycle approach and links to the PQS of the company.

⚫ Once the CCS is implemented, it needs to be maintained regularly and

made part of the periodic product quality review to ensure that any
changes in the input materials, facility design or the production process
have been implemented in accordance with the CCS and PQS. 23
References

1.European Medicines Agency and Pharmaceutical Inspection

Convention/Pharmaceutical Inspection Co-operation Scheme. Concept Paper on the
Revision of Annex 1 of the Guidelines on Good Manufacturing Practice – Manufacture
of Sterile Medicinal Products, EMA/INS/GMP/735037/2014. February
2015. https://www.ema.europa.eu/en/documents/scientific-guideline/concept-
paper-revision-annex-1-guidelines-good-manufacturing-practice-manufacture-
sterile-medicinal_en.pdf.

2.European Commission. EU GMP Annex 1 Revision: Manufacture of Sterile Medicinal

Products (Draft), Consultation Document. February
2020. https://ec.europa.eu/health/system/files/2020-
02/2020_annex1ps_sterile_medicinal_products_en_0.pdf.

24
25
Annex 1 : Key Takeaways
from PDA Workshop
Part II – Topic 3
Key elements in Annex 1

⚫ Contamination Control Strategy is not a new concept ever since

quality risk management implemented.
⚫ Knowledge management to accumulate insight understanding of
science, technology and process.
⚫ CCS serves as a continuous improvement approach.
⚫ VHP sterilization tool?
⚫ Cleanroom behaves heavily rely on quality culture.
⚫ Unidirectional airflow, smoke study, first air protection
⚫ Implementation of Annex 1 by CMO?
⚫ CCIT as batch release criteria?
2
Contamination Control Strategy

⚫ Contamination control strategy (CCS) and quality risk management

(QRM) go hand in hand and are synonymous.

⚫ Therefore, a good practical understanding of QRM is key to creating

a successful CCS.

⚫ Similarly, knowledge management is a very important factor within

a company to ensure that the rationale and justification are
captured for the design, control and operation of the process and
facility in all its elements.

⚫ Hence, the use of knowledge and data are of paramount importance

as these provide the scientific evidence required to support your
CCS.
3
Contamination Control Strategy cont’d

⚫ TheCCS Summarized all elements that are in place regarding

the underlying documents.

⚫ The monitoring process is the listening system and show that

all elements are still operating as designed.

⚫ CCSgovernance is another key factor; however, who is

responsible for maintaining the strategy?

⚫ Eachorganization should establish this to ensure the CCS’s

successful implementation and ongoing maintenance.

4
Contamination Control Strategy cont’d

⚫ It is imperative that the entire team takes ownership of the

implementation of the strategy, as it is of paramount
importance that the CCS is maintained as a live document and
is not left sitting on a shelf to tick a regulatory compliance box.

⚫ The CCS must drive continuous improvement and, therefore,

must be periodically reevaluated and adjusted where necessary,
particularly when the underpinning risk assessment has been
revised based on the change management and deviation
processes.

5
Sterilization of Indirect Contact parts

⚫ Another topical subject was the sterilization of indirect contact parts.

⚫ Although vaporized hydrogen peroxide (VHP) is a robust process,

EU regulators do not view VHP as a sterilization process.

⚫ It is not a silver bullet, and many things can still go wrong.

⚫ Additionally, as VHP is nonpenetrative, occluded surfaces pose a risk

for effective decontamination.

⚫ Therefore, materials are expected to be cleaned and sterilized before

the decontamination of VHP in an isolator.

6
Sterilization of Indirect Contact parts cont’d

⚫ Another question was asked about what can be done with indirect
product parts that cannot be disassembled and put through the
sterilization process.

⚫ It may be the case that a redesign of the unit is required to allow an

engineering solution for the removal and reassembly of indirect
product contact parts such as stopper bowls and tracks.

⚫ Companies now need to consider how to bring their technology up

to the required standards to meet the expectations of Annex 1.

7
Sterilization of Indirect Contact parts cont’d

⚫ To prevent unwanted contamination from disassembling and

reassembling parts, the packaging, storing, transporting and
reinstalling of parts must be considered while applying the
principles of QRM.

⚫ We must be present to assess how the process is executed and not

rely solely on procedural checks to ensure the correct handling of
such materials.

⚫ It is important to engineer out as much as possible and to ensure

Grade A continuity.

8
Cleanroom Practices

⚫ Cleanroom practices and the importance of a strong quality culture

concerning good cleanroom behavior are key elements in
implementing the revised Annex 1 guidelines.

⚫ As industry leaders, we need to ensure personnel working in

cleanroom environments understand what they do, how it impacts
product quality and, ultimately, how it affects patient safety.

⚫ For example, are personnel aware of the risks associated with the
manufacturing steps they are involved with?

⚫ Educating people empowers them to embrace this responsibility, and

selecting personnel with the right attitude engages teams and
promotes good behavior. 9
Cleanroom Practices cont’d

⚫ Therefore,it is essential we embed a healthy quality culture in

this environment rather than the more traditional approach of
relying on monitoring alone, which is problematic with limited
effect.

⚫ Froma regulatory perspective, when engaging with an

inspector, personnel must display a deep understanding of
process knowledge and the impact of their role and its
importance.

10
Airflow-visualization (Smoke) Studies

⚫ Airflow
visualization or smoke studies and their requirements
are described in the revised Annex1.

⚫ The expectation for Grade A areas is that these studies are

mandatory, demonstrating unidirectional airflows, and that
first-air airflows are not obstructed due to equipment design or
operator interventions.

⚫ Grade B studies are required at potential ingress points (e.g.,

mouseholes) to demonstrate that there is no ingress into the
Grade A area or from lower-grade cleanrooms into the Grade B
areas.
11
Airflow-visualization (Smoke) Studies cont’d

⚫ Smoke studies are not required for Grade C and D cleanrooms.

⚫ However,the data can be useful to identify locations of

increased risk for accumulation of contamination due to
inadequate airflows or obstructions caused by equipment.

⚫ As expected, the regulator’s perspective focuses on the areas

of the highest risk.

12
Airflow-visualization (Smoke) Studies cont’d

⚫ Ifan area is found to have poor environmental monitoring data,

however, there may be a request to demonstrate that
ventilation is adequate, and smoke studies may be appropriate
to demonstrate compliance in this case.

⚫ For standard Grade C rooms, where normal activities occur and

there is relatively low risk, there is no point in conducting
smoke studies as no sterile product is in the area.

13
Implementation of Annex 1 by Contract Manufacturing Organizations

⚫A highly discussed point is the implementation of Annex 1 by

contract manufacturing organization (CMO).

⚫ How can one manage compliance and maintain oversight?

⚫A huge challenge encountered by the industry is how to obtain

the information required to ensure the CMO implemented the
revised Annex 1 requirements.

⚫ Riskassessments are often confidential due to other clients’

involvement, and those provided with redacted information
are often almost useless.
14
Implementation of Annex 1 by Contract Manufacturing Organizations cont’d

⚫ Incases where a company has only one or two manufacturing

slots with a CMO yearly, it can be very hard to influence the
CMO to share this information.

⚫ In
addition, these companies often do not have the power
other larger clients may have to implement the required
changes.

⚫ Asknown, the qualified person (QP) must have sufficient

oversight of drug substance, drug product and packaging
activities, even when multiple sites are involved.

15
Implementation of Annex 1 by Contract Manufacturing Organizations cont’d

⚫ Moreover, per EU Annex 16: Certification by a Qualified Person and

Batch Release, it is the QP’s responsibility to ensure there is evidence
that Annex 1 requirements are in place and that there is knowledge
of all activities performed at the CMO.

