GOOD MANUFACTURING PRACTICE (GMP)

GOOD
MANUFACTURING PRACTICE

CONTENTS

Current GMP in manufacturing processes 

Packaging and holding of drugs

Finished pharmaceuticals 

General provisions 

Organization and personnel 

Building and facilities 

Equipment

Control of components

Containers and closures 

Production and process control 

Packaging and labeling control 

Holding and distribution 

Records and reports

Returned savaged drug products

The inspection for compliance with GMP regulations 

Controlled substances safeguards

References

What is GMP?

(Good Manufacturing Practices)

•       GMP
is that part of Quality assurance which ensures 
that the products are consistently manufactured and  controlled to the Quality standards
appropriate to  their intended use

•       A
set of principles and procedures which, when followed by manufacturers for
therapeutic goods, helps ensure that the products manufacture will have the
required quality.

•       A
basic tenet of GMP is that quality cannot be tested into a batch of product but
must be built into each batch of product during all stages of the manufacturing
process.

•       It
is designed to minimize the risks involved in any pharmaceutical production
that cannot be eliminated through testing the final product.

Some of the main risks are

–      Unexpected
contamination of products, causing damage to health or even death.

–      Incorrect
labels on containers, which could mean that patients receive the wrong
medicine.

–      Insufficient
or too much active ingredient, resulting in ineffective treatment or adverse
effects.

Why GMP is important

•      
A poor  quality  medicine
may contain toxic substances that have been unintentionally
added.

•       A
medicine that contains little or none of the claimed ingredient will not have
the intended therapeutic effect.

GMP

QA, GMP & QC inter-relationship

QA

It is the sum total of the organized arrangements with the
objective of ensuring that products will be of the quality required for their
intended use

GMP

GMP is that part of Quality Assurance aimed at ensuring that
products are consistently manufactured to a quality appropriate to their
intended use

QC and QA

QC is that part of GMP which is concerned with sampling, specifications,
testing and within the organization, documentation and release procedures which
ensure that the necessary and relevant tests are carried out

•       QA
is the sum total of organized arrangements made with the object of ensuring
that product will be of the Quality required by their intended use.

•       Operational
laboratory techniques and activities used to fulfill the requirement of Quality

•       All
those planned or systematic actions necessary to provide adequate confidence that
a product will  satisfy the
requirements  for quality

•       QC
is lab based

•       QA
is company based

GMP

•       The
Quality of a formulation or a bulk drug 
depends on the Quality of those producing it

•       GMP
is the magic key that opens the door of 
the Quality

•       In
matter of GMP, swim with the current and in matter
of Quality stand like a rock!

GMP helps boost pharmaceutical export opportunities

•       Most
countries will only accept import and sale of medicines that have been manufactured
to internationally recognized GMP.

•       Governments
seeking to promote their countries export of pharmaceuticals can do so by
making GMP mandatory for all pharmaceutical production and by training their
inspectors in GMP requirements.

GMP Covers…

•       All
aspects of production; from the starting materials, premises and equipment to
the training and personal hygiene of staff.

•       Detailed,
written procedures are essential for each process that could affect the quality
of the finished product.

•       There
must be systems to provide documented proof that correct procedures are
consistently followed at each step in the manufacturing process – every time a
product is made.

GMP guidelines

•       GMP
as per Schedule “M”

•       GMP
as per WHO

•       GMP
as per MCA now known as MHRA

•       GMP
as per TGA

•       GMP
as per US FDA

•       GMP
as per ICH guidelines

•       WHO:
World Health Organization

•       MHRA:
Ministry of Health and Regulatory Affairs 
TGA: Therapeutic Goods Affairs

•       FDA:
Food And Drug Administration

•       ICH:
International Conference on Harmonization

•       GMP
as per Schedule “M”

•       www.cdsco.nic.in  GMP as per WHO  www.who.int

•       GMP
as per MCA now known as MHRA

•       www.mca.gov.uk  GMP as per TGA  www.tga.gov.au
 GMP as per US FDA  www.fda.gov

