Transcript Code of Federal Regulations Parts 210 and 211

Code of Federal Regulations
Parts 210 and 211
Module – III, Section - 1
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Code of Federal Regulations
•21 CFR Part 210
Current Good
Manufacturing Practice
in Manufacturing,
Processing, Packing or
Holding of Drugs;
General.
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•21 CFR Part 211
Current Good
Manufacturing Practice
for finished
Pharmaceuticals
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Code of Federal Regulations
Part 210
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Part 211
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PART 210 – CURRENT GOOD MANUFACTURING
PRACTICE IN MANUFACTURING, PROCESSING,
PACKAGING OR HOLDING OF DRUGS; GENERAL
Section
210.1
210.2
210.3
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Status of current good
manufacturing practice
regulations.
Applicability of current good
manufacturing practice
regulations.
Definitions
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Status of current good manufacturing practice regulations
• Regulations of the section give about minimum cGMP’s
for all manufacturing operations.
• Failure to comply with these minimum requirements 210
through 226 shall render the product adulterated and the
personnel involved in such manufacturing operations shall
be subject to regulatory action.
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Applicability of cGMP regulations




Regulations of parts 210 through 226 – applicable to
drug.
Regulations of parts 600 through 680 – applicable to
biological product for human use.
No documents or regulations mentioned here shall
supercede each other, they shall be supplemented.
Personnel engaged in the operations subject to these
regulations partially need to comply to those partial
operations only.
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Definitions
Act,
 Batch,
 Component,
 Drug,
 Fiber,
 Non- Fiber- releasing
filter,
 Active ingredients,
 Inactive ingredients,
 In-Process material,
etc. are defined

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








Lot,
Lot number,
Strength,
Quality,
Control,
Theoretical yield,
Actual yield,
Acceptance criteria,
Representative samples
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•
•
•
•
•
•
•
•
Batch: A specific quantity of a drug or other material that is intended to have
uniform character and quality, within specified limits, and is produced according
to a single manufacturing order during the same cycle of manufacture.
Component: Any ingredient intended for use in the manufacture of a drug product,
including those that may not appear in such product.
Drug: A finished dosage form, for example, tablet, capsule, solution etc. that
contains an active ingredient generally, but not necessarily, in association with
inactive ingredients.
Fiber: any particulate contaminant with length at least three times greater than its
width.
Non Fiber Releasing filter: any filter which after an appropriate pretreatment
such as washing or flushing, will not release the fibers into the component or the
drug product that is being filtered.
Active ingredient: Any component that is intended to furnish pharmacologically
activity or other direct effect in the diagnosis, cure, mitigation, treatment or
prevention of any disease, or to affect any structure or any function of the body of
man or animals.
In-Process material means any material fabricated, compounded, blended or
derived by chemical reaction that is produced for, and used in the preparation of
the drug product.
Lot or Batch: Specific identified portion of a batch, having uniform character and
quality within specified limits, In case of a drug product produced continuous
process, it is a specific identified amount produced in a unit of time or quantity in a
manner that assures its having uniform character and quality within specified
limits.
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




Strength:

The concentration of the drug substance (for example,
weight/weight, weight/Volume,e, or unit dose/volume basis of
time or quantity in a manner that assures its having uniform
character and quality within specified limits.

The potency that is the therapeutic activity of the drug product as
indicated by appropriate laboratory tests or by adequately
developed and controlled clinical data(expressed, for example, in
terms of units by reference to a standard).
Theoretical Yield: The quantity that would be produced at any
appropriate phase of manufacture, processing, or packaging of a
particular drug product, based upon the quantity of components to be
used, in the absence of any loss or error in actual practice.
Actual Yield: The quantity that is actually produced at any appropriate
phase of manufacture, processing or packing of a particular drug
product.
Acceptance Criteria: the product specifications and
acceptance/rejections criteria, such as acceptable quality level
unacceptable quality level, with an associated sampling plan, that are
necessary for making a decision to accept or reject a lot or a batch.
Representative sample: A sample that consists of a number of units
that are drawn based on the rational criteria such as random sampling
and intended to assure that the sample accurately portrays the
material being sampled.
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Flow chart for Training program on CFR 211
CFR-PART 211
cGMP for Finished Products
General
Scope & Definition
Organisation & Personnel
Production
QA & QC
Equipment
Laboratory Controls
Control of Component.
Buildings
Facilities
Holding
& &Distribution
Pro. & Pro Controls
Holding & Distribution
Packing & Labelling Con.
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Records & Reports
Returned & Salvaged Drugs
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PART 211 – CURRENT GOOD MANUFACTURING
PRACTICE FOR FINISHED PHARMACEUTICALS
Part 211
cGMP for Finished Products
Subpart A
General Provisions
Subpart B
Organisation & Personnel
Subpart C
Buildings & Facilities
Subpart D
Equipment
Subpart E
Control of Components & Drug Product
Containers & Closures
Subpart F
Production & Process Controls
Subpart G
Packaging & Labelling Controls
Subpart H
Holding & Distribution
Subpart I
Laboratory Controls
Subpart J
Records & Reports
General
Subpart K
Returned & Salvaged Drug Products
Production
QA QC
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PART 211 – CURRENT GOOD MANUFACTURING
PRACTICE FOR FINISHED PHARMACEUTICALS
Part 211
cGMP for Finished Products
Subpart A
General Provisions
Subpart B
Organisation & Personnel
Subpart C
Buildings & Facilities
Subpart D
Equipment
Subpart E
Control of Components & Drug Product
Containers & Closures
Subpart F
Production & Process Controls
Subpart G
Packaging & Labelling Controls
Subpart H
Holding & Distribution
Subpart I
Laboratory Controls
Subpart J
Records & Reports
Subpart K
Returned & Salvaged Drug Products
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PART 211
Sub Part A – GENERAL PROVISIONS


