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’ 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)
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
1.Basic rules of GMP.2. Personal hygiene practices.3.Personal hygiene practices.4.Exact cleaning methods/procedures
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”
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.
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.
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
#Documentation Line Clearance
#Change Control On Line Rejection
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 statusstages
=> 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 MachineAreastages
=> 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 MCAREASTAGE
CLEANED TO BE CLEANED MACHINE UNDER MAINTENANCE
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
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
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
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.
• 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.
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.
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.
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 materiallabeling production processproduction 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.
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
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.
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
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”
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 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..
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
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