•       GMP
as per ICH guidelines

•       www.ich.org

GMP

•       GMP
in solid dosage forms

•       GMP
in semisolid dosage forms

•       GMP
in Liquid orals

•       GMP
in Parenterals Production

•       GMP
in Ayurvedic medicines

•       GMP
in Bio technological products

•       GMP
in Nutraceuticals and cosmeceuticals

Ten Principles of GMP

1. Design
   and construct the facilities and equipments  properly
2. Follow
   written procedures and Instructions
3. Document
   work
4. Validate
   work
5. Monitor
   facilities and equipment
6. Write  step by step operating procedures and
   work on  instructions
7. Design
   ,develop and demonstrate job competence
8. Protect
   against contamination
9. Control
   components and product related processes
10. Conduct
    planned and periodic audits

List of important documents in GMP

•       Policies

•       SOP
(Standard Operating Procedure)

•       Specifications

•       MFR
(Master Formula Record)

•       BMR
(Batch Manufacturing Record)

•       Manuals

•       Master
plans/ files

•       Validation
protocols

•       Forms
and Formats

•       Records

10 attributes of a good document

1. Accurate
2. Clear
3. Complete
4. Consistent
5. Indelible
6. Legible
7. Timely
8. Direct
9. Authentic
10. Authorized

API Manufacturing Process

Secondary Manufacturing Dosage Forms

Secondary Manufacturing Process – Tablets

Secondary Manufacturing Process – Sterile parenteral for
injection

Biotechnology Manufacturing Process

What are cGMPs?

•       cGMP
refers to the Current Good Manufacturing 
Practice regulations enforced by the US Food and  Drug Administration (FDA).

•       cGMP
provide for systems that assure proper design, 
monitoring and control of manufacturing processes  and facilities.

•       Adherence
to the cGMP regulations assures the 
identity, strength, quality and purity of drug products  by requiring that manufacturers of
medications  adequately control
manufacturing operations

Why are cGMP so important?

•       A
consumer usually cannot detect (through smell, touch, or sight) that a drug
product is safe or if it will work.

•       While
cGMPs require testing, testing alone is not adequate to ensure quality.

•       In
most instances testing is done on a small sample of a batch (for example, a
drug manufacturer may test 1000 tablets from a batch that contains 2 million
tablets), so that most of the batch can be used for patients rather than
destroyed by testing.

Packaging

Primary packaging is the packaging used to form a container for product and which is in
direct contact with the product.

Eg. Sterile vials,
medicine bottle, tablet blisters pack.

Secondary Packaging
is any subsequent packaging which helps to inform about, display and product. It
include all required labeling and information leaflets.

Tertiary Packaging
is any final packaging grouping the products for storage and transportation.

Packaging and holding of drugs

•       Care
shall be taken when using automatic tablet and capsule counting, strip and blister
packaging equipment to ensure that all ‘rogue’ tablets, capsules or foils from packaging
operation are removed before a new packaging operation is commenced.

•       There
shall be an independent recorded check of the equipment before a new batch of tablets
or capsules is handled.

Finished pharmaceuticals

Appropriate specifications for finished products shall
include: –

•       The
designated name of the product and the code reference.

•       The
formula or a reference to the formula and the pharmacopoeial reference.

•       Directions
for sampling and testing or a reference to procedures.

General provisions

•       The
processing of dry materials and products creates problems of dust control and
cross- contamination. Special attention is therefore, needed in the design,
maintenance and use of premises and equipment in order to overcome these problems.
Wherever required, enclosed dust control manufacturing systems shall be
employed.

Organization and personnel

1. Responsibilities
   of quality control unit.
2. Personnel
   qualifications.
3. Personnel
   responsibilities.
4. Consultants.

Building and facilities

1. Design
   and construction features.
2. Lighting.
3. Ventilation,
   air filtration, air heating and cooling.
4. Plumbing.
5. Sewage
   and refuse.
6. Washing
   and toilet facilities.
7. Sanitation.
8. Maintenance.

