Seminar on…

GMP, Quality Assurance,

Documentation.

Presented by:
Mr. Kailash Vilegave
Shivajirao S. Jondhle
college of Pharmacy
Asangaon
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 Contents

 Good Manufacturing Practices.

 Basic rules of GMP
 Various aspects of GMP.
 How do GMP change.
 Comparison of GMP.
 Quality assurance
 Principles of QA
 Functions of QA department.
 Documentation
 Importance of documentation of records
 Important areas of documentation
 Components of documentation
 References.
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 Good Manufacturing Practices

• "GMP" - A set of principles and procedures which, when followed by

manufacturers of therapeutic goods, helps ensure that the products
manufactured will have the required quality.

• Usually see “cGMP” – where c = current, to emphasize that the

expectations are dynamic

• 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.

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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.
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• For e.g.

• USA - 1937 Sulphanilamide Elixir

• Used Diethylene Glycol to suspend drug
• 107 deaths due to renal failure – mostly children
• Manufacturer fined $26 000
• Led to Food, Drug and Cosmetic Act 1938

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 Ten Basic Rules of GMP

• Be sure that the written instructions before any job is started.

• Always guard against labeling errors.
• Always follows those instructions EXACTLY with no “cutting
corners”
• Ensure that the correct material being used.
• Ensure that the correct equipment being used, & that is CLEAN.
• Prevent contamination & mix up.
• Always work accurately & precisely.
• Keep thing (including personnel) clean & tidy.
• Always be on the look out for mistakes errors and bad practices &
report them immediately.
• Make clear, accurate records of what has been done & the checks
carried out.
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 Various Aspects of GMP

 Personnel

 Buildings and facilities

 Raw materials

 Equipment and utensils

 Storage

 Waste disposal.

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 Personnel

• Personnel Qualification:
Persons should be qualified with appropriate education.
Responsibilities must be specified in writing.
Training should be conducted by qualified person.

• Personnel Hygiene.
Should practice good sanitation and health habits.
Should wear clean clothing suitable for manufacturing activity.
Must avoid direct contact with intermediates or active ingredients.
Smoking, eating, drinking, chewing and storage of food must be
restricted.
Personnel suffering from infections or any disease should not
engaged in activities.
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 Building and Facilities

• Design and Construction

Must be located, design and constructed to facilitate cleaning,

maintenance and operations as appropriate to the type & stage of
manufacture.
Adequate space for equipment & materials.
Premises must be well drained.
Flow of materials & personnel should be such that it avoids
contamination.
Adequate cleaning, washing & toilet facilities.
Laboratory areas or operation areas must be separate from production
areas.

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• Utilities
• All utilities must be qualified and appropriately monitored.
• Adequate ventilation, air filtration & exhaust system must be
provided.
• If air is re-circulated to production areas measures must be taken.
• Permanently installed pipe work must be appropriately identified.
• Drains must be of adequate size & must be provided with an air
break.

 Lighting:
• Adequate lighting must be provided in all areas.
• The fitting of lighting should be done inside the walls to avoid the
corner and crevices for microbial contamination
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 Containment:
• Means dedicated production areas, employed in the production of
highly sensitizing materials like: steroid, penicillin's, and cytotoxic
anticancer drugs etc.
• This must requires special production area, special equipments and
special storage area than the other APIs area to avoid contamination
and toxicity.

 Sewage and Refuse

 Sanitation and Maintenance

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 Raw Materials

• Responsible person should keep an inventory of raw materials &

maintain records as per schedule-U

• Schedule-U:
Records of each raw materials shall be maintained
indicating the date of receipt, number, name and address of
manufacture/supplier, batch no. quantity received, pack size, date of
manufacturing & expiry, if any.

• General Controls :
• Written procedures for receipt, identification, quarantine, handling.
• Manufacturers must have system for evaluating the suppliers of
critical materials.

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• Receipt and Quarantine.

