Company Name:

PHARMACURE PLC. IV FLUIDS PLANT

Document No:
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Issue
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1. Preface..............................................................................................................................................2
2. Corporate Mission of Pharmacure Plc..............................................................................................4
3. Quality Policy....................................................................................................................................5
4. Quality Objectives.............................................................................................................................6
5. 5. SCOPE..........................................................................................................................................7
6. Definitions and Abbreviations...........................................................................................................7
7. Quality Management System.............................................................................................................8
8. Structure of the Quality System Documentation..............................................................................12
9. Organizational Structure.................................................................................................................14
10. Resource Management................................................................................................................18
11. Product Realizations....................................................................................................................19
12. Description of main functions......................................................................................................26
13. Process descriptions.....................................................................................................................34
14. Essential Elements of Good Manufacturing Practices for Pharmaceutical Products And Conformance
Matrix To GMP............................................................................................................................................. 37

FOR DOCUMENT
CONTROL USE ONLY

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1. Preface

Pharmacure is settled on 100,000m2 of land surrounded by picturesque mountains in the newly developed
suburb of Addis Ababa in Bole Sub City Kebele 16.

It is a private limited company owned by the multi-sectoral investor Sheik Mohammed Al-Amoudi for the
manufacture of pharmaceutical products.

The company was established in 1998, with an investment capital of 100 million birr. The first phase is the
production of intravenous fluid plant with a capacity of 5,000,000 liters that has been operational
since 2003.

The intravenous fluid plant is a complete pharmaceutical production facility which consists of pre-fabricated
modules for the preparation of solutions in 500 and 1000 mililitre PVC container.

The modules for the preparation, filling, sterilization, water treatment, air handling, bag production and
quality control functions were designed and constructed in Sweden.

The premises with the equipments installed were inspected by the Swedish Medical Inspectorate and was
certified for GMP compliance. Installation and Operational Qualifications (IQ, OQ) of the equipments, Air
handling units, Water treatment unit and the instruments in the Quality Control had been successfully
performed by the technology supplier in collaboration with Pharmacure staff.

After successful process validation and product qualification the following four types of intravenous fluid
products are currently being produced in one liter and half liter PVC bags,

1. Dextrose 5% W/V
2. Dextrose 5% W/V in normal saline
3. Ringer Lactate
4. Sodium Chloride 0.9%

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The plant had been inspected by the Drug Administration and Control Authority of Ethiopia before
commencing production and regularly after. It is the first company to be awarded Certificate of Competence
which is equivalent to GMP certificate.

The plant had also been inspected by the inspectors from Medicines Control Authority of Zimbabwe in 2004
and been certified for GMP compliance.

The huge investment made on the plant in adopting the latest and appropriate technology together with its
qualified and experienced personnel and the use of correct material and right procedure, it was possible to
fulfill the requirements of current Good Manufacturing Practice principles and to provide the public with
high quality, safe and effective products.

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2. Corporate Mission of Pharmacure Plc.

 To manufacture and market safe and effective drugs of the highest quality that mitigates discomfort
and suffering, by means of using superior level of technology.

 To create partnership with health care providers and enable them to successfully fulfill their mission.

 To recognize the key role employees play in the achievement of the corporate goal, and to commit to
fair and just treatment of all employees at all levels by creating an exceptional environment within.
The development and uplifting of employees will therefore promote company stability as well as
growth and profitability.

 To commit to behaving with high level of ethic and integrity and become good corporate citizens.

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3. Quality Policy

PHARMACURE Plc. is committed to produce high quality, safe and effective drugs
which satisfy the needs and expectations of its customers through implementation of
current good manufacturing practices and quality assurance systems.

________________ ____________
(Date) (signature)
General Manager

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4. Quality Objectives

 To produce 5,000,000 bags of IV fluids annually.

 To improve quality system documentation. based on past experience, self-inspections and

external GMP audit

 To train employees so as to increase their awareness of cGMP and Quality system installed in the
company.

 To be GMP certified company.

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5. 5. SCOPE
5.1 General

This quality system complies with the requirements of GMP

6. Definitions and Abbreviations.

6.1 Definitions
Management: The Management of Pharmacure includes the following:
- Deputy General Manger
- Production Manager
- Engineering and Maintenance Manager
- Quality Assurance Manager
- Quality Control Manager
- Finance Manager Manager
- Human Resource Manager
- Marketing and Sales Manager

6.2 Abbreviations

OP: Operational Procedure

QA: Quality Assurance Department
RM: Raw Materials
PM: Packaging Materials
HRD: Human Resource Department
CAPA: Corrective action Preventive action
cGMP: Current Good Manufacturing practice

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7. Quality Management System

7.1. General Requirements

7.1.1.Pharmacure PLC has established, maintains, and ensures the effectiveness of a documented quality
management system designed and implemented to fulfill the requirements of cGMP and applicable laws and
regulations. The company maintains the effectiveness of the quality management system through a range of
activities such as internal audits, management review, corrective and preventive actions and external audits.

7.1.2. Planning for quality is a cooperative effort amongst all Pharmacure’s main functional heads. All main
functional heads are responsible for identifying the processes needed for the quality management system and
implementing the system throughout their areas of responsibilities.

7.1.3. The main functional units determine the sequence and interaction of interrelated processes required to
ensure that customer needs are met and applicable regulatory requirements are effectively maintained and
continuously improved.

7.1.4. Designation of key performance indicators and methods of verification for the outputs as well as the
operation and control of quality management system processes are established to ensure effectiveness.

7.1.5. The Management ensures the availability of resources and information necessary to support the
operation and monitoring of these processes.

7.1.6. The quality system is monitored, measured, and analyzed to identify and implement actions necessary
to achieve planned results and maintain the effectiveness of quality management system processes.

7.1.7. Whenever outsourcing of resources is undertaken for processes that affect product conformity,
appropriate controls are put in place to ensure that requirements are met in accordance with Clause 7.4 of
this Quality Manual.

