Contamination Control Strategy

protocol
QA Dept.
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ORCHIDIA
Contamination Control Strategy Protocol

Sign / Date. Name Function Approval

Prepared
Asmaa Gamal QA Compliance Specialist
by
Senior Risk & CAPA
Kawther Shaaban
Assessor
Ossama Mohamed Production Section Head
Engineering Section Head Reviewed
Mahmoud Soliman (Act As Engineering by
Manager)
Marwa Fawzy QC Manager

Mohamed Etman Production Manager

Mohamed Eltoukhy QA Compliance Manager

Approved
Mohamed Abdel by
Plant manager
Gawad

DOCUMENT HISTORY
Changes History Page No. Issue Date Issue No.
First Issue All Pages 06/09/2023 001
Update CCS All Pages 31/10/2024 002
Update whole protocol All Pages
22/06/2025 003
Update the format

Effective date
Copy number /DCC sign.

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Purpose .1
This Protocol is based on Annex 1, which requires to develop of a Contamination Control Strategy based
on the following principles (quoted from EU – GMP, Volume 4 Annex 1):
“to establish confidence and provide documented evidence with high degree of assurance that the
products when manufactured at production have subjected to special requirements in order to minimize
risks of microbial, particulate and endotoxin / pyrogen contamination and scale of operation will be
consistently produced with the quality that meets the product specification.”

The elements to be considered are listed in Annex 1:

i. Design of both the plant and processes, including the associated documentation.
ii.Premises and equipment.
iii.Personnel.
iv.Utilities.
v.Raw material controls – including in-process controls.
vi.Product containers and closures.
vii.Vendor approval includes key component suppliers, and critical service providers.
viii. Management of outsourced activities and availability/transfer of critical information between
parties, e.g. contract sterilization services.
ix.Process risk Management.
x.Process validation.
xi.Validation of sterilization processes.
xii.Preventative maintenance – maintaining equipment, utilities, and premises (planned and unplanned
maintenance) to a standard that will ensure there is no additional risk of contamination.
xiii. Cleaning and disinfection.
xiv. Monitoring systems – including an assessment of the feasibility of introducing scientifically sound,
alternative methods that optimize the detection of environmental contamination.
xv.Prevention mechanisms – trend analysis, detailed, investigation, and root cause determination,
corrective and preventive actions (CAPA), and the need for comprehensive investigational tools.
xvi. Continuous improvement based on information derived from the above

This CCS-Protocol summarizes how Orchidia Pharmaceutical Industries approached each of the
elements and how we maintain the standard to ensure an adequate level of contamination control.
2. Scope
This Protocol considers quality risk assessment and the overall approach to managing microbiological,
particulate, and cross-contamination of the manufacturing of all sterile products that are produced in
building #1 and building#2 in Orchidia Pharmaceutical co., Obour city, Egypt. It makes to relevant
documents, where details are defined and documented to avoid mismatches; this CCS protocol does not
repeat details provided in other documents.

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Term / Definition / Long Version

Abbreviation
CCS Contamination Control Strategy:
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 the active
substance, excipient and drug product materials and components, facility and equipment
operating conditions, in-process controls, finished product specifications, and the
associated methods and frequency of monitoring and control.
CCS-Protocol This Protocol compiles references to all documents related to the CCS as well as conclusions
on how to ascertain and maintain contamination control.

The Elements The elements mentioned in Annex 1 under i – xvi, which refer to Sections 2.1 – 2.16 of this
Protocol.
PV Process Validation
QRM Quality Risk Management
RA Risk Assessment / Risk Analysis
SMF Site Master File
SV Sterilization Validation
SOP Sterilization out of place.
SIP Sterilization in of place.
HVAC Heating, Ventilation and Air Conditioning.
BMS Building management system.

3. Abbreviations and Definitions:

4. Flowchart: None

5. Responsibilities:
5.1. Production department:
Ensure use of appropriate materials and equipment to minimize contamination risks
Ensure that all production areas and equipment are cleaned and disinfected according to
validated procedures
Implement procedures to control the movement of personnel and materials to avoid cross-
contamination
Support routine environmental monitoring during manufacturing processes
Provide regular training to operators on contamination risks and mitigation practices

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5.2. Engineering department:

 Maintain cleanroom structures (walls, ceilings, floors, doors) in accordance with
regulatory requirements.
 Ensure HVAC systems support classified areas and are maintained to control
airborne contamination.
Monitor and control pressure differentials, air change rates, and filtration systems
(HEPA).
 Perform periodic preventive maintenance and filter integrity testing.
 Monitor water systems (WFI, purified water), compressed air, and clean steam
systems to avoid microbial and particulate contamination
5.3. Microbiology department:
 Develop, implement, and manage the environmental monitoring process for
cleanrooms and controlled areas.
Monitor viable (microbial) and non-viable (particulate) contamination in air, surfaces,
and personnel.
 Trend and analyze EM data to detect contamination patterns and identify potential
risks
Perform routine microbiological testing for water systems (e.g., purified water, WFI)
and other utilities (e.g., compressed gases)
Promote microbiological awareness and contamination prevention culture across
departments.
5.4. QA Compliance department:

Ensure that all departments align with the CCS and that roles and responsibilities are clearly
defined and documented
Ensure all contamination control practices are appropriately documented and controlled under
the quality system
Ensure changes are evaluated for contamination risk and properly documented and approved
before implementation

6. Procedures:

6.1.Documentation of the Contamination Control Strategy:

6.1.1. Design of both the plant and processes including the associated documentation
The types of Orchidia products currently produced on-site include sterile items (ophthalmic
solutions, suspensions, gels, emulsions, ointments, and single-dose units) as well as non-
pharmaceutical products such as contact lens solutions and medical devices. The details are
covered in Site Master File “SMF-0001” Appendix 2 (List of Products).
6.1.1.1. The plant

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a) General
The plant is designed to ensure the process steps are performed in the clean room Grades are
required according to Annex 1.Access to the clean room grades is via separate air-locks for
personnel and material. Layouts of the different areas which show hygienic zones, personnel, and
material flow are covered in Site Master File “SMF-001” Appendix 9 (Flow chart of production
operations & Layouts of Production for eye drops)

b) Aseptically Manufactured Products

All types of Orchidia products currently produced on-site include sterile items (ophthalmic
solutions, suspensions, gels, emulsions, ointments, and single-dose units) as well as non-
pharmaceutical products such as contact lens solutions) are Aseptically Manufactured Products,
The details of all products are covered in Site Master File “SMF-001” Appendix 2 (List of
Products)

c) Low Bioburden Processes / Bioburden-Controlled Processes

Process Step Clean room High level Contamination control measures
grade
Raw Material C&B Make triple bag for the dispensed material inside LAF
Total Aerobic Viable Count test
Water C&B Total Microbial Count test
Water system Objectionable Microorganisms detection
Bulk C&B The sterilizing filter (0.2 micron) and the pre-filter (0.2 micron) can be
used for only one batch that it passes integrity testing before and after
each filling, the second sterilizing grade filter always installed near to
the point of fill (refer to SOP Sterilizing filters changing procedures
PR-P-0038)

6.1.1.2.The Processes
a) Aseptic Manufacturing
All types of Orchidia products currently produced on-site include sterile items (ophthalmic
solutions, suspensions, gels, emulsions, ointments, and single-dose units) as well as non-
pharmaceutical products such as contact lens solutions) are Aseptically Manufactured
Products,The details of all products are covered in Site Master File “SMF-001” Appendix 2
(List of Products)I

b) Low Bioburden Processes / Bioburden-Controlled Processes

NA, as all types of Orchidia products (ophthalmic solutions, suspensions, gels, emulsions,
ointments, and single-dose units) as well as non-pharmaceutical products such as contact lens
solutions) are sterile products.
6.1.2. Premises and Equipment
6.1.2.1. Premises
The plant is designed to ensure the process steps are performed in the clean room Grades are required
according to Annex 1.

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- Access to the clean room grades is via separate air-locks for personnel and material. Layouts
of the different areas which show hygienic zones, personnel, and material flow are covered in
Site Master File “SMF-001” Appendix 9 (Flow chart of production operations & Layouts of
Production for eye drops)
- type of contamination control systems in place are:

Production area1: clean room C classified

Personal air lock
Material air lock is 2 min.
Pass boxes

Production area 2: clean room B classified

Personal air lock
Material air lock is 2 min.
Pass boxes

- Drawing of the facility HVAC systems are covered in Site Master File “SMF-001” Appendix
9 (Flow chart of production operations & Layouts of Production for eye drops)

- The utilities being used for the process “for the contamination control”
Water stations
Pure stream generators
Compressor for compressed air
Nitrogen generator
Industrial boiler
HVAC system
- General cleanroom information:

Production area 1:
Partition HPL for walls and ceilings: for clean room, anodized aluminum with round coves
and corners for effective cleaning and disinfection [smooth, impervious and unbroken]

Floors: smooth self-leveling epoxy

Production area 2:
Partition HPL for walls and ceilings: for clean room, anodized aluminum with round coves
and corners for effective cleaning and disinfection [smooth, impervious and unbroken]

Floors: smooth self-leveling acrylic

Production areas accessed via personal air locks & material air locks
Mouth holes & drains
Information on the cleanroom contamination control:
- Rooms qualification are done according to the requirements of ISO 14644-1:2015 for

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particulate monitoring, HVAC system, temperature, relative humidity

- Room monitoring is done as per risk assessment of the micro lab FQAP-0011/02 and
SOP QC-P-0004 & QC-P-0083
- For prevention of airborne contamination: differential pressure controlled via BMS & LAFs
- Preventative maintenance plan code FEG-P-0201/01 is implemented for the BMS, HVAC
system
- Annual calibration plan code FVAL-P-0003/02 including the gauges monitoring the
differential pressure
- For AHU supplying air through HEPA filters
- Monitoring for the temperature in the clean rooms on batch basis with reference to
SOP EG-P-0516