 Visual inspection for labeling, container damage, broken seals.

 Before incoming materials are mixed with existing stocks, they

should be identified as correct, tested, if appropriate, & released.

 If bulk deliveries are made in non-dedicated tankers, there should be

assurance of cross contamination from tankers.

 Each container of material should be assigned and identified with a

distinctive code, batch, or receipt number.
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• Sampling and Testing:

At least one test to verify the identity of each batch of material.

Sample should be representative of the batch of material from which

they are taken

Sampling should be conducted at defined locations and by

procedures.

Container should be opened and closed carefully for sampling & they
are marked to indicate that sample has been taken.

Organisation of raw material is like that first in first out. 14

 Equipment and Utensils

• Design and Construction:

Must be constructed so that surface that contact raw material,

intermediates or active ingredients do not alter quality.
Should only be used within its qualified operating range.
Major equipments and permanently installed processing lines must be
appropriately identified.
Any substances associated with the operation of the equipment, such
as lubricants, heating fluids or coolants, should not contact
intermediates or active ingredients.
A set of current drawings must be maintained for equipments and
critical installations.

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• Equipment Maintenance and Cleaning.

Schedules and procedures must be established.

Non dedicated equipments must be cleaned between productions of
different materials.
Continuous production- cleaned at appropriate intervals.

• Calibration:

Control, weighing, measuring, monitoring and test equipment must

be calibrated according to written procedures.
Records of these calibrations are maintained.
Equipment that do not meet calibration must not be used
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 Storage

• To insure stability of a pharmaceutical preparation for a period of its

intended shelf life, the label should contain desired conditions of
storage.

Storage Specifications Temperature

Cold Not to exceed 80c
Freezer -100C to –200C
Cool 80C to 150C
Room temp. 150c to 300c
Warm 300c to 400c
Excessive heat Above 400c
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• Ware Housing Procedure:

Records of store items should contain following data.

Name of the material and manufacturer.
Quantity and strength of material.
Batch number and control number.
Date of manufacture and expiry.
Method of dispense and
Special precautions as per necessary.

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 Waste Disposal

• Pharmaceuticals that should never be used and should always

be considered as pharmaceutical waste are:

All expired pharmaceuticals

All unsealed syrups or eye drops (expired or unexpired)
All cold chain damaged unexpired pharmaceuticals that should
have been stored in cold chain but were not. (insulin,
polypeptide hormones, gamma globulins and vaccines.)
All unsealed tubes of creams, ointments etc. (expired or
unexpired)

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• Disposal Methods:

 Return to donor or manufacturer.

 Landfill
 Highly engineered sanitary landfill
 Waste immobilization: Encapsulation.
 Waste immobilization: Inertization.
 Sewer
 Burning in open containers
 Chemical decomposition

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 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.

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 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.

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 How Do GMPs Change?

GMPs change formally and informally.

GMPs are currently undergoing significant changes.

Example of formal change:

The U.S. medical device GMPs have been completely rewritten,

making them more compatible with the ISO-9001 quality document.
In fact device GMPs were renamed - FDA now calls them the Quality
System Regulation (QSR).

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Example of informal change:

Expectations that inspectors have evolved over time.

In the U.S., these changes are communicated by seminars and papers

presented by FDA personnel and through agency Guides and
Guidelines.

One other way industry personnel can keep track of changes in

expectations is by watching the FDA-483s (inspectional
observations) and Warning Letters issued to firms by the agency.

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 How do GMPs of different countries compare?

At a high level, GMPs of various nations are very similar; most require
things like:

 Equipment and facilities being properly designed, maintained,

and cleaned
 Standard Operating Procedures (SOPs) be written and approved
 An independent Quality unit (like Quality Control and/or Quality
Assurance)
 Well trained personnel and management

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 Quality Assurance

• Quality :
it can be defined as
 Fitness for use.
 Conformance to specifications or to some standard.
 Ability to fulfill the customers expectations & thereby provide
satisfaction.
 Freedom from deficiencies.