211.1
Scope:
a) Regulations in this part contain those minimum cGMP’s for preparation
of drug products and biologicals for administration of humans or
animals.
b) cGMP regulations in this part pertain to drug products and in parts 600
through 680 pertain to biologicals intended for human use.
c) Requirements may not be met for OTC drug products when those and
their ingredients are marketed and consumed as human food.
211.3
Definitions:
 Same definitions given under CFR 210 are applicable to
this section
too.
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PART 211
Sub Part B – ORGANISATION & PERSONNEL
211.22 Responsibilities of Quality Control Unit.
a) A Quality Control Unit shall be responsible for authorizing of various
materials in several stages along with their documents.If any errors
were observed they should be investigated fully.
b) Adequate lab facilities for testing approval or rejection of components
shall be available.
c) QC shall Approve or Reject the materials after testing as per
procedures.
d) All responsibilities and procedures applicable to QC shall be written
down and they shall be followed.
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PART 211
Sub Part B – ORGANISATION & PERSONNEL
211.25
a)
b)
c)
211.28
a)
b)
c)
d)
Personnel Qualification
There shall be adequate number of trained, experienced and qualified
people for supervising the manufacturing operations.
All personnel involved in the manufacturing and its ancillary services
shall be literate, qualified, experienced and trained.
All personnel shall protect themselves and the products integrity by
following the GMP’s
Personnel Responsibilities
Personnel shall wear clean clothing appropriate for their duties who
were engaged in manufacturing operations.
Personnel shall practice good sanitation and health habits.
Authorization shall be given to Personnel along with limited access to
buildings and facilities.
Any person with illness shall be excluded from all those operations
which deal with direct product contact.
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PART 211
Sub Part B – ORGANISATION & PERSONNEL Contd.
211.34
Consultants
 Consultants advising on the manufacturing operations shall be highly
qualified and experienced.
 A record shall be maintained stating complete detail of the consultants.
Reject the materials after testing as per procedures.
What does UK MCA say about Organisation and
personnel
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PART 211
Sub Part C – BUILDINGS & FACILITIES
211.42
Design & Construction features
a) Buildings used in the manufacturing operations shall be suitably
constructed to facilitate maintenance and cleaning.
b) Buildings shall be provided with adequate place and equipment shall
be placed orderly. Adequate space shall be provided for proper storage
of materials in various stages.
c) All operations shall be performed within specifically defined areas of
adequate size. All the areas and process flow should be such that it
prevents the contamination and mix ups during course of following
operations.
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PART 211
Sub Part C – BUILDINGS & FACILITIES
211.42
Contd.
1) Receipt, identification, storage and withholding from use of
components, drug product containers, closures and labeling,
pending the appropriate sampling, testing, or examination by the
quality control unit before release for manufacture.
2) Holding rejected components, drug product containers, closures
and labeling before disposition.
3) Storage of released components, drug product containers, closures
and labeling.
4) Storage or In-process materials.
5) Manufacturing and processing operations.
6) Packaging and labeling operations.
7) Quarantine storage before release of drug products.
8) Storage of drug products after release.
9) Control and laboratory operations.
10) Aseptic processing, which includes as appropriate
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PART 211
Sub Part C – BUILDINGS & FACILITIES
211.42
Contd.
i.
Floors, walls and ceilings of smooth, hard surfaces that are easily
cleanable.
ii. Temperature and humidity control.
iii. Proper Air Handling Systems, HEPA filters and LAF’s.
iv. System of monitoring environmental conditions.
v. Systems for cleaning and disinfecting rooms and equipment.
vi. System for maintaining any equipment used to control aseptic
conditions.
d) Any operations involving manufacture of penicillin shall be
performed in separate facilities.
211.44 Lighting
 Adequate
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PART 211
Sub Part C – BUILDINGS & FACILITIES
211.46
a)
b)
c)
d)
211.48
a)
b)
Ventilation, Air Filtration, Air Heating & Cooling
Adequate ventilation shall be provided.
Adequate control over air pressure, temperature, humidity, dust etc.
Air filtration systems shall be used when appropriate at defined areas.
AHU systems for penicillin's shall be completely separate.
Plumbing
Plumbing system free of defects shall be used to supply potable water
under positive pressure continuously. Potable water shall meet the
standards set by Environmental Protection Agency’s Primary Drinking
Water Regulations set forth in 40 CFR part 141.
A proper drainage system shall also be provided.
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PART 211
Sub Part C – BUILDINGS & FACILITIES
211.50

211.52

211.56
a)
b)
c)
d)
Sewage and Refuse
Sewage, Trash and other refuse from the buildings and immediate
premises from the building shall be disposed safely.
Washing and Toilet Facilities
Adequate washing facilities shall be provided (includes Hot, cold
water, Detergent or Soap solution, Air Dryers).
Sanitation
Buildings used in manufacturing operations shall be maintained in
clean and sanitary condition.
There shall be written down procedures assigning responsibilities for
sanitation, cleaning schedules, procedures etc.
Good sanitation facilities , along with written down procedures for
Sanitation, Pest Control & Cleaning etc. shall be maintained.
Sanitation procedures shall apply to all workers and employees in the
premises.
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PART 211
Sub Part C – BUILDINGS & FACILITIES
211.58
Maintenance
 Proper maintenance shall be provided to all buildings involved in
manufacturing operations
What does UK MCA say about Premises and
Equipment
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PART 211
Sub Part H – HOLDING AND DISTRIBUTION
211.142 Warehousing procedures
 There shall be written procedures for warehousing of drugs.
a) Quarantine of drug products before release by quality control unit.
b) Storage of drug products under controlled conditions shall be
followed to preserve the identity, strength, quality and purity of
the drug.
211.150 Distribution Procedures
 There shall be written procedures for Distribution of drugs. They shall
include
a) Oldest approved drug product shall be distributed first.
b) Distribution records of each drug product shall help in tracking
the movement of the drug product and easy recalls when needed.
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Flow chart for training program on MCA Guidelines
Training Program on Guidelines of MCA (Orange Guide)
General
Personnel
Premises & Equipment
Production
QA & QC
Production
Quality
Management
Manufacture of
Sterile Medicinal
Products
Documentation
Quality Control
Contract Manufacture
& Analysis
Complaints &
Product recall
Self Inspection
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PERSONNEL


MAINTENANCE OF A SATISFACTORY QA SYSTEM AND
QUALITY PRODUCTS RELIES UPON.

People

Training

Personnel Hygiene
PREMISES AND EQUIPMENT.

Premises

Equipments
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PERSONNEL

PEOPLE.

Manufacturing has the responsibility to provide sufficient
Qualification personnel for carrying out various tasks.

Individual responsibilities must be clearly understood by
the individual

All personnel must be aware of GMP’s / GLP’s

All personnel must receive initial and containing
training, including hygiene instructions

The responsibilities placed on any one individual should
not be extensive as to present any risk to quality.

The manufacturer must have an organisation char.
People in responsible should have specific duties,
written job description and adequate authority.
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PERSONNEL


PEOPLE.

Key posts should be occupies by full time personnel.

Heads of production and QC must be independent from
each other.
TRAINING.

The manufacturer should provide training for all the
personnel, whose activities should effect the quality of
the product..

New recruits should receive training appropriate to the
duties assigned to them.

Training should be ongoing and its effectiveness
periodically assessed.

Training records should be kept
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PERSONNEL


TRAINING

Training programs should be available and approved by
QC or production head, as appropriate.

Visitors or untrained personnel should be given
information in advance on hygiene and protective
clothing. They should be closely supervised.
PERSONNEL HYGIENE

Hygiene programs should include procedures related to
the health, hygiene practices and clothing. The
Procedures should be understood and practiced strictly.

All personnel should receive medical examinations on
recruitment and thereafter periodically.
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PERSONNEL

PERSONNEL HYGIENE

Steps must be taken to ensure that no person affected
by infectious diseases or having open cuts on exposed
surfaces of body is engaged in the manufacturing
process.

Every person entering manufacturing areas should wear
protective garments, appropriate to the operations to be
carried out.

Direct contact between operator's hands and the
exposed product or m/c contact parts should be
avoided.

Personnel should be instructed to use hand washing
facilities.
Continue with CFR
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PREMISES AND EQUIPMENTS

PREMISES

Premises should be situated in an environment which
presents minimal risk of contamination.

Premises should be carefully maintained, ensuring that
repair or maintenance so not present any hazard to
product quality.

Lighting, temperature, humidity and ventilation should
be appropriate.