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7.2 MANAGEMENT RESPONSIBILITIES

I. Management Commitment
The Management of Pharmacure has demonstrated its commitment to the implementation and improvement
of the Quality System through the provision of necessary resources, and their involvement in improvement
programs.

To reinforce this commitment, management ensure that:

a) The importance of meeting customer and regulatory requirements is effectively and consistently communicated
throughout the organization using any of the following means: Meetings, Awareness training sessions; etc…

b) The quality policy, defined under Clause III of this quality manual, continues to remain relevant and consistent with
the overall organizational policies and provides a suitable framework for setting quality objectives;

c) Quality objectives continue to be identified for the relevant functions and levels within the company as defined
under Clause IV of this quality manual and remain measurable while consistent with the quality policy.

d) Management reviews continues to be conducted, as defined under Clause VI of this quality manual, to ensure the
continuing suitability, effectiveness and efficiency of the Quality System.

e) The necessary resources for the implementation and improvement of the processes of the Quality System and to
address customer satisfaction continue to be made available, as defined under Clause 4.3 of this quality manual.

II. Customer Focus

All Managers ensures that customer requirements are determined and fulfilled with the aim of
enhancing customer satisfaction through the determination of requirements related to the product.
This is typically achieved through any of the following:

 Determining the requirements specified by the customer, including the requirements for
delivery activities through past history, experience, and/or customer needs.

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 Determining the requirements not stated by the customer but necessary for specified use or
known and intended use through past history, experience and/or customer needs.

 Determining the regulatory requirements related to the product or service.

 Monitoring information relating to customer perception as to whether Pharmacure has

fulfilled customer requirements through customer satisfaction, rejections, performance, on-
time delivery.

 Promoting continual learning and skills training to employees for quality system awareness.

 Focusing on process improvement thus ensuring values to the customers.

III. Planning
a) Quality Objectives

 The Management ensures that quality objectives, including those needed to meet requirements for
product or service, are established at relevant functions and levels of Pharmacure. These objectives
are communicated for planning and implementation.
 Management ensures that quality objectives are measurable with appropriate time frames for
completion and are consistent with the Quality Policy.

b) Quality Management System Planning

 Quality management system planning consists of the implementation, updating, and maintenance of
this Quality Manual and all supporting specifications and procedures. Customer and supplier
feedback, as supplied through formal reports, performance reviews, during audits or through surveys
are considered during the update reviews of this Quality Manual. The approach and deployment of
quality planning includes safeguarding the integrity of the quality management system to ensure the
system is maintained effectively when changes are planned and implemented. These may include, as
appropriate:

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 Short- and long-term plans with objectives for improving quality and customer satisfaction.
Performance of these objectives are monitored and reported. Examples include: Product
quality, cycle time, scrap costs, delivery commitments.

 Maintaining methods for disaster recovery

 Inspection plans/test plans
 Process validation
 Equipment qualifications
 Identification of customer specified characteristics
 Internal audits
 Strategic and business planning
 Consideration of safety issues
 Utilization of mistake proofing methodologies when planning processes, facilities, equipment
and tooling
 Regulatory and industry requirements

IV Responsibility, Authority, and Communication

Responsibility and Authority

 Pharmacure has established and communicated the organizational structure, including definitions of
responsibilities and authorities.

 An organizational chart has been established, which provides an overview of Pharmacure’s

management structure.
\

 Responsibilities and authorities within the organization are defined in in job description and all
employees are communicated with.

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8. Structure of the Quality System Documentation

1st
Level----------------
Quality Manual

2nd
Level-------------- Standard Operating Procedures
(SOPs)

3rd Level--------- Specifications, Batch Records, Lab. Reports, Instrument

Operating Instructions and Forms

A. All Document control system shall address the following requirements

a) New documents and changes to existing documents shall be reviewed and approved for adequacy and
completeness by the QA Department before release for implementation.
b) All documents shall be legible, dated, readily identifiable with unique numbers, titles, and revision
levels, and maintained in an orderly manner.
c) Documents shall be readily available to all users within PHARMACURE.
d) The latest approved policies regulations and directives shall be properly identified and available to users.
e) All documents shall be reviewed by process owners and updated as necessary in accordance with
document change control system.

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B. Documents Control Identification Template

For Original/Master Documents

(Blue Stamp) QA
ORGINAL
For Registered Documents
(Blue Stamp)
REGISTERED COPY
No.____________ Date and Sig._______________

or documents of external origin EXTERNAL ORIGIN

(Blue Stamp)
CONTROLLED
DOCUMENT

For Obsolete Documents OBSOLETE DOCUMENT

(Red Stamp)

C. Documents /Forms/ Log Book Requisition and Issuance

a. Any department or Section may request reference document, books, pharmacopeia etc
shall fill Reference Material or Document Request and Follow up Form (QA/001F9)
b. QA will approve the request and QA clerk should issue the documents
c. Regarding request of blank Forms and Log Books (Which is Working documents) the
department or Section should fill Blank Forms and Log Books Requisition and Issuance
Form.(QA/001F10)

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GENERAL MANAGER
Ato.Abnnet G.Meskel
9. Organizational Structure

Deputy General Manager

Abebe Hagos
Executive Secretary
Azeb Mengestu

Technical Manager Procurement S . Marketing

Administration Finance Manager Pool secretary Manager
Abebe Hagos officer (foreign)
Manager Ashenafi Abera Getachew Sahilu Belay
Sofia Haile Quality Assurance
Bethelehem Gulelat QA Clerk
Ermias Sales clerk
Cost and
Budget Production Preparation Sterilization/
Demere Terefe Asfaw Water treatment Section
legese Abera Kassa
Canteen Head
QC Manager
Packing Section
Lensi Kumssa Property and
Asmar Adugna
General Supplies (Local)
General Service Accounts Physio-Chemical Section
Haregu Mengistu Abebayehu Belayne
officer
Laundry Unit
Shibere Geremew