⚫ It is important to ensure that discussions between the contract-

giving firms and CMOs remain fully transparent and maintain an
open relationship so that issues are communicated promptly.

⚫ A QP does not have to be on site all the time; however, they should
evaluate the quality culture at the CMO and assess if it meets the
expectations of the company the QP is representing.

16
Implementation of Annex 1 by Contract Manufacturing Organizations cont’d

⚫ In
relation to aging facilities, such as technologies and utilities at
CMOs, it can be challenging to implement Annex 1 requirements.

⚫ Many CMOs in Europe have not implemented pre-use/post-

sterilization integrity testing (PUPSIT), which is the norm in
Ireland and the United Kingdom.

⚫ It is now described as a requirement in the revised Annex 1.

⚫ Educating the CMO about updated regulations and pointing out

the risks of noncompliance with these regulations are keys to
success.
17
Container-Closure Integrity

⚫ Most companies still use a lifecycle approach to demonstrate

container-closure integrity (CCI) for units other than closed by
fusion.

⚫ Thelifecycle approach uses data from the initial validation,

transportation, equipment (capper) set-up and stability testing.

⚫ Some companies are moving to in-line/off-line periodic CCI

testing of vails or syringes at set intervals.

⚫ Other organizations use periodic torque-testing or residual

seal-force as additional information to ensure CCI.
18
Container-Closure Integrity cont’d

⚫ It is still unclear if regulatory bodies expect CCI testing for units

other than those closed by fusion as part of batch-resale testing.

⚫ Some regulatory authorities indicated that regulators are currently

not looking specifically for batch-by-batch testing and still accept
the lifecycle approach.

⚫ For marketing authorization holders, it is important to know what is

registered in the marketing authorization and to adhere to it.

⚫ USP General Chapter <1207> Package integrity Evaluation –Sterile

products and PDA Technical Report No. 26 (Revised 2008): Sterilizing
Filtration of Liquids provide overviews of methods available and
guidance for the selection of CCI.
19
Container-Closure Integrity cont’d

⚫ Potentialmethods to consider are headspace analysis and

high-voltage testing.

⚫ Itis the responsibility of the company to assess what the most

suitable option is based on product knowledge and primary
packaging configuration.

⚫ There is an expectation that companies will move to more

detrimental methods as more technologies become available.

20
Summary

⚫ Although companies have many questions about implementing the

requirements of the revised Annex 1 and are still experiencing
challenges at their sites, many are progressing through the gap-
analysis process and planning remediation activities for identified
gaps.

⚫ In addition, most companies indicated a medium level of

compliance with the updates and are ironing out the logistics to
reach the highest possible level of compliance.

21
References

⚫ Annex 1 Workshop summary from Dublin in 2022, published in PDA

Letter
⚫ PDA Letters

22
23
How to Establish Effective
CCS with TR-90
Part II – Topic 4
Introduction cont’d

⚫ The manufacturing of medicinal products is critical to minimize

the likelihood of contamination ingress into the product flow
path.

⚫ This
is especially true in the production of sterile medicinal
products that cannot undergo terminal sterilization.
⚫ The August 2022 revision to EU Annex1: Manufacture of Sterile
Medicinal products was a significant change in the expectations
of industry members and has impacted the biopharmaceutical
industry as it pertains to the specific and integral parts of
pharmaceutical product manufacturing that is centered around a
proper contamination control strategy (CCS).

2
Introduction cont’d

⚫ The Annex 1 glossary defines a holistic CCS as：

⚫ “A planned set of controls for microorganisms,

endotoxin/pyrogen, and particles, derived from current product
and process understanding that assures process performance
and product quality.

⚫ The controls can include parameters and attributes related to

active substance, excipient, and drug product materials and
components, facility and equipment operating conditions, in-
process controls, finished product specifications, and replacing
equipment components.”
3
Introduction cont’d

⚫ Thisexplanation of CCS gives manufacturers a complete

approach regarding CCS, which is one of the more
significant additions to the revision of Annex1 compared to
the 2008 version (see Table 1)

4
Introduction cont’d

⚫ Comparison between 2008 Annex 1 and 2022 Annex 1

EU Annex 1 - 2008
Contamination 32
Control 11
Strategy 0
Contamination Control Strategy 0

EU Annex 1 -2022
Contamination 115
Control 111
Strategy 5
Contamination control Strategy 54
5
Introduction cont’d

⚫ Nonetheless, CCS is not a new concept, as manufacturers

have employed contamination controls for decades to
mitigate the impact on the product, minimizing product loss
and producing high-quality medicinal products for patients.

⚫ Now, regulatory authorities have placed the CCS at the

forefront of sterile product manufacturing.

6
The Publication of TR-90

⚫ The recently published PDA Technical Report No. 90:

Contamination control Strategy Development (TR-90) in February
2023 presents the CCS through a combination of theses
linked elements: foundation, contamination controls,
validation of controls, monitoring of controls and
governance, demonstrating the CCS in a methodical
manner (see Figure 1)

7
The Publication of TR-90 cont’d

8
The Publication of TR-90 cont’d

⚫ Industry
subject matters wrote this technical report to provide
guidance on how to establish an effective CCS.

⚫ Thereport is applicable for new, existing or retrofitted facilities

or processes.

⚫ TheCCS focusses on practices associated with the control of

microorganisms, endotoxins/pyrogens and particulate matter in
the manufacturing of sterile drugs.

⚫ TheCCS, however, can be used for processes for low bioburden

drug substances and nonsterile drugs as well.
9
Foundations

⚫ TR-90 establishes foundations for the CCS that are crucial to

developing, implementing and continuously improving an
effective CCS.

⚫ This
includes scientific knowledge, QRM and personal
awareness/quality culture.

⚫ Scientific
knowledge encompasses two different but equally
important aspects – process knowledge and technical
knowledge.

⚫ Thesetwo types of knowledge form the initial foundation of

the CCS. 10
Foundations cont’d

⚫ Process knowledge is critical to ensure a robust understating

of the specific manufacturing steps and the potential for
contamination ingress, proliferation, reduction and removal
associated with the manufacturing process.

⚫ Furthermore,
technical knowledge is critical to understanding
the mechanisms that may be employed to prevent, reduce
and remove contamination.

11
Foundations cont’d

⚫ Quality risk management (QRM) is a systematic process for

assessing, controlling, communicating and reviewing risk that
is to be employed in the manufacture of medicinal products.

⚫ In
addition, QRM is to be used in new and existing processes
and facilities to identify and assess the risk of contamination
ingress.

⚫ Contamination control risk analysis should identify which

individual controls are unacceptable, and the CCS must be
designed with reductant individual control elements to ensure
a single failure will not result in a contamination event.
12
Foundations cont’d

awareness/quality culture must be a priority for

⚫ Personnel
companies to ensure a proper understanding of the CCS.

⚫ Thefirm should have a dedicated champion or a cross-

functional team to oversee the overall performance of the
CCS.

⚫ In
addition, personnel awareness of the CCS can, directly and
indirectly, impact the strategy each employee employs, and a
company’s strong quality culture will ensure that
contamination control is a priority.
13
Foundations cont’d

⚫ The foundational elements discussed in TR-90 align with

what industry enablers described in international Council
for Harmonization Quality Guideline Q10: Pharmaceutical
Quality System.

⚫ Therefore, the CCS must be established based on the

identified foundations discussed in PDA TR-90 to ensure the
reliability of the CCS.

14
Contamination Controls

⚫ Contamination controls are the pillars of the CCS and must be

identified early in the development of new manufacturing
processes.

