April 2015 | Chemistry Notes Info - Your Chemistry Tutor provide notes for Classes, BSc, MSc, Chemistry Test

cGMP - Current Good Manufacturing Practices

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

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
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