cGMP
Current
Good Manufacturing Practices
What for us all are here?
To
Make Medicines.
What are Medicines?
Medicines
are those which cures a patient without give any adverse reaction.
A
medicinal product is fit for its purpose only when …………
=> It is the right product ,It
is the right strength ,It is free from
contamination
=> It has no way decorated
‘GONE OFF’ .It is the right container .It is correctly labeled .It is properly
sealed in the container and protected against damage and Contamination.
QUALITY:
‘QUALITY’ IS ONE OF THOSE WORDS THAT MEAN A
LOT OF DIFFERENT THINGS.
SOME
TIMES THE WORD IS USED TO MEAN ‘EXCELLENCE’ ‘GOODNESS’ ON THE OTHER HAND, SOME
PEOPLE SAY THAT A THING IS THE RIGHT WHEN IT MEETS OR COMPLIES WITH
SPECIFICATION.
THEREFORE
QUALITY IS THE KEY ELEMENT OF MEDICINES
Quality
shall build into the product using GMP, which Assures Quality
Total Quality Assurance:
1.Consistent
and safe,2.Product Quality by manufacturing. Defect/Error free Operations 3.Consistent Quality of service to
Customers. 4.Product defect
prevention and continued improvement of technical Operations.5.For Shop floor, Upgrading skill
levels is the prime consideration as . 6.Development tool for individuals.7.Looking at problem from the
perspective of Customers
“A
set of practices followed in every manufacturing related operation to obtain
the product
Of predefined specifications with as close to
zero defect as possible”
“GMP
is continuously upgrading hence cGMP”
Objective of GMP
1.Avoid mix up and cross contamination,2.Produce
drugs/medicines of reproducible quality to predefined specification (Validated
Process)
In Other words GMP is …….
GOOD SCIENCE, COMMON SENSE, A DYNAMIC QUALITY
MANAGEMENT SYSTEM, PHILOSPHY WHAT REGULATORY AUTHORITIES HOPES IS THE BASIS FOR
CONTROL OF OUR PRODUCTS
BASIC RULES OF GMP
1. Be sure you have the
correct written Instructions before start of any job.
2.
Always follow those instructions EXACTLY with no ‘cutting corners’. Ask if
don’t understand, if you can’t ask don’t do.3.Ensure that correct material
being used.4.Ensure that correct cleaned equipment being used.5.Prevent
Contaminations and Mix Up.6.Always guard against labeling error.7.Always work
accurately and precisely 8.Keep things (including yourself) clean and tidy.
9.Always
report mistake error and bad practices immediately (Covering up could cost
lives).10.Make clear, accurate records of what has been done and checks carried
out.
PERSONAL HYGIENE AND ITS IMPORTANCE IN THE GM
Personal
Cleanliness is key for Cleanliness at work and ultimately this leads to
achieving one aspect of GMP.
Word
‘Hygiene’ is of Greek origin. Hygiene is covered with the prophylactic
(preventive) maintenance of health and hence with prevention of disease.
Many
disease, which can also lead to the epidemics are caused by microorganisms.
These words are also derived from Greek and means ‘very small living beings)
Example : Bacteria, Virus, Fungi.
Some Rules for Personal Hygiene
1.In
case of any ill health report to your supervisor immediately, particularly if
you suffering from skin rashes, cough & cold, measles, stomach upset etc.2.Take
bath every day and keep your head clean.3.Keep your hair short.4.Keep your ears
clean.5.Brush your teeth daily..6.Maintain clean Shave.7.Keep you nails short
and clean. Never you nail polish.8.Never use Tilak/Bindi/Vibhuti/Dots on your
forehead.9.Don’t put fingers into nostrils and ears while you are at work.
10.Don’t
attend duties if you are under teh influence of alcohol or any hallucinogenic
drugs or any problem of vision/body movement.11.Wear clean cloths 12.Wear clean
gloves13.Don’t take medicines, food, chew, smoke and drink in production.Keep
personal belongs in change room lockers provided.Wear primary and secondary
dresses as per SOP..Never use bare hand to touch product or secondary PM .Always
wash your hands properly, particularly after visiting toilets and canteen.