⚫ Theuse of the foundational elements in the development and

implementation of the contamination controls will ensure a
high-functioning CCS.

⚫ Furthermore, the contamination controls are designed to

utilized the fundamental elements described in the
foundations section to prevent, then mitigate contamination
ingress.
15
Contamination Controls cont’d

⚫ Thesecontrols include container closures, consumables,

design (e.g., facility, process, utility), equipment, materials,
personnel and vendors to ensure all interconnected
linkages are recognized to establish a strong CCS.

16
 Contamination Controls cont’d

⚫ Incorporation of proper risk-based designs for equipment,

facility, utility and process are essential to proper CCS
integration.

⚫ Equipment of poor design adds risk and may lead to

contamination ingress and proliferation. During routine and
ongoing use, microbial control of equipment is vital to
maintain its functional condition.

⚫ Moreover,throughout a production area’s initial design (or

redesign) phase, the facility and utility systems must
incorporate key elements of the CCS.
17
 Contamination Controls cont’d

⚫ Properfacility designs provide the appropriate production

environment through multiple design aspects (e.g., pressure
cascades, segregation, flow).

⚫ Themanufacturing processes should be designed to

prevent contamination ingress from microorganisms,
endotoxin/pyrogens and foreign particulates.

18
 Contamination Controls cont’d

⚫ Material and waste pathways must be defined within the CCS.

⚫ Facilitycleaning and disinfection are imperative for the

holistic CCS to minimize human-borne and transient
contamination from equipment transfer.

⚫ Thetransfer of materials and equipment within and between

the manufacturing zones must be properly defined and
repeatable to ensure the mitigation of contamination ingress.

19
 Contamination Controls cont’d

⚫ Personnel
is the number one source of microbiological
contamination within the manufacturing environment.

⚫ Thisrequires that multiple contamination controls should be

defined within the CCS according to the individual steps in
the manufacturing process.

⚫ Personnelcontrols (e.g., people flow, gowning, hygiene)

must be identified within the CCS to minimize contamination
ingress.

20
 Validation of Controls cont’d

⚫ Thepillars of contamination control must be properly qualified

and validated to ensure proper contamination control is
maintained throughout routine processing and use within the
defined manufacturing space.

⚫ This
qualification and validation should be risk-based and
appropriate for analytical methos, equipment, facility, processes
and personnel.

⚫ Also,materials that undergo quality control testing must have

validation associated with all methods.
21
 Validation of Controls cont’d

⚫ Ifa third party executes the testing of materials, the method

validation should be included in the quality agreement with
the provider, and the lifecycle of the testing must be
included within the scheduled CCS review.

22
 Validation of Controls cont’d

⚫ Good qualification and validation for manufacturing

equipment, facilities and processes should be appropriately
defined within the CCS and be risk-based.

⚫ There should be a defined risk-based approach to routine re-

qualification, including documentation of the equipment’s
lifecycle, facilities and processes.

23
Validation of Controls cont’d

⚫ Thequalification interaction between personnel and the

equipment and facility is an important piece for the CCS and
should be identified for all necessary process.

⚫ This
should also include an approach to personnel re-
qualification for risk-based activities within the processes.

24
 Monitoring of Controls cont’d

⚫ Monitoring controls are a central part of a holistic CCS, as they

provide feedback on the contamination controls, including
but not limited to, the design, validation and qualification of
equipment, facilities and process.

⚫ Consequently, Monitoring controls should be based on sound

scientific principles, risk assessment and regulatory
requirements.

25
 Monitoring of Controls cont’d

⚫ Severalmonitoring controls (e.g., personnel, in-process,

material, environmental, utility) may be captured through
multiple mechanisms (e.g., gauges, growth media, probes,
sensors).

⚫ This
data should be continuously evaluated to determine the
appropriateness and the performance of the associated
contamination control(s).

26
 Monitoring of Controls cont’d

⚫ Monitoring controls, while a key part of the holistic CCS, need

to be understood based upon what contamination control the
data is representing.

⚫ Notall data is directly linked to a failure of a single (or

multiple) control, but a rather normal variation within a robust
program.

27
 Governance

⚫ Thegovernance of the CCS shall include inputs from multiple

aspects of the quality management system (e.g., CAPA,
change management).

⚫ The CCS should be considered a “living” document that is

periodically reviewed to ensure all components of the strategy
are functioning as expected.

⚫ TheCCS requires a defined governance structure to oversee

the program’s overall effectiveness.

28
 Governance cont’d

⚫ This
governance structure must include a cross-functional
teams with the appropriate authority to oversee the program
and mechanisms that allow escalating adverse trends and
events.

⚫ Oversight performed by the cross-functional team should

include ongoing performance reviews of the CCS at regular
intervals (e.g., weekly, monthly, quarterly) based on identified
key process indicators.

29
 Governance cont’d

⚫ Adverse trends and events associated with the CCS, which

may occur occasionally, should be quickly communicated to
the cross-functional team, who will respond appropriately.

⚫ Iffirms have a robust knowledge management program for all

manufacturing processes, this will ensure historical events and
trends are maintained and incorporated into future process
modification.

30
 Conclusion

⚫ Lastly,
because of TR-90 and its elements above, creating a
sturdy CCS will allow an organization to assess and
continuously improve its level of contamination control,
which can reduce manufacturing losses and better attend to
the patients the industry serves.

31
 Reference

⚫ PDATechnical Report 90 : Contamination Control Strategy

Development

32
33
Understanding Disinfectant
Efficacy for Off-Label
Microorganisms
Part II – Topic 5
Introduction

⚫ Environmental monitoring (EM) for microbial contamination in

pharmaceutical and medical device cleanrooms is required and important in
assessing the ongoing state of control.

⚫ A hygiene program should focus primarily on reducing the ingression of

microbes into controlled spaces from personnel, supplies and outside air.

⚫ However, the appropriate use of disinfectants is also required to kill

microorganisms that will trespass into the cleanroom and, potentially, into
the product or preparation itself.

⚫ Even then, viable bacteria and fungi will occasionally be recovered from EM
and prompt an investigation.

2
Frequently asked questions during EM investigation

⚫ While there are many potential root causes, the question below is
frequently asked during the EM investigative process
⚫ Our environmental monitoring recovered two bacterial, one
identified as the Micrococcus/Kocuria species and the other
identified as a Bacillus species.
⚫ When I reviewed our disinfectants, I could not find these
microorganisms listed on the the EPA label or in our validation
studies.
⚫ Did we recover these microbes because our disinfectant is not
effective against them?

3
Frequently asked questions during EM investigation cont’d

⚫ For both types of microbes, the results of EM do not match any of the
species listed on the labels for the disinfectants or isolates tested
previously during the validation of the disinfectant.

⚫ In either case, there is a concern that the disinfectants are ineffective in

killing the isolate, which is understandable given some disinfectants can
only kill certain microorganisms.

⚫ In addition, repeated application of antimicrobial agents is often

associated with the perception that microbes will develop some level of
resistance.