Premises should be designed and equipped so as to
afford maximum protection against the entire of insects,
rodents or other animals.

Entry to production, storage and CC areas should be
restricted to authorized people only.
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PREMISES AND EQUIPMENTS

PREMISES

Dedicated and self contained facilities to avoid cross
contamination e.g., penicillin's, biological preparation,
hormones, cytotoxics, nonmedicinal products, highly
potent drugs etc..

In exceptional cases, principle of campaign working in
the facility can be accepted, provided that specific
precautions are taken and necessary validations are
made.

Poisons, pesticides, herbicides not allowed in premises,
used for medicinal products.

Premises should be laid so as to allow production in a
logical order.
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PREMISES AND EQUIPMENTS

PREMISES

In process storage space should permit orderly and
logical positioning of materials.

Where starting and primary packaging materials,
intermediates, bulk products are exposed, the walls
floors and ceiling should be smooth, free from cracks,
crevices, open joints etc.

Concealed fittings to avoid the creation of recesses
which are difficult to clean.

Drain points must be designed to avoid back flow.

Production areas should be effectively ventilation with
air control facilities, (including temperature and where
necessary, humidity and filtration) appropriate booth to
products handled and operations undertaken.
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PREMISES AND EQUIPMENTS

PREMISES

Weighing of stating materials usually should be carried
out in a separate weighing room, designed for that use..

Where powder dust is generated, specific provisions
should be taken on ensure dust containment.

Packaging area must be designed to avoid mix-ups or
cross contamination.

Production areas should be well lit, particularly where
visual on line control are carried out.

Storage areas should be sufficient capacity to allow
orderly storage of RM’s, PM’s, intermediates, bulk and
finished products.
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PREMISES AND EQUIPMENTS

PREMISES

Storage area should be designed to ensure good
storage conditions and maintained within acceptable
temperature limits, where required, temperature and
humidity controls must be provided, which need to be
checked and monitored.

Receiving and dispatch bays should protect goods from
weather. Receiving areas should be designed and
equipped to allow cleaning of oncoming materials,
before storage.

Physical quarantine or any system which should give
equivalent security. Restricted to authorized parsons
only.
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PREMISES AND EQUIPMENTS

PREMISES

Separate sampling area preferable. If performed in
storage area, all precautions to be taken t prevent
contamination / cross contamination.

Segregate areas for the storage of rejected, recalled or
returned goods.

Safe and secure storage of printed packaging materials.

QC laboratory should be separated form production
areas.

QC laboratory should be separated from production
areas.

Control laboratories should be designed to suit the
operations to be carried out in them. There should be
adequate storage space for samples and records.
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PREMISES AND EQUIPMENTS

PREMISES

Separate rooms to protect sensitive instruments.

Rest and refreshment areas should be separate from
other areas

Facilities for changing cloth, hand /foot wash and
toilets.

Toilets should not directly open to production or storage
areas.

Maintenance workshops should be separate from
production areas.

Animal house must be well isolated form other areas.
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PREMISES AND EQUIPMENTS

EQUIPMENTS

Designed to suit intended purpose and offer easy
cleaning as per written procedure.

Contact parts of the equipment must not be reactive,
additive or absorptive.

Contact parts of the equipments must not be reactive,
additive or absorptive.

Measuring, weighing recording and control equipment
should be calibrated and checked at defined intervals
and record maintained.

Fixed pipe work should be labeled with flow direction.

Water system should be sanitized at defined intervals
as per written procedures.
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PREMISES AND EQUIPMENTS

EQUIPMENTS

Defective equipments should be removed or labeled as
defective.
Continue with CFR
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PART 211
Sub Part D – Equipment
211.63