• Philip Crosby defines quality as „to meet customers requirements‟

• By doing things right first time and every time.

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• QA is the heart and soul of quality control.

• Definition:
Activity of providing the evidences needed to establish
confidence, among all concerned that the quality function is
effectively being followed.

QA = QC + GMP

• It consist of guaranteeing that a consumer can purchase a product

with confidence and enjoy its satisfactory use for a long period.

• Need of central quality assurance system. 27

 Principles of Quality Assurance

• To achieve consumers trust the following principles must be

followed:

 Adopt a 100% consumer first approach & obtain a firm grasp of

consumers requirement.
 Hammer out a clear customer- first philosophy and ensure that
everybody from the company president down is concerned with
quality.
 Constantly rotate the quality cycle (the deming cycle) and never stop
improving quality.
 Producers and marketers are responsible for QA.
 Follow „the next process is your customer‟
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 Quality Assurance System Organization.

Chief Executive of the Company

director of the division

R&D production marketing QA

basic manufacture QC lab

formulation QC lab
third party QC lab

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 Functions Of Quality Assurance Department

Issue of batch production records.

Review of batch production records.
Review of quality control reports.
Issue of product release certificates.
Shop floor inspection.
Upkeep of reference samples.
Validations.
Preparation & review of SOP‟s.
Self inspections.
Complaint handling and investigations.

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Audit preparations.
Vendors audit
Audit of contract manufacturing unit.
Trend charts.
Salvaging.
Training and development.
Documentation.
Check samples.
Post production stability studies.
Product recall.

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 Issue of Batch Production Records.

• The QA dept. issue BPR‟s when the batch is planned for

production.
• Batch no., signature, date of issue, BPR issue register.

 Review of batch production records.

• All BPR are received by QA immediately after the batch is
completed.
• QA personnel checks
1. Correctness of entries.
2. Conformance to manufacturing instructions.
3. Occurrence of deviations, if any deviations are found whether it
has been made with proper authorization and documentation.
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4. Signature in all pages of BPR.
5. Presence of dispensing cards.
6. Calculation of yields.
7. Reconciliation of primary and secondary packing materials.
8. Signature of production manager.
9. Attachment of in-process reports.
10. Attachment of specimens of packing materials.

After review of BPR sign & date of review will be written on

BPR. Also finished product analysis report, microbiological report
and product release certificate will be attached to BPR.

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 Review of Quality Control Reports.

• All finished product analysis report are also received by QA after the
analysis is completed by QC.
• Thoroughly checked against specifications.
• Batch will be released by only after the review of QC reports along
with BPR‟s by QA.

 Issue of product release certificates.

• Completed BPR will come to QA from production. If found

satisfactory QA person give PRC no. in computer.after this material
shifted from FP stores to dispatch center. Then batch will be
dispatched to various depots.

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 Shop Floor Inspection
• Inspection consist of judging whether an individual article/lot is
defective or nondefective by comparing the test results with an
acceptability criterion.

• Quality checked by:

1. General monitoring.
2. Production:
a. Rechecking wt. Of dispensed materials.
b. Observing processing operations.
c. Checking BPR instruction.
d. In process check
e. Line clearance.
f. Collection of in process & finished products.
g. Inspection after packing.
h. Checking of material/equipment sanitation prior to operations.35
3. Packing:
a. line clearance.
b. checking of details on first pack.
c. frequent in process check.
d. random inspection of completed batches.
e. checking of completed BPR‟s.

4. Deviations.

5. Co-ordination

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 In Process Control.
• Parenterals.
 fill volume
 Clarity inspection. – glass particles
– white & black particles.
– particles of dust
- fibers.
• Tablets:
 Uniformity in wt.
 Hardness
 Thickness
 Friability
 Disintegration test
 Blister packing sealing test.
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• Liquid:
fill volume
Clarity of washing / washed water.

