Subject Name: Quality Assurance Module -III

Subject Code: BP 606T

Objectives of the course

➢ Understand the scope of quality certifications applicable to pharmaceutical industries.

Learning outcomes
➢ Students learnt about the quality assurance and quality control parameters which affects
academics as well as pharmaceutical industry.
➢ Students learnt about the good laboratory practices in association with equipment
documentation, testing facilities operation and records.
 Structure of Module -3BP 606T
Learning Material

Quality Control- Quality control test for containers, rubber closures and secondary packing materials.
Good Laboratory Practices- General Provisions, Organization and Personnel, Facilities, Equipment,
Testing Facilities Operation, Test and Control Articles, Protocol for Conduct of a Nonclinical
Laboratory Study, Records and Reports, Disqualification of Testing Facilities.
 GOOD
LABORATORY
PRACTICES
GLP: GOOD LABORATORY PRACTICE

GLP is an FDA regulation.

GLP is a formal regulation that was created by the FDA (United states food
and drug administration) in 1978.
What is GLP?

Good Laboratory Practice (GLP) is a quality system concerned

with the organisational process and the conditions under
which non-clinical health and environmental safety studies are
planned, performed, monitored, recorded, archived and reported.
WHY WAS GLP CREATED?

In the early 70’s FDA became aware of cases

of poor laboratory practice all over the
United States.
They discovered a lot fraudulent activities and
a lot of poor lab practices.
Examples of some of these poor lab
practices found were
1. Equipment not been calibrated to
standard form , therefore giving wrong
measurements.
2. Incorrect/inaccurate accounts of the
actual lab study.
3. Inadequate test systems.
Purpose of GLPs:

• GLP is to certify that every step of the

analysis is valid or Not.

• Assure the quality & integrity of data

submitted to FDA in support of the safety
of regulated products.

• GLPs have heavy emphasis on data

recording, record & specimen retention.
Scope of GLP

Principles of GLP apply to all non-clinical health and

environmental safety studies required by regulations
for the purpose of registering or licensing -

Pharmaceuticals
Pesticides
Food and feed additives
Cosmetic products
Veterinary drug products and similar products
Industrial chemicals
 Objectives of GLP
True reflection
Ensure Honesty International acceptance
GLP makes sure Promotes
that the data GLP also makes internation
submitted are a sure that not to al
true reflection of indulge in any acceptance
the results that are fraud activity by of tests
obtained during labs
the study.
Protocols of GLP
 Ensure sufficient number of qualified personnel, appropriate
facilities, equipment, and materials

Ensure the maintenance of a record of the qualifications, training,

experience.

Proper training of personnel to assigned functions

Job description for each professional and technical individual.

To establish and follow SOP

Quality assurance program with designated personnel

Organisation & Personnel – Study Director’s responsibi
Approval of protocols & the study plan including
amendments

Ensure QA personnel and study personnel are

updated with study plans & SOP

Ensure the follow up of SOPs periodically and

take appropriate corrective action

Archiving Raw data, supporting materials and

final report.
 Organisation & Personnel
Principal Investigator’s Responsibilities

Ensures the study is conducted in

accordance with GLP
Study Personnel’s Responsibilities
Recording of all raw data in compliance
with the principles of GLP

Deviations from the instructions to be

reported the PI or SD

Takes health precautions and personal

safety
 Quality Assurance Programme
An individual or a group designated
by management to assure studies are
in compliance with GLP Principles
Maintains copies of protocols & SOPs

Inspects each laboratories and man at work –

inspections based-Study
Facility-based inspections
Process- based inspections

Determines any deviation from approved protocol and report to

SD, PI & management

Prepare a statements to be included in final report containing

dates & types of inspection
 13
Facilities

Test System Facilities

Sufficient amount of rooms and areas to assure isolation
of test systems

Adequately protected storage area separate from test

systems
Areas available for the diagnosis, treatment and control
of diseases
Archive facilities

Secure storage and retrieval of study plans, raw data, final

reports & specimen to prevent deterioration

Waste Disposal

Appropriate collection, storage & disposal facilities and

decontamination procedures
Apparatus, Materials & Reagents

Apparatus to be
Apparatus, including periodically inspected,
validated computerised cleaned, maintained,
systems should be of and calibrated
appropriate design & according to Standard
adequate capacity Operating Procedures.