6.1.2.2. Equipment
Major equipment related to contamination prevention
1- Autoclave
2- sanitization program “sterile sprayers “
3- Fumigation “forgers”
4- Mobile LAFs
Refer to the measure in place in the section of the CCS e.g. 6.9 “Validation of
sterilization processes”

6.1.3. Personnel
Personnel is trained in all areas of their responsibilities. More details about the areas and the
applicable procedures are provided:

Type of Training Reference Document

Title No.
Induction training Training Attendance Sheet FHR-P-006/03
General GMP-training Training Attendance Sheet FHR-P-006/03
Hygienic behavior PR-P-0067
personal hygiene procedures
PR-P-0001
Personnel Qualification Personnel Behavior inside the Sterile
PR-P-0040 009
Area
Garment Qualification & Package Seal
QUL-O-0008
Integrity Protocol

a) Gowning Requirements

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Description Reference Document

Title No.
Gowning requirements for the different Gowning Procedures in Production PR-P-0014
clean room grades are defined. Area
Garment Qualification & Package Seal
QUL-O-0008
Integrity Protocol

b) Clean Room Clothing

Description Reference Document
Title No.
Material, quality, and design of clean room
clothing is Garment Qualification &
QUL-O-0008
Package Seal Integrity Protocol
adequate for the respective clean room Grade
Changing and replacement of clean room Gowning Procedures in PR-P-0014
clothing Production Area
Material, quality, and design of clean room
clothing is adequate for the respective clean room Facility Maintenance SOP EG-P-0011
Grade
Cleaning of clean room clothing Garment Handling and cleaning PR-P-0082
procedures inside the sterile area
for plant 2
Cleaning Procedure for the PR-P-0004
Production Department
Preparation and Filtration of PR-P-0032
Disinfectants Used in Production
Area Procedures
Sterilization of clean room clothing Preparation of loads to be
PR-P-0055
sterilized in autoclave
Fedegari Autoclave Performance
Qualification Protocol Area 1 QUL-O-0009
(Building 1)
Validation of the sterilization process Fedegari Autoclave Performance
Qualification Protocol Area 1 QUL-O-0009
(Building 1)

6.1.4. Personnel Monitoring

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Note: Section 14 in Annex 1 is about monitoring, thus, Personnel Monitoring is mentioned in

Section 14.3. Personnel monitoring may either be mentioned in Section 6.12.2.4. – A matter of
taste. But: cross-reference should be made.

The personnel contamination control methods in place and the gowning “the qualification
process and periodic qualification“
1- All persons entering production area apply hygienic measures:
 Shaving
 Nails cut.
 Haircut.
 Tooth cleaning.
 Hand disinfection
 Electronic devises are forbidden in case of entering the sterile area
2- All persons entering production areas through primary gowning rooms (F11 & E 13 for male
gowning and F12 & E14 for female gowning in production I) , (F 107 & E 106 for male
gowning and F105 & E 104 for female gowning in production II) acc. to SOP PR-P-0014
3- Second change (secondary gowning) for class C area acc. to SOP PR-P-0014
4- Tertiary gowning for class A/B acc. to SOP PR-P-0014
5- De-gowning procedures are vice-versa gowning procedures
6- Frequency of exchange:
- Change manufacturing gowns for non-sterile area twice per week and When needed.
- Clean manufacturing shoes for non-sterile area at regular intervals at least weekly and when
needed.
- Change the secondary gowns for the sterile area each entry and when needed
7- Regarding garments used in corticosteroids containing preparations:
- Dedicated garments are used (C1, C2, C3………).
- Used garments collected in separate container.
- Then washed in separate washing cycle

 Initial Gowning Check-up testing:

- 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).
- The unsupervised access to the grade A and grade B areas where aseptic operations are or will be
conducted should be restricted to appropriately qualified personnel, who have passed the gowning
assessment and have participated in a successful APS.
- For New Personnel, Initial gowning qualification Consists of 3 Consecutive Gowning Check-ups
after training on Gowning.
 Routine Gowning Check-up testing:
The operator‘s gown should be tested Per batch.
 Re-qualification of Gowning Check-up:

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Gowning requalification of personnel allowed entry into sterile area is repeated annually.
 Disqualification of Gowning :
The disqualification of personnel from working in or given unsupervised entry into cleanrooms
that is based on Aspects including ongoing assessment and/or identification of an adverse trend
from the personnel monitoring programme and/or after being implicated in a failed APS.
Once disqualified, retraining and requalification should be completed before permitting the operator
to have any further involvement in aseptic practices. For operators entering grade B cleanrooms or
performing intervention into grade A, this requalification should include consideration of
participation in a successful APS

Description Reference Document

Title No.
RAs, SOPs, evaluation Refer to section 6.12.

Information around aseptic media fill, aseptic intervention risk assessment, monitoring after
intervention and residual risk accepted.
Aseptic preparation/processing: The handling of sterile products, containers, and/or devices in a
controlled environment in which the air supply, materials, and personnel are regulated to prevent
microbial, endotoxin/pyrogen, and particle contamination
 The APS includes various aseptic manipulations and interventions that occur during normal
production as well as worst-case situations,
 And take into account the following:
a) Planned interventions:
1. Routine intervention:
 Operators and personnel, who are directly involved in the critical operation and perform
interventions under the critical zone, are considered as directly involved and they should have
to follow strict aseptic practice and appropriate aseptic behaviors in the area during
manipulation and intervention handling.
 Each person in the aseptic area (e.g., operations, engineering, quality any other) has the
potential to introduce microbiological contamination. The risk of finished product sterility
increases as operator activities increase in an aseptic processing operation.
 Each person in the aseptic area (e.g., operations, engineering, quality any other) has the
potential to introduce microbiological contamination. The risk of finished product sterility
increases as operator activities increase in an aseptic processing operation
 Glove change after machine assembly or any hygiene incident in a clean room.
 Entry of environmental monitoring microbiologists in the filling room during the filling
operation and performing the environmental monitoring during the media fill

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 Monitoring of non-viable count using off line particle counters.

 Simulation of full door opening of filling room.
 Media fill simulate EM as intervention in critical zone

2. Non-Routine intervention:
 Apart from these, some of the operators, who are responsible for area cleaning and
sanitization, supervision and quality oversight and not involved directly or indirectly in the
aseptic manipulation and interventions in critical zone.
 Operator Fatigue.
 Entry of the maintenance person into the filling room, when the filling operation is going on
and performing the maintenance activity in a simulated during the filling
 Maintenance activity simulation: It will be simulated to assess the ability of the operator/
mechanic to intervene in the process to fix a “mechanical failure” for the type of intervention
at the respective stage of aseptic processing which will differ from line to line-based on the
line configuration
 Open the front machine door
b) Unplanned interventions:
Any interventions that happen incidentally during filling as follows:
 Disruptions of exit sensor
 Jamming (cups/ tubes/ machine/ nozzle/ cap/ bottle)
 Adjustment (volume/ cap head/ nozzle head/ sensor eye mark)
 Remove the excess plastic from the machine knife with a cupper brush
 Change the machine knife
 Adjustment of the plastic deformation or leakage
All routine & non routine interventions are mentioned at SOP QC-P-0016
Aseptic processing:
The type of aseptic processing is differentiated by the presence or absence of human
operators.
An advanced aseptic process is one in which direct intervention with open product
containers or exposed product contact surfaces by operators wearing conventional
cleanroom garments is not required and never permitted.
Advanced aseptic technologies can be defined as those that do not rely on the direct
intervention of human operators during processing. Such as blow/fill/seal.

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The testing procedures for environmental monitoring include the following tests:
 Settle Plates Testing SOP. No. QC-P-0005
 Particle count testing SOP. No. QC-P-0009
 RODAC Plates Testing SOP. No. QC-P-0007
 Swab Testing SOP. No. QC-P-0008
 Active Air Sampling SOP. No. QC-P-0006
 Gowns check-up testing SOP. No. QC-P-0011
 Fingerprint testing SOP. No. QC-P-0010
 Microbiology department records all media fill units during these interventions, incubation
and evaluation of inspection results.
 Microbiologist records all interventions and all microbial EM data performed during the APS,
including the start and end time of each intervention and other testing data in the APS batch
record
 Where the root cause investigation indicates that the failure was related to operator activity,
actions are taken to limit the operator’s activities, until retrained and re-qualified

6.2.Utilities

Refer to SMF “SMF-0001”

Method of preparation / distribution:
Compressed air being supplied from compressed air station and supplied through network of pipes to
the production area end use points, passing by dryers after compressor stage refer to SOP code
EG-P-0008
Nitrogen gas being supplied from Nitrogen generator and supplied through network of pipes to the
production area end use points, refer to SOP code EG-P-0054
Purified water is pumped to the stiller so that evaporation take place then condensation for steam is
done to produce WFI
Purified water is pumped to steam generator evaporation take place to produce pure steam
Contamination prevention program in place
Air is supplied through air handling unit systems that contain pre filters, bag filter and 99.95%
absolute H13 HEPA filters to produce pretreated air. This pretreated air supplied through Duct
System then passes through a set of terminal H14 HEPA filters with 99.997% efficiency. Refer to
SOP code EG-P-0007

6.2.1. Water

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6.2.1.1. WFI
Description Reference Document
Title No.
Specification Operation of Pharmastill Unit EG-P-0503
Preparation Operation of Pharmastill Unit EG-P-0503
Distribution Operation of Pharmastill Unit EG-P-0503
Monitoring Refer to Section 6.12.