Time Keeper sse

Microblogical Section Electro-Mechanical
Security Section
Casher

Solomon Mekebeb Senior Mechanic

Engineering and
Gardeners Maintenance Manager
Mequanent widu Spare part Unit
Drivers
Warehouse Section Utility and Workshop unit
Gizachew
Cleaning Crew
Warehouse Clerk/ Attendants
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9.1 Specific responsibilities and authorities

Responsibilities & Authorities

Function
Deputy General - Ensure the preparation and implementation of strategic plan
Manager - Assure the development and implementation of reviews quality policy
- Reviews quality policy
- Provides resources necessary to maintain and continuously improve the
effectiveness of the quality system
- Ensure Management Reviews is conducted as scheduled
- Assure high purchase documents
Marketing and - Market research to establish the desired quality characteristics of products or
Sales services
- Advertises and promotes company products and services emphasizing quality
- Monitors industry views of competitive products and services
- Reviews contracts and orders
- Communicates requirements customers
- Collects field performance, post-market surveillance
- Acts as initial recipients for customer complaint information
Engineering - Control engineering drawings
- Manage calibration program
- Performance of equipment and utility installation qualifications
- Maintain all production equipment in good operating condition including
preventive maintenance
- Setting up production equipment
- Maintenance and operation of all facilities and support utilities
- Maintenance of all facilities-related equipment as per the preventive
maintenance program schedule
- Responsible for insuring the facility meets all standards required for air quality
in a drug manufacturing facility
- Maintenance of interior/exterior of buildings and grounds
Production - Prepares production plan and schedules
- Controls production processes to ensure products meet predetermined
requirements
- Assists with verifying input specifications
- Initiates process improvement efforts
Procurement - Prepares and approves purchasing documents
- Assesses supplier performance, issuance, storage and handling of products and
materials
Human - Manage Employment processes
Resources - Salary administration
- Employees benefit administration
- Employee orientation

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- Employee services
- Responsible for providing a clean, safe, and comfortable environment for all
users of the facilities
- Maintenance and operation of all facilities and support utilities
- Responsible for housekeeping activities
Quality - Establishes, maintains, and continually improves the effectiveness of the quality
Assurance management system
- Manages Nonconforming material processes
- Maintains and controls quality system documents
- Ensure the completion of Corrective and Preventive Action Process
- Assists in the investigations associated with customer complaints
- Identifies/recommends suppliers for materials
- Manages Customer Complaint/Feedback system
- Maintains Internal and External quality audits
- Manage products disposition
- Verification and validation of manufacturing processes
- Selects qualified suppliers
- Performs Microbiology and Analytical Chemistry testing in accordance with
quality plans and relevant standards
- Assure that test and control articles or mixtures are appropriately tested for
identity, strength, purity and uniformity as applicable
Assure that personnel, resources, facilities, equipment, materials and
methodologies are available as scheduled for testing
- Produce BMR
- Initiates BMR reviews
- Qualifies process change
Finance - Prepare financial statements
- Accounts receivable
- Accounts payable
- Bank reconciliation
- Prepare annual plan and budgets
Quality Control - Follow the daily activities of the department
- Approves/rejects the in-process, physicochemical and microbiological tests
done on the starting materials, intermediates and finished products.
- Approves samplinig procedures for starting materials, intermediates and
finished productes
- Responsible for assigning properly trained personnel for the department; for
having adequate testing facilities, reference materials, chemicals reagents,
glassware and any other required materials.
- Ensures that high standard of personal hygiene is practiced by everyone
working both in production and quality control areas.
- Ensure that high standard of cleanliness is followed in all working areas.
- Shall follow up that all working equipments in the laboratory and production
area caliberated at regular intervals and are maintained according to the given

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programs and instructions.

- Shall follow up that appropriate validations are performed for testing methods,
working procedures, cleaning procedures and equipment.
- Investigate the reason for the defect of the quality that has occurred and
participates in making decision wheather to recall the product or not.
-

9.2 Internal Communication

The above management personnels and responsible bodies communicate information regarding Quality
System processes and their effectiveness through training, the internal audit process, continual improvement
and corrective/preventive action processes, and regular formal meetings and informal communications.
9.3 Management Review

The management reviews various aspects of the quality system at once in a year. The purpose of these
reviews is to assess the adequacy, effectiveness and continuing suitability of the quality system in meeting
customers’, regulatory requirements, the quality policy, and quality objectives.

The results of Management Review are documented and circulated to all members of the review team. Each
is responsible for implementing remedial, corrective, or preventive action in areas under his/her control.

 Review Inputs
Inputs to Management Review include at minimum information related to:
 Results of audits
 Customer feedback
 Process performance and product conformity
 Status of Preventive and Corrective Actions
 Follow-up actions from previous Management Reviews
 Changes that could affect the quality management system
 Recommendations for improvement, and
 New or revised regulatory requirements
 Review Outputs

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Outputs from Management Reviews shall include any decisions and actions related to:
 Improvements needed to maintain the effectiveness of the quality management system and its
processes (i.e. CAPA)
 Improvement of product related to customer requirements.

10. Resource Management

10.1 Provision of Resources

 Resource allocation is primarily the responsibility of the owners; and they depleted investment from
time to time as the company demands. It is the responsibility of the managements to ensure specific
resources are identified, fulfilled and attained.

10.2 Human Resources

10.2.1 General
It is Pharmacure’s policy to determine the necessary competence level and ensure that all personnel possess
the necessary training, skills, experience, and education to perform their assigned responsibilities
adequately. As appropriate, written job descriptions for each position contain the minimum education,
training experience and skills requirements of that position.

10.2.2 Competence, Training and Awareness

The competency of people; assigned responsibilities and authorities defined in the Quality System is
determined on the basis of staffing plan for appropriate education, training, skills, and experience for each
required competency or work assignment.
This is undertaken based on the human resource manual.

10.3 Infrastructure

Management determines, provides, and maintains the infrastructure needed to achieve conformity to product
requirements. Infrastructure includes:

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10.4 Work Environment

The management determines the work environment needed to achieve conformity to product requirements.
The work environment shall have a positive influence on motivation, satisfaction, and performance of
people in order to provide continuity in performance and development.