211.65
a)
b)
211.67
a)
Equipment design, size and Location
All equipment shall be of appropriate design, adequate size & suitably
located.They shall provide ease of maintenance.
Equipment Construction
Material of construction of all equipments shall not be reactive,
additive, absorptive.
Lubricants & Coolants shall not come in contact with the product.
Equipment cleaning & maintenance
Equipment and utensils shall be cleaned, maintained and sanitized at
appropriate intervals.
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PART 211
Sub Part D – Equipment
b)
Written down procedures shall be established for cleaning and
maintenance of the equipment and other utensils used in manufacturing
operations. These procedures shall include, but are not necessarily
limited to,
1) Assigning responsibilities for cleaning.
2) Maintenance and cleaning schedules along with sanitization
schedules.
3) Description of methods, materials to be used to clean equipment.
4) Removal of previous batch identifications if any.
5) Protection of cleaned equipment from contamination.
6) Inspection of equipment and area cleanliness.
c) Record maintenance for cleaning sanitization operations and
schedules.
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PART 211
Sub Part D – Equipment
211.68
Automatic, mechanical and electronic equipment
a) Any automatic, mechanical or electronic instruments used in the
manufacturing process including computers shall be checked and
calibrated at regular intervals and the results documented.
b) Appropriate controls and personnel shall be authorised over computer
related systems to avoid changes in master records and control
records.
211.72 Filters
 Non-Fiber-releasing filters shall be used in filtration processes.
( especially for liquid dosage form manufacturing units)
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PART 211
Sub Part E – Control of Components & Drugs product
Containers and Closures
211.80
a)
b)
c)
d)
General requirements
Written down procedures shall exist for Receipt, Identification,
Storage, Handling, Sampling, testing, approval and rejection of
materials.
Storage of the component containers and closure shall prevent
contamination.
Storage of bagged or boxed containers should suffice cleaning of floor.
Distinctive code number shall be given for separate containers having
different Lot numbers, each lot shall be identified appropriately as to
its status.( Quarantined, approved or rejected).
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PART 211
Sub Part E – Control of Components & Drugs product
Containers and Closures
211.82
a)
b)
211.84
a)
b)
Receipt, Storage of untested components, drug product, containers
and closures.
All received materials shall be physically examined for appropriate
labeling, container damage or broken seals and contamination.
Materials shall be quarantined as per standard procedures till they are
examined and approved.
Testing, approval or rejection of components, drug products,
containers and closures.
Lot shall be withheld in quarantine till the material is approved.
Representative sample of each shipment of each lot shall be collected
for testing and examination.Sampling shall be done as per the standard
procedures( No. of containers to be sampled, amount of material to be
taken etc).
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PART 211
Sub Part E – Control of Components & Drugs product
Containers and Closures
c)
d)
Sampling shall be done as per the standard procedures.
1) Containers of components selected shall be cleaned.
2) Opened containers shall be resealed securely to prevent
contamination.
3) Sterile equipment and aseptic sampling shall be followed where
ever necessary.
4) Containers shall be sampled from top, bottom and middle.
5) Sample containers shall be properly labeled.
6) Containers from which were taken shall be marked.
Samples shall be examined and tested as follows.
1) Atleast one test for identity of each component of drug product,
specific identity tests if any.
2) Each component shall be tested for conformity with written
specifications for purity, strength and quality.
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PART 211
Sub Part E – Control of Components & Drugs product
Containers and Closures
3)
e)
Each component shall be tested for conformity with written
specifications for purity, strength and quality. A certificate of
testing may be obtained from the manufacturer.
4) When appropriate components shall be examined microscopically.
5) Established specifications and storage conditions shall be
followed for those drugs products and their closures which are
prone to contamination by filth and insects.
6) Those container and products prone to microbial contamination
shall be checked with specific microbial tests.
Tests done on the lot if prove the product to be as per specification only
then shall the products be used or else they shall be rejected.
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PART 211
Sub Part E – Control of Components & Drugs product
Containers and Closures
211.86
Use of Approved components, drug product containers and
closures.
 Oldest Approved stock shall be used first. Deviation from this
requirement shall be permitted only if it is appropriate and temporary.
211.87 Retesting of approved components, drug products, containers
and closures.
 Retesting shall be done on the materials as per the appropriate
procedures for their identity, strength, quality and purity. This shall be
done after storage for long periods or after exposure to air, heat or any
other conditions which may adversely effect the drug quality.
211.89 Rejected components, drug product containers and closures.
 A proper identification, control and quarantine system shall exist for
rejected materials.
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PART 211
Sub Part E – Control of Components & Drugs product
Containers and Closures
211.94
a)
b)
c)
d)
Drug product containers and closures.
Drug product containers shall be clean shall provide adequate
protection to and shall remain inert towards the drug.
Drug product containers shall provide adequate protection against
external foreseeable external factors.
Containers shall be clean and they shall be sterilized and
depyrogenated where ever applicable.
Standards or specifications, methods of cleaning and sterilizing etc
shall be followed on the drug product containers where ever
applicable.
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PART 211
Sub Part F – Production and Process Controls
211.100 Written Procedures; Deviations
a) Written down procedures for production and process controls shall
exist to produce a quality product once and always. Any changes in
such procedures shall be drafted, reviewed and approved by
appropriate organizational units.
b) Written procedures shall be followed for all production process and
any deviations shall be recorded and justified.
211.101 Charge – in of Components
 Written procedures for production and process controls shall include
the following.
1) Batch formulation is done with an intent to provide 100 % of the
label claim of the active ingredient.
a) All components for drug product manufacturing shall be weighed,
measured or subdivided appropriately. If components are taken
from new containers they shall be identified with following
information.
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PART 211
Sub Part F – Production and Process Controls
b)
All components for drug product manufacturing shall be weighed,
measured or subdivided appropriately. If components are taken from
new containers they shall be identified with following information.
1) Component name, item code.
2) Receiving or control number.
3) Weight or measure in new container.
4) Batch for which the component was dispensed including the
product name, strength and lot number.
c) Weighing and measuring or subdividing operations for components
shall be adequately supervised.
1) The component was released by the quality control unit.
2) The weight or measure is correct as stated in BPR,
3) Each component shall be added to the batch by one person and
shall be verified by the second.
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PART 211
Sub Part F – Production and Process Controls
211.103 Calculation of Yield
 Actual yield and percentage of theoretical yield shall be calculated
after every operation and recorded.
211.105 Equipment identification
a) All compounding and Storage containers, processing lines other
equipment used in production operation shall be identified properly.
To indicate their contents, phase of processing of batch.
b) A distinctive identification code number shall be assigned to all major
equipment. This helps in precise identification of the specific
equipment used in the manufacturing process while noted in the Batch
Production Record.
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PART 211
Sub Part F – Production and Process Controls
211.110 Sampling and testing of in-process materials and drug products.
a) To assure batch uniformity and integrity of the drug products written
procedures shall be established. Such control procedures of in-process
materials help in monitoring the output and validating the performance
of the processes. Such controls shall include but are not limited to the
following.
1) Tablet or capsule weight.
2) Disintegration time
3) Adequacy of mixing (time)
4) Dissolution time and rate,
5) Clarity, pH of solutions etc.
b) All such inprocess specifications shall be derived from previous
acceptable process average and process variability estimates.
c) In-process materials shall be tested for identity, quality, purity and
strength during the production process, after short or long breaks in
process.
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PART 211
Sub Part F – Production and Process Controls
d)
211.111

211.113
a)
A system shall be followed where in the rejected materials shall be
identified, quarantined and prevented from usage in manufacturing
operations.
Time limitations on Production.
If any time limits are framed for different stages in manufacturing of
the batch, deviation from the time limits shall be recorded and
justified. The deviations are acceptable only if they do not pose
damage to the quality of the drug product.
Control of microbial contamination.
Written procedures designed to prevent objectionable micro organisms
in drug products shall be followed. Such procedures shall be properly
validated.
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PART 211
Sub Part F – Production and Process Controls
211.115 Reprocessing
a) Written procedures shall be established for reprocessing of the batches
to ensure the established standards, specifications and characteristics.
b) Reprocessing shall be performed only with review and approval of
quality control unit.
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PART 211
Sub Part G – Packaging and labeling Controls
211.122 Materials examination and usage criteria
a) Written down procedures shall exist. Labeling and packaging materials
shall be representatively sampled, examined and tested.
b) Only approved labeling and packing materials shall be used.
Unapproved materials shall be rejected.
c) Records shall be maintained of all the received shipments indicating
receipt, examination or testing and whether accepted or rejected.
d) Different product labels shall be stored separately with suitable
identity. Access to the storage area shall be limited.
e) Obsolete and out dated labels and other packaging materials shall be
destroyed.
f) Use of gang printed labeling for different drug products, or different
strengths or net contents of same drug product, is prohibited unless
labeling from gang-printed sheets is adequately differentiated by size,
shape and colour.
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PART 211
Sub Part G – Packaging and labeling Controls
g)
If cut labeling is use packing and labeling operations shall include
following procedures
1) Dedication of labeling and packing lines to each different strength
of each different drug product.
2) Use of electronic equipment to conduct a 100% examination for
correct labeling.
3) Use of visual inspection to check proper labeling, such operations
shall be done by one person and supervised by another.
h) Printing devices and equipment in the manufacturing lines shall be
monitored.
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PART 211
Sub Part G – Packaging and labeling Controls
211.125 Labeling Issuance
a) Strict control shall exist on issuance of labels.
b) Careful examination for identity and conformity to labels specified in
the MFR/ BPRR shall be done.
c) Reconciliation procedures shall exist for quantities of labeling
materials used, returned etc.
d) All excess labels shall be destroyed.
e) Returned labels shall be maintained and stored to prevent mix ups and
provide proper identity.
f) Written controlled procedures for issuance of labeling material shall
exist.
211.130 Packing and labeling Operations
a) Procedures for preventing mix ups and contaminations,
b) Identification and handling of filled drug product containers that are
set aside and held.
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Sub Part G – Packaging and labeling Controls
c)
d)
e)
211.132
a)
211.134
a)
b)
c)
Identification of drug product with lot number or control number.
Examination of packing and labeling materials before using for the
suitability and correctness.
Inspection of the packing and labeling facilities before use to assure
that the area is clean from products of previous batch.
Tamper-Resistant packing requirements for the Over – the –
Counter (OTC) human drugs.
General. The FDA has authority to establish a uniform requirement for
tamper resistant packaging of OTC drug products. Any OTC drug
product that is not packed, or properly labeled is considered to be
adulterated or misbranded.
Drug product inspection.
Packaged and labeled products shall be examined during finishing
operations to provide assurance and correctness of labeling.
Representative sample of units shall be retained.
Results of these examinations shall be recorded in BPR or control
records.
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PART 211
Sub Part G – Packaging and labeling Controls
211.137 Expiration Dating
a) To assure that the drug product meets applicable standards of identity,
quality, strength and purity appropriate stability testing shall be done.
b) Expiration dating shall be related to any storage conditions stated on
the label as determined by stability studies.
c) If the drug product is to be reconstituted expiration dating shall be
given to both un reconstituted drug and reconstituted solution.
d) Expiration dating shall be as per the requirements.
e) Homeopathic drug products shall be exempted from these
requirements.
f) Allergenic extracts that are labeled “no U.S Standard of potency” are
exempted from these requirements.
g) New drug products for investigational use shall be exempted when
they meet appropriate standards and specifications as demonstrated by
stability studies data.
What Does ORANGE GUIDE tell about Production Aspects.
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UK MCA
4.5. PRODUCTION