6.2.2. Steam
Description Reference Document
Title No.
Specification Operation of Pure Steam Generator EG-P-0504
Unit
Preparation Operation of pure Steam Generator EG-P-0504
Unit
Distribution Operation of pure Steam Generator EG-P-0504
Unit
Monitoring Refer to Section 6.12.

6.2.3. Gases

6.2.3.1. Product-contact-compressed air (direct or indirect product contact)

Description Reference Document
Title No.
Specification Atlas Copco Air Compressors & EG-P-0008
Dryers Operation and Maintenance
Preparation Atlas Copco Air Compressors & EG-P-0008
Dryers Operation and Maintenance
Distribution Atlas Copco Air Compressors & EG-P-0008
Dryers Operation and Maintenance
Monitoring Refer to Section 6.12.

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6.2.3.2. N2
Description Reference Document
Title No.
Specification Nitrogen generator Operation and EG-P-0054
Maintenance Procedure
Preparation Nitrogen generator Operation and EG-P-0054
Maintenance Procedure
Distribution Nitrogen generator Operation and EG-P-0054
Maintenance Procedure
Monitoring Refer to Section 6.12.

6.3. Raw Material Controls – including in-process controls

 how starting materials are sampled and tested

Raw materials are received from external suppliers and by the platform of the warehouse and
receiving area [as per SOP WH-P-0001]
The GRA cycle is initiated by the warehouse, filling the form code FWH-P-0001/02 and proceed in
further steps passing by QC Lab [sampling, testing according to raw material Method of Analysis,
refer to Appendix III and quality compliance department for final material release on the Oracle
system

 microbiological requirements are part of the raw material specification as the below:
- Sampling tools check
- Cleaning of sampling area as per SOP QC-P-0507
- Physical inspection before sampling “pre-sampling check”
- Transfer & sanitization raw material containers from receiving area to sampling area
- For sterile raw material, gowning instruction in sterile area, refer to SOP Code No.:
QC-P-0075 Gowning procedure for sterility testing lab
- For Non- sterile raw material, gowning instruction, refer to SOP Code No.: QC-P-0507

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Raw Material (Starting Material) Reference Document

Controls Description
Title No.
Test specifications for each starting Raw Material Specification FRD-P-0032-
material are prepared and approved; 002
specifications follow the Marketing
Authorization
Incoming goods' testing Raw Materials Sampling, QC-P-0507
Receiving & Retaining Procedure
Sampling Raw Materials Sampling, QC-P-0507
Receiving & Retaining Procedure
QC-Testing Raw Materials Sampling, QC-P-0507
Receiving & Retaining Procedure QC-P-0014
QC-P-0001
Starting Material release procedure Raw Materials Sampling, QC-P-0507
Receiving & Retaining Procedure
Material Transfer Controls Material Flow in Production Area PR-P-0027
Material Flow in Production PR-P-0063
Area- Plant II

6.3.1. In-Process Controls

 the stages for contamination-control-related IPC-testing

Receiving as per GRA cycle includes container physical check, MSDS

Sampling is done in class C sampling area as per SOP QC-P-0507

Operator \ sampler enter to the room as per the gowning procedure mentioned in SOP QC-P-0075
Gowning procedure for sterility testing lab &For Non- sterile raw material, gowning
instruction, refer to SOP Code No.: QC-P-0507

 the limits

Inside the sampling area: temp 22.5 ± 2.5 ˚C + RH 45 – 65 %+ Differential pressure

 link this section to the section 6.1.1.1

Description Reference Document

Title No.
Stages at which IPC-tests are performed
Microbial Bioburden Testing QC-P-0020
Bioburden limits for the respective stages
Total Aerobic Viable Count QC-P-0014
Procedures for Raw Materials

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6.4. Product Containers and Closures

 different products, their container and closures
The primary packages container and closures could be categorized in 3 groups:
1. For Conventional filling lines, primary packages consists of plastic bottles, dropper and
Cap.
2. For Blow Fill Seal BFS lines which formed from Low density polyethylene granules
supplied to the machine to form BFS units “Multi dose Bottles & SDUs”
3. For Ointment filling line, primary packages consists of aluminum or laminated tube
with plastic cap.
 CCI tests
Test method of CCI Test is:

Microbial Immersion test

Microbial challenge test includes the use of media fill units of aseptic production simulation
which represent container closure packages which contains TSB as growth promoting media,
followed by immersion of these units in bacterial suspension as per protocol QC-O-0035

 Routine process for testing container closure integrity

All units produced from filling machines are subjected “per batch” to vacuum leak testing in
vacuum chamber as per SOP PR-P-0074 &IPC leakage testing for filled units as per SOP QA-
P-0008

 When containers are a SUS or other material refer to the extractible and leachable
reports and include the monitoring on these containers to prevent contamination (e.g.
particulate, integrity test).
All Single Dose Units “SDU” Products “Containers” produced from SDU filling machines are
subjected “per batch” to vacuum leak testing in Vacuum chamber as per SOP PR-P-0074 &
IPC leakage testing for filled units as per SOP QA-P-0008

Description Reference Document

Title No.
Container Type - Specification Primary packaging material FQA-P-0072/01
Specification
Closure Type - Specification Primary packaging material FQA-P-0072/01
Specification
Container System Qualification 1ry Packaging Machine Qualification Report
Container Closure Integrity Testing Validation protocol for Microbial QC-O-0035
Container Closure
Integrity Testing

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Description Reference Document

Title No.
Routine tests for container closure integrity Operation and Cleaning of SDU PR-P-0074
ampules & multi-dose BFS bottles QA-P-0008
leak check chamber Procedures
Leakage Test for Primary Packaged
containers
Extractables & Leachables (where applicable) Report on analysis of trace and heavy metals
0097-20211223-01
of
samples by ICP-OES

6.5. Vendor approval – such as key component suppliers, sterilization of components

and single-use systems (SUS), and critical

6.5.1. General processes

 SOP for vendor qualification (presumably the same SOP as for supplier qualification,
which is relevant in Section 6.6.) – consider combining Sections 6.5 and 6.6

Qualification of the contract acceptor “Suppliers & service providers”, inspections and audits:

- The contract acceptor requires a manufacturing and testing authorisation.

To be granted this authorisation, the contract acceptor must be able to carry out the
work outsourced to him/her by Orchidia satisfactorily.
For example, adequate premises, equipment, knowledge, experience, and competent
personnel must be available.
- The contract acceptor should be aware of the fact that contract manufacture can be the
subject of an official inspection. It should therefore be contractually agreed who is
responsible for the organisation and additional costs incurred during these inspections.
- Prior to outsourcing activities, Orchidia is responsible for assessing the legality,
suitability and competence of the contract acceptor to carry out successfully the
outsourced activities. Orchidia must ensure that the contract acceptor carries out the
activities in compliance with the specified instructions and is the holder of an
authorisation as required in accordance with the applicable national regulations.
- In other words, Orchidia must qualify the contract acceptor before contract manufacture
begins. Their suitability is checked and evaluated during the supplier qualification.
- For this reason, the contract should allow Orchidia inspect and audit the premises of the
contract acceptor. The contract acceptor must also agree to official inspections.
- As an alternative to carrying out audits themselves, the company does not have to carry
out its own audit. Cascading audits carried out by every single manufacturer or customer
of the contract acceptor involved are no longer required. For further information on the
auditing of contractors, please refer to an official inspection does not release the
pharmaceutical company from their absolute liability for the medicinal product
including all purchased supplies. This also applies to the legal responsibility of Qualified
Persons.

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- No objections can be raised during an inspection if a medicinal product manufacturer

relies on the official inspection of a contract manufacturer or active ingredient
manufacturer who is known to be reliable. Of course, this requires that the
pharmaceutical company is in possession of the inspection report for the manufacturer
and the manufacture of the product that was purchased. In addition, compliance of the
manufacturer with the pharmaceutical company's own quality management system
should have been tested and assessed in writing.
Refer to Control of Supplier & Service Providers SOP QA-P-0068 & Supplier
Evaluation and qualification Procedures FP-P-0002

 Routine vendor evaluation / auditing

1- Evaluation:
Supplier performance in meeting requirements for the purchased product shall be
monitored. The results of the monitoring shall provide an input into the supplier re-
evaluation process
Non-fulfilment of purchasing requirements shall be addressed with the supplier
proportionate to the risk associated with the purchased product and compliance with
applicable regulatory requirements
The qualification status must be evaluated periodically. This is done by collecting
various different types of information. The assessment models used in this process are
based on potential risks to the supply chain and quality. The information collected
relates to both clearly quantifiable aspects
- Aspects of the periodic supplier evaluation:
1. Benchmarking, key performance indicators (KPI) (e.g. delivery reliability, prices)
2. Response times, information management
3. Number of complaints, OOS, trends, audit findings
4. Analysis results
5. Number of goods receipts in the assessment period
6. Identified risk rating
7. Qualification stat
Refer to Control of Supplier & Service Providers SOP QA-P-0068, Supplier Evaluation and
qualification Procedures FP-P-0002&Supplier Evaluation Procedures LP-P-0002

2- Supplier Auditing:
1.The term audit is used to denote all inspections and reviews of the supplier or the
supplier’s systems and processes. It is used more specifically here to denote on-site
audits. In the context of international approval procedures and inspections, documented
evidence (audit report including tracking of CAPA measures) and the qualification of
auditors are growing in importance. The requirement to carry out on-site audits involves
a great deal of effort on the part of both the pharmaceutical manufacturer and the
supplier. Critical aspects include:

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- Large supplier pool/large number of audits

- Small order sizes with the supplier
- Available audit dates with the supplier
2.Even when annual planning is completed in good time, problems with the arrangement of
audit dates can arise, particularly if the supplier has little commercial interest because
order sizes are small. This situation poses problems primarily for smaller companies.
One approach to resolving it may therefore be to conduct joint audits. This can however
also involve challenges, for example adequate handling of confidential, company-
specific information in the audit. Associations such as APIC also offer options for joint
audits in the interest of manufacturers. In addition, standardised certifications such as
Excipact™ for GMP and GDP aspects are becoming increasingly important with regard
to excipients.