Equipment

1. Equipment
   design, size, and location.
2. Equipment
   construction.
3. Equipment
   cleaning and maintenance.
4. Automatic,
   mechanical, and electronic equipment.
5. Filters.

Control of components

1. General
   requirements.
2. Receipt
   & storage of untested components, drug product containers and
   closures.
3. Testing
   and approval or rejection of components, drug product containers and
   closures.
4. Use
   of approved components, drug product containers, and closures.
5. Retesting
   of approved components, drug product containers, and closures.
6. Rejected
   components, drug product containers, and closures.
7. Drug
   product containers and closures.

Containers and closures

•       All
containers and closures intended for use shall comply with the pharmacopoeial
requirements.  Suitable validated test
methods, sample sizes, specifications, cleaning procedure and sterilization procedure,
wherever indicated, shall be strictly followed to ensure that these are not
reactive, additive, absorptive, or leach to an extent that significantly
affects the quality or purity of the drug. No second hand or used containers and
closures shall be used.

Production and process control

1. Written
   procedures; deviations.
2. Charge-in
   of components.
3. Calculation
   of yield.
4. Equipment
   identification.
5. Sampling
   and testing of in-process materials and drug products.
6. Time
   limitations on production.
7. Control
   of microbiological contamination.
8. Reprocessing.

Packaging and labeling control

1. Materials
   examination and usage criteria.
2. Labeling
   issuance.
3. Packaging
   and labeling operations.
4. Tamper-evident
   packaging requirements for over-the-counter (OTC) human drug products.
5. Drug
   product inspection.
6. Expiration
   dating.

Holding and distribution

1. Warehousing
   procedures.
2. Distribution
   procedures.
3. Prior
   to distribution or dispatch of given batch of a drug, it  shall be ensure that the batch has been
   duly tested, approved  and released
   by the quality control personnel. Pre-dispatch inspection shall be
   performed on each consignment on a random basis to ensure that only the
   correct goods are dispatched. Detailed instructions for warehousing and stocking
   of Large Volume Parenterals, if stocked, shall be in existence and shall
   be complied with after the batch is released for distribution. Periodic
   audits of warehousing practices followed at distribution centers shall be
   carried out and records thereof shall be maintained. Standard Operating
   Procedures shall be developed for warehousing of products.

Records and reports

1. General
   requirements.
2. Equipment
   cleaning and use log.
3. Component,
   drug product container, closure, and labeling records.
4. Master
   production and control records.
5. Batch
   production and control records.
6. Production
   record review.
7. Laboratory
   records.
8. Distribution
   records.
9. Complaint
   files.

Returned savaged drug products

1. Returned
   drug products.
2. Drug
   product salvaging.
3. Adequate
   areas shall be designed to allow sufficient and orderly warehousing of returned
   or recalled products.
4. Segregation
   shall be provided for the storage of rejected, recalled or returned
   materials or products.

The inspection for compliance with GMP regulations

•       Short
description of the self-inspection system indicating whether an outside, independent
and experienced external export was involved in evaluating the manufacturer’s compliance
with Good manufacturing Practices in all aspects of production.

•       Periodic
inspection of the garments shall be done by responsible staff.

Controlled substances safeguards

•       Hazardous,
toxic substances and flammable materials shall be stored in suitably designed
and segregated, enclosed areas in conformity with Central and State
Legislations.

•       Highly
hazardous, poisonous and explosive materials such as narcotics, psychotropic
drugs and substances presenting potential risks of abuse, fire or explosion
shall be stored in safe and secure areas. Adequate fire protection measures
shall be provided in conformity with the rules of the concerned civic
authority.

References

•       EU
Good Manufacturing Practice (GMP) 
Guidelines, Volume 4 of “The rules governing  medicinal products in the European Union”

•      
US FDA current Good Manufacturing Practice (cGMP)
for finished pharmaceuticals, 21 CFR, 210 and 211

•      
WHO Good Manufacturing Practices for  pharmaceutical products, Annex 4 to WHO  Technical Report Series, No. 908, 2003