4.5.1
GENERAL
Production should be performed & supervised by competent people.
Production activities from receipt of materials to packing & distribution
should be done in accordance with written procedures & recorded.
Any damage to raw material containers should be investigated, recorded &
reported.
All incoming materials should be checked to ensure that the consignment
corresponds to the order.
Incoming materials and finished product materials should be quarantined
until release or use for distribution.
Materials & products should be stored as per the manufacturers instruction.
Checks on yields & reconciliation on quantities should be carried out.
Operations on different products should not be carried out simultaneously or
consecutively in the same room, unless there is no risk of mix ups or cross
contamination.
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PRODUCTION






General contd..
At every stage of processing, microbial or other contamination should be
avoided.
Power dust should be contained during processing.
Equipments shall be clearly labeled to indicate the product, strength, stage
batch number etc.
Use different colour labels to indicate status.
If deviation occurs it should be approved in writing by a competent person
with the involvement of QC.
Access to production premises should be restricted to authorised personnel.
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PRODUCTION
4.5.2.
PREVENTION OF CROSS CONTAMINATION IN
PRODUCTION.
 Contamination and cross contamination shall be avoided.
 Using dedicated areas
 Providing air locks
 Avoiding re-circulation of air
 Laying emphasis on clothing & gowning
 Using closed systems of production
 Testing for residues, after cleaning.
4.5.3.
VALIDATION
 Carry out validations in accordance to defined procedures.
 New manufacturing formula should be shown to yield a product
consistently of the required quality
 Amendments to the manufacturing process or change in equipment or
materials should be validated.
 Process & procedures should undergo periodic revalidation.
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PRODUCTION






4.5.4. STARTING MATERIALS
Starting materials should be purchased only from approved vendors.
Containers of starting materials shall be checked for integrity of packing and
seal.
If one material delivery is made up of different batches, each batch must be
considered as separate for sampling, testing and release.
Labels on the containers of the starting materials should indicate
o
Name of product
o
Code number
o Batch number
o
Status
o
Expiry date
o
Retest date
Released starting materials should be used.
Dispensing of the starting materials should only be done designated person as
per written down procedures.
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PRODUCTION


Starting Materials Contd..
Dispensed materials & their weights/volumes should be independently
checked & recorded.
Materials dispensed for each batch shall be kept together and labeled.
4.5.4.