⚫ Several arguments, however, support that a lack, or gap, of disinfectant

efficacy is rarely the root cause for recovering microbes during the EM of
cleanroom.
4
Frequently asked questions during EM investigation cont’d

⚫ In
order to help support these arguments, it is important to
understand these three issues:
⚫ (1) how disinfectants vs. antibiotics kill microbes
⚫ (2) the hierarchy of microbial susceptibility to disinfectants
⚫ (3) how disinfectants are regulated in the United States by the
Environmental Protection Agency (EPA), in Europe and the United
Kingdom under the Biocidal Products Regulation (BPR), and in GMP
facilities as guided by USP <1072> Disinfectants and Antiseptics

5
Mechanisms of Action of Disinfectants

⚫ Disinfectants
kill microbes through various mechanisms that target
components like the cell wall, cell membrane, proteins or nucleic
acids.
⚫ Disinfectants based on oxidizers, like hypochlorous acid, hydrogen
peroxide or peracetic acid, readily react with multiple components
of cells to cause irreversible damage leading to cell death.
⚫ Non-oxidizingchemistries, such as quaternary ammonium or
phenolic compounds, also cause lethal damage by denaturing and
disrupting essential cellular structures and processes.
⚫ Incontrast, antibiotics and antifungal drugs inhibit the growth of or
kill microbes by more specific mechanisms.
6
Mechanisms of Action of Disinfectants cont’d

⚫ The nonspecific mechanism of action explains why disinfectants can kill a

broad spectrum of microbes and why microbes are unlikely to develop
resistance to disinfectants through repeated exposure, which is good
news.
⚫ However, the relatively nonspecific and reactive nature of disinfectants
and sanitizers also explains why disinfectants can cause negative effects
on organisms, such as humans, if not used as directed to reduce exposure.
⚫ Additionally, disinfectants and sanitizers can react not only with
macromolecules associated with living cells but also with dead cells, dirt
and soiling.
⚫ This issue is the basis for cleaning before disinfecting or using an EPA-
registered one-step disinfectant that can disinfect in low-to-moderate
soiling.
7
The Hierarchy of Susceptibility

⚫ While disinfectants function in nonspecific ways, differences among some

types of microbes can impact the efficacy of disinfectants.
⚫ This hierarchy of susceptibility is often described using a scheme
originally proposed by Earle Spaulding regarding the use of disinfectants
and sterilants on medical devices. (Figure 1)

8
The Hierarchy of Susceptibility cont’d

⚫ All bacteria share some common properties because they are

prokaryotic organisms.

⚫ One of the most critical properties that impacts susceptibility is the

lack of intracellular membranes.

⚫ The vegetative form of a bacterial cell is essentially a balloon

containing a mixture of proteins, carbohydrates and nucleic acids
floating in what is called cytoplasm.

⚫ Once a disinfectant penetrates the cell wall and membranes that

make up the skin of the balloon, the chemicals can diffuse through
the cytoplasm and interact with these intracellular target.

9
The Hierarchy of Susceptibility cont’d

⚫ Some differences in the composition of the cell walls and

membranes of bacteria can impact susceptibility.

⚫ These differences in ultrastructure between Gram-negative and

Gram-positive bacteria can be relatively subtle and non-impactful
concerning most disinfectants.

⚫ However, some bacteria (e.g., mycobacteria) or forms of bacteria (e.g.,

endospores) possess a unique cellular skin that greatly reduces the
access of a surface disinfectant to intracellular targets.

⚫ The intrinsic resistance of mycobacteria and bacterial spores to

disinfectants warrants their location on the pyramid of susceptibility.

10
The Hierarchy of Susceptibility cont’d

⚫ Unlike bacteria, fungi are eukaryotes like plants and animal.

⚫ The structure of fungal cells and their spores is considerably more
diverse and complicated than vegetative bacteria, sometimes
creating additional challenges of penetration and access of
disinfectants to critical sites.

⚫ There are five major phyla within the kingdom of fungi, with
examples ranging from relatively simple cells like yeast to complex
morphologies in true molds, that involve vegetative and
reproductive components.

⚫ While there is some debate among scientists and regulatory

authorities regarding the term ”sporicide” as related to bacterial vs.
fungal spores, it is generally accepted that fungal spores are more
susceptible to disinfectants than bacterial spores.
11
The Hierarchy of Susceptibility cont’d

⚫ The reduced susceptibility of eukaryotes to disinfectants also adds

some margin of safety of reducing the deleterious toxicological
effects of nontargeted organism (plant, animal, humans) from
unintended exposures to these chemical agents.

⚫ Although not typically the target of EM, the hierarchy of

susceptibility of viruses is worth mentioning as the manufacturing of
cell and gene therapy products (also known as advanced therapy
medicinal products) continues to grow.

⚫ The susceptibility of viruses to disinfectants is somewhat analogous

to the availability of critical sites in bacteria and fungi.

12
The Hierarchy of Susceptibility cont’d

⚫ However, in the case of enveloped vs. non-enveloped viruses, the key

to susceptibility is that a critical site associated with enveloped
viruses is located on the outside of the skin (a proteinaceous shell
called a capsid).

⚫ While this relatively fragile, lipid-rich envelope is critical to evading

host immune responses and infecting cells, it is highly susceptible to
disruption by disinfectants.

⚫ Despite the formidable challenges presented by enveloped viruses

(e.g., SARS-CoV-2), once they enter the host, they are considered the
easiest to deactivated by even low-level disinfectants.

13
Disinfectant Efficacy Testing in Support of Regulatory Approvals

⚫ Both EPA and BPR recognize the broad-spectrum activity of

disinfectants.

⚫ When products are registered as a specific type of disinfectant

(e.g., bactericide, fungicide, virucide or sporicide), the EPA usually
only requires testing against a few (or one) species of each type.
(see Table 1).

14
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

Table 1 EPA disinfectant claims summary. Information from EPA’s OCSPP 810
Guidelines

Claim Levels Minimum Species for EPA Registration

Bacteria (broad-spectrum) Staphylococcus aureus (Gram +) or Pseudomonas
aeruginosa (Gram --)
Fungicide Trichophyton interdigitale (athlete’s fungus)
Virucide Claim the species (or surrogate) that is tested and
approved
Tuberculocide Mycobacterium bovis (surrogate for M.tuberculosis)
Sporicide Endospores of Closteroides difficile(surface
sporicide) or (Bacillus subtilisand Clostridium
sporogenes(sterilant))

15
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

⚫ For example, to receive EPA registration as a fungicide, products

must demonstrate and acceptable level of efficacy against
Trichophyton interdigitale (athlete’s foot fungus) using a
specified test method.

⚫ Although other fungi can be tested with the same method,

registration as a fungicidal disinfectant only requires testing
against this species of fungi.

⚫ Ifa registrant wants their product to carry a label claim against

a different fungus, that species of fugus must also be tested.

16
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

⚫ Some ask, “Why are so few fungal species typically listed on the
labels for fungicidal disinfectants?” Most products registered as
disinfectants are targeted for use in healthcare or public-health
settings, not cleanrooms.

⚫ Therefore, testing focuses on the pathogens that cause the greatest

concern for community- or healthcare-associated infections, not
typical isolates from cleanrooms.

⚫ While some fungi can be extremely pathogenic (e.g., Candida auris),

most healthcare-and community-associated infections are caused by
bacteria or viruses, respectively.

17
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

⚫ As shown in Table 1, the EPA regulatory scheme for claims against

known viruses is more specific than that of bacteria and fungi.

⚫ For example, while demonstrating efficacy against any virus might

qualify a product to be a virucide, the EPA requires efficacy test data
for each virus (or an acceptable surrogate) listed on the label.

⚫ Yet, there are cases where the Agency has adopted a hierarchical
argument that used existing label claims to address emerging viral
pathogens.

18
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

⚫ Thus, the regulatory approval process presents a mixed signal:

⚫ Products can be broad-spectrum with testing against a few species
is accepted,
⚫ Registered products cannot list specific species on their label
unless they have been tested and authorities have approved the
efficacy test results.

⚫ A similar situation exists with disinfectants regulated under the BPR.

