CONTAMINATION & CONTAMINATION CONTROL STRAGETY

What is Contamination?
 The act of contaminating or polluting, including either intentionally or accidentally, unwanted, and potentially dangerous
substances or factors.
 Also, simply the state of being contaminated (with something you don’t want and don’t expect to be present)
 Contamination can be:
 Physical – e.g. dust, fibres, human skin cells, particles
 Chemical – e.g. cleaning agent residues, process gasses, molecules, vapour
 Microbiological – e.g. bacteria, virus, yeast, mould
Where can Contamination Come From?
There is a multitude / massive amount of potential sources of contamination; some are listed below:
 Buildings and Premises
 Services and Utilities
 Environment
 Equipment
 Starting and Packaging Materials
 Process and Production
 Sampling Procedures
 Cleaning Agents

 And the biggest star of contamination – PEOPLE!

What is Contamination Control?

Contamination Control is a set of systems and techniques that ensure the minimisation or reduction of contamination.
"A Quality Risk Management process…should be used to assess and control cross-contamination risks presented by the products
manufactured"

PIC/S Guide to Good Manufacturing Practice for Medicinal Products PE-009-16 Part I, clause 5.20 (part)
"The outcome of the Quality Risk Management process should be the basis for determining the extent of technical and
organisational measures required to control risks of cross-contamination."
PIC/S Guide to Good Manufacturing Practice for Medicinal Products PE-009-16 Part I, clause 5.21 (part)
Examples of technical measures:
 Dedicated manufacturing facility
 Design of manufacturing process, premises, and equipment
 Dedicated equipment
 Use of airlocks
 Use of single-use technologies
Examples of organisational measures:
 Supervision of working behaviour to ensure training effectiveness and compliance with relevant procedural controls
 Recording of spills, accidental events or deviations from procedures
 Cleaning verification
 Specific processes for waste handling

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
"Measures to prevent cross-contamination and their effectiveness should be reviewed periodically
according to set procedures"
PIC/S Guide to Good Manufacturing Practice for Medicinal Products PE-009-16 Part I, clause 5.22
An initial risk assessment should be a critical step in implementing the CCS…but don’t ‘set and forget! The CCS should be
considered a living document and can continually be strengthened. Ongoing risk assessment should be applied whereby the
initial risk assessment for the area/facility/process should be periodically reviewed and updated as necessary.

Why is Contamination Control Critical to Product Quality?

1. To minimise risk to patient
2. To ensure the product remains safe, pure and effective
3. Because we cannot test for each contaminant and impurity
4. To avoid costly recalls (both dollar value and company reputation)
When manufacturing pharmaceuticals, the risk of contaminants impacting pharmaceutical safety, efficacy and purity is real.
Contamination control is increasingly becoming a focus for regulatory bodies (although it has always been important), with
the expectation to now have a documented Contamination Control Strategy (CCS) for pharmaceutical manufacturers.
"Contamination of a starting material or of a product by another material or product should be prevented…contamination of all
products poses risk to patient safety dependent on the nature and extent of contamination"

PIC/S Guide to Good Manufacturing Practice for Medicinal Products PE-009-16 Part I Clause 5.18 (part)
CCS is a critical strategic document/plan that describes the contamination risk management strategy and associated governance
to decide the continuous improvements and investment plans to prevent contamination. Therefore, developing such a
document requires a cross-functional team of experts with good production, QRM, and regulatory knowledge.

UNDERSTANDING THE ENEMY: TYPES OF CONTAMINATION

To fight off contamination effectively, you need to know what you're up against. Contamination can come from various sources,

and it's important to understand these to develop an effective CCS.

For sterile products, the main types of contamination include:

 Microbial contamination: This involves bacteria, viruses, fungi, and other microorganisms. These invisible invaders can

come from the environment, personnel, or raw materials and can potentially ruin your product.

 Particulate contamination: This refers to physical particles like dust, fibers, or metal shavings that can contaminate the

product. Imagine finding a piece of metal in a vial of medicine!

 Chemical contamination: Extractable and leachable contaminants are a concern for both sterile and non-sterile

products. It happens when unwanted chemicals are released into the product, either from the manufacturing process

or from cross-contamination with other products.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
 The following could be considered while defining CCS:

Firstly, Secondly, Thirdly, Fourthly, Finally,

it is important to the strategy should the strategy should documentation is regular reviews and

identify the potential outline the measures include clear key to a well- updates to the

sources of available OR to be instructions documented cross- strategy are crucial

contamination, taken to prevent (procedures) for contamination to ensuring that it

including the types cross-contamination. sampling and testing strategy. The remains practical,

of products This may include to ensure that cross- strategy should be effective, and up-to-

manufactured at the implementing contamination is clearly documented date. Any changes to

site, and the cleaning procedures detected and in a written policy, the manufacturing

processes involved in for equipment, using addressed promptly. and all procedures process, equipment,

manufacturing/ dedicated areas for This should include should be or materials should

packing, storage, and specific processes, routine and testing documented in be evaluated for

handling of drug and establishing in response to standard operating their potential

products, procedures for specific incidents or procedures (SOPs) impact on cross-

equipment, personnel hygiene. concerns. and training contamination, and

personnel, and materials. Records of the strategy updated

materials. testing and other accordingly.