3. Evaluation of the suppliers will be based on the risk and purchased item or the service
provided and the evaluation conducted according to the form "Supplier evaluation form"
(FFP-P-0002/01)

4. Audit visit for API supplier will be done whenever possible based on location and can be
conducted on virtual basis [remote audit] in case there is limitation, & Audit frequency
depend on supplier evaluation result according to Supplier Evaluation Procedure (FP-P-
0002) as following:

Audit Evaluation Audit Frequency

More than 90% Every 3 years

More than 80% to 90% Every 2 years

70% - 80% Annually

Refer to Control of Supplier & Service Providers SOP QA-P-0068

3- Service providers Auditing
- The contract should allow Orchidia inspect and audit the premises of the contract
acceptor. The contract acceptor must also agree to official inspections.
- As an alternative to carrying out audits themselves, the company does not have to carry
out its own audit. Cascading audits carried out by every single manufacturer or customer
of the contract acceptor involved are no longer required. For further information on the
auditing of contractors, please refer to an official inspection does not release the
pharmaceutical company from their absolute liability for the medicinal product
including all purchased supplies. This also applies to the legal responsibility of Qualified
Persons.
- No objections can be raised during an inspection if a medicinal product manufacturer
relies on the official inspection of a contract manufacturer or active ingredient
manufacturer who is known to be reliable. Of course, this requires that the
pharmaceutical company is in possession of the inspection report for the manufacturer
and the manufacture of the product that was purchased. In addition, compliance of the

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manufacturer with the pharmaceutical company's own quality management system

should have been tested and assessed in writing.

Refer to Control of Supplier & Service Providers SOP QA-P-0068

Description Reference Document
Title No.
Vendor / supplier qualification Control of Supplier & Service QA-P-
process Providers 0068
Vendor / supplier evaluation Supplier Evaluation Procedures LP-P-
0002
Supplier Evaluation and FP-P-
qualification Procedures 0002
Vendor / supplier auditing Control of Supplier & Service QA-P-
Providers 0068

6.5.2. Detailed information regarding vendors

Component Vendor Reference Document
Title No.
Refer to Qualification document FQA-P-0068/05
Approved suppliers listFFP-P-
Audit Report FQA-P-0068/02
0002/02/04,
List of Service providers FQA-P- Annual evaluation:
0068/08/01, 1- Evaluation of external
Approved suppliers list and Sub-Contractor calibration agent 1- FVAL-P-0003/10
ListFLP-P-0002/02/03&List of Calibration 2- Supplier Evaluation 2- FFP-P-0002/01
Service ProvidersFVAL-P-0003/07/03 3- Form 3- FLP-P-0002/01
4- Supplier Evaluation 4- FQA-P-0068/06
5- Form
6- Service Providers
7- Evaluation Form

6.6. Management of outsourced activities and availability/transfer of critical

information between parties, e.g. contract sterilization services
Refer to section 2.7.

6.6.1. General processes

Refer to Section 6.5.1.

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6.6.2. Detailed information regarding suppliers

Refer to Section 6.5.2

6.7. Process Risk Assessment

Decisions on Quality Risk Management – suggestion to broaden the scope (but still keep the
title for clear reference to Annex 1)

Quality Risk management system at Orchidia is established according to ICH Q9 “Refer to SOP QA-
P-0011”

Failure Mode and Effects Analysis (FMEA)

- FMEA is a quantitative method which can in principle be used during every
stage of the product life cycle, both as a proactive and as reactive tool. The
key feature of the method is quantitative prioritisation, i.e. priority of risks
expressed in numeric terms. Risks with a high priority must be dealt with
first when risk reduction measures are defined in order to achieve risk
acceptance. Priority is expressed by the so-called risk priority number –
RPN which is calculated by multiplying the failure ratings for probability
of occurrence (P), detectability (D) or likeliness of not being detected, and
the potential severity of harm (S): Calculation of the risk priority number
RPN (RPN = P * D * S)
- The objective of the risk assessment or stage of the product life cycle or
project. This applies to both proactive and reactive FMEA. The quality of
the risk assessment, risk analysis and risk evaluation depends strongly on
the quality, validity and reliability of the collected information which is
used to assign values to the failure characteristics ("garbage in = garbage
out").
- If a large amount of data is available, a proper evaluation of the probability
of occurrence, detection and severity of harm is possible. If no data or
experience is available, the assigned values are only estimates. It is
essential that the evaluation of the three individual failure characteristics is
carried out independently. For example, when evaluating the potential
severity of harm of a failure, the probability of this failure occurring or
being detected or the probability of it not being detected should not be
included in the evaluation. If the potential severity of harm of a failure is
assigned a very high rating, i.e. if the failure has the potential to cause very

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serious harm to the patient, the numeric value should not be reduced just
because this failure is extremely unlikely or occurs very rarely (but should
always be kept in mind)
Refer to Departmental process Risk assessment sheet“FQA-P-0011/02”

RAs for aseptic manufacturing processes:

Intervention scoring in devising a risk-based intervention system, an assessment of a number
of factors is required. With this, and any risk-based system, professional judgement plays an
important role in the final assessment. Either a qualitative of quantitative approach can be
adopted; the example quoted here uses a numerical system. The use of a numerical score not
only allows for a decision to be made as to the relative and absolute risk of any intervention, it
also allows different filling operations to be compared and trended if necessary. The use of a
numerical score also allows a cut-off value to be applied. A cut-off value is a score which,
when exceeded during the filling runs, indicates to the filling team that a decision is required
whether filling should continue. Devising a scoring system, the first step in developing an
intervention scoring system is to devise the numerical ranges. Once developed, different types
of interventions can be assigned. The scoring system used in the example weights each
intervention based on the perceived contamination risk to product or product components. The
greater the risk then the higher the score assigned. The risk scores used are in multiples of 5,
with 0 being of minimal risk, up to 30 for the highest risk. Of course, other scoring systems
can be selected. This is detailed in the table below:

Score Explanation of Risk

0 Activities which assigned a Zero score because the activity take place every
filling operation (One or twice at defined locations depending on the length of
fill), furthermore the activity is simulated during each media fill.

5 This score is assigned to the manual interventions that take place for containers
which are stoppered, where the interventions of less than 5 minutes as duration
and the operators use a sterile instrument.

10 This score is assigned to the manual interventions that take place for components
where the interventions of less than 5 minutes as duration and the operators use a
sterile instrument, however for such intervention’s containers are not stoppered,
The score also applies to intervention which do not involve contact with
components, however it takes place not close to the critical zone (like stopper
bowls).
15 This score is assigned to the manual interventions that take place for components
where the interventions of less than 5 minutes as duration and the operators use a
sterile instrument, however for such intervention’s containers are not stoppered,
The score also applies to intervention which do not involve contact with
components, however it takes place close to the critical zone (like point of fill)

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20 This score is assigned to minor spillages which require the manual interventions
to the filling machine, and for cleaning to take place,

30 This score is assigned for applying major adjustment, such as removal or

replacement of machine parts which take place close to or at the critical areas
(like point of fill), such interventions take more than 5 minutes as duration and
the operators use a sterile instrument

The above scoring system was based on accounting for three factors:
1. The location within the filling machine where the intervention takes place. Here it is
recognized that different parts of the filling machine pose different risks to exposed
containers. The point of fill, for example, presents a bigger risk of contamination ingress than
a partially stoppered container.
2. The height at which the intervention takes place relative to ‘working height.’ Here, working
height, which is equivalent to the product container, presents a bigger risk than a height below
the container. This is because below the containers the unidirectional airflow is more likely to
sweep contamination away.
- In relation to points '1' and '2' above, some aseptic come the terms 'critical' and 'non-critical'
interventions in relation to height and position.
- By this, it can be inferred:
 Critical intervention: when the body/ glove is exposed above (within vertical unidirectional
air- flow) open vials/ hopper / product contact surfaces and disrupts unidirectional air flow.
Actions in response may include line clearance.
 Non-critical intervention: the gloves or body parts are not disrupting the unidirectional air
flow. It is performed with sterile tools above the open vials/ above hopper/ product contact
surfaces; stopper bag addition, bulk container addition. While these differences are important,
the phrases 'critical' and 'non-critical' can detract from the potential risk that any intervention
presents to the process.
3. Time and complexity taken to complete the intervention. This informs whether an
intervention is classed as a ‘major’ (of more complexity or taking a relatively longer time) or
‘minor’ (undertaken within a short time or of a relatively less complex nature). In assigning
scores, the use of tools, such as using or not using forceps to remove a container, with
developing scores, especially in relation to time and complexity, useful information can be
obtained from media fills, such as from the viewing of digitally recorded footage.
- Following this, the scoring system can be matched up with different types of interventions.
This is presented in Table 2 below. Table 2 takes the intervention score table and pairs the
score options with common types of interventions. A rationale for the score selection is also
provided, in the end column

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Routine
Intervention type Single intervention score Justification of score
task
This activity has not been assigned
a score because it takes place
during every filling operation
Placement of (once or twice at defined locations
Y 0
air sampler depending upon the length of the
fill). The activity is practiced
during each media trial. It is not
considered to be a variable risk.
This activity has not been assigned
a score because it takes place
during every filling operation
Placement of (once or twice at defined locations
Y 0
settle plates depending upon the length of the
fill). The activity is practiced
during each media trial, it is not
considered to be a variable risk.
This activity has not been assigned
a score because it takes place
during every filling operation
(once or twice at defined locations
depending upon the length of the
fill). The activity is practiced
Addition of
during each media trial, it is not
sterilized
Y 0 considered to be a variable risk.
stoppers to
The operator who performs this
bowl
task is regularly assessed during
each filling operation through the
taking of their finger plates. To
date the data collected does not
suggest that this is a significant
risk.
Machine set Y 0 This activity has not been assigned
up prior to fill a score because it takes place
during every filling operation
(once or twice at defined locations
depending upon the length of the
fill). The activity is practiced
during each media trial, it is not
considered to be a variable risk.
This activity is not directly related
to the fill; however, it could
theoretically increase the
bioburden to the filling machine.
This is assessed through the