• Aerosols:
 Fill wt. Of active drug concentrate
 Fill wt of propellants
 Pressure
 Wt of container
 No of doses
 Dose evaluation.
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 Up Keep of Reference Sample.

• The quantity sufficient for 2 analysis will be collected & kept in

reference room.
• Records of date of collection, batch no., quantity, date of
manufacture date of expiry are maintained.
• These samples are destroyed after 3 months after the expiry period of
time.

 Validation :

• “to prove that process works”

• Determines process variables & acceptable limits for these variables
and accordingly set up appropriate in process controls which specify
alert and actions. 39
• Validation is a chain of activities which include

Plan/protocol
Installation qualification
Operation qualification
Performance qualification
Report
Certification
Revalidation

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 Types of Validation

Prospective validation.
Concurrent validation.
Retrospective validation.
Equipment validation.
Cleaning validation.

validation includes all subjects like instruments, personnel, raw

and packing materials, equipment design, installation, operation,
critical support system ( water, steam, compressed air, inert gases,
drainage) manufacturing process, analytical and quality procedures.

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 Preparation and Review of SOP‟s

• Definition of SOP :
These are written instructions and
procedures for carring out specific operations systematically
and in accordance with the cGMP.

 Self inspection :
 Complaint handling and investigations.
Objective is to investigate thoroughly and
impartially regard less of nature &/or source of complaint

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 Audit preparations.
 Vendors audit.
 Audit of contract manufacturing units.

 Trend charts :
These are prepared for various quality and process
parameters of all the batches manufactured during a particular year.

 Salvaging :
finished goods are returned to central ware house from
various depot due to
- Received in soiled and damaged conditions
- Completion of shelf life.
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 Training and Development
• Basic principles are-
 Employee should know what he is supposed to do.
 Employee should know what is his influence on work.
 Employee should know result of his own work.

 Documentation:

 Check samples: evaluation of test results of check samples will

contribute to judgement of quality level within manufacturing unit.

 Post production stability studies

objective is to generate data that supports intended stability
during the expiration time of the product and when necessary initiate
proper action
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 Product Recall :

It is a speedy and efficient removal of unsatisfactory material

from the market and assigning the responsibilities.

The following parameters are considered for product recall.

1. The health hazards that the user is likely to be exposed to because
of product defect.
2. The extent of recall i.e. consumer, retail, wholesale, company‟s
own stock.

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 Responsibility of Quality Assurance

Assuring that the adopted policies by a company are followed.

Serves as contact with regulatory agencies

Final authority for product acceptance and rejection

Identify and prepare the necessary standard operating procedures

relative to the control of quality.

During final product release it must be determined that the product

meets all the applicable specifications and that it was manufactured
according to internal standards & GMP.

Major responsibility is a quality monitoring and audit function.

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 Documentation

• Document is a paper that provides information especially of

an official or legal nature, written report or record.

• Documentation is a method of preparing a written

material, which describes the process in terms of
specifications, instructions etc.

• Documentation and records are essential for obtaining

accreditation, certification of ISOs and approvals by Federal
Bodies.

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 Importance Of Documentation of Records

• Provide working details necessary for manufacturing, packaging and

QC.

• Reduce the risk of mistakes inherent in verbal communication.

• Help in tracing the deviation from the expected yields.

• Help in decreasing the batch to batch variations so that the quality of

product kept within the limit of acceptability.

• Considered as history of batch operations.

• Self inspection of procedures in order to achieve better control of

operations and improvement of product design.
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 Important Areas of Documentation

 Particulars with respect to their storage, stability & handling.