⚫ To address these ambiguities, the EPA has explored the concept of

susceptibility hierarchy and how it might be applied to the
registration of disinfectants; however, this has not yet resulted in any
changes in the registration process.
19
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

⚫ Using a similar scheme for cleanroom facilities operating under

GMP, USP<1072> Antiseptics and Disinfectants indicates testing
only one to three species of bacteria, fungi and spores during the
initial qualification of disinfectants.

⚫ Subsequentefficacy testing is based on what types of

microorganisms are typically isolated from the facility.

20
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

⚫ While registration with the EPA or BPR may not provide ultimate
clarity regarding the spectrum of disinfectant activity, it is
helpful to understand the conditions used in the efficacy test
methods required for registration.

⚫ Theprimary markets for registered disinfectants are healthcare

and public facilities where microbial contamination is likely
associated with fluids or particles from humans or other
animals.

21
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

⚫ Assuch, for disinfectants that do not require precleaning on the

label instruction, products must be tested for efficacy in the
presence of 5% bovine serum of comparable soiling simulants.

⚫ Asdescribed above, disinfectants and sanitizers can become

neutralized by interactions with soiling, so the conditions used
in efficacy tests for registration are considerable harsher than
those expected in a controlled environment such as a
cleanroom.

22
Disinfectant Efficacy Testing in Support of Regulatory Approvals cont’d

⚫ Additionally,the bioburden used in efficacy tests for both

registration and disinfectant validation is 104 ~ 106 microbial
cells dried onto a relatively small area ( 3 cm2 – 25 cm2).

⚫ Again, this is a greater challenge for the disinfectant than the

level of contamination typically recovered in cleanrooms during
EM of surfaces.

23
Summary

⚫ There are several issues to consider if an isolate is recovered during EM that

is not listed explicitly on the EPA label or during previous disinfectant
validation.

⚫ Returning to the original question regarding Micrococcus/Kocuria or

Bacillus species, the first description is complicated by the description of
the isolate.

⚫ A brief internet search or conversation with a microbiologist can help reveal

that Micrococcus and Kocuria are two closely related genera of Gram-
positive bacteria often associated with normal human skin.

⚫ The two genera are so closely related phenotypically that many

identification methods cannot differentiate between the two, so the lab
indicates the result with both names.
24
Summary cont’d

⚫ But to confirm if a disinfectant will kill these bacteria, the actual genus
does not matter.

⚫ Any product with broad-spectrum bactericidal claims used as directed

is very likely to kill these bacteria.

⚫ The likelihood increases if the disinfectant can also kill fungi, non-
enveloped viruses or mycobacteria.

⚫ That these bacteria were isolated is not because the cells encountered
the disinfectant and were unaffected, it was because the bacteria (likely
shed from human skin or saliva) entered the cleanroom after the
cleaning process or were not contacted by the disinfectant during the
cleaning process.
25
Summary cont’d

⚫ Ifthese types of bacteria have been recovered repeatedly or the

level of contamination exceeds action limits, appropriate
responses would include a review or retraining of handwashing,
gowning and disinfection procedures.

⚫ Regarding the Bacillus spp. Isolate is a bit more complicated as

the techniques used for EM do not differentiate between
vegetative bacteria and spores.

⚫ However, one should assume that recovery of a Bacillus species

(or any of the dozens of related genera ) originated from the
spore form.
26
Summary cont’d

⚫ Bacterial spores can enter the cleanroom from several environmental

sources, including air, shoes and cardboard packaging.

⚫ Interestingly, the one spore-former that can likely be ruled out is the
species that appears on EPA-registered surface sporicidal agents,
now identified as Chloridoids difficile (“C-diff”).

⚫ Although these bacteria do produce bacterial spores and are a

substantial healthcare concern, they are strictly anaerobic and
cannot reproduce or produce spores outside the body of animals.

⚫ Yet, it is the only spore-forming species for which EPA permits a

surface-sporicidal (vs. sterilant/immersion) claim.
27
Summary cont’d

⚫ Can a surface sporicidal disinfectant kill other genera and species of

spore-forming bacteria as well as C-diff?

⚫ The hierarchical scheme described above does not answer the

question on its own.

⚫ However, if one considers the bioburden (presence of soiling,

number of spores, required log kill) associated with the C-diff test
method, it is very likely that the sporicide will inactivate spore-
forming bacteria recovered in cleanrooms.

⚫ Rather than focusing on the disinfectant, reducing the ingress of the

spores into the cleanroom is likely to yield improved outcomes.
28
References

⚫ USP <1072> Disinfectants and Antiseptics

⚫ McDonnel, G.E. Antisepsis, Disinfection, and Sterilization: Types, Action, and
Resistance: Joh Wiley & Sons, 2020
⚫ Spaulding, E.H. “Chemical Disinfection and Antisepsis in the Hospital.” J.
Hosp. Res. 1957, 9, 5-31
⚫ US Environmental Protection Agency. Product Performance Test Guidelines
OCSPP Disinfectants for Use on Environmental Surfaces – Guidance for
Efficacy Test. EPA 712-C-17-004, Washington, DC, 2018

29
30
In process microbial control
during aseptic processing

Part II – Topic 6
Introduction

⚫ Last year 2022, 37 microbial contamination recalls were listed on the

US FDA Drug Recalls website.

⚫ Five recalls of sterile drug products due to microbial contamination

have been added, and three people have died due to eye infections
caused by contaminated products.

⚫ Obviously, there are still practices being employed by some drug

manufacturers that pose the risk of contamination for sterile drug
products.
⚫ This presentation will address best practices that should be
employed to further reduce the risk of microbial contamination of
sterile drug products and bacterial infection in patients.
2
Introduction cont’d

⚫ Looking at current practices that are used in the manufacture of

sterile injectable drug products, there are three general risk classes
based on the presence of personnel in proximity to open containers
and routes of exposure to contamination sources.

⚫ Each of the following risk classes is associated with specific aseptic

processing manufacturing operations currently in use:
⚫ High-risk : Practiced by 503A and 503B compounding pharmacies, small
start-up biologic and drug manufactures, clinic drug manufacturers,
radiopharmaceutical, biologics, and ATMP (Advanced Therapy Medicinal
products)

3
Introduction cont’d

⚫ Medium-risk : Predominantly practiced by many generic drug

manufactures, contract manufacturing organizations (CMOs) and some
smaller new drug or biologic manufacturing companies

⚫ Low-risk: Predominantly practiced by major drug and biologics

manufacturing companies and slowly being adopted by generic drug
manufacturers, CMOs, and other drug manufactures.

⚫ Drug and biologics manufacturers should carefully evaluate the risk

class that applies to their aseptic manufacturing process.
⚫ The practice of high-risk aseptic processing should be avoided
unless a firm can repeatably demonstrate that it has a highly trained
workforce and appropriate controls to mitigate contamination risks.
4
Introduction cont’d

⚫ Even in facilities that utilize sterile-to-sterile drug transfers, there is

an approximately 37% chance of contamination of the drug product,
for example, due to needle penetration through a vial rubber
septum when microorganisms have not been effectively removed
from the septum.

⚫ Environmental monitoring evaluates processing and operational

task suitability and the cleanliness levels achieved in cleanroom and
work environments used during aseptic processing.

⚫ Moreover, an effective environmental monitoring system is a

prerequisite that must be established before aseptic operations
commence. (Additional information on environmental monitoring can
be found in PDA’s Technical Reports No. 13 (Revised 2022) and 13-2
(2020) 5
Introduction cont’d

⚫ All aseptic drug manufacturers should consider using low-risk

aseptic processing to ensure that patients, who are often in poor
health, receive the highest level of protection against infection when
they receive ophthalmic or injectable drug products.