This should be done relevant data should

by conducting a be maintained and

thorough risk easily accessible for

assessment of the review.

manufacturing

process, including

both the equipment

and the materials

involved.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
 Contamination Control Strategy (CCS) for Pharmaceutical Industry
This is the first time that an overview strategy is required for the area of contamination control that links the various aspects of
contamination control and associated measures, records the interactions and facilitates a corresponding analysis for gaps in the
system. This can be used in existing companies to meaningfully record, coordinate and supplement existing measures or, in
newly emerging facilities, to coordinate the implementation of the necessary contamination control measures across
departments.

What is CCS?
A contamination control strategy (CCS) is a comprehensive approach to prevent and manage contamination in the
manufacturing of pharmaceutical products. It involves a planned set of controls for microorganisms, Endotoxins / Pyrogens,
and particles, ensuring process performance and product quality.
The strategy is based on current product and process understanding and includes parameters and attributes related to
materials, facility and equipment operating conditions, in-process controls, finished product specifications, and the methods
and frequency of monitoring and control.
The CCS is a key element of Annex 1 of the EU GMP Guide, which emphasizes a risk-based and holistic approach. It requires
documenting all aspects of contamination control, including organizational, technical, and procedural measures, to ensure
comprehensive effectiveness.
This strategy helps identify, assess, and mitigate risks associated with contamination, aiming to enhance product quality and
patient safety.

Implementing a CCS involves three main pillars:

Prevention: Establishing controls to avoid contamination.
Remediation: Addressing any contamination that occurs.
Verification: Monitoring and verifying the effectiveness of the controls in place.
Defining a well-documented cross-contamination strategy involves several key steps.
When defining a CCS (contamination control strategy), it is recommended to consider not only cross-contamination but also all
other types of contaminants.

Building your fortress: developing a solid CCS strategy

Creating a CCS strategy is about being proactive, not reactive. By anticipating all the risks ahead of time you can put all the right
controls in place to keep contamination at bay. Here's how companies typically go about it:
1. Risk Assessment: This is the first step in building your own CCS. It involves identifying potential sources of contamination and
assessing their risk.
2. Preventive Measures: Based on the risk assessment, companies implement measures to prevent contamination. This could
include things like proper sanitation practices, air filtration systems, and personnel training.
3. Monitoring: Regular monitoring is crucial to ensure that the preventive measures are working. This can involve environmental
monitoring, product testing, and audits.
4. Corrective Actions: If contamination is detected, companies need to take swift corrective action. This could mean recalling
contaminated products, investigating the source of contamination, and implementing measures to prevent recurrence.
ECA´s Task Force prepared a Guideline document that supports the user in creating a CCS, building up the documentation
(comparable to a Site Master File – SMF) and thereby fulfilling the requirements of EU GMP Annex 1.
The ECA Guide contains a 3-stage-approach to achieve "CCS-readiness."
 Stage 1: Development (or review and refinement/improvement) of the CCS

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  State 2: Compilation of the CCS documents
 Stage 3: Evaluation of the CCS
This document is intended to provide guidance for two possible cases:

1. For a new plant, new equipment, e.g., for:

 Mapping of the manufacturing processes to identify possible sources of contamination.
 Carrying out a risk assessment to evaluate the risk of contamination.
 Establishing preventive measures and their controls in a holistic system (including the definition of responsibilities).
 Assessing and managing the residual risk of contamination.
2. For an existing facility that has already carried out a risk assessment, e.g., for:
 Evaluation of existing contamination control measures
 Analysis and overview of possible gaps
 Risk assessment and, if necessary, the addition of further measures and integration into the overall system (including
determination of responsibilities)
 Managing the residual risk of contamination

Contamination Control Strategy

The Annex states that “A contamination control strategy (CCS) 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 to medicinal product quality and safety. The combined strategy of the CCS
should establish robust assurance of contamination prevention. The CCS should be actively reviewed and where appropriate,
updated and should drive continuous improvement of the manufacturing and control methods.”
The CCS should describe the control measures and steps to minimize the risk of contamination from microbial, Endotoxin/
pyrogen and particle contamination. It should include a series of interrelated events and measures which even if they assessed,
controlled and monitored individually their collective effectiveness should be considered together.
The main elements will include:
A. Design of the plant and processes including the associated documentation

 A university degree or an equivalent diploma in the field of microbiology (or other natural sciences, or

medicine) together with a good understanding of the manufacturing processes under consideration are

required for the person in charge of supporting the design of manufacturing activities and environmental

monitoring.

 As for raw materials, the need for microbiological testing should be evaluated taking into consideration

their nature and respective use in the process. All specifications should be discussed and justified in the

CCS.

 As for extractables, the end user is expected to assess the data provided by the suppliers in order to define

the need for additional evaluation or leachable studies.