PROCESSING OPERATIONS INTERMEDIATE AND BULK
PRODUCTS
Before starting any processing operations, line clearance must be taken.
Inprocess controls & environmental controls should be carried out &
recorded.
Any significant deviation from the .only be done designated person as per
written down procedures.
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PRODUCTION
4.5.5.
PACKING MATERIALS
Printed packaging materials should be stored in secured condition.
Cut labels and loose printed materials should be transported in separate
close containers.
Only authorised persons should issue the packaging materials.
Each delivery or batch of materials should be given a specific reference
number.
Out dated or obsolete materials should be destroyed & recorded.
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PRODUCTION
4.5.6.
PACKING OPERATIONS
Different products should not be packaged in close proximity unless there is
physical segregation.
Before any packaging operation, line clearance should be taken as per the
check list.
Name & batch number of the product being packed should be displayed at
each packing line.
Containers for filling should be cleaned before filling.
Filling & sealing should be immediately followed by labeling.
Special care should be taken when using cut labels. Roll feed labels are
preferable to cut labels.
In-house printing on packaging materials must be resistant to fading or
erasing.
Online inprocess controls on packing lines are to be carried out.
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PRODUCTION
4.5.6.
PACKING OPERATIONS contd.
Final re-conciliation of the product & printed packaging material should
carried out. Any deviation should be investigated and recorded.
Upon completion of packing operation, unused batch coded printed
packaging materials should be destroyed & recorded.
Documented procedure should be followed if un-coded printed materials are
returned to the stock.
4.5.7.
FINISHED PRODUCTS
Finished products should be held in quarantine until release.
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PRODUCTION
4.5.8.
REJECTED, RECOVERED AND RETURNED MATERIALS
Rejected materials should be stored separately in a restricted area.
Reprocessing of rejected products should only be permitted if the quality of
the final product is not affected. Reprocessing report should be kept.
Addition of recoverable residues into fresh batch of the products should be
authorised & carried out in accordance with a defined procedure.
Returned goods should be destroyed unless there is no doubt that their
quality is satisfactory. The decision lies with QC.
End Session
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PART 211
Sub Part I – Laboratory Controls
211.160
General requirement:
a) The establishment of any specifications, standards, sampling plans,
test procedures or other laboratory control mechanisms required by
this subpart, including any change in specifications, standards,
sampling plans, test procedures or other laboratory controls shall be
drafted by the appropriate organizational unit and reviewed and
approved by the quality control unit. The requirements in this subpart
shall be followed and shall be documented at the time of performance.
Any deviation from the written specifications, standards, sampling
plans, test procedures or other laboratory control mechanisms shall be
recorded and justified.
b) Laboratory controls shall include the establishment of scientifically
sound and appropriate specifications standards, sampling plans and
test procedures designed to assure that the components of the drug
product containers, closures, in-process materials, labeling and drug
products conform to appropriate standards of identity, strength, quality
and purity. Laboratory controls shall include...
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PART 211
Sub Part I – Laboratory Controls
211.160
General requirement:
1) Determination of conformance to appropriate written specifications for
the acceptance of each lot within each shipment of components, drug
product containers, closures and labeling used in the manufacture,
processing, packing or holding of the drug products. Samples shall be
representatives and adequately identified.
2) Determination of conformance to written specifications and a
description of sampling and testing procedures and a description of
sampling and testing procedures for in-process materials. Such
samples shall be representative and properly identified.
3) The calibration of instruments, apparatus, gauges and recording
devices at suitable intervals in accordance with an established written
program containing specific directions, schedules, limits for accuracy
and precision and provisions for remedial action in the event accuracy
and precision limits are not met, instruments, apparatus, gauges and
recording devices not meeting established specifications shall not be
used.
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PART 211
Sub Part I – Laboratory Controls
211.165
Testing & Release for Distribution:
a) For each batch or drug product, there shall be appropriate laboratory
laboratory determination of satisfactory conformance to final
specification for the drug product including identity the identity and
strength of each active ingredient prior to release.
b) There shall be appropriate laboratory testing, as necessary, of each
batch of the drug product required to be free of objectionable
microorganisms.
c) Any sampling and testing plans shall be described in written procedure
that shall include the method of sampling and the number of units per
batch to be tested; such written procedure shall be followed.
d) Acceptance criteria for the sampling and testing conducted by the
quality control unit shall be adequate to assure that the batches of drug
products meet each appropriate specification and appropriate statistical
quality control criteria as a condition for their approval and release.
e) The accuracy, sensitivity, specificity and reproducibility of test
methods employed by the firm shall be established and documented.
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PART 211
Sub Part I – Laboratory Controls
211.166
Stability testing:
a) There shall be a written testing program designed to asses the stability
characteristics of the drug products. The results of such testing shall be
used to determine the storage conditions and expiration dates. The
written program shall be followed and includes.
1. Sample size and test intervals based on statistical criteria for each
attribute examined to assure valid estimate of stability;
2. Storage conditions for samples retained for testing;
3. Reliable, meaningful and specific test methods;
4. Testing of the drug product in the same container closure system
as that in which the drug product is marketed;
5. Testing of the drug products for reconstitution at the time of
dispensing(as directed on the labeling) as well as after they are
reconstituted.
b) An adequate number of batches of each drug shall be tested to
determine an appropriate expiration date and record of such datd shall
be maintained.
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PART 211
Sub Part I – Laboratory Controls
211.166
Stability testing:
b) Accelerated stability studies along with the basic stability data on the
components and the drug products and container closure system may
be used to support tentative expiration dates provided full shelf life
studies are not available and are being conducted. Where the data
from the accelerated studies are used to project a tentative expiration
date that is beyond a date supported by actual shelf life studies, there
must be stability studies conducted, including the drug product testing
at appropriate intervals, until the tentative expiration date is verified or
the appropriate expiration date is determined.
c) For homeopathic drug products, the requirements are as follows.
1. Written assessments of stability data, of the drug product
compatibility with other ingredients shall exist. The data proving
that no degradation of the drug has occurred in normal period of
use shall also be provided.
2. Container-closure system compatibility with the drug and its
stability data shall exist.
3. Allergenic extracts that are labeled :No U.S. standard of potency
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PART 211
Sub Part I – Laboratory Controls
211.167
Special Testing Requirements:
a) Each batch of product purporting to be sterile or pyrogen free
shall have a specific laboratory test procedure and it shall be
documented.
b) Ophthalmic ointments shall have specific documented test
procedures showing their conformance with the foreign particles,
harsh or abrasive substances.
c) For controlled release dosages, written test procedures
determining the rate of release of the drug product shall exist.
211.170
a)
QA APL U – XII
Reserve Samples:
An appropriately identified reserve sample shall be retained that
represents a specific lot. The reserve samples contain at least
twice quantity necessary for all tests required to determine
whether the active ingredient meets its established specifications,
except for sterility and pyrogen testing. The retention time is as
follows:
Training Division
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PART 211
Sub Part I – Laboratory Controls
211.170
1.
Reserve Samples:
For an active ingredient in a drug product other than those
described in paragraphs (a) (2) and (3) of this section, the reserve
samples shall be retained for 1 year after the expiration date of the
last lot of the drug product containing the active ingredient.
2. For an active ingredient in a radioactive drug product, except for
nonradioactive reagent kits, the reserve samples shall be retained
for:
i.
Three months after the expiration date of the last lot of the
drug product containing the active ingredient if the expiration
dating period of the drug product is 30 days or less; or
ii. Six months after the expiration date of the last lot of the drug
product containing the active ingredient if the expiration
dating period of the drug product is more than 30 days.
iii. For an active ingredient in an OTC drug product that is
exempt from bearing an expiration date under 211.137, the
reserve sample shall be retained for 3 years after the
distribution of the last lot of the drug product containing
active ingredient.
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PART 211
Sub Part I – Laboratory Controls
211.170
Reserve Samples:
b) The reserve samples shall be stored under the conditions
consistent with product labeling. The samples shall be stored in
the same container closure system. Reserve samples shall be at
least twice the quantity to perform all the tests. Reserve samples
shall be examined visually at least once a year for evidence of
deterioration unless the visual examination would affect the
integrity of the reserve sample. Any evidence of the deterioration
of the reserve samples shall be recorded and shall be maintained
with other stability data on the drug product. Reserve samples of
compressed gases need not be maintained.
211.173
Laboratory Animals:
Animals used in testing components, inprocess material, or drug
products for compliance with the established specifications shall
be maintained and controlled in a manner that assures their
suitability for their intended use. They shall be identified adequate
records shall be maintained showing the history of their use.
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PART 211
Sub Part I – Laboratory Controls
211.176
QA APL U – XII
Penicillin Contamination:
Lot/ batch
of drug products suspected for penicillin
contamination shall be vigorously tested. Penicillin levels shall be
detected as per the procedures for Detecting and Measuring the
penicillin contamination in drugs.
Training Division
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PART 211
Sub Part J – Records and Reports
211.180 General Requirements:
a) Any production, control or distribution record that is required to be
maintained in compliance with this part and is specifically associated
with a batch of a drug shall be retained for at least 1 year after the
expiration date of the batch.
b) Records shall be maintained for all components, drug product
containers, closures and labeling for at least 1` year after the
expiration date.
c) All records required under this part, or copies of such records shall be
readily available for authorized inspections during the retention period
at the establishment where the activities described in such records
occurred.records that can be immediately retrieved from another
location by computer or other electronic means shall be considered as
meeting the requirements of this paragraph.
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PART 211