Chemicals, reagents
and solutions should Should not
be labelled to indicate interfere adversely
identity, DOE & with the test
storage instructions systems.
5. Test Systems

Physical/ Chemical

Biological
6. Test and Reference Items

• Receipt, handling, sampling and storage

• Characterization.
• Known stability of test and reference items.
• Stability of the test item in its vehicle
(container).
• Samples for analytical purposes for each
batch
 7.Standard Operating Procedures (SOP)
1. Test facility should have a written SOP approved by management

2. SOPs should be available wherever applicable e.g.

Test and reference items

reagents and materials Apparatus,
Record keeping, reporting, storage and retrieval
system Test
Quality assurance procedures

3.Any deviations from SOP should be

documented & acknowledged by SD and PI
Performance of The Study
For each study, a written plan –
• Approved by SD, management, sponsor
• Verified for GLP compliance by QAU
• If required, national regulation

Contents of Study Plan

Identification of the study, the test and

reference item
Information - sponsor and the test facility, SD,
PI
Test methods – reference to OECD/other test
guidelines
Issues – justification of selection
Records
 Storage & Retention of Records 21

The study plan, raw data, samples of test and

reference items, specimens and the final
report of each study.

Records of all inspections by QAP

Records of qualifications, training, experience

and job descriptions of personnel.

Records and reports of the maintenance and

calibration of apparatus.

Historical files of all SOP.

Definition
Role Of Packaging Material
Types Of Packaging Material
Quality Control Test for Glass Container
Quality Control Test For Plastic Container
Conclusion
Reference
•Packaging
Packaging is the science, art and technology of enclosing or protecting
products for distribution, storage, sale, and use.

Production marketing
Role of Packaging:

Protection -against light

-against reactive gases
-against moisture
-against microbes
-against physical damage
-against adulteration

Presentation
Identification
Information
Convenience
Primary packaging
Primary Packaging is the material that first envelops the product and holds it. This
usually is the smallest unit of distribution or use and is the package which is in direct
contact with the contents.
Secondary Packaging
Secondary Packaging is outside the primary packaging perhaps used to group
primary packages together
Tertiary Packaging
Tertiary Packaging is used for bulk handling , warehouse storage and
transport shipping.
◦ Ampoules
◦ Vials
◦ Containers
◦ Dosing dropper
◦ Syringe
◦ Strip package
◦ Blister packaging
• Paper and boards
• Cartons
• Box manufacture
 TYPES OF GLASS:
1) Type I ( Neutral or Borosilicate Glass)

Type I

2) Type II ( Treated Soda lime glass)

3) Type III ( Soda lime glass)

4) Type IV ( General purpose soda lime glass)

Type II /III
QUALITY CONTROL TESTS FOR GLASSES
1) CHEMICAL RESISTANT OF GLASS CONTAINERS
A) Powdered Glass Test:
It is done to estimate the amount of alkali leached from the powdered glass which
usually happens at the elevated temperatures. When the glass is powdered, leaching of alkali
is enhanced, which can be titrated with 0.02N sulphuric acid using methyl red as an indicator

Step-1: Preparation of glass specimen:

Few containers are rinsed thoroughly with purified water and dried with stream of
clean air. Grind the containers in a mortar to a fine powder and pass through sieve no.20 and 50.