 A redundant filtration step through a sterile sterilising grade filter, to be included as close to the point of

fill as possible, is also encouraged, and its absence has to be justified. A risk analysis is required to justify

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
 the choice not to include pre-use/post-sterilisation integrity testing (PUPSIT) of sterilising grade filters

used in aseptically processes.

 Separate AHU systems should be present for the manufacturing and aseptic areas (Critical and support

areas) to avoid cross contamination.

 Qualified air handling systems should be available desired environmental condition in

processing/manufacturing areas.

 Positive room pressurization is a necessity to ensure product contamination control. Adjacent rooms of

different grades should have pressure differentials of a minimum of 10 pascals. The controls around

pressure differentials include:

 Indicators of pressure differences must be fitted between cleanrooms and/or isolators.

 Pressure differentials need to be monitored and recorded at regular intervals.

 The control of pressure regimes should be outlined in the site HVAC specification, where the pressure

differentials and alarm parameters are justified and documented.

HVAC systems are typically divided into separate Air Handling Units (AHUs) for control. Systems should be

designed, maintained, and classified according to ISO 14644 and operated according to a local HVAC

specification. Air handling plant (AHP) has been designed, installed and qualified to provide the requisite

environment for the preparation of aseptic medicines.

 Humidity Control where applicable should be available and control

 Building Management System (BMS) / Control system should be available

 Pre-filters / HEPA filters Grade should be mentioned in the documents (grade and location in AHU)

 Planned Preventative Maintenance programme should be available and defined and periodically

reviewed.

 Schematic of ductwork should be available

 Good design relates to both selecting a suitable grade of cleanroom together with a design intended to

minimize contamination. This includes the use of appropriate construction materials and spending time on

the suitability of the layout, covering elements like process and material flows.

 Good Design Control process includes the elements of planning, defining inputs such as specifications and

requirements, producing outputs such as manufacturing specifications, validation, verification, design

reviews, risk analysis etc.

 The design sub-elements are the facility layout, cleanroom design and classification, cross-contamination

management where appropriate, and people and material flow

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581
Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  Bio contamination control measures any associated equipment such as cleaning, disinfection, sterilization

systems/processes, and related validations should be available

 Cleanrooms classification, qualification, and monitoring program should be available

 Qualified HVAC, pressure cascade, utilities, Pressure alarms setting should be available.

 Pest control programs should be available.

 Preventive and corrective maintenance programs should be available.

 Good housekeeping programs should be available

B. Premises And Equipment

 The manufacture of sterile products should be carried out in appropriate cleanrooms.

 The Processing area / Rooms entry should be through change rooms that act as airlocks for personnel and

airlocks for equipment and materials.

 Cleanrooms and change rooms should be maintained to an appropriate cleanliness standard and supplied

with air that has passed through filters of an appropriate efficiency.

 Controls and monitoring should be scientifically justified and should effectively evaluate the state of

environmental conditions of cleanrooms, airlocks and pass-through hatches.

 The various operations of component preparation, product preparation and filling should be carried out

with appropriate technical and operational separation measures within the cleanroom or facility to prevent

mix up and contamination.

 Restricted Access Barrier Systems (RABS) or isolators are beneficial in assuring required conditions and

minimizing microbial contamination associated with direct human interventions in the critical zone.

 In cleanrooms and critical zones, all exposed surfaces should be smooth, impervious and unbroken in order

to minimize the shedding or accumulation of particles or micro-organisms.

 Materials used in cleanrooms, both in the construction of the room and for items used within the room,

should be selected to minimize generation of particles and to permit the repeated application of cleaning,

disinfectant and sporicidal agents where used.

 Ceilings should be designed and sealed to prevent contamination from the space above them.

 Sinks and drains should be prohibited in the grade A and grade B areas.

 The transfer of materials, equipment, and components into the grade A or B areas should be carried out via

a unidirectional process. Where possible, items should be sterilised and passed into these areas through

double-ended sterilisers (e.g. through a double-door autoclave or depyrogenation oven/tunnel) sealed into

the wall. Where sterilisation upon transfer of the items is not possible, a procedure which achieves the

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
 same objective of not introducing contamination should be validated and implemented, (e.g. using an

effective transfer disinfection process, rapid transfer systems for isolators or, for gaseous or liquid

materials, a bacteria-retentive filter). The removal of items from the grade A and B areas (e.g. materials,

waste, environmental samples) should be carried out via a separate unidirectional process. If this is not

possible, time-based separation of movement (incoming/exiting material) by procedure should be

considered and controls applied to avoid potential contamination of incoming items.