⚫ The diligent application of low-risk aseptic processing could reduce

patient adverse event, recalls and drug shortages.

⚫ Although low-risk aseptic processing may have higher initial costs

due to design, high-risk aseptic processing could reduce that cost of
manufacturing due to lower facility, labor and cleaning costs.

6
Introduction cont’d

⚫ The following analysis identifies significant issues in high-risk-class

aseptic processing and provides the best practices that should be
utilized.

⚫ A firm must understand and follow all regulatory guidance as a

prerequisite to its aseptic filing operations.

⚫ This presentation does not address terminally sterilize drug

products.

7
High-Risk Aseptic Processing (Manual Filling, Open Containers)

⚫ Tasks associated with this risk category include:

⚫ Manual facility cleaning and disinfection
⚫ Cleaning of components
⚫ Preparation of bulk solutions
⚫ Sterilization of components and equipment
⚫ Aseptic filling of primary containers
⚫ Aseptic sealing of primary containers.

⚫ In high-risk operations, the distance of personnel from open containers or

access ports is critical in determining contamination risk.

⚫ The closer a person or any part of their body is to open containers or

access ports/IV spike needles, the higher the risk of contamination.

8
Proper Design of the Cleanroom and ISO 5 Equipment

⚫ Cleanrooms should be constructed with enough space to allow all

work tasks to be conducted without interference from other
workspaces.
⚫ The proper flow of materials, suppliers and finished drug products
should be designed to follow a one-flow from entry to exit from the
workspace.

⚫ This linear flow can minimize the chance of contamination.

⚫ There should be adequate storage space designed to accommodate

anticipated production volumes, and provisions should be made to
ensure that materials do not block return air vents.

9
Proper Desing of the Cleanroom and ISO 5 Equipment cont’d

⚫ Furthermore, doors should have automatic, touchless controls with

airlocks rather than door handles, and air/material locks should be
used when moving from a less-clean area to an area of higher
cleanliness with controls that prevent both doors from being open
at the same time except for emergency egress.

⚫ All surfaces used for the cleanrooms and floors should be

compatible with the cleaning agents and the drugs that will be
produced.

⚫ Heating, ventilation and air conditioning (HVAC) systems should be

designed by experienced pharmaceutical cleanroom fabricators or
contractors that follow pharmaceutical engineering standards.
10
Proper Desing of the Cleanroom and ISO 5 Equipment cont’d

⚫ Prior to purchasing equipment that meets ISO 5 grade air, which is a

space that has been classified to meet ISO 14644-1 requirements
(3520 particles/cubic meter) for airborne 0.5 μm particulate in the
in-operation state, an ergonomic design analysis that addresses
microbial and particulate contamination risks and safe personnel
movements should be completed.

⚫ The analysis will specify the proper size, features and construction of
biological safety cabinets (BSCs) or unidirectional flow.

⚫ Properly designed BSCs or laminar airflow hoods are recommended

to reduce potential contamination from personnel.

11
Proper Desing of the Cleanroom and ISO 5 Equipment cont’d

⚫ The actual aseptic work zone within the equipment should be established
using dynamic smoke studies, showing areas of minimal turbulence and
unidirectional airflow.

⚫ Routine calibration and certification of high-efficiency particulate air

(HEPA) filters and control equipment are essential to proper facility
operation and can provide early warning of a contamination control failure.

⚫ HEPA filters, control dampers, control systems, humidifiers, heat

exchangers and pressure fans/fan drive belts can all fail over time.

⚫ They should be included in a preventive maintenance program that utilizes

the mean time between failure calculations, allowing a company to
schedule maintenance before equipment fails and thereby preventing
contamination events.
12
Personnel Flow

⚫ Personnel flow should be designed to allow one entry into a

gowning room and, after gowning, entry into the cleanrooms.

⚫ A separate exit pathway should be in place to prevent cross-

contamination.

⚫ Space limitations may prevent a separate entry and exit, but this
should only be allowed when strict personnel movement
procedures prevent personnel from entering and leaving the
cleanrooms simultaneously.

⚫ Personnel movement within the cleanrooms should be designed to

prevent employees from becoming a source of cross-contamination.

13
Personnel Gowning and Aseptic Practices

⚫ The foundation of personnel gowning and aseptic practices relies

on employees being taught effective personal hygiene practices.

⚫ Personal hygiene practices should not be assumed to be practiced

by all employees.

⚫ Training and verifying all employees in aseptic operations to

establish a baseline for acceptable personal hygiene practices is a
best practice.

⚫ This is the first line of defense to minimize microbial contamination.

14
Personnel Gowning and Aseptic Practices cont’d

⚫ Personnel wearing street shoes or personal clothing except

underwear in work areas is not recommended.

⚫ Personal clothing and street shoes can have elevated levels of

particulates (dust, hair, pollen, pet dander and dirt) on them that
could be transferred into cleanrooms if worn under sterile garment.

⚫ Even if an employee wears freshly washed clothing, the act of going

to work can expose the employee and their clothing to numerous
contamination sources.

⚫ There should be a locker room where personnel remove street

clothing and shoes and then wash their hands with soap.

15
Personnel Gowning and Aseptic Practices cont’d

⚫ Additionally, there should be dedicated plant uniforms with long-

sleeve shirts that are made of low particle-shedding cloth and
dedicated plant shoes.

⚫ Protection of the drug product from employee-associated microbial

contamination is a fundamental requirement for aseptic processing.

⚫ Wearing sterile protective garments such as face masks, coveralls,

hoods, gloves and goggles is mandatory to minimize the transfer of
microorganisms from people to the environment and drug products.

16
Personnel Gowning and Aseptic Practices cont’d

⚫ The sterile garments used should be selected for ease of donning

and an appropriate standard operating procedure (SOP) should be
followed that will prevent nonsterile clothing, skin, or hair from
contacting the outer surfaces of the garment.

⚫ Garment suppliers should be able to provide proof of sterility for

each batch of garments received and should provide them folded
and prepared for ease of donning.

⚫ Not all sterile garments on the market have the same ability to
contain personnel-generated particles and microorganisms,
however.

17
Personnel Gowning and Aseptic Practices cont’d

⚫ The garments supplier should be able to demonstrate the retention

levels of particles and microorganisms for the garments chosen.

⚫ Personal comfort and reduction of bellow effects should also be

determined for the garments to be included in the gowning
procedure.

⚫ All outside surfaces of garment packages are contaminated, and

proper cleaning and disinfection of the surfaces should occur before
opening.

18
Personnel Gowning and Aseptic Practices cont’d

⚫ The packages themselves should be designed to minimize

particulate generation during opening.

⚫ Sterile gloves should be donned without touching the outside of the

glove and disinfected after every touch of a surface or on a routine
basis while they are worn.

⚫ Sterile 70% isopropyl alcohol is a recommended disinfectant and

surfactant for gloves if properly saturated.

19
Personnel Gowning and Aseptic Practices cont’d

⚫ Sterile tools such as forceps, tweezers, holders or manipulators

should be used to contact surfaces of vials, stoppers, seals, syringes,
plungers and IV bag ports.

⚫ Stoppers, plungers and plugs should not be placed on work surfaces

during processing.

⚫ Tubing and needle holders should be at least eight inches in length

when measured from hand to tip of holder.