MIX-UPS, CONTAMINATION & PREVENTION
Chances
of contamination in production is due to inadequate care taken in day to day
activity……...
Transfer
of Raw Materials from Original Container and re-labeling.Wrong labeling of
dispensed raw materials and Inprocess containers during various manufacturing
stages.Use of same container for different products without cleaning.Use of
same primary packing materials for more than one product of same color.Keeping
same product on same pallet.Non adherence of line clearance procedure during
change over procedure. This results in contamination of one product with other
(Cross contamination)
Things that can contaminate products includes
1.Dust,
Grit, Particles 2.Active chemical substances from other ingredients or teh
product.3.Germs (Bacteria, Virus, fungi)
CONTAMINATION
What
is contamination?
“Any
substance, which can spoil product by physical or chemical means”
Contamination
happens through…….
People
: 80% of contamination is due to people
Microorganisms:
Bacteria, Virus and fungi
Chemicals:
Active materials, sanitization agents, cleaning agents etc.
PREVENTION OF CONTAMINATION
By
following
1.Basic
rules of GMP.2. Personal hygiene practices.3.Personal hygiene practices.4.Exact
cleaning methods/procedures
CROSS CONTAMINATION
The
sort of contamination which comes from other products and materials is called
“Cross Contamination”. It can be very dangerous to patients, and must not be
allowed to happen
Example:
Beta Lactam Antibiotics
Water
is another source of contamination in two ways. Ordinary tap water has a number
of things dissolved in it (salts).But more important, stagnant water if just
left around on the
floors or surfaces, or in vessels, it is a
great thing for microbes to grow.
We
have millions of microbes on and in us .That is why we are given protective
factory clothing, including headwear (Cap). Its main purpose is not to protect
us but to protect products from us. An avg human body sheds 5gms of flakes per
day.
It
is important that it is worn properly.
It
is very dangerous for people to take food, drink,Cigarettes, Tobacco, own
personal medicines into any production area. All these items could contaminate
a product, therefore they are“BANNED
ITEMS”
CROSS CONTAMINATION
Preventions:
Product
containment in the fully closed system Multilevel concept Usage of large
technical floors rooms or corridors Minimum size of production area Automated
transportation of goods Extensive use of CIP/SIP .Fully automated warehouse Fully
computer integration Online analytical testing. Separation: Usage of dedicated
facility and equipment. Creation of Box in Box type facility. Product
containment in close systems during all major production steps. Rooms for
materials and personnel transition. Local sucking and conditioning of air Separate
Air Conditioning for each production room. Pressure cascade inside the
production. Periodic health checks Parallel production of similar product shall
be avoided. Cleaning, decontamination and disinfections following written and
validated procedures. Cleaning and washing of Gowning after each production
campaign. Additional gowning inside critical area. Labeling : For status,
identity, cleanliness etc.
As
we learned 80% of the cross contamination is from the human involved in the
production and proper gowning at work is answer to this.
CROSS CONTAMINATION
Why Gowning?
We
shed thousands of millions of dead cells & fragments per day. This amounts
to a total weight of somewhere between 5 to 15 gm per say of tiny bits and
pieces which fall of us
The
more we move and more vigorously that we move, the greater the shedding
becomes. We shed 3 to 4 times more particles when we move about than we are at
rest. A Human being sheds something like 1000 bacteria carrying particles per
minute.
CROSS CONTAMINATION
Some Codes for Gowning
Gowning
shall be done as per SOP Always check yourself for correct gowning Do not allow
others to deviate from the gowning procedure. Always tuck the hands of the gown
inside the gloves Always tuck the Head Gear inside the gown (Particularly
inside the core area) Head gears are meant for covering of Nose,
Ears, head and Neck. (only eye portions is allowed to uncovered). Only fresh gowns
shall be used inside the production area. Gowning shall be done at designated
area only. De Gowning shall be done properly and used gowns shall stored
properly to send it for cleaning/washing. Do not touch product without hand
gloves .Gloves shall be protected as good as product.
