Starting materials

Api + excepients
Medicinal product: subs or compination of subs represented the process
and represented for medicinal purposes
Finished products : medicinal products which has undergo all stages of
production up to packaging
Purpose of finished product:
Diagnosis, profilactic, treatment for the couse or symptoms,
anaesthesia, psychological
Dosage form : the physical intity of the product

utilities in GMP are :

production , manufacturing, QC

personnel
The responsibility of the Qualified Person

must ensure that each batch has been manufactured and checked in accordance with the
requirements of the marketing authorisation.

Basic requerments of GMP

 Personnel

Premises

Outsourced activities

Self Inspection

Equipment Materials

Validation and Qualification

Documentation

COMPLAINTS QUALITY DEFECTS PRODUCT RECALLS

Sanitation and Hygiene  Water Treatment System      HVAC System

Self-Inspection
• Purpose: to evaluate whether a company’s operations remain
compliant with GMP
• Assists in ensuring quality improvement

Items of Self-Inspection:
• Written instructions provide minimum and uniform standard
• Covering all aspects of GMP:
 personnel
 premises including personnel facilities
 maintenance of buildings and equipment
 storage of starting materials and finished
products
 equipment
 production and in-process controls
 quality control
 T F
1) Self-inspection is carried out formally on daily bases (F)

Formal (quarterly)Improve systems

Informal (daily)immediate correction
QC - Internal Confirm compliance
(half-yearly)

2) Self-inspection is carried out by Team appointed by ministry of

health and normally every 5 years (F)
Team appointed by management, with:
a. authority
b. sufficient experience
c. may be from inside or outside the company
d. experts in their own field
e. familiar with GMP
Frequency should be at least once a year

Depends on company size, requirements, actrivities

Often, departments are inspected according to a calender – one department per month over
a one year cycle

Critical Defects examples:

• Those defects which can be life-threatening and require the
company to take immediate action by all reasonable means,
whether in or out of business hours
Examples
ä Product labelled with incorrect name or incorrect strength
ä Counterfeit or deliberately tampered-with product
ä Microbiological contamination of a sterile product

Major Defects
• Those defects which may put the patient at some risk but are not
life-threatening and will require the batch recall or product
withdrawal within a few days
Examples
ä Any labelling/leaflet misinformation (or lack of information)
which represents a significant hazard to the patient
ä Microbial contamination of non-sterile products with some
risk for patients
ä Non-compliance to specifications (e.g. active ingredient
assay)

Root Cause Analysis purpose:

 for identifying the source of a good manufacturing practice (GMP) deviation and
determining an appropriate corrective and preventive action

Root Cause of product defect are:

CAUSES (METHODS)
Personnel / MATERIALS/ MACHINERY/ procedure/ environment

• Recall
Removal from the market of specified batches of a product

May refer to one batch or all batches of product

Dealing with Rejected materials

may be defined as materials at any stage, which have been tested against a set of
predefined specifications and found not meeting the specification fully.
 We can deal with such materials mainly in two ways
: 1. Reprocess and retest the materials to see whether it meets our specific requirements.
2. Destroy or send it to the supplier. 
Rejected materials and products should clearly marked as such and stored separately in
restricted areas
Action – returned to supplier/destroyed, etc. in timely manner
Action approved by authorized personnel – records maintaine
Reprocessing(f)
The reworking of all or part of a batch of product of an unacceptable quality from a defined
stage of production so that its quality may be rendered acceptable by one or more
additional operations

- A reprocessed batch should be given a new batch number. Some manufacturers

introduce part or all of a previous batch, into a batch of the same product.
-Additional testing of the reprocessed batch can be done, such as stability test, active
ingredient content
- Proper and complete records should be maintained for reprocessed materials.

RECOVERY
The introduction of all or part of previous batches of the required quality into another batch
at a defined stage of manufacture.
QC
Resources of QC include
• Adequate facilities
• Trained personnel
• Approved procedures for all activities
• Specifications and test procedures
• Pharmacopoeia