11. Product Realizations

11.1 Planning of Product Realization

8.1.1 Processes needed for product realization are planned and developed. Planning of product realization is
consistent with the requirements of other processes of the quality management system.

11.1.2 When planning product realization, the company determines the following as appropriate:

 Quality objectives and requirements for the product.

 The need to establish processes, documents, and provide resources specific to the product.
 Required verification, validation, monitoring, inspection, and test activities specific to the product
acceptance.
 Records needed to provide evidence that the realization process and resulting product fulfill
requirements.

11.1.3 Outputs of planning are documented appropriately for company’s method of operations and
controlled through documentation requirements.

11.2 Customer Related Processes

11.2.1 Determination of Requirements related to the Product

Pharmacure determines and ensures that:

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 Requirements specified by the customer can be met, including requirements for delivery and post-
delivery activities
 Requirements not stated by the customer but necessary for specified use or known and intended use
to the final product can be met.
 Statutory and regulatory requirements related to the product can be met.
 Additional requirements determined necessary by Pharmacure based on experience, knowledge, and
history of the product can be met.
11.2.2 Review of Requirements related to the product
 The purpose of contract review is to define and document customer requirements in order to identify
and resolve any differences in the customer’s expectations and Pharmacure’s ability to meet those
expectations. It is also to guarantee that Pharmacure has the resources to meet the contract or order
specifications. The managements ensure the technical and quality requirements are reviewed.

 All proposals and contracts are reviewed prior to the submission of Pharmacure commitment to
supply a product/service to the customer and ensure:

 Product requirements are defined and accepted;

 Contract or order requirements differing from those previously expressed are resolved and
accepted;
 Pharmacure has the ability to meet the defined requirements;
 The delivery schedule and pricing has been agreed to;
 Any use of subcontractors has been pre-approved;
 Any special skills or training requirements have been identified;

 Where the customer provides no documented statement of requirements, the customer requirements
are confirmed by assigned person and the customer and documented before accepting the order;

 Any contract change, order amendments, specification changes, product requirements, or delivery
variations to an existing order or contract, are subjected to the contract review stated above. The

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changes received from the customer are clearly identified, documented, and forwarded to the
respective function.

 Records of the results of the review and actions arising from the review are maintained.

11.2.3 Customer Communication

 Management determines and implements effective arrangements for communicating with customers
relative to product information; inquiries, contacts or order handling, including amendments;
customer expectations, special requirements, or arrangements that may be necessary; customer
feedback, including customer complaints.

 Communication with customers is documented as required and these communications become part of
the records. Communications requiring documentation are those requiring a change to product or
process, procedures, corrective action, scheduling changes.

11.3 Purchasing

Purchasing processes are conducted and controlled according to documented procedures to ensure purchased
products conform to purchase requirements. The type and extent of controls exercised over suppliers and
purchased products is dependent upon the effect of the purchased product on subsequent processes, or on the
final deliverable to the customer.

Material and products procured are subject to verification by authorized personnel as required.

11.3.1 Evaluation and Selection of Suppliers

 Documented Procedures defines the methodology and the personnel responsible for evaluating and
selecting suppliers. This process is based on the suppliers ability to meet the contract/order
specifications; etc….

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 The criteria for supplier selection, evaluation and re-evaluation are based on the criticality and
classification of the products or services purchased.

 Records of the results of supplier evaluations and subsequent necessary actions are maintained
according to Vendor Evaluation Standard Operating Procedure (QA/030).

Procurement and Supply department is responsible to:

a) Maintain a register of approved suppliers that includes the scope of the approval;

b) Periodically review supplier performance; records of these reviews are used as a basis for establishing the
level of controls to be implemented;

c) Define the necessary actions to take when dealing with suppliers that do not meet requirements;

11.4.2 Purchasing Information

The Procurement and Supply ensures that purchasing documents contain a clear description of the items or services
required and include or reference any or all of the following:

a) Requirements for approval of product, procedures, processes and equipment;

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b) Requirements for personnel;

c) Quality Management System requirements;

d) Requirements for test, inspection and related instructions for acceptance;

e) Requirements for test specimens;

f) Requirements for the supplier to notify Pharmacure of changes in product and/or process definition and,
where required obtain approval;

The purchasing documents are reviewed for adequacy of requirements before orders are placed with the
supplier.

11.4.3 Verification of Purchased Product

a) Inspection and/or other activities necessary for ensuring purchase product meets specified purchase
requirements are established and implemented. As appropriate, verification activities include:
 Obtaining objective evidence of the quality of the product from the supplier, such as a certificate of
analysis;
 Inspection and audit at the supplier;
 Review of the required documentation;
 Inspection of products upon receipt;
 Delegation of verification to the supplier or supplier certification;

b) Purchased product is not used or processed until it has been verified as conforming to specified
requirements;

c) When verification activities are delegated to the supplier the requirements are defined, and a register of
delegations is maintained.

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d) If Pharmacure or the customer needs to perform verification at the supplier’s premises, the verification
arrangements and method of product release are documented in the purchasing information.

e) Where specified in the contract, the customer or the customer’s representative is given the right to verify
at the suppliers and at Pharmacure’s premises that product conforms to specified requirements.

f) We understand that verification of product conformance to customer requirements is not evidence of

effective quality control by the supplier, nor does it absolve our responsibility to provide its customers with
acceptable product or preclude possible subsequent rejection by the customer.

g) Any nonconforming product detected while verifying purchased product is processed in accordance and
contract agreement with the supplier.

11.5 Production and Service Provision

11.5.1 Control of Production and Service Provision

General Requirements

Pharmacure plans and carries out production and service provision under controlled conditions which
include, as applicable:
 The availability of information to describe the characteristics of the product in the form of batch
making records.
 The availability of documented procedures, requirements, work instructions, reference materials, and
reference measurement procedures as necessary.
 The use of suitable equipment.
 The availability and use of monitoring and measuring devices.
 The implementation of monitoring and measurement.
 The implementation of release, delivery and activities.
 The implementation of defined operations for labeling and packaging.