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operators taking finger plates after

the cessation of the activity. In
addition, settle plates are exposed
during the set-up for media trials
which provides information
relating to the likely settling of any
viable particles. To date both the
finger plates and the media trial
settle plates have been satisfactory
and do not suggest a significant
risk from this intervention.
The score assigned is dependent
upon the type of intervention (the
score given is for the operations
listed below). Should 3 or more
interventions occur during the
Occasional interventions are
period following machine set-up
required between the set-up of the
and the start of filling or the score
Interventions filling machine and the start of fill.
exceed 30, filling should not
during the It is recognized that this represents
commence until the fill supervisor
period an intervention into the Grade A /
has discussed the matter with
following N ISO class 5zone and after a point
qualified person. A major
machine set- where the machine has been
intervention may require a re-set
up and the cleaned. Different types of
up of the machine and all of the
start of fill interventions will score higher
appropriate environmental
depending the nature of the
monitoring to be undertaken. All
activity and the duration.
interventions will be assessed by
a review of microbiological data
post fill (a review of intervention
finger plates and exposed settle
plates)
Removal of N 10 This intervention relates to a
fallen bottle manual intervention into the filling
where no line machine. A member of operator
clearance will use a sterile implement (such
occurs as forceps) to make an adjustment
or to remove an object (such as a
container). Typically, this activity
would take less than five minutes.
The activity is also practiced
during a media trial (provided that
the activity has taken place within
the last six-months during the
filling run, in relation to the
specific filling line). The score of
ten is given because the risk is
higher than a machine stoppage

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but lower than a full line clearance.

This intervention relates to an
operation on the filling machine. It
does not involve touching any
Rotation of
vials and could be seen as a lower
stopper N 0
risk, However, as the operation
gripper cam
occurs close to the stopper bowl
the risk is elevated and a score of
10 is thus appropriate
This intervention relates to a
manual intervention into the filling
machine. A member of staff will
use a sterile implement (such as
forceps) to make an adjustment or
to remove an object (such as a
container).
Removal of Typically, this activity would take
jammed less than five minutes and the line
stoppered would be cleared. The activity is
bottles N 5 also practiced during a media trial
(outside of (provided that the activity has
point of-fill taken place within the last six-
area) months during the filling run, in
relation to the specific filling line).
A lower score is given than
intervention F because this
intervention would only occur after
vials have been stoppered and
transported away from the point of
fill and stoppering area.
Removal of N 10 This intervention relates to a
jammed manual intervention into the filling
stoppered machine. A member of staff will
bottles by use a sterile implement (such as
opening the forceps) to make an adjustment or
area at the to remove an object (such as a
point of-fill container).
Typically, this activity would take
less than five minutes and the line
would be cleared. The activity is
also practiced during a media trial
(provided that the activity has
taken place within the last six-
months during the filling run, in
relation to the specific filling line).
A higher score is given than

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intervention H because this

intervention occurs close to the
point of fill.
This intervention relates to a
manual intervention into the filling
machine. A member of staff will
use a sterile implement (such as
forceps) to make an adjustment or
to remove an object (such as a
Removal of vial).
jammed bottle
N 15 Typically, this activity would take
at the point of
fill less than five minutes and the line
would be cleared. The activity is
also practiced during a media trial
(provided that the activity has
taken place within the last six-
months during the filling run, in
relation to the specific filling line).
This intervention involves
manipulating the filling needle
with a sterile instrument. As the
Needle lift N 15
filling needle is a critical product
contact site a higher intervention
score is awarded.
Minor adjustment is defined as an
activity that does not involve the
Minor removal or replacement of any
mechanical machine parts and last for less than
adjustment to N 10 five minutes. A score of ten is
filling awarded because the activity could
machine potentially take place close to a
critical product surface, such as,
the point of ill or stopper bowl.
Major N 30 Major adjustment is defined as an
mechanical activity that does involve the
adjustment to removal or replacement of any
filling machine parts and last for more
machine or than five minutes. A score of thirty
change to a is awarded because the activity
critical could potentially take place close
component to a critical product surface, such
(such as a as, the point of fill or stopper bowl.
stopper bowl). At first view the score would
simply be doubled, that is, seen as
twice the risk as intervention N.
However, because the operator

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may need to work inside the filling

machine and could be taking the
machine apart, thereby exposing
additional surfaces, it was
considered that a score of twenty
was of insufficient proportion
given the nature of the task.
This is because of the long time
taken to complete this intervention
Spillage (typically longer than ten minutes)
clearance at and because the operator is
point of N 20 disturbing the air pattern at the
fill(classed as point of fill and there is a level of
minor) risk of close contact with critical
machine contact parts (such as
filling needles).
Replacement
of filling This risk is far higher than
pump or intervention N because the activity
change to a lasts typically fifteen to twenty
filling N 30 minutes and involves manipulation
machine of filling needles. The risk is
manifold for therefore of a greater proportion
other filling than intervention.
lines

Description Reference Document

Title No.
The concept of QRM is implemented Risk Management Procedures QA-P-0011
throughout the organization (SOP)
A register of RAs is maintained by QA Departmental process Risk FQA-P-0011/02
assessment sheet
RAs for manufacturing processes: Production Risk assessment sheet FQA-P-0011/02
RAs for aseptic manufacturing processes: Production Risk assessment sheet FQA-P-0011/02
RAs for cleaning processes: Cleaning Validation Risk Assessment FQA-P-0011/02

RAs for sterilization processes are part of 6.9.

6.8. Process Validation

Following the GMP-requirements, all manufacturing processes have been validated and re-validation
takes place on a regular basis / processes are under continuous verification Processes are re-validated
after Changes that require re-validation.

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Process Validation is based on a QRM approach and the underlying RAs mentioned in Section 6.7.
1- Process Validation:
- Process validation is a documented evidence which provides a high degree of assurance that a
specific process will consistently produce a product meeting its pre-determined specifications
and quality attributes.
- Minimum three consecutive batches shall be manufactured and considered for process
validation
- Process validation refers to the analysis of data gathered throughout the design and
manufacturing of a product. Process validation needs to be an ongoing process. This means
frequent (annual) review
- To undertake an effective process validation, it is recognized that those performing process
validation and product reviews require knowledge of contamination rates, particularly in
relation to in-process bioburden and to the supporting manufacturing environment. Process
validation also details the performance of
Aseptic Process Simulations
- Continued monitoring of the process variables and outputs enables adjustment to process
inputs, ensure output consistency and highlight opportunities for improvement.
- Periodic review of the collected information and the validation state shall be performed with
appropriate interval Three years, such review shall conclude maintenance of the validation
status. Or include recommended or planned improvements
- Reporting the validation study shall address the topics of the process protocol:
 Objective of the study.
 Scope of the study.
 Product registration specification within the scope of the study (and internal release
specifications if any).
 All used processes inputs including raw materials and packaging materials in details
and supplier& Manufacturer.
 Listing of all equipment/utilities and facilities used for processing and/or analysis
along with their qualification & calibration status.
 Analytical methods used for measuring.
 Results and data evaluation, with statistical methods to be used in analyzing collected
data as applicable.
 Evaluate any unexpected observations and additional data not specified in the
protocol.
 Summarize and discuss all manufacturing nonconformance such as deviations,
aberrant test results, or other information that has bearing on the validity of the
process.
 Describe in sufficient details any corrective actions or changes that should be made to
existing procedures and controls.
 Processes and procedures should be revalidated to ensure that they remain capable of
achieving the intended results. There should be periodic revalidation, as well as
revalidation after changes.
 Periodic Revalidation should be done in accordance with a defined schedule.
 The frequency and extent of revalidation should be determined using a risk-based
approach together with a review of historical data.

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 Products manufactured by processes that have been subjected to changes should not
be released for sale without full awareness and consideration of the change and its
impact on the process validation.
- Changes that are likely to require revalidation may include:
 Change of starting material manufacturer.
 Changes in starting materials (including physical properties that may affect the
process or product based on risk assessment).
 Transfer of processes to a different site (including change of facilities and
installations which influence the process).
 Changes of primary packaging material.
 Changes in the manufacturing process.
 Changes in manufacturing equipment’s
 Installation of new equipment.
 Production area and support system changes (e.g. rearrangement of areas, or a new
water treatment method)
2- Cleaning Validation:
- Cleaning validation is to prove with a documented evidence that cleaning procedures for
equipment is able to remove API residue, degradation product and microbial growth from a
surface to prevent contamination and cross contamination.
- Product grouping is allowed for the products with similar composition and physical
properties and the same equipment and shall be justified
- To support equipment operations, cleaning processes must be validated, and a detailed
assessment of cleaning validation and cross contamination exists in the form of a risk
assessment. Separate assessment may be needed for fixed, mobile, and single- use
equipment.
- Cleaning revalidation can be triggered by assessment of the controlled changes in either the
line design or the cleaning procedures or by the evaluation of the process performance
through routine monitoring.
- The revalidation activates scope shall be determined based on the assessment.
- Following conditions (but not limited to) require assessment to determine the impact of the
change on the validation status:
 Introduction of new product
 Change in worst case product formula
 Change in analytical method validation (LOD& LOQ)
 Change in equipment configuration.
 Change in cleaning agent type or concentration
 Significant Changes in the cleaning procedures
 Significant changes in the line designed or installation of new equipment