Step-2: Washing the specimen:

10gm of the above specimen is taken into 250 ml conical flask and wash it with 30 ml
acetone. Repeat the washing, decant the acetone and dried after which it is used within 48hr.
Procedure:
10gm sample is added with 50ml of high purity water in a 250ml flask. Place it in an
autoclave at 121⁰C±2⁰C for 30min.Cool it under running water. Decant the solution
into another flask, wash again with 15ml high purity water and again decant. Titrate
immediately with 0.02N sulphuric acid using methyl red as an indicator and record the volume.
B) Water Attack Test:
This is only for treated soda lime glass containers under the controlled humidity
conditions which neutralize the surface alkali and glass will become chemically more resistant.
Principle involved is whether the alkali leached or not from the surface of the container.

Procedure:
Rinse thoroughly with high purity water.
Fill each container to 90% of its overflow capacity with water and is autoclaved at 121⁰C for
30min then it is cooled and the liquid is decanted which is titrated with 0.02N sulphuric acid
using methyl red as an indicator.
The volume of sulfuric acid consumed is the measure of the amount of alkaline oxides
present in the glass containers.
 Test Limits

TESTS CONTAINER VOL.OF 0.02N H2SO4

Type I 1.0
Powdered glass test Type II 8.5
Type III 15.0

Type II (100ml or below) 0.7

Water attack test
Type II (above 100ml) 0.2
2) Hydrolytic Resistance Of Glass Containers:
Rinse each container at least 3times with distilled water and fill with the same to their
filling volume. Heat to 100⁰C for 10min and allow the steam to issue from the vent cork. Rise
the temp from 100⁰C to 121⁰C over 20min. Maintain the temp at 121⁰C to 122⁰C for 60min.
Lower the temp from 121⁰C to 100C over 40min venting to prevent vacuum.

Remove the container from autoclave, cool and combine the liquids being examined.
Measure the volume of test solution into a conical flask and titrate with 0.01M HCl using
methyl red as an indicator. Perform blank with water and the difference between the titration
represents the volume of HCl consumed by the test solution.

Nominal Number of Volume of test solution to be

Capacity Of containers used for titration (ml)
container (ml) to be used
5 or less at least 10 50.0
6 to 30 at least 5 50.0
More than 30 at least 3 100.0
15
03 Thermal Shock Test:
Place the samples in upright position in a tray. Immerse the tray into a hot water
for a given time and transfers to cold water bath, temp of both are closely controlled.
Examine cracks or breaks before and after the test. The amount of thermal shock a bottle can
withstand depends on its size and design. Small bottles withstand a temp differential of 60
to 80⁰C and large bottle 30 to 40⁰C. A typical test uses 45C temp difference between hot and
cold water.

04 Leakage Test:
Fill 10 containers with water, fit with intended closures and keep them inverted at
room temperature for 24hr.The test is said to be passed if there is no signs of leakage
from any container.
 The most common instrument used is American glass research increment
pressure tester .The test bottle is filled with water and placed inside the test
chamber. A scaling head is applied and the internal pressure automatically raised by
a series of increments each of which is held for a set of time. The bottle can be
checked to a preselected pressure level and the test continues until the container
finally bursts.
 Collapsibility test :
Applicable to containers which are to be squeezed in order to
remove contents. yield 90%of its contents at required rate of flow at ambient
temp.

Clarity of aqueous extract:

Clarity of aqueous extract Select unlabelled portion from a
suitable containers Cut these portions into strips Wash it with extraneous matter by
shaking with two separate portions of distilled water Transfer to flask – previously
washed with chromic acid Rinse with distilled water add 250ml d.w. Cover the
flask autoclave at 121Ċ, 30min Colourless , free from turbidity

Non-volatile residue
Evaporate 100 ml of the extract obtained in the test for Clarity of
aqueous extract to dryness and dry to constant weight at 105º. The residue weighs not
more than 12.5 mg.
Leakage test, Collapsibility test
Same As Describe in Non- Injectable

Clarity and colour of solution

Acidity or alkalinity
Light absorption
Reducing substances
Transparency
 Fill a container to its nominal capacity with water and close it, if possible
using the usual means of closure; otherwise close using a sheet of pure
aluminium. Heat in an autoclave so that a temperature of 121 ± 2º is reached
within 20 to 30 minutes and maintain at this temperature for 30 minutes. If
heating at 121º leads to deterioration of the container, heat at 100º for 2 hours.