Premises
Design Principles of premises

• Process flow
• Material flow
• People flow

Equipment
Cleaning of equipments after processing
 to prevent cross-contamination.
to prevent contamination or carry-over of a material that would
alter the quality of the intermediate or API beyond the official
or other established specifications.
Design prenciples of production equipment in GMP include
– easily and thoroughly cleaned
– Stored only in a clean and dry condition
-easily and thoroughly cleaned on a scheduled basis procedures and records
-No hazard to the products contact parts of suitable non-reactive materials
-non additive and not absorptive Defective equipment removed, or labelled
to prevent use
QC Access
QC personnel must have access to production and other areas
For specific reasons for:
Sampling e.g. water system, steam, environmental monitoring
For investigations
 Samples
Reduced Sampling Not applicable normally to:
• starting materials supplied through agents and brokers where the
source of manufacture is unknown or not audited;
• starting materials for use in parenteral products
• must test each individual product because the risk is high cannot
be returned

• Samples are retained to fulfill two purposes:

– Samples for analytical testing
– Specimen of finished product

Reference sample: sample of a batch of:

• Starting material
• Packaging material
• Finished product
Stored for the purpose of analysis during the shelf life of the
batch concerned

Retention sample: sample of fully packaged unit from a

batch of finished product:
purposes: stored for identification presentation, packaging,
labeling, patient
information leaflet, batch number, expiry date..etc..

• Duration of storage:
 – 1 year after the expiry date
– Samples of starting materials (other than solvents, gases or
water) shall be retained for at least 2 years after the release
of product
• Size of samples: sufficient to carry out minimum 2 x full analytical
controls
• Storage conditions: in accordance with the marketing
authorization

The main points in sampling SOP are?

• Samples should be representative of the batch of
materials/products
• Avoid contamination, cross-contamination and mix-ups during
sampling - no adverse effects
• Sampled containers labelled and re-sealed
• Clean sampling equipment used - stored separately from other
laboratory equipment
• All unique lots of ingredients, in-process product, packaging components,
labels, received bulk finished goods, finished goods and packaged finished
goods shall be sampled.

On-going stability program ‫نفس ساليد السامبل‬

Purpose: program to monitor stability of medicinal products over
its shelf life

• Applies to the finished medicinal product in its final package

• Described in a written protocol & results formalized as report
• Equipment used for on-going stability (e.g. stability chambers)
should be qualified and maintained

The stability protocol should include:

– Number of batches per strength and different batch sizes
– Test methods (physical, chemical, microbiological and
biological)
– Acceptance criteria
– Reference to test methods
 – Description of the container closure systems
– Testing intervals
– Storage conditions
– Other applicable parameters specific to the medicinal
product

QC/TESTING
Testing record incude?
– Name of material/product with dosage form
– Batch number, manufacturer/supplier
– References to the relevant specifications and testing procedures
– Test results and calculations
– Dates of testing
– Initials of analysts who performed the tests
– Initials of persons who verified the testing and calculations
– Clear statement of approval or rejection and the dated signature of
responsible person
 • The stability protocol should include:
– Number of batches per strength and different batch sizes
– Test methods (physical, chemical, microbiological and
biological)
– Acceptance criteria
– Reference to test methods
– Description of the container closure systems
– Testing intervals
– Storage conditions
– Other applicable parameters specific to the medicinal
product

During processing production area, rooms they are identified

with product and bach NO only (F)
• During processing label& identify:
All materials, Bulk containers, Major items of equipment ,Rooms used
(product, strength, BN, stage of production)

pressure differential in processing rooms

assist in preventing cross-contamination.
for achieving containment between two adjacent zones
to ensure containment and prevention of fl ow reversal

measures to prevent contamination/cros-contamination

Design Opportunities : The design of a facility, its Heating Ventilation and Air
Conditioning (HVAC) system and equipment is the first and critical step in preventing
contamination and cross- contamination.
Manufacturing Process :
Personnel Training and Clothing:
Effective Cleaning Procedures:
 ‫تووصيل‬
• The Contract : Written agreement defining each party’s
responsibilities and technical aspects – activities, products,
operations, communication process

Quality risk management QRM : is a systematic process for the assessment, control,
communication and review of risks to the quality of the medicinal product. It can be applied
both proactively and retrospectively.

Technology transfer: New products transfer during development through manufacturing

• Transfers within or between manufacturing and testing sites for marketed products

Records:( documents) provides evidence of various actions take

BATCH (OR LOT) A defined quantity of starting material, packaging

material or product processed in one process or series of processes so
that it could be expected to be homogeneous.
How do you act in the following situations
1)Defective equipment in production?
removed – labelled
2)different fixed pipes in production?
 Fixed pipework: – clearly labelled – indicate contents – direction
of flow
 Service pipings – adequately marked – non-interchangeable
connections or adaptors • Dangerous gases and liquids

3)purchasing balance for QC?