Description Reference Document

Title No.
The concept of PV is described Validation Master Plan VAL-L-0001
in SOP
The concept of continuous Validation Master Plan VAL-L-0001
process verification is described
in SOP

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Description Reference Document

Title No.
Aseptic process simulation is Media Fill Procedures QC- P-0016
performed according to SOP
PV-reports for manufacturing Validation Master Plan VAL-L-0001
processes: Process Validation Protocol
Process Validation Report
Aseptic process simulation Aseptic Process Simulation validation QC-O-0037
reports (media fill reports) Protocol for SDU Bottelpack / Rommelag
460 321 filling line IV
Validation Report for Aseptic Processing RQC–O-
for SDU Bottlepack Rommelag machine 0037/01/02
Media fill simulation for Rommelag SDU MF/A
Filling line Batch Record
Media fill simulation for Rommelag 460 MF/O
SDU Filling line Batch Record
Aseptic Process Simulation Validation QC-O-0019
Protocol
For IMA filling line II
Validation Report for Aseptic Processing RQC–O–
for IMA filling line 0019/01/01
Media fill simulation for IMA Filling line MF/D
Batch Record
Media fill simulation for IMA Filling line MF/P
Batch Record
Media fill simulation for IMA Filling line MF/R
Batch Record
Media fill simulation for IMA Filling line MF/R2
Batch Record
Media fill simulation for Sterile MF/N
dispensing of IMA Filling line Batch
Record
Media fill simulation for Sterile MF/N2
dispensing of IMA Filling line Batch
Record
Media fill simulation for Sterile MF/Q
dispensing of IMA Filling line III Batch
Record
Aseptic Process Simulation Validation QC-O-0026
Protocol for

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Description Reference Document

Title No.
IWK Ointment Filling Line I
Validation Report for Aseptic Processing RQC–O–
for IWK machine 0026/01/02
Media fill simulation for IWK Filling line MF/W
Batch Record
Aseptic Process Simulation Validation QC-O-0025
Protocol
For BAUSCH+STRÖBEL Filling Line III
Validation Report for Aseptic Processing RQC–O–
for BAUSCH+STRÖBEL filling line 0025/01/02
Media fill simulation for Sterile MF/B
dispensing of Bausch Filling line Batch
Record
Media fill simulation for Sterile MF/T
dispensing of Bausch Filling line Batch
Record
Media fill simulation for Sterile MF/T2
dispensing of Bausch Filling line Batch
Record
Media fill simulation for Sterile MF/S
dispensing of Bausch Filling line Batch
Record
Media fill simulation for Bausch Filling MF/U
line Batch Record
Media fill simulation for Bausch Filling MF/V
line Batch Record
Media fill simulation for MF/Y
BAUSCH+STRÖBEL filling line Batch
Record
Aseptic Process Simulation validation QC-O-0001
Protocol for
Rommelag / Bottelpack 312 filling line II
Validation Report for Aseptic Processing RQC–O–
for Rommelag machine, including: 0001/01/02
Media fill simulation for Rommelag 2 MF/L
Filling line Batch Record

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Description Reference Document

Title No.
Media fill simulation for Rommelag 2 MF/X
Filling line Batch Record
Media fill simulation for Rommelag 2 MF/Z
Filling line Batch Record
Aseptic Process Simulation validation QC-O-0006
Protocol for
Rommelag / Bottelpack 321 Filling Line I
Validation Report for Aseptic Processing RQC–O–
for Rommelag machine 0006/01/02
Media fill simulation for Rommelag I MF/C
Filling line Batch Record
Media fill simulation for Rommelag I MF/K
Filling line Batch Record
Media fill simulation for Rommelag 321 MF/G
Filling line Batch Record
PV-reports for cleaning Validation Master Plan VAL-L-0001
processes: Cleaning Validation Protocol
Cleaning Validation Report
PV-reports for depyrogenation Validation Protocol for Depyrogenation QC-O-0031
processes: cycle
validation Report for Depyrogenation QC-O-0031/R
cycle validation

6.9. Validation of sterilization processes

Following the GMP-requirements, all sterilization processes have been validated and re-validation
takes place on a regular basis / processes are under continuous verification Processes are re-validated
after Changes that require re-validation.
Validation of sterilization processes is based on a QRM approach and the underlying RAs mentioned
in Section 6.7.
Sterilization in place (SIP) & Bulk sterilization:
- Sterilization process thermal validation is to prove that the temperature is uniformly
distributed, penetrated, and within the accepted limits at any time through the sterilization
phase during the sterilization run (taking into consideration that the suitable time of the
sterilization phase left for achieving the temperature and pressure set points).
- Bulk sterilization is used for Gel or suspension phases which are difficult to be sterilized
through sterilizing grade filter as this will lead to filter blockage.
- In Bulk sterilization industrial (black) steam is generated from the Boiler and introduced into

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the tank Jacket for Sterilization of gel or suspension phases with pro-spore strips (ampoule)
are placed within the load to challenge the bulk sterilization performance.
- Thermocouples and BIs will be distributed during bulk sterilization validation into bulk
product inside the tank by inserting a specially designed tool for bulk sterilization made from
(316 L) stainless steel at three levels (at the bottom of tank, Middle of solution and Upper
part of solution
- Report of Sterilization process thermal validation implemented by service provide.
- Bulk sterilization report /include
 The objective of the validation report.
 Scope of bulk sterilization validation study
 Bulk sterilization condition
 Pre-calibration and post calibration data
 Summary of the results of the three cycles executed.
 Summary of the acceptance criteria.
 Evaluate any unexpected observations and additional data not specified in the
protocol
 Summarize and discuss all nonconformance such as deviations, or other information
that has bearing on the validity of the process.
- Revalidation of SIP & Bulk sterilization are implemented annually

Description Reference Document

Title No.
The concept of SV is described in SOP Validation Master Plan VAL-L-0001
or VMP
The concept of continuous process Validation Master Plan VAL-L-0001
verification
or re-validation of sterilization processes
is described in SOP or VMP
SV-reports for sterilization processes Validation Master Plan VAL-L-0001
SIP Validation Protocol
SIP Validation Report
Bulk Sterilization Report

6.10. Preventative maintenance – maintaining equipment, utilities, and premises

(planned and unplanned maintenance) to a standard that will ensure there is no
additional risk of contamination
Relevant aspects – presumably covered in SOP(s):
Engineering Maintenance Procedures SOP EG-P-0201

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 The way to define maintenance requirements (e.g., vendor involvement, in-house-

experience, involvement of external companies)

The production dept. issue repair order according to that request spare parts from vendors
/then fixed this issue by maintenance team or external service by contract

 QA involvement
QA approved the repair order after fixed
 How are maintenance plans developed (servicing / inspection / replacement actions and
for the system) - Are log-book-entries considered
We do analysis to all data during the quarter by Pareto chart and check the maintenance log
book to development

 The basis for the development of the maintenance program (frequency for performing
maintenance actions)
According to data analysis to failure and calculate MTBF and machines manual and
experience of engineers

 Calibration
By validation team internal according to calibration plan

 Responsibility for system approval after maintenance

Production and QA department

 Risk assessments
In the event of sudden malfunctions, the engineering risk assessment sheet is referred to the
engineering department to update

If CC aspects are addressed in the documents for preventive maintenance programs, an

additionally reference to these documents may be useful.

6.11. Cleaning and Disinfection

- Cleaning of the production area is handled in a manner and frequency listed in SOP Cleaning
Procedure for the Production Department PR-P-0004
- Disinfection of the production areas is handled in a manner and frequency listed in SOP
Cleaning Procedure for the Production Department PR-P-0004
-
- The list of disinfectant used and the frequency basis are listed in SOP Cleaning Procedure for
the Production Department PR-P-0004, where rounding is done on weekly basis with reference
to SOP PR-P-0004
- Environmental monitoring reflect the process effectiveness and the disinfectant efficacy

6.11.1. Equipment
Equipment Reference Document
Activity
Type Title No.

OLSA Cleaning Operation/Cleaning of OLSA mixing PR-P-0036

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Equipment Reference Document

Activity
Type Title No.
Preparation Disinfection
tank
Tanks
FrymaKoruma Cleaning
Operation Cleaning of FrymaKoruma
Preparation PR-P-0077
Disinfection Tanks
Tanks
BRAM-COR Cleaning
(Operation Cleaning of BRAM-COR
Preparation Disinfection PR-P-0054
Tank Procedures
Tanks
BRAM-COR Cleaning
150L Operation Cleaning of BRAM-COR
Disinfection PR-P-0059
Preparation Tank 150L Procedures
Tanks
CLA Cleaning
Preparation Disinfection Operation Cleaning of CLA Tank
Tank PR-P-0072
Procedures

BRAM-COR Cleaning
300 500 Liter
Disinfection Operation Cleaning Of BRAM-COR
Preparation PR-P-0061
Tanks Tank 300 500 Liter

Syhaco Cleaning
Preparation Disinfection operation Cleaning of Syhaco PR-P-0081
Tank
Weighing Cleaning (Calibration check operation and
PR-P-0051
Balances Disinfection cleaning of weighing balances
Cleaning Operation monitoring and cleaning of
LAF units PR-P-0073
Disinfection LAF units

Filters Integrity Cleaning

Operation of Palltronic integrity tester PR-P-0028
Tester Disinfection
Cleaning Autoclave Operation and Cleaning
Autoclaves PR-P-0035
Disinfection Procedure
LDPE Cleaning (Handling of Polyethylene Plastic PR-P-0089
Granulate Granules inside Production Area II
Disinfection
Handling Plant

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Equipment Reference Document