Use solution S within 4 hours ofpreparation

Blank.
Prepare a blank by heating water in a borosilicate glass flask closed by
a sheet of pure aluminum at the temperature and for the time used for the
preparation of solution S.

Clarity and colour of solution S.

Solution S is clear and is colorless.

Acidity or alkalinity.
To a volume of solution S corresponding to 4 per cent of the nominal
capacity of the container add 0.1 ml of phenolphthalein solution. The solution is
colorless. Add 0.4 ml of 0.01M sodium hydroxide. The solution is pink. Add 0.8 ml
of 0.01M hydrochloric acid and 0.1 ml of methyl red solution. The solution is
orange-red or red.
Light absorption.
The light absorption in the range 230 nm to 360 nm of solution S using a blank
prepared as described under Solution S is not more than 0.20

Reducing substances.
To 20.0 ml of solution S add 1 ml of dilute sulphuric acid and 20.0 ml of
0.002M potassium permanganate. Boil for 3 minutes. Cool immediately. Add 1 g of
potassium iodide and titrate immediately with 0.01M sodium thiosulphate, using 0.25
ml of starch solution as indicator. Carry out a titration using 20.0 ml of the blank
prepared as described under Solution S. The difference between the titration volumes
is not more than 1.5 ml.

Transparency
Fill the container previously used for the preparation of solution S to its
nominal capacity with a 1 in 200 dilution of the standard suspension for
a container made from polyethylene or polypropylene. For containers of
other materials, use a 1 in 400 dilution. The cloudiness of the
suspension is perceptible when viewed through the container and
compared with a similar container filled with water
Fill 5 containers with nominal volume of water and heat seal the bottles with
aluminium foil.

Weigh accurately each container and allow to stand for 14 days humidity-
60±5% temp. 20Ċ and 25Ċ.

Reweigh the containers.

Loss in wt in each container is NMT 0.2%

Thank You
 A presentation on
QUALITY CONTROL TESTS FOR CONTAINERS,CLOSURES AND
SECONDARY PACKAGINGING MATERIALS

BY: IQRA RAHAT

ASSISTANT PROFESSOR
GLOCAL SCHOOL OF PHARMACY
GLOCAL UNIVERSITY Type to enter a caption.
2/27/2019 7:08 1
AM
 PACKING MATERIALS
• Any material that is used for packaging of products for their distribution and sale is said to be the packing material.
• Two types of packing material:
i. Primary packing material
Comes in direct contact with the product e.g. bottles, vials, ampoules, tin, etc.

ii. Secondary packing material

Used to cover primary packs e.g. cartons, boxes, etc.

Type to enter a 2
 QUALITY CONTROL TESTS FOR GLASS CONTAINERS

1. Powdered glass test:

Done to estimate the amount of alkali leached from the powdered
glass, which usually happens at elevated temperatures.

Sample containers are rinsed with purified water and dried.

↓
The containers are grinded in a mortar to a fine powder and passed through
sieve no. 20 and 50.
↓
10gm of the sample is washed with acetone and dried.
↓
50 ml of purified water is added to the dried sample and autoclaved at
121°C for 30 mins and cooled and decanted.
↓
The decanted liquid is titrated with 0.02 N H2SO4 using methyl red as
indicator.

3
 2. Hydrolytic resistance of glass containers:

Each container is rinsed at least three times with CO2

free water and filled with the same to their filling
volume.
↓
Vials and bottles are covered and autoclaved at
100°C for 10 mins.
↓
The temp. is risen from 100°C to 121°C over 20
mins.
↓
The temp. is maintained at 121°C to 122°C for 60
mins.
↓
The containers are cooled and the liquids are
combined and volume measured.
↓
It is titrated with 0.01M HCl using methyl red as an
indicator.

4
3. Arsenic test:
This test is for glass containers intended for aqueous parenterals.