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 Pharmacure establishes and maintains a record for each batch of drug products to provide traceability
and to identify the amount manufactured and amount approved for distribution. The batch record is
verified and approved.

11.5.2 Validation of Processes for Production and Service Provision

General Requirements
Pharmacure validates processes for production, such as, sterilization where the resulting output cannot be
verified by subsequent monitoring or measurement. This includes any processes where deficiencies become
apparent only after the product is in use. Validation demonstrates the ability of these processes to achieve
planned results. Pharmacure has established arrangements for these processes including as applicable:
 Defined criteria for review and approval of the processes
 Approval of equipment and qualification of personnel
 Use of specific methods and procedures
 Requirements for records and revalidation
 Records of validation shall be maintained.

12. Description of main functions

12.1 Quality Assurance

The Quality management system of the company determines and implements the quality policy of
the company. The quality policy of the company states that “Pharmacure Plc is committed to
produce high quality, safe and effective drugs which satisfy the needs and expectations of its

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customers through the implementation of Good Manufacturing Practices and Quality Assurance
Systems.

The quality assurance department is responsible for the implementation of good manufacturing and
control operations. It distributes approved Standard Operating Procedures (SOPs). The department
is organized with a quality control laboratory which consists of chemical and microbiological
sections.

The personnel working in the quality control laboratory are qualified in the field of pharmacy,
chemistry and biology and have got wide experience in quality control activities of pharmaceutical
industry.

Sampling of starting materials and all the necessary chemical and biological tests are performed in
the two sections and the result is reviewed and released by the department manager.

In-process control, analysis of the finished products is done by the laboratory and results are
reviewed together with the batch manufacturing record by the quality assurance manager who is
responsible for the release or rejection of the batch for sale. For every batch of the product that is
released or rejected, a certificate of analysis is provided by the department.

The laboratory performs accelerated and real time stability tests on products. The department also
checks that drugs are properly stored and distributed.

12.2 The Chemical Lab.

The Chemical lab which is responsible for performing physical, chemical and instrumental analysis
on raw materials, in-process control and finished products as well as stability studies. It is also
responsible for calibrating instruments, preparing and standardizing reagents. Besides the above
tasks it performs in-process control which includes inspection of production processes, especially
visual inspection of finished products on sampling basis.

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The Physico-Chemical Lab is equipped with high-tech instruments like particle counter, Polarimeter,
Atomic Absorption Spectrophotometer, Infrared Spectrometer and Ultraviolet-Visible Spectrometer.

The particle counter is used to measure the size and quantity of particles present in IV fluids, it
measures up to 5m, 10m and 25m size of particles.

It has its own IR Sensor which is calibrated every one year period. The sensor is connected to PC for
displaying result and printout will be attached to the result which will be retained in the document
store.

The Polarimeter is used to measure the concentration of dextrose in IV solutions. The instrument
performance is checked every six month using a standard sucrose solution.

Atomic Absorption Spectrophotometer is used to measure potassium and sodium content in ringer
lactate IV solution. This instrument is also attached to the computer then the result is printed and
retained in the document store.

The UV-VIS spectrophotometer is usually used to measure 5-hydroxylmethylfurfral present in

dextrose solution and scanning of leaching solution of IV fluid bags. This instrument has its own
calibration validation unit. Every time before it starts measuring, it checks its performance by its
own CVU. The CVU checks wavelength accuracy, absorbance accuracy, stray light resolution, noise
and instrument stability.
The other room of the lab is equipped with different types of instruments, like Automatic titrator,
sensitive balances, pH meter, conductivity meter, melting point apparatus, refractometer, furnace and
glasswares.

The automatic titrator is much different than the previously used titration apparatus. It can measure
up to 0.01ml, which can never be possible by burret that can only measure up to 0.05ml. It is
attached with printer that prints the test results and its statistical analysis.

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The balances are very sensitive and have their own automatic internal calibration system. It is also
checked every time by using standard weights. Once a year they are calibrated by metrology
laboratory of Quality and Standards Authority of Ethiopia.

12.3 Microbiology lab.

The microbiology section is responsible for the biological quality of the raw materials, packaging
materials, water, environment and hygiene status of the personnel working in critical areas.

To verify that the set standard for microbiological cleanliness of surfaces within the different hygiene
classes, equipment, floor, walls is maintained, surface swabs are taken or contact plates re prepared
with suitable media and checked.

Operator’s gloves who are working in critical areas are also frequently checked. Airborne micro
organisms in critical areas is also checked using settle plates and air sampler model MAS 100.

Measurement of airborne particulate contamination of critical areas is performed using Metone

model 3313 particle counter. This is performed every month for particle sizes from 0.5m to 10m.

Particulate matter test, microbial test and air velocity test is done on LAF (Laminar Air Flow) found
both in production and laboratory.

Raw water from the source and tap water is being checked every month for pathogenic organisms
like E.coli and other organisms using microbiological methods. De-mineralized water is checked for
its biological quality every month.

The process water, water for injection is checked for total count and endotoxin test every week. If
the result is out of the limit corrective action is taken and use of water for manufacturing is
discontinued.

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Bio-burden test is performed both on pharmaceutical raw material and primary packaging materials.
Endotoxin test using LAL reagent is performed on empty bags and administration sets used for
intravenous solutions.

Bio-burden test is performed on every batch of production before sterilization. Sterility test and
endotoxin test is performed on each batch before final release of the product by the Quality Control.
Both sterility and bio-burden tests are performed using membrane filtration apparatus.

12.4 Production

The production department is responsible in managing the production process. The head of the
production department ensures that IV fluids are produced according to given specifications and
installed standard operating procedures to obtain the required quality.

Within the department the raw materials are received, solutions are prepared, filled, sterilized and
packed. During these processes the department head ensures that the production records are
evaluated and signed by a designated person before they are made available to the quality assurance
department.

Planning activity is carried out on what type and quantity of IV fluid to be produced in a monthly
and weekly programme based on the annual plan.