Activity
Type Title No.
II
Cleaning Operation and cleaning of
R 460 PR-P-0090
Disinfection Bottlepack® 460 SDU filling Machine
Cleaning Operation and Cleaning of IMA filling
IMA Filling PR-P-0062
Disinfection Machine Procedures
Cleaning Operation and Cleaning of
B&S BAUSCH+STRûBEL filling Machine PR-P-0071
Disinfection Procedures
Cleaning Operation and cleaning of IWK filling
IWK PR-P-0078
Disinfection and packaging line machine SOP
Cleaning (Operation Cleaning of Bottle pack
R 312 PR-P-0002
Disinfection Machine Procedures)
Cleaning Operation and Cleaning of CAM
CAM filling PR-P-0006
Disinfection filling Machine Procedures
Cleaning Operation and Cleaning of CAM
CAM Capping PR-P-0010
Disinfection Capping Machine Procedures
LDPE Cleaning
Granulate Handling of Polyethylene Plastic
PR-P-0015
Disinfection Granules inside Production
Plant I
Cleaning (Operation and cleaning of Bottle
R 321 PR-P-0044
Disinfection pack 321 filling Machine
Cleaning Operation and Cleaning of Bottle
R 321 M PR-P-0057
Disinfection pack® SDU filling Machine...
(SDU)
Qualification Qualification protocol
HI-TEK Cleaning
Operation and Cleaning Of HI-TEK
Capping PR-P-0058
Disinfection Capping Machine
Machine

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6.11.2. Clean Rooms / Clean Areas

Reference Document
Room No. / Area Grade Activity
Title No.
Cleaning
Operation monitoring and
LAfs A Disinfectio PR-P-0073
cleaning of LAF units
n
Filling machine Cleaning
Operation monitoring and
Class A A Disinfectio PR-P-0073
cleaning of LAF units
n
Class B and filling Cleaning Cleaning Procedure for the
machine Class A B Production Department PR-P-0004
Disinfectio
n
Cleaning Cleaning Procedure for the
Grade C Rooms C Production Department PR-P-0004
Disinfectio
n
Cleaning Cleaning Procedure for the
Grade D Rooms D Production Department PR-P-0004
Disinfectio
n

6.11.3. Clean Room Clothing

Refer to Section 6.1.3. (b)

6.12. Monitoring Systems - including an assessment of the feasibility of the

introduction of scientifically sound, alternative methods that optimize the detection of
environmental contamination
 Reference to Risk Assessments, which lead to the sampling points
- Selection of Sample Locations and Sampling Frequencies based on risk assessment and
guidelines.
- Same sized (area) and same class rooms may have different numbers of required sample sites
based on risk of contamination in each room

- Reference the summary reports and the description of how trending is done
- Review the Microbiological results and issue a trend analysis quarterly & Establish a statistical
trend for viable and non-viable air monitoring & share in the investigation with QA
- Alert levels are periodically assessed based on data obtained during subsequent re-
qualifications, routine monitoring, and investigations
- Calculation of alert & action limit, the data are collected, sorted, and ranked from the lowest to
the highest.
- The alert level is set at the 95th percentile
- The action level is set at the 99th percentile

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6.12.1. General Procedures

Description Reference Document
Title No.
////Instruction on how to develop Risk Assessment Report for QC- P-0004/R-
sampling points / frequency / warning Environmental Monitoring Locations 01
and action limits (Viable tests)
Environmental Monitoring Program QC-P-0083
for Plant II
Environmental Monitoring Program QC-P-0004
for Plant I

Alert and Action Levels Procedure for QC-P-0060

Environmentally Controlled Clean
Rooms
Instruction for the preparation of Alert and Action Levels Procedure for QC-P-0060
reports Environmentally Controlled Clean
Rooms
SOP on how to perform trending Alert and Action Levels Procedure for QC-P-0060
Environmentally Controlled Clean
Rooms

6.12.2. Monitoring of Systems

6.12.2.1. Water and Steam

Type Activity Reference Document
Title No.
City Water RA QC Chemistry Risk Assessment FQA-P-
0011/02
Monitoring Water Sampling & Analysis QC-P-0523
SOP Procedure
Water Sampling Procedure QC-P-0021
Summary Certificate of Monthly Analysis of FQC-P-0523
Report City Water of Stilmas Water Station /07

Certificate of Monthly Analysis of FQC-P-0523

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Type Activity Reference Document

Title No.
City Water (Bram Cor Water Station) /08

Purified Water RA QC Chemistry Risk Assessment FQA-P-

QC Microbiology Risk Assessment 0011/02
Monitoring Water Sampling & Analysis QC-P-0523
SOP Procedure
Water System Total Microbial Count QC-P-0002
Procedure
Water system Objectionable QC-P-0002
Microorganisms detection procedures
Summary Certificate of Daily Analysis of Water FQC-P-
Report for Injection & Purified Water of 0523/03
Stilmas Water Station
Certificate of Daily Analysis of Water FQC-P-0523
for Injection & Purified Water (Bram /04
Cor Water Station and New Factory)
Certificate of Weekly Analysis of FQC-P-
Water for Injection & Purified Water 0523/05
of Stilmas Water Station

Certificate of Weekly Analysis of FQC-P-

Water for Injection, Purified Water 0523/06
and RO Water (Bram Cor Water
Station and New Factory)
Stilmus Water pretreatment and FQC-P-
Purified Water (PW) Microbial 0002/01
examination report
Bram Cor Water Microbial FQC-P-
Examination - Water Pretreatment and 0002/07
Purified Water (PW) Report

Clean Steam RA QC Chemistry Risk Assessment FQA-P-

0011/02
Monitoring Water Sampling & Analysis Procedure QC-P-0523
SOP

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Type Activity Reference Document

Title No.
Summary Water Sampling & Analysis Logbook FQC-P-
Report 0523/ 01

Certificate of Weekly Analysis of FQC-P-

Water for Injection & Purified Water 0523/05
of Stilmas Water Station

Clean Rooms RA Production Risk Assessment FQA-P-

0011/02
Monitoring Monitoring Procedures of Relative PR-P-0019
SOP Humidity (RH %), Temperature, and
Pressure in Production Areas
Summary Report Monitoring of RH%, Temp, and FPR-P-
pressure of Class-C area (Production I) 0019/01/05
Monitoring of RH%, Temp, and FPR-P-
pressure of Class-B area (Production I) 0019/02/06
Monitoring of RH%, Temp. of FPR-P-
non-sterile areas in production First 0019/03/06
floor
Monitoring of RH%, Temp. of the FPR-P-
non-sterile area in production Ground 0019/04/06
Floor
Monitoring of RH%, Temp, and FPR-P-
pressure of new Class-B area 0019/05/07
(production II)
Monitoring of RH%, Temp, and FPR-P-
pressure of new Class-C area 0019/06/07
(production II)
Monitoring of RH%, Temp. of the FPR-P-
non-sterile area in the (production II) 0019/07/07

Monitoring of Hatches FPR-P-

0019/08/03

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6.12.2.2. Clean Rooms

The viable and non-viable monitoring and testing methods associated, sampling and the overall
oversight by the quality department.
The testing procedures for environmental monitoring include the following tests:
- Viable Monitoring
 Settle Plates Testing SOP. No. QC-P-0005
 RODAC Plates Testing SOP. No. QC-P-0007
 Swab Testing SOP. No. QC-P-0008
 Active Air Sampling SOP. No. QC-P-0006
 Gowns check-up testing SOP. No. QC-P-0011
 Fingerprint testing SOP. No. QC-P-0010

- Non-Viable Monitoring
 Particle count testing SOP. No. QC-P-0009
EM Sites:
- Production filling lines:
 Rommelag “BFS” Filling lines
 Conventional Filling Lines.
- Capping lines, (Production Supporting Rooms).
- Sterility testing room in Microbiology laboratory.
- Biosafety Cabinet & Microbial Testing rooms in Microbiology Laboratory.
- Weighing (Dispensing) area. & Sampling area.
- Production mobile LAFs, Pass Boxes & Packaging Area
- Microbiology Department: carry out the environmental testing as per SOPs QC-P-0004 &
QC-P-0083

The frequency, location, and type of sampling, including the definition of the alert and action
limits and frequency of the historical EM data review and analysis.
 Selection of Sample Locations and Sampling Frequencies based on risk assessment and
guidelines.
 Same sized (area) and same class rooms may have different numbers of required sample sites
based on risk of contamination in each room.
 Locations of Routine E.M activities for each test are shown in Environmental monitoring SOPs
QC-P-0004 & QC-P-0083
 Alert levels are periodically assessed based on data obtained during subsequent
requalification’s, routine monitoring, and investigations

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
Calculation of alert & action limit, the data are collected, sorted, and ranked from the lowest to
the highest.
 The alert level is set at the 95th percentile
 The action level is set at the 99th percentile
 Viable tests: It includes tests of
- Settle plate: Using TSA Plates
- Surface test: for regular surfaces as wall and floor (Using RODAC Plates)
- Surface test: for irregular surfaces (Using Sterile Swabs)
- Active Air Sampling :( Using TSA Plates and Air Sampler device)
 Steps For EM Risk Assessment (RA)
- Map the layout of the room(s), overlay with grids and combine them into functional sections
- Walk the process with an RA team, noting in detail the process activities grid-by-grid
- Assess each grid against the risk factors and score them to determine the relative probability
of contamination
- Evaluate the results by functional sections to select sampling locations and methods
For Class A, the following tests are executed semiannually as per the Periodic Qualification
Protocol for LAFs (Code QUL-O-0004):
 Installed HEPA Filter Leakage Test (DOP Test)
 Air Velocity Test
 Differential Pressure across HEPA Filter
 Airborne Particle Count Test (Rest & Operation)
 Recovery Time Test
 Airflow Visualization Test (Rest & Operation)
 Airborne Viable Microbial Count Test
For Class B the following tests are executed semiannually and for Class C & D Annually in
accordance with protocols Code QUL-O-0001 & QUL-O-0003:
 Installed HEPA Filter Leakage Test (DOP Test)
 Number of Air Changes Test
 Differential Pressure Test
 Temperature & Humidity Test
 Airflow Visualization Test
 Airborne Particle Count Test (Rest & Operation)
 Recovery Rate Test
 Airborne Viable Microbial Count Test

Microbial media and incubation program used, air exposure of the media
Incubate all plates for five days (3 days at 30-35 ̊C then 2 days at 20-25 ̊ C).
 Max. time of Air Exposure of the media is 4 hours

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Further differentiation into different areas and / or clean room grades

Location/Area Zone Grade

area where aseptic filling and/or manipulations of sterile product

Grade A
e.g.-(under laminar air flow) (LAF)

Background environmental for grade A zones.