 Cleanrooms should be supplied with a filtered air supply that maintains a positive pressure and/or an

airflow relative to the background environment of a lower grade under all operational conditions and

should flush the area effectively. Adjacent rooms of different grades should have an air pressure difference

of a minimum of 10 Pascals (guidance value). Particular attention should be paid to the protection of the

critical zone. The recommendations regarding air supplies and pressures may need to be modified where it

is necessary to contain certain materials (e.g. pathogenic, highly toxic or radioactive products or live viral or

bacterial materials). The modification may include positively or negatively pressurized airlocks that prevent

the hazardous material from contaminating surrounding areas. Decontamination of facilities (e.g. the

cleanrooms and the heating, ventilation, and air-conditioning (HVAC) systems) and the treatment of air

leaving a clean area, may be necessary for some operations. Where containment requires air to flow into a

critical zone, the source of the air should be from an area of the same or higher grade.

 Airflow patterns within cleanrooms and zones should be visualised to demonstrate that there is no ingress

from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor)

or over operators or equipment that may transfer contamination to the higher grade areas. Where

unidirectional airflow is required, visualisation studies should be performed to determine compliance.

When filled, closed products are transferred to an adjacent cleanroom of a lower grade via a small egress

point, airflow visualization studies should demonstrate that air does not ingress from the lower grade

cleanrooms to the grade B area.

 Facilities should be designed to permit observation of production activities from outside the grade A and B

areas (e.g. through the provision of windows or remote cameras with a full view of the area and processes

to allow observation and supervision without entry). This requirement should be considered when

designing new facilities or during refurbishment of existing facilities.

 Advanced technology should be use to minimize the manual intervention during the production.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  Equipment management system should be in place (like qualification/ re-qualification, monitoring. All

equipment's are non-reactive, smooth surface, easy to clean, free from scratches/cracks and qualified

for intended use.)

 Validation Master Planner should be in place.

 Preventive maintenance (PM) program should be place.

 Cleaning validation document should be place.

 Cleanrooms and clean air equipment such as unidirectional airflow units (UDAFs), RABS and isolators, used

for the manufacture of sterile products, should be qualified according to the required characteristics of the

environment.

 Appropriate cleanliness levels in the “at rest” and “operational” states should be maintained.

 The microbial contamination level of the cleanrooms should be determined as part of the cleanroom

qualification. The number of sampling locations should be based on a documented risk assessment and the

results obtained from room classification, air visualization studies and knowledge of the process and

operations to be performed in the area.

 The requalification of cleanrooms and clean air equipment should be carried out periodically and the

requalification should include at a minimum the following:

- Cleanroom classification (total particle concentration).

- Integrity test of final filters.

- Airflow volume measurement.

- Verification of air pressure difference between rooms.

- Air velocity test (Note: For grade B, C and D the air velocity test should be performed according to a risk

assessment documented as part of the CCS. However, it is required for filling zones supplied with

unidirectional airflow (e.g. when filling terminally sterilised products or background to grade A and RABS).

For grades with non-unidirectional airflow, a measurement of recovery testing should replace velocity

testing).

The maximum time interval for requalification of grade A & B areas, is 6 months.

The maximum time interval for requalification of grade C & D areas, is 12 months.

 Adequate lighting should be in all the areas to perform operations adequately.

 Water supplied under continuous positive pressure in a plumbing system for the free of defects that could

contribute contamination to any drug product.

 closed system Type Equipment should be use wherever possible.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581
Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  Equipment System Surfaces should be smooth and easy to clean .

 Equipment Parts are designed to be sterilized

 Sterile pathways should be covered during setup, removing covers only at the end

 Mechanical and electrical adjustments designed should be made outside the aseptic processing area .

 All Equipment designs result in slopes for drainage and there is no any chance of stagnate of water or

material .

 Source air for air-break filters on autoclaves or lyophilizers drawn from the cleanroom rather than from

the plant area

 Electronics are covered or provided with a wipeable surface that is resistant to disinfectants (e.g.,

equipment computers or keyboards)

 Equipment can be easily protected during storage

 Describe frequency of requalification testing

C. Personnel
 People are the major variable within pharmaceutical processing.

 The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified, trained

and experienced in the manufacture and testing of sterile products, and any of the specific manufacturing

technologies used in the site’s manufacturing operations, to ensure compliance with GMP applicable to the

manufacture and handling of sterile products.

 Only the minimum number of personnel required should be present in cleanrooms. The maximum number

of operators in cleanrooms should be determined, documented and considered during activities such as

initial qualification and APS, so as not to compromise sterility assurance.

 All personnel including those performing cleaning, maintenance, monitoring and those that access

cleanrooms should receive regular training, gowning qualification and assessment in disciplines relevant to

the correct manufacture of sterile products.

 This training should include the basic elements of microbiology and hygiene, with a specific focus on

cleanroom practices, contamination control, aseptic techniques and the protection of sterile products. For

Example : The Personnel should be trained on Basic microbiology , Personnel flow and associated

requirements. , Material and waste flow. , Environmental control , Cleaning and disinfection , Process

design.

 The Adequate training and qualification of all people which are working in grade A and B areas, including

aseptic gowning and aseptic behaviours, is essential and important.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  According to Annex 1, this should include an annual successful APS.

 The personnel accessing grade A and B areas should be trained for aseptic gowning and aseptic behaviours.