The inner and outer surface of container is washed with fresh

distilled water for 5 min.
↓
Then similar steps are followed as performed in the hydrolytic test,
previously described, till obtaining the final combined solution.
↓
10ml from the final combined volume is pipetted out and to it 10 ml
of HNO3 is added and dried in an oven at 130°C.
↓
10ml of hydrogen molybdate is added and refluxed for 25 mins.
↓
It is cooled and absorbance is measured at 840nm.
↓
The absorbance of the test solution should be less than the
absorbance obtained using 0.1ml of arsenic standard solution
(10ppm).

5
QUALITY CONTROL TESTS FOR PLASTIC CONTAINERS FOR NON-PARENTERAL PREPARATIONS

1. Leakage test:
10 containers are filled with water and fitted with intended closures.
↓
They are kept inverted at room temperature for 24 hours.
↓
The test is said to be passed if there is no sign of leakage from any
container.

2. Collapsibility test:
• This test is applicable to containers which are to be squeezed
in order to remove the contents.
• A container by collapsing inward during use, yield at least
90% of its normal contents at the required rate of flow at
ambient temperature.

Type to enter a
caption. 6
3. Clarity of aqueous extract:

A suitable container is taken at random, and unlabeled, unmarked and non-

laminated portions is selected.
↓
These portions are cut into strips, none of which has a total surface area of 20cm2.
↓
The strips are washed free from extraneous matter by shaking them with at least
two separate portions of distilled water for about 30 secs.
↓
The processed sample is taken in to the flask, previously cleaned with chromic
acid and rinsed with distilled water.
↓
250ml of distilled water is added to the flask, covered and autoclaved at 121°C for
30 mins.
↓
The extract is cooled and examined. It should be colorless and free from turbidity.

7
 QUALITY CONTROL TESTS FOR CLOSURES

Preparation of sample:
• The closures are washed in 0.2% w/v of anionic surface active agents for 5
mins.
• Rinsed five times with distilled water and 200ml water is added.
• Subjected to autoclave at 119°C to 123°C for 20-30 mins covering with
aluminum foil.
• Cooled and solution is separated from closures (Solution A).

1. Residue on evaporation:
• 50ml of Solution A is evaporated to dryness on a water bath and dried at
105°C.
• The residue weighs not more than 4 mg.

8
2. Sterilisation test:
The closures used for the preparation of the sample solution shall not
soften or become tacky and there shall be no visual change in the closure.

3. pH of aqueous extract:
To 20ml of solution A, 0.1ml of bromothymol blue solution is added.
↓
NMT 0.3ml of 0.01M NaOH or 0.8ml of 0.01M HCl is rqd. to change the color of the
solution to blue or yellow respt.

9
 4. Self stability test:

Pierced ten times with hypodermic needle

↓
Immersed in 0.1% methylene blue solution and subjected to a pressure of about
27 KPa
↓
Restored to ATM pressure and made to stand for 30mins
↓
Traces of colored solution should not be found.

10
 QUALITY CONTROL TESTS FORCARTONS

1. Compression:
• Used to assess the strength of erected package there by
estimating the degree of protection that it confers on the
contents.
• This is useful for products with no inherent strength in one
plane or another.

2. Carton opening force: Type to enter a caption.

• The carton should spring open in to its original shape without a need for unreasonable force.
• If the carton does not spring open or buckles in on itself, it may cause problems on cartooning
machine.

11
 QUALITY CONTROL TESTS FOR PAPER ANDBOARD

Test conditions:
Temperature- 23 ± 1°C ; Relative humidity- 50±2%

12
REFERENCES:
• C, Rambabu, V, Ananth, R. T, Srikanth, S. K, Dona, K. G, Arun, T, Tinu, Manavalan, B. M, Venkanna, S. H, Viswa, J. K,
Ghaharin. A Concise Textbook of QC & QA. KMCH College of Pharmacy, Coimbatore. 2011. 179-189.
• Government of India, Ministry of Health. Indian Pharmacopoeia Volume I. The Indian Pharmacopoeia Commission,
Ghaziabad. 2010. 683-692.