“Apply
common sense for gowning”
“Tomorrow’s
illiterate will not be the man who can not read; he will be the man who has not
learned how to learn”
Guide lines for GMP
# Labeling SMR
#Deviation MRN
#SOP OOS
#Documentation Line Clearance
#Change Control On Line Rejection
#Non Conformance
LABELING
Most
important step is labeling. All containers and materials have to be labeled for
its
identification,
in order to avoid mix up’s and contamination..
Important
parts of a label:
DOSAGES-As
Directed By the physicianM.L.NO: xxxxxxxxxxxxxxxxxXName of the
manufacture-XXXXXXXXXXxMARKETED BY –XXXxXXXXXXXXXXBATCH NO-MFG. Date-EXP.
Date-PRICE-MRP Not to exceed
IMPORTANTANCE OF LABELING
=> For easy identification
\retrieval of product\ batch\ lot\ status\stages
=> One of the control to avoid
contamination and mix up
=> Labelling is one of the
most important measures in pharma
industry
TYPES OF LABELS
=> Labels to express the
status of the material
=> Labels to
express the status of the Machine\Area\stages
=> Labels specific to the
requirement
LABELS TO EXPRESS THE STATUS OF THE MATERIAL
UNDER
TEST APPROVED REJECTED DISPENSING LABEL STATUS LABEL
LABELS TO EXPRESS THE STATUS OF THE M\C\AREA\STAGE
CLEANED
TO BE CLEANED MACHINE UNDER MAINTENANCE
LABEL IDENTITY
Approved
materials and cleaned labels will be in green colour. Ex. Approved, Cleaned
Labels Material whose disposition not known\ under analysis will be given in
yellow/orange colour labels Ex. Under
test All materials not fit for use will be identified with RED color labels.
Ex. Rejected, Online rejection.
RULES OF LABELING
Labels
shall be written in the legible form Correct details to be written on the label
with out any strikeouts Correct label to be pasted to the correct container /
machine / Area. Correct label to be used, to suit the requirement. Filled label
should be pasted immediately Never stick a new label over an old one unless the
one underneath has been very obviously defaced Labels used during the
manufacturing & packing shall be retained and stored along with BMR .Filled
labels should not be left lose on the lid or container Labels shall be stored
securely .Old labels shall be destroyed immediately by tearing into two pieces
and all empty container shall have either “To Be Cleaned” or “Cleaned” Label
Unused
area/machine shall have only “To Be Cleaned” or “Cleaned” Label
DEVIATION
Any
temporary alteration from existing procedures/ practices / established
standards /equipment is DEVIATION. It cannot be raised for any change against
statutory/pharmacopoeia requirement or if it
affects product quality.
Initiator
proposes this in Deviation Form and forwards this to QA for comments and then forwarded
to Department Head for checking and corrective action and finally QA head shall
Approved .A copy of the same shall attached to BMR/BPR
A
copy of the same shall be filed with QA
OBJECTIVE:
1. Planned
alteration or replacement of an established standard.
2 Un planned or accidental deviation due to non
conformance of a specified requirement from quality view point.
Reason for unplanned Deviation:
Training
programs not followed .Lack of documentation
Written
down procedure not followed
STANDARD OPERATING PROCEDURE
Every
work should be carried out according to standard operating procedure.
No
one should be allowed to deviate SOP in any condition
SOP
should be reviewed from time to time according to the need of the system
Before
following any SOP this should be approved by appropriate person \team of person
CONTENTS OF SOP
Name
of the facility: Name of the companyPage No.: - Running page number followed by
total no of pagesSOP NO-A unique number consists of 8 characters broken down as
follows
Ex-xxxxxxxxxx,
where,
x- xxxxxxx x- xxxxxxxxx
x- xxxxxx x-xxxxxxxxx
x– xxxxxx. x- xxxxxxxxx
Title
– Heading of SOP .Revision Number – No. of revisions done Written by – Sign and
date of person who prepares SOP .Approved by - Sign and date of person who
edits the SOP.Authorization signature - Sign and date of person who authorizes
SOP.Department – The department to which SOP belongs.Date – Date on which SOP
is written.Effective date – Date from which SOP is effective.