Compliance with aseptic gowning procedures should be confirmed by assessment and periodic

reassessment at least annually, and should involve both visual and microbial assessment (using monitoring

locations such as gloved fingers, forearms, chest and hood (facemask / forehead).

 Unqualified personnel should not enter grade B cleanrooms or grade A in operation.

 The Personnel variables should be minimized through good training and educational programs. Included

within ‘personnel qualification’ and that is

 Sufficient personnel are qualified, trained and experienced in the manufacture and testing of

sterile products to ensure compliance with GMP

 Unqualified personnel should not enter Grade B cleanrooms or Grade A zones in operation

 With visitors, they must always be accompanied by a trained operator

 Requirements for gowning and monitoring including:

 Knowledge of contamination risks and appropriate control measures

 Annual initial qualification of personnel

 Gowning assessment should be present

 Training on specific requirements depending on criticality of the work performed should

be present

 As a personnel represent the primary source of contamination in any production process, personnel

training is a key contributor towards implementation of an effective contamination control strategy, so

training is very important and the regular training programme should be present.

 All personnel who access cleanrooms should receive regular training, gowning qualification, and

assessment in disciplines relevant to the correct manufacture of sterile products. Specific elements of the

training should include: Microbiology, personal hygiene ,aseptic technique ,Cleanroom practices ,

Contamination control techniques , Protection of sterile products.

 Training should cover a broad range of areas ranging from personnel movement and behaviour in

cleanrooms to the impact of cleanroom behaviours on the quality of the finished product.

 Personnel training should be practical, frequent, and continuous and should cover theoretical, practical and

cGMP aspects with the curriculum including basic microbiology, personal hygiene, and aseptic technique.

 Training should cover a broad range of areas ranging from personnel movement and behaviour in

cleanrooms to the impact of cleanroom behaviours on the quality of the finished product.
Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581
Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  A documented program should also be established to provide the criteria that disqualifies personnel from

cleanroom entry based on insufficient gowning technique and/or exceeding established microbial counts

and/or trends from personnel monitoring.

 The procedure for should be available for disqualification of Operators if the observation of poor aseptic

/cleanroom behaviour and return to accessing cleanrooms based upon appropriate corrective actions being

taken and successful completion of qualification.

D. Utilities (Water, Pure Steam, Gases)

 Utilities should be designed, installed, qualified, operated, maintained and monitored in a manner to

ensure that the utility system functions as expected.

 Results for critical parameters and critical quality attributes of high risk utilities like Purified Water , Water

for Injection , Pure Steam Generator should be subject to regular trend analysis to ensure that system

capabilities remain appropriate.

 Pipes, ducts and other utilities should not be present in cleanrooms. If unavoidable, then they should be

installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean.

Installation should allow cleaning and disinfection of outer surface of the pipes.

 The water generation system , that should be designed to allow for routine sanitisation and/or

disinfection. Procedures are needed to define regular preventive maintenance of the reverse osmosis

system, including the regular change of membranes.

 A suitable sampling schedule should be in place to regularly check water quality.

 More stringent controls are needed for the sampling of water-for-injection distribution systems, including

daily microbial and bacterial Endotoxin testing.

 Regular ongoing chemical and microbial monitoring of water systems should be performed to ensure that

the water continues to meet compendial expectations. Alert levels should be based on the initial

qualification data and thereafter periodically reassessed on data obtained during subsequent re-

qualifications, routine monitoring, and investigations. Review of ongoing monitoring data should be carried

out to identify any adverse trend in system performance.

 WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and

conductivity.

 Gases used in aseptic processes should be filtered through a sterilising grade filter (with a nominal pore size

of a maximum of 0.22 μm) at the point of use.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  The filter is used on a batch basis (e.g. for filtration of gas used for overlay of aseptically filled products) or

as product vessel vent filter, then the filter should be integrity tested and the results reviewed as part of

the batch certification/release process.

 When gases are used in the process, microbial monitoring of the gas should be performed periodically at

the point of use.

 The monitoring of the process gas should be performed as close as possible before the sterilisation filter.

 Feed water to a pure steam (clean steam) generator should be appropriately purified. Pure steam

generators should be designed, qualified and operated in a manner to ensure that the quality of steam

produced meets defined chemical and Endotoxin levels.

 Periodic sterilization or disinfection of the water system should be in place

 Water-for-Injection (WFI) storage tanks should be equipped with hydrophobic bacteria retentive vent

filters, the filters are sterilized, and the integrity of the filter tested before installation and after removal

following use.

 Gases used in aseptic processes need to be filtered with a sterilizing grade filter at the point of use.

 Microbial monitoring of the gas should be performed periodically at the point of use.

E. Personnel /material movement

 Separate entry-exit should be available for Man and materials .

 Separate change rooms should be available to remove street wear and wear clean factory linen.

 Gowning and de gowning procedure should be in place and displayed in respective processing area where

there is requirement of secondary gowning.

 The Material transfer to Grade A/B should be through Dynamic Pass box followed by effective cleaning and

sanitization.