Sub Part J – Records and Reports
211.180 General Requirements:
d) Records under this part shall be retained as original records or as true
copies such as photo copies, microfilm etc.
e) Written records required by this part shall be maintained so that the
data can be evaluated at least annually, for determining the quality
standards of the drug product, need for changed in drug product
specifications or manufacturing or control procedures. Written
procedures shall be established and followed for such evaluations and
shall include provisions for:
1) A review of representative number of batches, whether approved
or rejected and where applicable records associated with the
batches.
2) A review of the complaints, recalls, returned or salvaged drug
products and investigations conducted under 211.192 for each
drug product.
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PART 211
Sub Part J – Records and Reports
211.180 General Requirements:
f) Procedures shall be established to assure that the responsible officials
of the firm , if they are not personally involved in or immediately
aware of such actions, are notified in writing of any investigations
conducted under 211.198, 211.204 or 211.208 of these regulations, any
recalls, reports, of inspectional observations issued by the Food and
Drug Administration, or any regulatory actions relating to good
manufacturing practices brought by the Food and Drug
Administration.
211.182 Equipment Cleaning and use log:
A written record of major equipment cleaning, maintenance and use
shall be included in individual equipment logs that show date, time, product
and a lot number of each batch processed. If the equipment is dedicated to the
manufacture of one product, then individual equipment logs are mot required,
provided that lots or batches of such product follow in numerical order and
are manufactured in numerical sequence in case where dedicated equipment
is used, the records of cleaning,maintenance and use shall be part of the batch
record.
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PART 211
Sub Part J – Records and Reports
211.184 Component, drug product container, closure and labeling records:
These records shall include the following:
a) The identity and quantity of each shipment of each lot of
components, drug product containers, closures and labeling; the
name of the supplier; the supplier’s lot number if known; the
receiving cods as specified in 211.80; and the date of receipt. The
name and location of the prime manufacturer, if different from the
supplier, shall be listed if known.
b) The results of any test examination performed(including those
performed as required by 211.82(a), 211.84(d) or 211.122(a) and
the conclusions derived there from.
c) An individual inventory record of each component, drug product
container and closure and for each component, a reconciliation of
the use of each lot of such component. The inventory shall contain
sufficient detail to allow determination of any batch or lot of drug
product associated with the use of each component, drug product
container and closure.
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PART 211
Sub Part J – Records and Reports
211.184 Component, drug product container, closure and labeling records:
d) Documentation of the examination and review of labels and
labeling for conformity with established specifications in accord
with 211.122(c) and 211.130 (c ) .
e) The disposition of rejected components, drug product containers,
closure and labeling.
211.186 Master Production and control records:
a) To assure uniformity from batch to batch, master production and
control records for each drug product, including each batch size
thereof, shall be prepared dated, and signed by one person and
independently checked, dated and signed by a second person. The
preparation of master production and control records shall be
described in a written procedure and such written procedures shall
be followed.
b) Master production and control records shall include:
1) The name and strength of the product and a description of the
dosage form.
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PART 211
Sub Part J – Records and Reports
211.186 Master Production and control records:
1) The name and strength of the product and a description of the
dosage form.
2) The name and weight or measure of each active ingredient per
dosage unit or per unit weight or measure of the drug product,
and a statement of the total weight or measure of any dosage
unit.
3) A complete list of components designated by names or codes
sufficiently specific to indicate any special quality
characteristics.
4) An accurate statement of the weight or measure of each
component, using the same weight system(metric, avoirdupois
or apothecary) for each component. Reasonable variations
may be permitted, however they should be justified.
5) Statement concerning any calculated excess of component.
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PART 211
Sub Part J – Records and Reports
211.186 Master Production and control records:
6) A statement of theoretical weight or measure at appropriate
phases of processing;
7) A statement of theoretical yield, including the maximum and
minimum percentages of theoretical yield beyond which
investigation according to 211.192 is required;
8) A description of the drug product containers, closures and
packaging materials, including specimen copy of each label
and all other labeling signed and dated by the person or
persons responsible for approval of such labeling.
9) Complete manufacturing and control instructions, sampling
and testing procedures, specifications, special notations and
precautions are to be followed.
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PART 211
Sub Part J – Records and Reports
211.188 Batch production and control records:
Each batch of drug product shall have a batch production record. it shall
contain complete information relating to the production and control of the
batch. These records shall include.
a) An accurate reproduction of the appropriate master production record
or control record, checked for accuracy, dated and signed.
b) Documentation that each significant step in the manufacture,
processing, packaging or holding of the batch was accomplished,
including;
1) Dates;
2) Identity of individual major equipment and lines used;
3) Specific instrumentation of each batch of component or in-process
material used.
4) Weights and measures of components used in the course of
processing
5) Inprocess and laboratory control results
areasDivision
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QA APL U –6)XII Labeling and packing
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PART 211
Sub Part J – Records and Reports
211.188 Batch production and control records:
7) A statement of the actual yield and a statement of the percentage of
theoretical yield at appropriate phase of processing.
8) Complete labeling control records, including specimens or copies of
all labels used
9) Description of the drug product containers and closures used.
10) Any sampling performed
11) Identification of the persons performing and directly supervising or
checking significant steps in the operation.
12) Any investigation made according to 211.192
13) Results of the examinations made in accordance with 211.134
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PART 211
Sub Part J – Records and Reports
211.192 Production Record Review:
All drug product production and control records, including those for packing
and labeling, shall be reviewed and approved by the quality control unit to
determine compliance with all established, approved written procedures
before a batch is released or distributed. As unexplained discrepancy or the
failure of a batch or any of its components to meet any of its specifications
shall be thoroughly investigated whether or not the batch has already been
distributed.
211.194 Laboratory Records:
a) Laboratory records shall include complete data derived from all tests
to assure compliance with established specifications and standards,
including examinations and assays. As follows.
1) Description of the sample received for testing with identification
of source, quantity, lot number or other distinctive code, date on
which sample is taken etc.
2) A statement of each method used in the testing of the sample. The
suitability of all testing methods used shall be verified under
of use. Division
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PART 211
Sub Part J – Records and Reports
211.194 Laboratory Records:
3) Statement of the weight or measure of sample used for each test,
where appropriate.
4) Complete record of all data secured in course of each test,
including graphs, charts and spectra, properly identified to show
the specific component, drug product container, closure, inprocess
material etc.
5) Record of all calculations of test, including units of measure,
conversion factors equivalence factors etc.
6) A statement of results, how results are compared with established
standards of identity, strength, quality and purity fot the
component.
7) The initials of the person who performed the test and date.
8) Initials and date of the second person showing that the original
record have been reviewed for accuracy, completeness and
compliance.
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Sub Part J – Records and Reports
211.194 Laboratory Records:
a) Complete records shall be maintained of any modifications of any
modification of an established method employed in testing. Such
records shall include reason for modification.reviewed for accuracy,
completeness and compliance.
b) Records of any testing and standardization shall be maintained. Of
laboratory reference standards, reagents and standard solutions.
c) Records for periodic calibration of laboratory instruments, apparatus,
gauges and recording devices required by 211.160(b)(4)
d) Complete records shall be maintained of all stability testing performed
in accordance with 211.166
211.196 Distribution Records:
Distribution records shall contain name, strength of product and description
of dosage form, name and address of the consignee, date and quantity
shipped, lot number etc.
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PART 211
Sub Part J – Records and Reports
211.198 Complaints files:
a) Written procedures describing handling of all written and oral
complaints regarding the drug product shall be established and
followed. Such provisions shall include provisions for review by the
quality control unit. If the drug product fails to meets the
specifications an investigation shall be carried on as pre procedures.
b) A written record for each compliant shall be maintained in a file
designated for drug product complaints.the complaints record file shall
be filed up along with other manufacturing, packing records and shall
be easily retrievable. They shall be retained Atleast 1 year after
expiration date.
1) Written records shall include following information, wherte
known the name and strength of the drug product, lot number,
name of the complaint, nature of the compliant and reply to
compliant.
2) Where an investigation is conducted the finding of the same and
follow-ups shall be recorded.
3) Where an investigation was not conducted, a written record shall
include the reason that an investigation was found not to be
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Training
name of Division
the responsible person
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PART 211
Sub Part K – Returned and Salvaged Drug Products
211.204 Returned drug products:
Returned drug products shall be identified as such and held. If the different
conditions under which the returned products, casts doubt on the safety,
identity, strength, quality or purity of the drug product, the returned goods
shall be destroyed, unless the examination shall prove that the product meets
the quality requirements. The drug may be reprocessed if it is found to meet
appropriate standards, specifications and characteristics. Records of such
returned drug products shall be maintained.
211.208 Drug product salvaging
drug products subjected to improper storage conditions including extremes in
temperature, humidity, smoke, fumes, pressure or radiations shall not be
salvaged and returned to market place. Salvaging operations may be
conducted only if there is
 Evidence from laboratory tests and assays that the drug products meet
all the applicable standards of identity, strength, quality and purity.
 Evidence from the inspection of the premises that the drug products
and their associated packing materials were not subjected to improper
storage conditions.
What does ORANGE GUIDE tells about Quality Aspects
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QUALITY MANAGEMENT