⚫ All personnel should have extensive training in aseptic practice

before completing aseptic process simulation (media fill)
qualification.
20
Personnel Gowning and Aseptic Practices cont’d

⚫ PDA offers excellent courses that teach proper aseptic technique,

donning of sterile garments and appropriate behavior in the
cleanroom.
⚫ Additionally, the FDA’s Center of Compounding Excellence offers
online courses that address gowning and aseptic practices.
⚫ Media-fill qualifications for personnel should duplicate actual
manufacturing operations, including filling duration and type of
products filled.
⚫ A second-person observation or video recording of media-fill
qualifications should be performed to document practices of
concern or deviations from SOPs.
21
Ready-to-Sterilize or Ready-to-Use Components

⚫ Firms must ensure that suppliers of ready-to-sterilize or ready-to-

use components have designed effective cleaning processes and are
using cleanroom-appropriate protective packaging; low particulate
shedding provides contamination protection for components.

⚫ Suppliers should use laminar airflow hoods (horizontal or vertical

airflow designs) and/or separate cleanrooms for manual cleaning
and preparing components.

⚫ Supplies employee behavior, oversight and the use of ergonomic

process designs are essential to reduce the risk of microbial
contamination.

22
Ready-to-Sterilize or Ready-to-Use Components cont’d

⚫ Firms should use their suppliers’ audit programs or quality

agreements to determine whether the quality requirements needed
for their components are met.

23
Design of Material Flow and Usage

⚫ Firms must design effective processes to transfer materials from

warehouses to support areas to process cleanrooms and into BSCs,
reducing access barrier systems or isolators.

⚫ Soil and microbial contamination can occur while components and

supplies are in transit from the original manufacture’s facilities until
materials are processed into the cleanrooms for use in drug
manufacturing.

⚫ These contaminants need to be removed from outside surfaces of

packages when packages are transferred from a dirtier area to a
cleaner area since mostly manual processes are employed and
contaminants can be easily transferred during each stage of entry
from warehouse to ultimate use in an ISO 5 class filling zone.
24
Design of Component and Equipment Cleaning, Sterilization and Usage

⚫ Design, purchase and implementation of proper cleaning equipment

are critical to removing soil and debris from components before use.

⚫ Equipment must be designed to gently handle the components to

avoid particle generations.

⚫ Also, cleaning processes should be designed to remove soil,

microorganisms, endotoxins, exotoxins, hydrocarbons, lubricants and
mold release agent.

⚫ Qualification of the cleaning processes should be designed to assess

the removal of each type of contaminant.

25
Design of Component and Equipment Cleaning, Sterilization and Usage cont’d

⚫ Purchase of purified water, water for injection, compressed air or

nitrogen (gas or liquid) needs to be sourced from reputable
suppliers and have certificates of analysis for each batch received.

⚫ These materials must be effectively controlled upon receipt, storage

and use to prevent contamination of components during cleaning
and sterilization/dehydrogenation.

⚫ Containers of these materials can be significant sources of

contamination once opened.

26
 Design of Component and Equipment Cleaning, Sterilization and Usage cont’d

⚫ Compressed gases used during processing need to be sterile-filtered

and, if gasses are compressed on site, the compressors should be oil-
free and have systems to remove water from the compressed gas
storage tanks since storage tanks have been found to be significant
sources of microbial contamination.

⚫ Another significant problem that must be addressed is storage time

after cleaning, which could allow microorganisms to proliferate on wet
components waiting to be sterilized or dehydrogenated.

⚫ Hold-time studies during storage must be conducted to determine the

maximum time components can remain wet before further processing.
27
Design of Component and Equipment Cleaning, Sterilization and Usage cont’d

⚫ With effective planning, components should be processed as soon

as possible after cleaning.

⚫ Additional information can be found in PDA’s Technical Report No. 69:

Bioburden and Biofilm Management in Pharmaceutical Manufacturing
Operations.

⚫ Cleanroom-designed transfer bags/containers should be utilized to

store components after cleaning and sterilization.

⚫ Firms must ensure that the bags/containers used are clean and
particle-free prior to use.

28
Design of Component and Equipment Cleaning, Sterilization and Usage cont’d

⚫ Reusable containers must have qualified cleaning processes

established before use and suitable storage methods that prevent
recontamination before use.

⚫ All components being processed should be properly identified for

the stage of processing, and segregation methods should be
established to prevent mix-ups that could allow components that
are not cleaned to be used.

29
 Cleaning and Disinfectant Issues cont’d

⚫ Personnel and processing operations all contribute contaminants to

cleanroom air and surfaces, which environmental contamination
studies have repeatedly demonstrated.

⚫ Cumulative effects over time can allow microorganisms to be present

in the cleanroom air and on work surfaces, including equipment and
stainless-steel benchtops.

⚫ Environmental contamination has been observed even where full

sterile gowning is used.

⚫ Effective cleaning procedures must be designed to remove all previous

drug products, particulate matter and microbial contaminants from
equipment contact surfaces and cleanrooms.
30
 Cleaning and Disinfectant Issues cont’d

⚫ Cleaning agents, disinfectants and sporicides should have low

chemical residues, or there should have procedures in place designed
to remove residues on a periodic basis.

⚫ Another source of contamination routinely found in high-risk aseptic

processing is dirty cleaning equipment, utensils, buckets and mops.

⚫ This equipment should be cleaned and sterilized after each use, stored
in proper locations and protected from contamination during storage.

⚫ Surface disinfectant or sporicide wet-contact times are routinely

ignored by personnel assigned to cleaning and must be strictly
enforced to ensure that surfaces are thoroughly cleaned.
31
Cleaning and Disinfectant Issues cont’d

⚫ Many facilities rely on ready-to-use, presterilized cleaners,

disinfectants and sporicides, but some firms are still observed to be
using nonsterile materials.

⚫ Facilities must ensure that sterilization of cleaning, disinfecting and

sporicidal agents has occurred and that cleaning wipes, mop heads
and utensils are also sterilized before use or are purchases sterile.

⚫ The complexity of high-risk aseptic processing is often overlooked

by the firms using this methodology.

32
Cleaning and Disinfectant Issues cont’d

⚫ Operational designs should be objectively scrutinized to ensure that

contamination risks are minimized, and human factor analysis has
been used to reduce operational errors that could jeopardize the
sterility of the drug products being produced.

⚫ Additional information can be found in PDA’s Technical Report No. 62:

Recommended Practices for Manual Aseptic Processes.

33
Summary

⚫ Understanding the microbial contamination risks associated with

each type of aseptic processing currently used to manufacture drug
products is important.

⚫ This presentation provides information for aseptic compounders

and manufacturers to consider when they design their aseptic
process; the information can also be used to improve their aseptic
filling operations and reduce contamination risks.

⚫ The best practices needed for this high aseptic risk class should be
incorporated into each firm’s aseptic filling operations.

34
Summary cont’d

⚫ Knowledge of the sources and types of contamination can be used to

train personnel involved in aseptic process design, facility
construction, equipment design, preparation of SOPs and operations.

⚫ Moreover, effective and persistent training in how to reduce or

eliminate microbial contamination is essential to manufacturing
aseptic drug products.

⚫ Due to the significant contamination risks associated with high-risks

aseptic filling, it is strongly recommended that manual aseptic filling
not be used to prepare sterile drug products in factifies that are
poorly designed or where personnel do not have the knowledge or
experience to properly conduct aseptic operations.
35
Summary cont’d

⚫ Even if facilities are properly designed and operated by disciplined

and knowledgeable personnel, the risk of fatigue and complacency
may pose potential risks.

⚫ Nonetheless, advances in automation and robotics have clear

advantages over high-risk aseptic processing and, when possible,
these low-risk aseptic methodologies should be used in place of
manual aseptic processing.