 Materials entering into the aseptic areas should be sterilized by using autoclaves, depyrogenation tunnels,

or triple wrapped single ready to use sterile disposable items.

 The movement or “flow” of personnel, material, and wastes should be established using QRM principles.

 People are the primary source of microorganisms in cleanrooms, so personnel flow is critically important to

contamination control.

 Gowning and behaviour are key controls to limit contamination from personnel so these things are very

important to control the contamination.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
F. Health and hygiene
 High standards of personal hygiene and cleanliness are essential to prevent excessive shedding or increased

risk of introduction of microbial contamination.

 Personnel involved in the manufacture of sterile products should be instructed to report any specific health

conditions or ailments that may cause the shedding of abnormal numbers or types of contaminants and

therefore preclude cleanroom access.

 Health conditions and actions to be taken with regard to personnel who could be introducing an undue

microbial hazard should be provided by the designated competent person and described in procedures

 Regular Medical check up should be available.

 Proper training should be available regarding the Health & Hygiene.

G. Raw material controls - Product containers and closures / Vendor approval

 Procedure for Receipt of materials should be in place and at the time of receipt of mate1ial, and

warehouse personnel should be check the details of approved vendor and verify the received materials

with purchase requisition slip.

 The Vendor management system should be available for RM , Excipients & miscellaneous items and

qualify periodically.

 All Raw Materials/ PPM tested prior to use for chemical and micro/ BET test and Re-tested as definite

interval should be available.

 quality agreements should be in place between the firm and the vendor.

 Once qualified and approved, vendors should be audited on a frequency commensurate with the criticality

of the supplied materials or service.

 Routine vendor audits should be present for both API and Excipients and the vendor’s practices should be

evaluated as part of the vendor qualification.

 All manufactured drug product tested as per approved method of analysis against In-process and Finished

product specification.

 OOT/OOS handling procedure should be in case of any abnormal results , which is against the pre-defined

specification limit.

H. Monitoring systems The purpose of the environmental monitoring programme is to provide data that can be used to
assess the adequacy of contamination controls in the cleanroom or manufacturing area.
An environmental monitoring programme, which provides assurance of compliance with regulatory

requirements is established. This programme also is designed to detect excursions from environmental limits

triggering investigation and assessment of risk to product quality (annex 1, 2022). The environmental

programme covers both viable and non-viable particles.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581
Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  Environmental monitoring should be targeted at critical points of operator and material transfer and key

interactions in the preparation process. In addition, results should be considered in conjunction with air

changes, air flow patterns and pressure cascades.

 According to ICH Q9 (R1), the frequency of the risk review should be based on the level of risk determined

for the specific process under consideration, as well as on the level of uncertainty of previous assessments.

 For the new plants is to review the risk assessment after the first year of operations, so to take into due

consideration the acquired experience. The document also suggests cases where more stringent action

limits may be needed, and the type of statistics to be used to establish alert levels.

 The Environmental Monitoring (EM) program for a facility is used to monitor and determine the type and

level of microbial and non-viable particulate contamination present in a cleanroom environment.

 Viable environmental monitoring is performed by exposing microbiological nutrient medium plates in

sampling locations that represent the areas of highest contamination risk in the cleanroom.

 Non- viable particle monitoring is performed using Isokinetic probes and a laser particle counter to assess

the number of non-viable particles in the air and are also used for classification purposes as per ISO 14644.

The sampling locations for both viable and non-viable monitoring are selected using a documented risk

based approach that is reviewed and repeated periodically to account for any changes in the process or the

cleanroom.

 Appropriate alert levels and action limits should be set for the results of viable and non-viable particle

monitoring. Alert levels should be established based on results of cleanroom qualification tests or trend

data and should be subject to periodic review.

 Define adequately the sampling points. We will conduct a risk analysis to define the type, sampling

frequency, location and coding

 Define sampling plans. That is, routine control plans, batch-related plans, at-rest control plans, control

plans after cleaning and/or disinfection, aseptic filling plans and, finally, define sampling patterns for

incidents during manufacture.

 Set alert and action limits. These limits should allow to react to changes in results trends.

 Controls to be considered within this element of the CCS for the viable particles :-

Use of risk assessments to determine :-

 Sampling/ test locations – during operations and at rest – risk based

 Frequency of monitoring – include continuous monitoring for non-viable particles and pressures

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  Monitoring methods (including an assessment of the feasibility of the introduction of scientifically

sound, modern methods that optimise the environmental detection of environmental contamination,

and do not pose a risk of contamination to the product – Rapid Micro Methods (RMM)

 At rest and operational monitoring

 Acceptance criteria

 Risk assessment review

 The microbiological contamination control strategy covers CAPA associated with repeated results above

alerts levels or results reported above regulatory action levels.

1) Identification of potential sources/routes of microbiological contamination

2) Risk assessments, mitigation and controls

3) Describe the monitoring programme

4) Media used – provide a description and refer to product specifications for settle plates, contact

plates, liquid media etc.

5) Refer to alert and action limits noted in (ii) Premises and equipment

6) Alert and action limits. For Grade A – no growth i.e. every recovery requires an investigation.