QUALITY MANAGEMENT

DOCUMENTATION

QUALITY CONTROL


Documentation

Sampling

Testing
CONTRACT MANUFACTURER AND ANALYSIS

Contract Giver

Contract Acceptor
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QUALITY MANAGEMENT


COMPLAINTS AND PRODUCT RECALLS

Complaints

Recalls
SELF INSPECTION
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QUALITY MANAGEMENT

QUALITY MANAGEMENT.
The holder of a manufacturing authorization must
manufacture medicinal products so as to ensure that.

They are fit for their intended use

Comply with the requirements of the marketing
authorization

Products are safe and therapeutically effective
Attainment of quality objective is the responsibility of
“SENIOR MANAGEMENT” and requires participation
and commitment of people at all levels within and
outside.
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QUALITY MANAGEMENT
TO ACHIEVE QUALITY OBJECTIVE
There must be a comprehensively designed and
correctively implemented system of QA, which
should be fully documented and its
effectiveness monitored.
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
DOCUMENTATION

Documentation should be approved, signed and dated
by authorized persons.

Documents should have unambiguous contents.
Purpose should be clearly stated.

Reproduced documents should be clear and legible.

Documents should be regularly reviewed and kept up to
date.

There must be a system to retrieve superseded
documents before issuing revised one. (controlled
concept).

Documents should not be hand written, however data
recording by hand is acceptable if clear and legible
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
DOCUMENTATION

Any alteration, should be signed and dated with reason
for alteration. The alteration should permit the reading
of original information.

Records should be retrained for at least one year after
the expiry of product.

The records should be made or completed at the time,
each action is taken.

Batch records, electrically stored should be protected by
backup support.

There should be approved and dated specifications for
RM / PM / In process / Bulk / Finished products.
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
DOCUMENTATION

Authorized manufacturing formula and processing
instructions should exists for each product and batch
size.

There should be authorized packaging instructions for
each product, pack size and type.

Batch processing record and batch packing records
should be kept for each batch processed / packed.

Line clearance records, wherever required should be
recorded.

There should be written and approved procedure of
each and every activity being carried out in the plant
(SOP’s).
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
DOCUMENTATION


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There should be written procedures and the associated
records for.

Validation

Calibration

Equipment assembly (IQ, OQ)

Maintenance, cleaning and sanitization

Training

Environmental monitoring

Complaints, Recalls, Returns

Pest and Rodent Controls
Machine usage log books should be maintained.
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QUALITY CONTROL
QC department should be independent for
mother departments and under the authority of a
person with appropriate qualifications and
experience.
Should have adequate, experienced and
qualified staff to carry out various activities.
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QUALITY CONTROL

Documentation

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Following shall be readily available with QC.

Specifications

Sampling procedures

Test procedures

Record including analytical work sheets and / or
laboratory note books.

Analytical reports

Environmental monitoring data

Validation records of test methods

Calibration records of instruments

Equipment maintenance records
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QUALITY CONTROL

Documentation

Trend data for analytical test results, yields,
environmental control etc. should be available .

Original data such as laboratory note books should be
retained and readily available.
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QUALITY CONTROL

Sampling

Sampling procedure should include, method of
sampling, equipment to be used, sampling quantity and
instructions for any subdivision of the sample, type of
sample container, special precautions for sterile
materials, storage conditions etc.

Reference samples should be batch representative.

Sample containers should bear label, indicating
materials name, sample data and container number.

Reference samples of finished goods should be
retained up to one year after the expiry data, in their
final pack.
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QUALITY CONTROL


Sampling

Samples of raw materials should be retained for at least
two years after the release of the product.

Reference samples should be of a size sufficient to
permit at least a full reexamination.

Analytical methods should be validated.
Testing

Testing should be carried out accordingly to approved
methods only.

Calculations should be critically examined.

Test performed should be recorded.
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QUALITY CONTROL

Testing

Laboratory reagents, volumetric solutions, reference
standards and culture media should be prepared in
accordance with written procedures.

Standard solutions should be marked with preparation
data, signature of person who prepared it, use before,
storage condition, next standardization date and last
current factor.

Date of receipt of any substances used for testing
operations should be indicated on the container.
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CONTRACT MANUFACTURE AND ANALYSIS
There must be a written contract between contract
giver and contract acceptor, which clearly
establishes the duties of each party.
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CONTRACT MANUFACTURE AND ANALYSIS

Contract Given

Contract giver is responsible for assessing the
competence of the contract acceptor.

Contract giver should provide the contract acceptor with
all the information necessary to carry out the contracted
operations, correctly.

Contract given should ensure that products delivered to
him by contract acceptor comply with specifications and
released by their QP.
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CONTRACT MANUFACTURE AND ANALYSIS

Contract Given

Contract acceptor should not pass to a third party any of
the work entrusted to him under contract.

Contract should specify the responsibilities of both
contract giver and acceptor.

The contract should permit the contract giver to visit the
facilities of the contract acceptor.
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COMPLAINTS AND PRODUCT RECALLS

Complaints

A person should be designed as responsible for
handling complaints.

QP should be made aware of complaint.

There should be a written procedure for handling
complaints or for recalls

Complaints should be thoroughly investigated, involving
QC as well.

If a product defect is discovered, other batches which
may contain reworks of defective batch should also be
investigated.

All decisions and measures taken as a result of
compliant should be recorded and referenced to the
corresponding batch records.
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COMPLAINTS AND PRODUCT RECALLS

Complaints


Complaint records should be reviewed regularly for any
indication of specific or recurring problems, requiring
attention.
Recalls

A person should be designed as responsible for
execution and coordination for recalls and should be
supported by sufficient staff to handle all aspects of
recall with degree of urgency.

There should be a written recall procedure.

Distribution records should be readily available to the
person responsible for recalls
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COMPLAINTS AND PRODUCT RECALLS

Recalls

Address, telephone or fax numbers of all distributors,
whole sellers and directly supplied customers should be
available.

Recalled products should be stored separately in a
secure way.

Progress of recall process should be recorded.

Reconciliation of delivered quantity and recovered
quantity should be done.

Effectiveness of recall producer should be evaluated
from time to time.
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SELF INSPECTION

SELF INSPECTION

Self inspection should be conducted in order to monitor
the implementation and compliance with GMP’s.

Self inspection should be conducted in an independent
way by designated competent persons from within /
outside.

Self inspections should be recorded.
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SAMPLING OF STARTING MATERIALS AND PACKING
MATERIALS

Raw Materials
 Individual samples taken form all containers and
identification test on each sample. It is permissible to
sample only few containers, where a validated
procedure has been established to ensure that no
container has been incorrectly labeled (Vendor
Confidence and History)

Packing Materials
 Company’s own statistical sampling plan
End Session
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