It is the responsibility of this department to follow-up the cleaning and disinfecting of materials used
for production.

Personnel working in this department are from different disciplines like pharmacist, druggist,
operators etc… The production department arranges the required initial and continuing training of
production personnel according to the need.

Validation and calibration of equipment are performed within this department in conjunction with
other departments.

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12.4.1 Preparation and Filling

Preparation and filling of IV fluids are carried out in clean areas, entry to which is through airlocks
for personnel and materials. These rooms are maintained to the GMP standard of cleanliness and
supplied with treated air that has passed through HEPA filters.

These rooms are classified according to the required characteristics of the air for grade “C”.

Laminar air flow (LAF) of the filling machine is provided with a homogeneous air speed of about
0.3m/s for vertical flow and 0.45m/s for horizontal flow. For attaining the “C” air grade of the room
the number of air change is maintained at 20 per hour.

The preparation room is equipped with two preparation vessels each capacity of 2600 liters per
batch. There are two weighing balances with a maximum capacity of 16Kg and 60Kg. These
balances are annually calibrated by the national metrology department of Quality and Standards
Authority of Ethiopia.

The filling room is equipped with two filling machines i.e. No. 1699 & 1700. The prepared solution
is passed through a pre-filter of pour size 1.2 and manual filter of 0.2.

All personnel including those concerned with cleaning and maintenance working in these rooms
have received training relevant to the correct manufacture of IV fluids.

In order to protect the product from contamination, appropriate clothing is adopted i.e. hair and beard
are covered, a single trouser suit gathered at the wrists and with a high neck and plastic doctor shoes
are worn. The closing virtually shed no fibres and particulate matter.

A filtered and treated air is supplied to maintain a positive pressure relative to the surrounding areas.

12.4.2 Sterilizing

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All IV fluids produced are terminally sterilized by using the two SBM autoclaves. Each heat
sterilization cycle is recorded by a time/temperature chart starting from heating, sterilizing and
cooling phase. The temperature is recorded from a probe at the coolest part of loaded chamber and
inside of the bag of product.

The autoclaves are calibrated every year using a standard thermocouple, Chemical and Biological
indicators. Each autoclave has a capacity of sterilizing 1300 bags of IV fluid per charge.

12.4.3 Inspection and Packing

Every batch of the product is 100% visually inspected if there are any visible particles present in the
solution within the PVC bag. Besides, visual inspection and pressure testing of filled bags is carried
out. Each bag with a giving set is over-wrapped with polyethylene film.

Twelve bags of IV fluids are packed in one carton box and labeled in both sides of the box. Packed
finished products are waiting for 15 days in quarantine before release.

12.4.4 Water treatment

The water treatment plant is producing WFI (water for injection) up to the quality of less than
1s/cm of conductivity. It starts with filtering of ground water using sand filter then pass through
carbon filter. There are two ion exchangers i.e. cation and anion exchangers in this room. These
exchangers lower the conductivity of the ground water up to 3s/cm. The resins are regenerated
automatically when the conductivity of the demineralised water exceeds 5s/cm or when 40,000
liters of water passed through the resin by using 30%HC1 and 45% NaOH.

After demineralization steam distillation continues in a water still with a capacity of producing 2,200
liters/hr of WFI.

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12.4.5 Air Handling

The air handling unit of the plant was designed and constructed to fulfill the requirements of current
Good Manufacturing Practice for large volume parenterals.

The air is filtered through different grades of filters that are F5, F7 and F9. The clean rooms where
preparation and filling operations is conducted and the sterility laboratory are provided with HEPA
filters. In these clean room 20 air changes per hour is installed and the pressure difference with the
adjacent rooms is set to be 20-25 Pascal.

The temperature is set to be around 210C and the relative humidity is maximum 60%.

The environment is appropriate for product quality, efficient operation and personnel comfort.

12.5 Storage Areas

The storage areas do have sufficient capacity that allow orderly storage of raw materials, packaging
materials, finished products, quarantined materials, rejected materials and recalled materials.

The storage areas are designed so as to ensure good storage condition. Temperature and humidity
measurement is provided, checked and monitored. Reception and dispatch areas are designed to
allow containers of incoming and outgoing materials to be cleaned and for inventory.

Quarantine status is ensured by storage in separate areas, these areas are clearly marked and their
access is restricted to authorized personnel. Sampling is performed in the area where it is separated
and sealed by sheet glass and there is LAF in it for taking samples from containers.

Printed packaging materials are kept in safe and secure area of separate room.

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13. Process descriptions

1) Raw material and packaging materials receiving

After purchasing the raw material and packaging materials shall be delivered to store using receiving
voucher. The store person shall receive the materials in the reception area of the store.

2) Physical Inspection

The store person shall inspect each material whether their packaging conditions are good or not as per
the SOP.

3) Rejection

When the store person finds any inconvenience on material he/she will inform to the quality assurance
manager and reject it as per the SOP.

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4) Cleaning and delivering to quarantine

Materials that are in good condition shall be cleaned and delivered to quarantine. The QC personnel
shall be informed by using analysis request form.

5) QC check

The quality control laboratory shall perform analysis in accordance to the specification by using SOPs
and lab reports.

6) Rejection

If the analysis result does not conform to the specification, the QC personnel shall reject it by using red
label on the container. Then the store person will take it to the rejected material store.

7) Labeling with green label and storing

If the analysis result conforms to the specification the quality control personnel will release the
material by using the green label. And the store person will take the material to the appropriate place
as per SOP.

8) Delivering to production

When the production personnel requests material using material requisition voucher, the store person
will deliver the material to production by using material issue voucher.

9) Disinfecting & weighing

The production personnel will disinfect the material container using 70% alcohol in the outer material
lock and weighs the required amount of raw material as per the batch record in the inner material lock.

10) Solution preparation & mixing

The production personnel with the supervision of the pharmacist will prepare the solution and mix it as
per the batch record. And requests assay determination by using analysis request form.

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11) QC check

QC personnel will perform assay and other in process quality tests.