7) OOS investigation, root cause analysis and CAPA

8) Trending, setting alert and actions levels, data patterns

9) Trending also applies to microbial speciation, A/B should be identified, C/D recommended

10) Media growth promotion – reference micro-organisms used / representation of facility flora / use of

wild type micro-organisms

11) Describe environmental monitoring training

 A similar approach should be taken for monitoring non-viable particles.

1) Identification of potential sources/routes of contamination

2) Risk assessments, mitigation and controls

3) Describe the monitoring programme

4) Use of Instruments like online or Portable Particle count

5) Refer to alert and action limits noted in (ii) Premises and equipment

6) Alert and action limits. For Grade A

7) OOS investigation, root cause analysis and CAPA

8) Trending, setting alert and actions levels, data patterns

9) Trending also applies to microbial speciation, A/B should be identified, C/D recommended
Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581
Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
 10) Describe environmental monitoring training

I. Process risk assessment

 The risk assessments that relate to all contamination control elements should be prepared.

 The Risk Assessment related to Process Personnel , Environment, Equipment , Utilities should be prepared.

J. Process Validation / Cleaning Validation / Media fill validation

 The cleaning process should be validated to be able to:

 Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting

agent used.

 Minimize chemical, microbial and particulate contamination of the product during the process and

prior to disinfection.

 The Periodic verification of the effectiveness of the controls for aseptic processing through Media fill

Validation should be in place by using a sterile nutrient media and/or surrogate in place of the product.

 The effectiveness of the aseptic process should be determined through process design, adherence to the

pharmaceutical quality system and process controls, training, and evaluation of monitoring data. Selection

of an appropriate nutrient media and/or surrogate should be made based on the ability of the media

and/or surrogate to imitate physical product characteristics assessed to pose a risk to product sterility

during the aseptic process.

 APS should be performed as part of the initial validation, with at least three consecutive satisfactory

simulation tests that cover all working shifts that the aseptic process may occur in, and after any significant

modification to operational practices, facilities, services or equipment which are assessed to have an

impact on the sterility assurance of the product (e.g. modification to the HVAC system, equipment, changes

to process, number of shifts and numbers of personnel, major facility shut down). Normally, APS (periodic

revalidation) should be repeated twice a year (approximately every six months) for each aseptic process,

each filling line and each shift. Each operator should participate in at least one successful APS annually.

Consideration should be given to performing an APS after the last batch prior to shut down, before long

periods of inactivity or before decommissioning or relocation of a line.

K. Cleaning and disinfection

 Regular cleaning (using a detergent to remove soiling) and disinfection (to inactivate microorganisms

through cellular destruction) should be required.

 Typically, two disinfectants are used in rotation, one of which is often a sporicide (capable of destroying

bacterial endospores and fungal spores). The frequency of cleaning and disinfection must be risk based,

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
 established during facility start-up and regularly reviewed as part of the Environmental Monitoring trend

review.

 Disinfectants that are selected for disinfection of a facility must be validated prior to use.

 Validation of disinfectants includes surface challenge testing in which coupons of the surface materials

used throughout the facility are inoculated with a known quantity of representative microorganisms,

exposed to the disinfectant for a specified contact time followed by calculation of the log reduction of the

microorganisms attributed to the disinfectant.

 Personnel who perform cleaning and disinfection of cleanrooms should undergo a tailored training

program that includes specific cleaning techniques that prevent contamination such as use of the triple

bucket system, basic Microbiology training and training on the action of the disinfectants selected for use.

L. Preventative maintenance
 To improve the cleanroom contamination control strategy, is to schedule regular maintenance on all

equipment.

 Regular Preventive maintenance Programme for the equipment and Utility system should be available and

it is the key to preventing failures of the cleanroom environmental control systems (HVAC) and production

equipment and ensuring the cleanrooms and equipment are operating in their validated state.

 Regular Preventive maintenance activities can also pose contamination if not done correctly.

 a triple-cleaning and disinfection cycle followed by EM before releasing the areas for routine operation

should be perform After the Preventive maintenance of equipment in cleanroom

M. Prevention mechanisms
All applicable QMS elements like Deviation , Change Control , Incident , CAPA , OOS , OOT should be

available and these are handle through QMS system.

As part of prevention mechanism, trend analysis, incident/ deviation, detailed investigation & root

cause analysis using different tools i.e. 5 WHY, Fish bone etc. and corrective and preventive actions

(CAPA) procedures should be in place and governed through respective SOPs.

Trending of all QMS elements i.e. incidents , deviations , Market Complaint , Change Control should be

available and prepare the same periodically.

N. Validation of sterilization processes

 All sterilisation processes should be validated.

 Before any sterilisation process is adopted, its suitability for the product and equipment, and its efficacy in

consistently achieving the desired sterilising conditions in all parts of each type of load to be processed

should be validated notably by physical measurements and where appropriate by Biological Indicators (BI).