Appropriate range
• Precision
• Available to: – production – quality control
• Calibrated – scheduled basis – checks – records maintained
4)Introduction of balance into weighing area?
Calibrated
Qualified
Cleaning
Doccumentatio
validation

5)line clearance?
Processing operations: intermediate and bulk products
• Line-clearance (before starting the operation)
• Kept under appropriate conditions e.g. temperature
• If purchased as such Handled on receipt as though these are starting
material
6)Any alteration made to the entry on a document ?
should be signed and dated. Any alteration should permit the reading of
the original information.

7)Secondary packaging of different product in close proximity?

risk of mix-ups, contamination and cross-contamination
• Preferably physical separation between lines
• Area indicates product under process
• Filling followed by sealing and labelling- no delays
• Correct performance e.g. overprinting, labels, leaflets
– Automated checks preferred

8)Employing a new section supervisor in production?

• Scientific education.
• Practical experience. – under professional guidance – able to take
difficult decisions in a professional and scientific way, – resolve the
problems encountered in manufacturing and QC
should have adequate education, training, and experience
should be given specific training
• The concept of QA and its understanding and implementation should
be fully discussed during training

9)applying consultant?
Should have adequate education, training, and experience
• Records should be maintained stating the name, address,
qualifications, and type of service provided by these consultants
10)Campaign production(manufacturing)?
Separation in time
– Followed by appropriate cleaning
– Validated cleaning procedure

11) Prevention of cross-contamination in production?

Campaign production: – Separation in time – Followed by appropriate
cleaning – Validated cleaning procedure • Clothing – Protection of
operator and product
Verification of cleaning of non product contact surfaces
• Monitoring of air within the manufacturing area
Recording of: – spills, – accidental events – Deviations from procedure
1. Segregated areas 2. Airlocks and pressure differentials 3. Treatment
of recirculated air 4. Protective clothing 5. Effective cleaning
procedures 6. Closed production systems 7. Residue testing 8. Status
labelling

12)identification and labelling of rooms during processing ?

To prevention of cross-contamination – separate biological ,
microbiological, radio-isotopic rooms
classification
Rooms Grade A, B, C, D according to the cleanliness level of the clean
room
Effective air handling to suit product – temperature – humidity –
filtration – monitoring
CONTAINMENT
The action of confining a biological agent or other entity within a defined
space.
Primary containment: A system of containment which prevents the
escape of a biological agent into the immediate working environment. It
involves the use of closed containers or safety biological cabinets along
with secure operating procedures.
Secondary containment: A system of containment which prevents the
escape of a biological agent into the external environment or into other
working areas. It involves the use of rooms with specially designed air
handling, the existence of airlocks and/or sterilisers for the exit of
materials and secure operating procedures. In many cases it may add to
the effectiveness of primary containment.

AIR-LOCK:
An enclosed space with two or more doors, and which is interposed
between two or more rooms, e.g. of differing class of cleanliness, for the
purpose of controlling the air-flow between those rooms when they
need to be entered. An air-lock is designed for and used by either people
or goods.

What is change control?

Any proposals for GMP relevant changes

Any changes in raw materials, specifications, analytical methods, facilities, support systems,
equipment (including computer hardware), processing steps, labeling and packaging materials,
and computer software.

Written procedures should provide for the identification, documentation, appropriate review,
and approval
What is the product life cycle?

 Pharmaceutical Development (manufacture of investigational medicinal

products)
 Technology Transfer:
 Commercial Manufacturing:
 Product Discontinuation:

What are the personal hygiene standards?

Personnel should practice good sanitation and health habits.

Personnel should wear clean clothing suitable for the manufacturing activity

Personnel should avoid direct contact with intermediates or APIs

Smoking, eating, drinking, chewing and the storage of food should be restricted to certain
designated areas separate from the manufacturing areas

Personnel suffering from an infectious disease or having open lesions on the exposed surface of
the body should not engage in activities that could result in compromising the quality of APIs.

Modes of cross-contamination?

Microbiological:   When cleaning equipment is left damp and dirty after use
Physical:   Dirt, grit and debris from cleaning equipment also represents a contamination
risk. 
Chemical:   Sometimes the chemicals used to clean hygiene equipment represent a
contamination risk if their concentration is too high.

All materials, Bulk containers, Major items of equipment ,Rooms used (product, strength,
BN, stage of production)