12) Adjustment

If the assay result is not conforming to the specification, the production personnel will adjust the
concentration of the solution and sends sample to chemical lab again.

13) Filtering

The production personnel will make integrity test on the filter.

14) Filling

Filling shall be done as per SOP.

15) QC check

QC performs checking whether the right packing material used or not, weight checking and take
sample for bioburden test (first filled bags)

16) 100% weight check

The two production personnel shall perform 100% weight checking of the filled bags.
17) Reject

If the filled bag weight does not conform to the specification the personnel will reject it. If it is OK the
autoclave personnel will load it to the trolley.

18) QC check

QC checks Autoclave tape (indicator) color change and the graph of sterilization.

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19) Sterilizing

The autoclave personnel will put the loaded trolleys into the autoclave. And then the autoclave starts
heating, then sterilization for 20 minutes finally into cooling phase and the autoclave personnel unload
it.

20) QC Sampling

QC personnel will take samples for chemical and biological tests as per SOP.

21) 100% Pressure Test and Visual Inspection

The packaging personnel will carry out the filled bag leakage checking and visual inspection as per
SOP.

22) Reject

If the filled bag leaks or contain visible particles, it will be rejected.

23) QC check

QC performs visual inspection by sampling 125 bags from 100% visual inspected bags.

24) Packing

Batch number, manufacturing date and expiry date shall be labeled correctly.

25) QC check

QC checks all the packing process and retain reference sample (Wrapped bags)

26) Quarantine

Packed bags shall be stored in quarantine with yellow label.

27) QC Check

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QC personnel shall make chemical and microbiological test while the packed products stay in
quarantine.
28) Reject

If the analysis result fails, the finished product will be rejected by labeling with red label.

29) Finished product store

If the analysis result passes, the product will be delivered to finished product store, by labeling it with
green label.

14. Essential Elements of Good Manufacturing Practices for

Pharmaceutical Products And Conformance Matrix To GMP.

14.1 Essential elements of Good Manufacturing Practices for pharmaceutical products

(Extracted from Good Manufacturing Practices and inspection, WHO, Vol 2, Geneva 1999).

Good Manufacturing Practices is part of Quality assurance which ensures that products are consistently
produced and controlled to the quality standards appropriate to their intended use and as required by
the marketing authorization.

GMP rules are directed primarily to diminishing the risks, inherent in any pharmaceutical production
that cannot be prevented completely through the testing of final products. Such risks are essentially of
two types: cross contamination (in particular by unexpected contaminants) and mix-ups (confusion)
caused by false labels being put on containers.

Under GMP:

14.1.1 All manufacturing process are clearly defined, systematically reviewed in the light of
experience, and shown to be capable of consistently manufacturing pharmaceutical products
of the required quality that comply with their specification.

14.1.2 Critical steps of manufacturing process and any significant changes made to the processes are
validated.

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14.1.3 All necessary facilities are provided, including

14.1.3.1 Appropriately qualified and trained personnel

14.1.3.2 Adequate premises and space
14.1.3.3 Suitable equipment and services
14.1.3.4 Correct materials, containers, and labels
14.1.3.5 Approved procedures and instructions
14.1.3.6 Suitable storage and transport
14.1.3.7 Adequate personnel, laboratories, and equipment for in-process
controls

14.1.4 Instructions and procedures are written in clear and unambiguous language, specifically
applicable to the facilities provided.

14.1.5 Operators are trained to carry out procedures correctly.

14.1.6 Records are made (manually and for by recording instruments) during manufacture to show
that all the steps required by the identified procedures and instructions have in fact been taken
and that the quality and quantity of the product are as expected; any significant deviations are
fully recorded and investigated.

14.1.7 Records covering manufacture and distribution, which enable the complete history of a batch
to be traced, are retained in a comprehensible and accessible form.

14.1.8 The proper storage and distribution of the produces minimizes any risk to their quality.

14.1.9 A system is available to recall any batch of product from sale or supply.

14.1.10 Complaints about marketed products are examined; the causes of quality defects investigated,
and appropriate measures taken in respect of the defective products and to prevent recurrence.

Signatories Signature Date Remark:

Prepared by QC Manager
Reviewed By Production Manager
Approved by QA Manager
Department: Quality Assurance Date of Issue: Page 38 of 42
 Company Name:

PHARMACURE PLC. IV FLUIDS PLANT

Document No:
Quality Manual
Issue
No.
Supersede No.
SOP/PHARMACURE/QA/004R5 SOP/PHARMACURE/QA/004R4
1
Effective Date 01/01/2020 Revision Date 01/01/2022

14.2 Conformance matrix to GMP

S/N

14.1.10
14.1.1
14.1.2
14.1.3
14.1.4
14.1.5
14.1.6
14.1.7
14.1.8
14.1.9
1 Sop, system QA/001R1 X
2 Training programme QA/021R1 X
3 Health check programme QA/027R4 X
4 Personal hygiene instructions within PR/002R4 X
“Unclassified area” (Corridor,
Packaging area, Stores & Quarantine)
5 Personal hygiene instructions within PR/004R4 X
“grade E area” (water treatment room,
laboratory & sterilizing area)
6 Handling of recalls QA/009R5 X
7 Personal hygiene instructions within PR/006R4 X
“grade C area”
8 Personal hygiene instructions within PR/003R4 X
“grade B area”
9 Maintenance programme for buildings EN/001R4 X
and facilities
10 Protection against vermin etc QA/017R4 X
11 Self – inspection QA/007R4 X
12 Handling of complaints QA/008R5 X X
13 Handling of complaints X X
15 Handling of emergency recalls QA/009R5 X X
16 Identification code number system QA/011R4 X
17 Batch number system QA/012R4 X
18 Dispensing of labels WH/006R4
19 Procedure for the disposal of rejected WH/012R4 X
labels, leaflets and other printed
materials
20 Cleaning of equipment used for QC/057R4 X
sampling of raw materials
21 Procedure for the disposal of rejected PR/032R4 X
labels, leaflets and other printed
materials
22 Plant steam and operation of the system PR/037R4 X