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  Validated loading patterns should be established for all sterilisation processes and load patterns should be

subject to periodic revalidation. Maximum and minimum loads should also be considered as part of the

overall load validation strategy.

 The validity of the sterilizing process should be reviewed and verified at scheduled intervals based on risk.

Heat sterilization cycles should be revalidated with a minimum frequency of at least annually for load

patterns that are considered worst case. Other load patterns should be validated at a frequency justified in

the CCS.

 Routine operating parameters should be established and adhered to for all sterilisation processes, e.g.

physical parameters and loading patterns.

 There should be mechanisms in place to detect a sterilisation cycle that does not conform to the validated

parameters. Any failed sterilisation or sterilisation that deviated from the validated process (e.g. have

longer or shorter phases such as heating cycles) should be investigated.

 Suitable BIs placed at appropriate locations should be considered as an additional method to support the

validation of the sterilisation process.

 Sterilisation records should be available for each sterilisation run. Each cycle should have a unique

identifier. Their conformity should be reviewed and approved as part of the batch certification/release

procedure.

 If the product cannot be sterilised in its final container, solutions or liquids should be sterilised by filtration

through a sterile sterilising grade filter (with a nominal pore size of a maximum of 0.22 μm that has been

appropriately validated to obtain a sterile filtrate) and subsequently aseptically filled into a previously

sterilised container.

The selection of the filter used should ensure that it is compatible with the product and as described in the

marketing authorization

O. Controls of aseptic processing

 To prevent the contamination in aseptic processing area / manufacturing areas, the operators should

follow the appropriate cleanroom behaviours like Move carefully , Minimize conversation , Maintain

unidirectional airflow (“first air”) , Perform interventions carefully ,Position body means keeping the entire

body out of the path of the unidirectional airflow , Maintain proper gown control ,Protect sterile parts ,

Minimize surface contact , Manage gloves.

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  Aseptic processing depends on personnel operating in a manner that does not disturb airflow, minimizes

the generation of particles, and does not introduce bioburden into the process through inappropriate

handling of product contact equipment or components.

 Aseptic operator trainees should only be permitted to perform interventions upon successful participation

with a process simulation.

 The operator has been initially qualified, the facility should schedule an annual refresher training program

as well as participation in routine aseptic process simulation.

 The retraining and requalification, reassignment, or permanent removal of operator from the cleanroom

should be available.

P. Failure Management
 Preventive maintenance program should be in place.

 Trained engineering staffs should be involved in the good engineering practices (GEP).

Q. Identification of Control System

 method validation

 Procedure for preparation of specification and method of analysis should be available.

 Environmental monitoring (EM) programs should be in place to monitor and control the environment

and the data being trended, reviewed, and acted upon to ensure the manufacturing operation is

under continuous control.

 Qualified integrity tester should be used to test the integrity of the gloves.

 Microbiological testing of finished products performed for the products being manufacture in the

facility.

R. Waste Management
 Facility design should minimize the movement of material and waste and separate them from the flow of

personnel between areas of different classifications.

 The separate and dedicated pathways will also help prevent cross-contamination between products.

 Move scrap should be always adequately in the closed condition

The Continuous Improvement .......

As part of a contamination control strategy it is imperative that a culture of continuous improvement is established. This is

based on information from the current PQS and quality risk management processes. It is important that there are systems

in place to continually review and identify where improvements are required for ongoing quality of Products and that

should be thoroughly review timely as below mentioned programme -----

 Deviation, complaints management should be thoroughly reviewed and trending

 Change Management
Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581
Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com
  Site self-inspection program, quality and sterility assurance field observation, global quality audits

 Supplier management and audit program

 Management review of the quality systems and process/product performance and quality metrics

 Regulatory inspections trends and observations

 Regulatory expectations and Technological evolutions survey

SOURCES OF CONTAMINATION
The possible origins of contamination sources:

 Problems in the design of facilities, equipment or services

 Insufficient or ineffective monitoring and control

 Insufficient calibration, maintenance or qualification plans.

 Insufficient tools for controlling starting materials (sampling, specifications, management).

 Inadequate personnel management (ineffective personnel qualification systems, insufficient personnel monitoring,

insufficient continuous training, etc.).

 Poor process design (material and personnel flows, insufficient monitoring tools, non-representative aseptic process

simulation…).

 Insufficient cleaning and disinfection systems (insufficient cleaning validation, frequency, rotation of disinfectants, etc.).

 Inefficient sterilization processes (inadequate sterilisation systems, insufficient sterilisation validation, loss of control of

the outsourced process, contamination of materials after sterilisation, etc.).

 Insufficient management of quality events (recurrence of deviations, poor root cause analysis, inadequate OOS or OOT

management, poor or insufficient trend assessment, insufficient management of corrective actions…).

References: Summarise the same through Some Paper through Google Search , PDA TR - 90 , PICS , EU GMP , WHO TRS

Presented By : Arvind Kumar Srivastava , Mobile No. :9817039581

Manager - Quality Assurance , Beta Drugs Limited , Baddi , India , Email ID : arvindsrisri82@gmail.com