TITLE
: Name of the SOP;Department: To which department it belongs
Area
: Area where it shall be displayed or kept SOP NO : Unique Numbering telling
how many times it has revised. Page
No: Number of the page of SOP telling total number of pages of the
SOP.Effective Date: Date form which it is effective.Review Date : Due date for
review.OBJECTIVE : What for SOP is ? SCOPE : Tells where this SOP is
applicable. RESPONSIBILITY : Tells who has to follow the SOP. ACCOUNTABILITY : Generally Department Head .PROCEDURE
: Step wise instructions to perform the activity. REVISION HISTORY: Gives
Reasons for revisions.
WHAT IS DOCUMENTATION
n Documentation is an
important part of GMP
It is
recording of an activity carried out as
per the written down instructions.
It
is an evidence of the activities carried out
REASON FOR DOCUMENTATION
1.To
be clear about what we are going to do.
n 2.To confirm what we have
it and done is correctly.
n 3.To keep record of what we
have done.
n 4.To enable us to
investigate complaints.
n 5.It is a regulatory
requirnment.
n 6.To help us to decide on ,
and take any necessary corrections.
DIFFERENT TYPE OF DOCUMENTS
n SMF-SITE MASTER FILE
n BMR-BATCH MANUFACTURING
RECORD
n BPR- BATCH PACKING RECORD
n SMR- SUPLIMENTARY MATERIAL
REQUISITION
n MWO –MANUFACTURING WORK
ORDER
n PMWO- PACKING MATERIAL WORK
ORDER
n GRN- GOODS RECEIPT NOTE
n STP- STANDARD TEST PROCEDURE
DIFFERENT TYPE OF DOCUMENTS
n CALIBRATION RECORD
n ENVIRONMENT CONDITION CARD
n EQUIPMENT LOG CARD
HOW TO RECORD
n Entries to be made on line
n Use only Black pen to make for entries
n Do not over write .
n Do not make illegible
corrections
n Correction by striking it
by one line.
n Put initial and date on
corrections
GOLDEN RULE FOR DOCUMENTATOION
n IF IT IS NOT WRITTEN IT IS
NOT FOLLOWED)
n “ RECORD ON LINE”
BATCH MANUFACTURING/PACKING RECORD
BMR/BPR
is prepared and issued by QA. Any changes to be made in.the BMR, it has to be
approved QA department by change control.
IMPORTANCE:
•
It
is an important part of Documentation
•
It
reveals the history of a batch
•
It
helps in investigating market complaints
•
It
is statutory requirement
•
It
provides formula of a product
•
It
provides method to be followed to produce the product.
•
It
provides self life of the product.
•
It
answers schedule ‘U’ requirement of FDA.
Contents of BMR & BPR
•
Manufacturing
and Packing Process Order
•
Manufacturing
and Packing Work Order.
•
Instruction
for Manufacturing, Washing, Filling, Sealing and Packing.
•
Manufacturing
and packing yield
•
MR,
MRN, LRN, Deviations, Release Reports, PGTN, QA
release certificate etc.
•
Reconciliation
of Primary and secondary Packing materials.
•
Destruction
details of Raw, primary and secondary materials.
Documentation review
n All the document are subjected at review for regular intervals
n Eg SOP- 3 years
n After review and Approval
from Quality Assurance Head, document shall be issued for actual usage byQA.
DOCUMENT STORAGE
n Batch document should be
stored till the expiry date of that product plus one year
n Eg- xxxxxxxxxx- 4 years(3years+1years)
n Reason for storage:
n To investigate the market
complaints even after expiry.