Signatories Signature Date Remark:

Prepared by QC Manager
Reviewed By Production Manager
Approved by QA Manager
Department: Quality Assurance Date of Issue: Page 39 of 42
 Company Name:

PHARMACURE PLC. IV FLUIDS PLANT

Document No:
Quality Manual
Issue
No.
Supersede No.
SOP/PHARMACURE/QA/004R5 SOP/PHARMACURE/QA/004R4
1
Effective Date 01/01/2020 Revision Date 01/01/2022

23 Waste disposal in production areas, QC/053R4 X

laboratory and stores
24 Visual inspection for polypropylene bag PR/024R4 X
25 Leakage test and visual inspection of PR/024R4 X
filled bags
26 Preparation of product – sequences PR/020R4 X
27 SIP of Preparation and Filling Systems PR/017R5 X
28 Procedure for the disposal of rejected WH/011R4 X
filled bags
29 Procedure for the disposal of unfit PR/032R4 X
labels, leaflets and other printed
materials during packaging
30 General sampling plan for raw materials QC/001R4 X
31 Sampling procedure for raw materials QC/001R4 X
32 Sampling of finished products QC/055R4 X
33 Cleaning of Glassware used in Chemical QC/042R4 X
Laboratory
34 Method for the disposal of used and QC/053R4 X
contaminated media in the biological
laboratory
35 Cleaning of Glassware used in QC/054R4 X
Biological Laboratory
36 Reception of raw materials and WH/001R4 X
packaging materials
37 Sampling of raw materials and QC/001R4 X
packaging materials QC/002R4
38 Storage of raw materials and packaging WH/002R4 X
materials
39 Dispensing of raw materials WH/003R4 X
40 Dispensing of packaging materials WH/004R4 X
within the storage area
41 Handling of printed packaging materials WH/005R5 X
42 Cleaning of warehouse WH/008R4 X
43 Inventory records for raw materials and WH/007R4 X
packaging materials using bin & stock
cards
44 Cleaning of warehouse WH/008R4 X
45 Cleaning of grade D and E (hygiene un- PR/004R4 X
classified areas) PR/005R4

Signatories Signature Date Remark:

Prepared by QC Manager
Reviewed By Production Manager
Approved by QA Manager
Department: Quality Assurance Date of Issue: Page 40 of 42
 Company Name:

PHARMACURE PLC. IV FLUIDS PLANT

Document No:
Quality Manual
Issue
No.
Supersede No.
SOP/PHARMACURE/QA/004R5 SOP/PHARMACURE/QA/004R4
1
Effective Date 01/01/2020 Revision Date 01/01/2022

47 Cleaning of grade B and C areas PR/003R4 X

PR/006R4
48 Cleaning of unclassified rooms PR/007R4 X
49 Ventilation EN/003R4 X
50 Cleaning of locker rooms PR/009R4 X
51 Test procedures and maintenance of QC/066R4 X
laminar air flow units
52 Water for injection (WFI) PR/010R4 X
53 De-mineralized water PR/011R4 X
54 Weighing equipment: checking and PR/014R4 X
maintenance
55 Documentation of manufacturing PR/001R4 X
56 Deviations: trouble-shooting, re-work, QA/019R4 X
rejects, reports, documentation
57 Receiving of materials in production PR/015R4 X
58 Sterilization & assembly of cartridge PR/021R4 X
filter housing
59 Manual integrity testing of final PR/022R4 X
cartridge filters
60 Product sterilization in autoclave PR/026R4 X
61 Sterilization in dry-heat sterilizer QC/058R4 X
65 Preparation & filling batch 1 (ta-001) PR/019R4 X
67 In-process control of packaging PR/024R4 X
operations
71 Cleaning of autoclaves PR/025R4 X
72 Preparation of filling equipment PR/018R4 X
73 Adjustment of volume at the filling PR/023R4 X
76 Packaging operations PR/030R4 X
77 Sanitization of the loop system PR/033R4 X
78 Sterilization of parts in autoclave PR/028R4 X
79 Storage and dispatch of finished drug WH/009R4 X
products
80 Handling of returned finished drug WH/009R4 X
products
81 Procedure for destruction of rejected WH/011R4 X
products
82 Sampling of printed matters QC/056R4 X
83 Handling of samples within the QC/060R4 X
chemical section

Signatories Signature Date Remark:

Prepared by QC Manager
Reviewed By Production Manager
Approved by QA Manager
Department: Quality Assurance Date of Issue: Page 41 of 42
 Company Name:

PHARMACURE PLC. IV FLUIDS PLANT

Document No:
Quality Manual
Issue
No.
Supersede No.
SOP/PHARMACURE/QA/004R5 SOP/PHARMACURE/QA/004R4
1
Effective Date 01/01/2020 Revision Date 01/01/2022

84 Retention of reference samples within QC/052R4 X

quality department
85 Documentation of analytical test data QC/051R4 X
86 Inspection, maintenance and calibration QC/061R4 X
of laboratory instruments
87 Handling of primary reference standards QC/050R4 X
and standard solutions
88 Handling of specifications and test QC/059R4 X
methods
89 Quality evaluation of raw materials and QC/046R4 X
packaging materials
90 Quality evaluation of batches of finished QC/051R4 X
drug products
91 Post production product inspection QC/069 X
92 Environmental control: monitoring of QC/008R5 X
airborne micro-organisms
93 Environmental control: micro biological QC/009R4 X
monitoring of surfaces
94 Environmental control: micro QC/010R4 X
biological hand set
95 Environmental control: measurement of QC/008R5 X
airborne particulate contamination with
optical particulate counter
96 Bioburden for sterile drugs before QC/011R4 X
terminal sterilization
97 Biological monitoring of raw and tap QC/012R5 X
water
98 Biological monitoring of process water: QC/013R5 X
water for injection
99 Stability studies QC/043R4 X

Signatories Signature Date Remark:

Prepared by QC Manager
Reviewed By Production Manager
Approved by QA Manager
Department: Quality Assurance Date of Issue: Page 42 of 42