 Instructions of all manufacturing & packaging procedures, preferably
batch wise are documented so that no further calculations are
required at the work of floor level.
 Instructions for non product related operations such as cleaning &
disinfections, maintenance of equipment, monitoring of working
conditions use of specific conditions.
 Records such as batch manufacturing record, batch packaging record,
test record for no product related operations as indicate.
 Procedures for testing for e.g. physical, chemical, microbiological.
Etc. to be followed.
 Specifications of starting material packaging materials and product
for the compliance by the quality control dept.
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 Components of Documentation

Numerical material identification system

Master formula records
Controls
Master production and control records
Batch production and control records
Equipment cleaning and use of log book
Records relating to container, closure and labeling.
Production record review
Distribution records
Complaints files.

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 Numerical Material Identification System

• Numerical codes are a means of identifying and specifying the

manufacturing lot/batch no. utilized in the production.
• Alfa numerical ordering system is used.

Code number Application of number

Item number Incoming raw materials, components
Stock number Materials received from vendors & lot
indication
Control number Receipt of raw materials(active
ingredients)
Batch number Manufacturing cycle of a products
Product number Product manufactured
Packaging control number Packaging order 51
 Master Formula Records

• It is defined as written procedures that give the complete

description of all aspects of its manufacture, packing and control
with an intension to ensure the purity, identity, quality & strength
of each dosage unit throughout the entire shelf life.

• Master formula includes

1. Specifying a fixed formulation
2. Identifying consistent quality criteria for components
3. Providing an explicit set of manufacturing instructions
4. Describing systematic sampling procedure
5. Listing precise assays & tests
6. Establishing methods for ensuring complete accountability for all
material including packing and labeling

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• Importance of master formula records
for maintaining uniformity of product from batch to
batch.

• Master production and control records are of two types

1. The master formula which gives proportion of ingredients in

the formulation.

2. Master batch formula, which specifies absolute amt. Of

specific potent ingredient and excipients.

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 Controls

• Control records are prepared by a competent individual and verified

as well as endorsed for its correctness by an independent competent
authority.

• Implementation of records
o Workers are expected to verify the relevant codes, instructions &
accordingly perform the manufacturing operations.
o Amt. Entering into next manufacturing process is determined.
o Machine identification bar code is useful to control & identification
of a process.
o After completion of operations, the persons performing, he/she has to
sign in the records with date & time. These are further signed by
supervisor

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 Master Production and Control Record

Name, strength, composition, physical and chemical description,

method of administration.
Name of active ingredient and excipients, total weight of dosage unit.
List of components by names and codes.
Weight/measure of each component.
Calculated excess of component.
Theoretical weight.
Theoretical yield, maximum %, minimum% of theoretical yield.
Description of containers, closures, labels, labeling packaging
materials.
Instructions, sampling testing procedures, specifications, special
notations, precautions.

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 Batch Production and Control Records

• Batch production and control records are detailed description of

instructions, procedures, controls & specifications for the production
of a batch of drug product.

• Importance
Serve as a manual (guide) for the actual production operations.
Medium for recording all processes & procedures, which are required
in pharmaceutical production.
Serve as identification as to when they are performed by whom &
where.
Useful for verification in case of complaints on that batch.

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 Equipment cleaning and use of log book.
 Records relating to container, closure and labeling.
 Production record review.
 Distribution records.
 Complaints file.
- Receiving and recording of a complaints
- Investigation of the complaints
- Defect reporting.

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 Document, Document, Document!!!

In FDA-speak:

“If it is not documented . . .

it did not happen!”
or, it’s a rumor!”

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 References

Theory And Practice Of Industrial Pharmacy By Leon

Lachman, H.A. Liberman, Verghese Publication House, 3rd
Edition, Dader, Bombay.

Laboratory Manual By Pamposh Kumar; V.P.S. Tomer; CBS

Publishers and Distributors, Ist edition, 2005.

Documentation Basics That Support GMP By Carol Desain,

Advanstar Communications, 1993.

Good Manufacturing Practices For Pharmaceuticals, A Plan for

Total Quality Control, 3rd edition, west publishing company.

www.google.com 59
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