CHANGE CONTROL
n It is a procedure for the
review and approval of any planned permanent alteration or replacement from the
existing procedure\ practices\ established standard\ equipment
Eg-Change
in the Raw material\ packing material\labeling\ production process\production
equipment\ key operation document\ specification\ test methods
TYPES OF CHANGE CONTROL
n Critical -All changes which
will effect the registration materials like registration application, Drug master file, product specification etc
n Major -All changes which
will not affect the registration
n Minor -All changes which
will effect updating of operational documents or apparatus or equipment.
NON CONFORMANCE
n Raw material \finished
product conforming to the regulatory specifications but does not conform to the
in house specification
n Eg-Assay, pH etc
n Non –critical defects in
packing Materials, which does not affect finished production quality
n Eg- shade variation, GSM
variation of the carton or foils
LRN
It is online rejection note.
It shall be generated by the user
department concern supervisor/executive. On
approval and authorization from the
Department Head and QA respectively material
shall be return to the Stores and on
copy of the same shall be filed in the BPR.
SMR
n It is supplementary
material requisition
n By any cause the dispensed
material is not sufficient, production dept will raise the additional material
requisition authorized by Production Head and approved by QA
n It is made in duplicate and
one copy is attached to the BMR
MRN
It
is Material Return Note. By any cause the dispensed material is remaining that
is sent back to the stores department and the same has to be intimated to QA.
It
is made in duplicate and one copy is attached to BMR
LINE CLEARANCE PROCEDURES...
The
object of these is to help prevent contamination or mix-up risks arising from
“left-overs”
E.g.:
Product
Materials
Labels from a previous batch.
Even
worse, hazards can occur due to labels and other printed packaging materials
left on the line, in label dispensers etc.,
To
guard against these before any packaging operation begins, checks should be
made to ensure that the work area, line
and equipment are clean(really CLEAN) and clear of any product, product
residues, materials, label or documents “left-over”, or not required for the
packaging run about to begin.
This
should not be a casual “once-over” but a thorough and specific check
carried-out in accordance with written instructions, item by item.
These
Line Clearance Checks should be carried-out by people authorized and instructed
to do so, who should record on the
written instruction (with signature or initials) that each item has, in fact,
been checked and recorded in Batch Record
OOS
OOS
means Out of Specification.
This
arises when any material / Product does
not comply with specification both In House and statutory. In this case the
material / product has to be rejected / discarded after proper investigation
and finalization..
ABBREVIATIONS
AHU : Air
handling unit
BP : British
Pharmacopoeia
HVAC: Heating Ventilation air Conditioning
CFR
: Code
of Federal Records
IP : Indian
Pharmacopoeia
FDA : Food
and Drug Administration
GLP : Good
laboratory Practices
IQ : Installation
Qualification
OQ : Operational
Qualification
PQ : Performance
Qualification
DMF : Drug
Master file
FOI : Freedom
of Information.
FIFO : First
in First Out
EDMA: European Diagnostic Manufacturers
Association
FBD : Fluid
Bed Dryer
HIMA: Health Industry manufactures Association
ISO
: International
Organization for for Standards
JP : Pharmacopoeia
of Japan
MHRA: Medicines Health Regulatory Agency
MCC : Medicines
Control Council (S Africa)
NF : National
formulary
MHW: Ministry of health and Welfare
TGA : Therapeutic
Goods Administration (Australia)
USP : United
States Pharmacopoeia
WHO : World
Health Organization
QA : Quality
Assurance
QC : Quality
Control
CIP : Cleaning
in Place
SIP : Sanitization/Sterilization
in Place
EU : European
Union
ICH : International
council for Harmonization
EPE : Expanded Poly Ethylene
EPE : Expanded Poly Ethylene
EPS : Expanded
Poly Urethane
PUP : Poly
Urethane Foam
OSHA: Environmental Safety & Health
Association
EPA : Environmental
Protection Agency
DOP : Di
Octyl Phthalate
BOPP: Bioxylic Poly Propylene
ROPP: Roll On Pilfer Proof
USES: United States Federal Standards
ASTM: American Standards for Material
Testing
BSC : Biological
Safety Cabinet
PET : Poly
Ethylene Terapthalate.
PVDC: Poly Vinylidine Choride