⚫ Alternatively, meticulously designed terminal sterilization (heat,

steam, chemical or radiation) processes should be evaluated to
determine if a drug product will not be degraded by terminal
sterilization.
36
Summary cont’d

⚫ Patients who receive aseptically filled drug products assume that the
drugs are sterile, and their health will not be negatively affected by
microorganisms that could cause hard-to-treat infections and
potentially lead to death.

⚫ Aseptic drug manufacturers must ensure that this scenario does not
happen.

37
Summary cont’d

⚫ The following resources should be used as a company evaluates

their aseptic processes:
⚫ PDA Technical Report No. 54: Implementation of Quality risk for Pharmaceutical
and Biotechnology Manufacturing Operations
⚫ PDA Technical Report No. 69: Bioburden and Biofilm Management in
Pharmaceutical Manufacturing Operations
⚫ PDA Technical Report No. 90: Contamination Control Strategy Development in
Pharmaceutical Manufacturing
⚫ PDA Technical Report No. 34: Desing and Validation of Isolator Systems for the
Manufacturing and Testing of Healthcare Products
⚫ PDA Points to Consider of the Aseptic Processing of Sterile Pharmaceutical
Products in Isolators

38
Potential contamination Summary Table

Contamination Explanation
Sources
People working in the cleanrooms and close to open containers can
induce turbulence and eddies in the air near open containers, which can
allow contaminants to enter the units being filled. Poor personnel
discipline and supervision cause deviations from aseptic practices and
Personnel result in drug product contamination. Untrained personnel or contractors
can cause significant contamination events to occur.
Poor training programs for all levels of personnel and contractors
contribute to the lack of personnel understanding and use of improper
aseptic techniques or contract services.
Manual use of disinfectants to clean surfaces of containers during transfer
from one clean zone to another for ready-to-use components may not be
performed correctly and risk microbial contaminants remaining on
Components and package surfaces and entering the aseptic filling zone.
Supplies
Even sterile-to-sterile compounding increases the risk of contamination
due to external contaminants on vials and syringes during storage and
use.
39
Potential contamination Summary Table cont’d

Contamination Explanation
Sources
APIs and components could have endotoxin and exotoxin contaminants
present in quantities that could cause physiological harm.
Liquids Manual manipulation of filters and use of improper grade filters are
common problems. Some solutions are filtered into the ISO 5 filling area
but are stored for periods of time that could allow contamination ingress if
not properly sealed and stored.
Tools Tool cleaning and disinfection are manual processes where human
variability can prevent removal of microorganisms
Equipment Tubing and pumps can cause contamination if not carefully selected for
aseptic processing. Hand tools used may place the hand close to open
container. Hand-crimping tools or plunger-placement tools can be
significant sources of contamination.

40
Potential contamination Summary Table cont’d

Contamination Explanation
Sources
HEPA-filter or filter-seal failures on laminar flow units or BSCs and leaks in
negative pressure isolators, if not detected and fixed, will allow airborne
microorganisms to contaminate the drug products being filled.
Processes Lack of ergonomic design increases the risk of contamination. The use of
first air principles is critical to reduce contamination risk.
Poor construction practices and materials of construction can cause
significant episodes of microbial and particulate contamination.
Cleanrooms in these facilities may not provide adequate segregation of
classified rooms from nonclassified areas surrounding the ISO 5
workspaces. The use of handwashing sinks in anterooms can be a source
Facilities of microbial contamination during gowning.
Gaps in ceiling tiles, cracks in walls and floors with cracks can lead to
persistent levels of microbial contamination. Door handles can allow
microorganisms to be transferred between personnel.
41
Potential contamination Summary Table cont’d

Contamination Explanation
Sources
Poor monitored air pressure differentials and open doors can cause the
mingling of air containing microbial spores to enter the cleanrooms
Water leaks or poorly maintained HVAC cooling coils are significant
sources of mold and fungi contamination.
Facilities Cleanroom HEPA-filter of filter-seal failures, if not detected and fixed, will
allow airborne microorganisms to contaminate the drug products being
filled.
Negative-pressure cleanrooms that are not properly sealed will allow
microorganisms and particulate matter to contaminate the room.
Skin cells and hair present in cleanrooms can contaminate ISO 5 work
Skin Cells and Hair areas during processing due to venturi effects and personnel intrusion or
poor aseptic manipulation practices.
Clothing, containers and cleaning supplies are the most likely sources of
Fibers fibers, and there is a high risk that they may be present in ISO 5 work
zones during all manual processes. 42
Potential contamination Summary Table cont’d

Contamination Explanation
Sources
Cleanrooms rely upon air filtration processes to control dust, but it may be
Dust
present on personnel or materials in the cleanrooms or ISO 5 filling zones.
Bacteria are present in the cleanrooms when personnel are present and
when materials are moved. If cleaning/disinfecting procedures are not
Bacteria
adequate to maintain a facility, and/or when facility or equipment used
are not suitable for aseptic operations, they will continue to be present.
Fungi are present in the cleanrooms when:
• Personnel are present
• Cleaning/disinfecting procedures are not adequate to maintain a
Fungi
facility
• Water leaks occur in areas adjoining the facility
• Facility or equipment used are not suitable for aseptic operations
Viruses are present in the cleanrooms when personnel are present,
Viruses organic materials are used and cleaning/disinfecting procedures are not
adequate to maintain the equipment.
43
Potential contamination Summary Table cont’d

Contamination Explanation
Sources
Lubricants Depending on the source and the use of equipment, lubricants can be a
source of contamination, for example, seal failure.
Metals Due to manual processes, unless mixers are used post-filtration, there is a
low probability of metals presenting a source of contamination.
Component Component particles are likely to be present in cleanrooms. Firms may
Particles rely upon component vendors to reduce particulates and recommend
component types. Many of these facilities rely upon ready-to-use or ready-
to-sterilize prepackaged components. Contamination sources are dirt
accumulated during shipping, packaging material and poorly cleaned
components.
Chemical Residues A manual cleaning process can allow chemical residues to accumulate
(Cleaning Agents over time.
and Previous Drug
Products)

44
 References

1. Microbial Control of Raw Materials Used in Pharmaceuticals. www.pda.org. https://www.pda.org/pda-

letter-portal/home/full-article/microbial-control-of-raw-materials-used-in-pharmaceuticals.
2. Office of Regulatory Affairs. Recalls, Market Withdrawals, & Safety Alerts. U.S. Food and Drug Administration.
https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts.
3. Eaton t., Whyte W., 2021, Effective Reusable Cleanroom Garments and Evaluation of Garment Life,
EJPPS European Journal of Parenteral and Pharmaceutical Sciences, January 2021 DOI:
10.37521/ejpps.25401.
4. PDA Training | Continuing Education for Pharmaceutical Manufacturers.
www.pda.org. https://www.pda.org/pda-training/home.
5. Bajerski F, Nagel M, Overmann J. Microbial occurrence in liquid nitrogen storage tanks: a challenge for
cryobanking? Appl Microbial Biotechnology. 2021 Oct;105(20):7635-7650. doi: 10.1007/s00253-021-
11531-4. Epub 2021 Sep 24. PMID: 34559283; PMCID: PMC8460408.
6. Favero et. al., 1966, Comparative Levels and Types of Microbial Contamination Detected in Industrial
Clean Rooms, Applied Microbiology, July, Vol. 14, No.4.
7. Sandle, T. (2011): ‘A Review of Cleanroom Microflora: Types, Trends, and Patterns’, PDA Journal of
Pharmaceutical Science and Technology, Vol. 65, No.4, July–August 2011, pp392-403

45
Thank you for your listening

46