Grade B
Requirements should be met when room is at rest. And class 10,000 at operational
(e.g.-filling room outside laminar flow
Area Where (e.g.- bulk preparation area - product is subsequently sterile filtered
Grade C
and blow, fill and Seal technique (BFS)

Any area external to the clean room e.g. where product materials may be stored in
a clean support room, Grade D
E.g. labeling documentation, checking.

unclassified area Grade E

Type Activity Reference Document

Title No.
Viable environmental RA Risk Assessment Report for QC- P-0004/R-
monitoring Environmental Monitoring 01
Locations (Viable tests)In
Production Areas Plant I &
Plant II
Monitoring SOP Environmental Monitoring QC-P-0004
Program for Plant I
Environmental Monitoring QC-P-0083
Program for Plant II
Summary Report Used Forms at SOPs of QC-P-0004
Environmental Monitoring QC-P-0083
Program
Non-viable (physical) RA Risk Assessment Report for QC- P-0078/R-01
environmental monitoring particle count
In Production Areas Plant I &

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Type Activity Reference Document

Title No.
Plant II
Monitoring SOP Environmental Monitoring QC-P-0004
Program QC-P-0083
Environmental Monitoring
Program for Plant II
Summary Report Used Forms at SOP QC-P-0004
Environmental Monitoring QC-P-0083
Program

6.12.2.3. Gases
Type Activity Reference Document
Title No.
Product-contact-compressed air RA Risk Assessment Report for QC- P-0004/R-
Environmental Monitoring 01
Locations (Viable tests) In
Production Areas Plant I &
Plant II
Monitoring SOP Compressed Gases QC-P-0067
Monitoring Procedure
Summary Report Certificates of Total FQC-P-0067/01
Microbial count for
compressed gas for Plant I
Certificates of Total FQC-P-0067/02
Microbial count for
compressed gas for Plant II
N2 RA Risk Assessment Report for QC- P-0004/R-
Environmental Monitoring 01
Locations (Viable tests)In
Production Areas Plant I &
Plant II
Monitoring SOP Compressed Gases QC-P-0067
Monitoring Procedure
Summary Report Certificates of Total FFQC-P-0067/01
Microbial count for
compressed gas for Plant
I
Certificates of Total FQC-P-0067/02
Microbial count for

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Type Activity Reference Document

Title No.
compressed gas for Plant
II

6.12.2.4. Personnel
Note: see remark in Section 6.14.

Area Grade Activity Reference Document

Title No.
Grade B RA Rational study Report QC-
for Gowning P-0004/R-02
Qualification
Locations (Viable-
Surface test) for
Garment
Risk Assessment QC-
Report for P-0004/R-01
Environmental
Monitoring Locations
(Viable tests)In
Production Areas Plant
I & Plant II
Monitoring SOP Environmental QC-P-0004
Monitoring Program QC-P-0083
Summary Report Environmental FQC-P-
monitoring report for 0004/013
(Production lines Class FQC-P-
B–Plant II) by 0004/014
Personnel Gowning &
Assembly Check-up FQC-P-
0083/12
FQC-P-
0083/13

Environmental FQC-P-
monitoring report for 0083/12
(Production lines Class
B – Plant II) by
Personnel Gowning
Check-up
Grade C RA Rational study QC- P-0004/R-

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Area Grade Activity Reference Document

Title No.
Report for Gowning 02
Qualification
Locations (Viable-
Surface test) for
Garment
Risk Assessment QC- P-0004/R-
Report for 01
Environmental
Monitoring
Locations (Viable
tests)In Production
Areas Plant I & Plant
II
Monitoring SOP Environmental QC-P-0004
Monitoring Program QC-P-0083
Summary Report Environmental FQC-P-
Monitoring report for 0004/034
Rommelag lines by FQC-P-
Personnel Check-up 0083/40
Test

6.13. Prevention mechanisms – trend analysis, detailed investigation, root cause

determination, corrective and preventive actions (CAPA), and the need for
comprehensive investigational tools
- Non-conformance CAPA Trending Analysis: “Refer to SOP QA-P-0183”
 A good CAPA system should enable management to identify emerging trends and any
areas of improvement. Therefore, analysis of the system should be established to identify
recurrent non-conformances and trends.
 This Analysis will be implemented annually on the first quarter of the next year.

- Trending analyses include, but not limited to：

 Ratios of different types of non-conformances, are the trends changing?
 How about individual departments, are their trends changing?
 Is the trend of completion times changing?
 How about the similar/same non-conformances recurring?
 What are the root causes – trend changes?

- Investigation: “Refer to SOP QA-P-0183”

 Start Investigation acc. to steps of CAPA Source SOPs and use the specific investigation
form or report related to CAPA Source SOPs (1- deviations QA-P-0033, Complaints

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QA-P-0040, 3- external & internal audit QA-P-0060 & QA-P-0068)

 The Investigation content as refer to SOP Handling of deviation / Incident (QA-P-
0033)
 Conclusion. Essentially, the document should contain all the details needed, without the
use of jargon.
 Investigation & Root cause analysis: may use one of the following tools according to the
non-conformance criticality
5W2H method (as shown in SOP QA-P-0183)
8D Problem solving methodology (as shown in SOP QA-P-0183)
Ishikawa Charts (Fish Bone) (as shown in attached SOP QA-P-0183)
Process FMEA
Brainstorming
Control charts
- Evaluation of the corrective and preventive action:
Follow Up frequency Criticality
1 time after 3 months of action Minor CAPA
implementation
2 times after action implementation Major CAPA
(each 3 months)
3 times after action implementation Critical CAPA
(each 3 months)

- Effectiveness Evaluation Steps:

 Verify that corrective action was properly implemented
 Determine data source for Effectiveness Evaluation
 Determine when to perform Effectiveness Evaluation
 Determine evaluation period
 Consider impact of learning curve
 Determine success criteria
- In the event of a failed Evaluation:
 Issue a new non-conformance.
 The Root Cause Analysis will need to be redone.
 Item to consider:
- There may have been multiple root causes that were not initially discovered.
-There may have been significant contributing factors that were not discovered.
Operations or Quality Assurance may perform a post corrective action audit to determine
overall effectiveness.
- All open CAPAs are reviewed in meetings and may continue review until the recommended
actions have been completed. Once completed, the official date of CAPA close-out is listed
and is determined once all corrective and preventive actions have been completed and
documented as required. Supporting documentation may be added as it becomes available (as
applicable). QA verifies completion of Close Out and Follow-up by signing/dating

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Description Reference Document

Title No.
Incidents and deviations are managed Handling of incident and deviation QA-P-033
via:
Investigation of incidents and Handling of incident and deviation QA-P-033
deviations (Root causes analyses) is
described in SOP:
Corrective and preventive actions corrective & preventive action QA-P-0183
(CAPAs) are managed according to: Procedures

6.14. Continuous improvement based on information derived from the above

Product quality reviews are prepared annually for each product completed 12 batches
manufactured.
Each product quality review contains trend analysis for all specifications of the product and
graphical analysis using data analysis tools (Dot plot, Interval plot & Individual – Moving
range chart) to calculate the UCL & LCL for each specification
- Evaluation of the corrective and preventive action:
Follow Up frequency Criticality
1 time after 3 months of action Minor CAPA
implementation
2 times after action implementation Major CAPA
(each 3 months)
3 times after action implementation Critical CAPA
(each 3 months)

- Effectiveness Evaluation Steps:

 Verify that corrective action was properly implemented
 Determine data source for Effectiveness Evaluation
 Determine when to perform Effectiveness Evaluation
 Determine evaluation period
 Consider impact of learning curve
 Determine success criteria
- Trending analyses include, but not limited to：
 Ratios of different types of non-conformances, are the trends changing?
 How about individual departments, are their trends changing?
 Is the trend of completion times changing?
 How about the similar/same non-conformances recurring?
 What are the root causes – trend changes?

 trending analysis of EM,“REFERE TO SOP QC-P-0060”

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- Review the Microbiological results and issue a trend analysis quarterly &Establish a statistical
trend for viable and non-viable air monitoring & share in the investigation with QA
- Alert levels are periodically assessed based on data obtained during subsequent re-
qualifications, routine monitoring, and investigations
- Calculation of alert & action limit, the data are collected, sorted, and ranked from the lowest to
the highest.
- The alert level is set at the 95th percentile
- The action level is set at the 99th percentile

 Internal communication/escalation via regular or extraordinary meetings with defined

participants.
- In the case of internal activity: the first level of escalation is the department manager. The
second level of escalation is the department director and/or plant manager
- In case of outsourced activities: outsourced activities follow the same systems of reminders. The
first level of escalation is the department manager. The second level of escalation is the
department director

7. References:
7.1.EU Guidance on good manufacturing practice
7.2.EU – GMP, Volume 4 Annex 1
7.3.Orchidia QMS

8. Used Forms: None

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