2/27/2019 7:08 13
AM
Quality control tests
 Quality control tests
1. For Plastic containers
• For Non-injectable preparation
Includes: Collapsibility test, Leakage test, Clarity
of aqueous extract, For non-volatile residue
• For injectable preparation
Includes: Collapsibility test, Leakage test,
Transparency test, water vapor permeability test
2. For Glass containers
• Powdered glass test
• Hydrolytic resistance test
• Water attack test
• Thermal shock test
• Leakage test
3. For metallic containers
• Descriptions
• Dimensions
• Diameter
• Cleanliness check
4. For Rubber closures
• Sterility test
• Penetrability test
• Fragmentation test
• Self sealibity test
• Extractive test
5. For secondary packaging materials
• Moisture content
• Folding endurance
• Air permeability
• Tensile strength
• Tear strength
• Stiffness
• Burst resistance
 QC For Rubber closures
• Sterility test
• Penetrability test
• Fragmentation test
• Self sealibity test
• Extractive test
Preparation of aqueous extract
1. Sterility test

 The ability of the container-closure system to maintain the integrity of its

microbial barrier, and, hence, the sterility of a drug product throughout its
shelf life, should be demonstrated.
 When treated closures are subjected to sterilization test at 64-66⁰C and a
pressure of about 0.7 KPa for 24hr.
 Closures are examined for any microbial growth.
2. Penetrability test
3. Fragmentation test
4. Self saleability
5. Extractive test

• Extract rubber closure with boiling water

under reflux for 4 hrs
• Evaporate the water upto dryness
• Weight of the residue must be within 2-4
mg
Quality control tests for
Glass containers
For Glass containers
 Powdered glass test
 Water attack test
 Hydrolytic resistance test
 Thermal shock test
 Leakage test
1. Powdered glass test/ glass grain test
 It is done to estimate the amount of alkali leached from the powdered glass
which usually happens at the elevated temperatures.
 When the glass is powdered, leaching of alkali is enhanced, which can be
titrated with 0.02N sulphuric acid using methyl red as an indicator
 Step -1 : Preparation of glass specimen :
Few containers are rinsed thoroughly with purified water and dried with stream
of clean air.
Grind the containers a mortar to a fine powder and pass through sieve no.20 and
50.
 Step -2 : Washing the specimen :
10gm of the above specimen is taken into 250 ml conical flask and wash it with
30 ml acetone.
Repeat the washing, decant the acetone and dried after which it is used within
48hr.
Powdered glass test/ glass grain test

 Procedure :
10gm sample is added with 50ml of high purity water in a 250ml flask.

Place it in an autoclave at 121⁰C±2⁰C for 30min.

Cool it under running water.

Decant the solution into another flask, wash again with 15ml high purity water and
again decant.

Titrate immediately with 0.02N sulphuric acid using methyl red as an indicator and
record the volume.
2. Water attack test
 This is only for treated soda lime glass containers under the controlled humidity
conditions which neutralize the surface alkali and glass will become chemically
more resistant.
 Principle involved is whether the alkali leached or not from the surface of the
container.
 Procedure:
Rinse thoroughly with high purity water.

Fill each container to 90%of its overflow capacity with water and is autoclaved at
121⁰C for 30min

then it is cooled and the liquid is decanted which is titrated with 0.02N sulphuric acid
using methyl red as an indicator.

The volume of sulfuric acid consumed is the measure of the amount of alkaline oxides
present in the glass containers
TESTS CONTAINER VOL.OF 0.02N H2SO4(ml)

Powdered glass test Type I 1.0

Type II 8.5
Type III 15.0

Water attack test Type II(100ml or below) 0.07

Type II(above 100ml) 0.02
3. HYDROLYTIC RESISTANCE OF GLASS
CONTAINERS
 Rinse each container at least 3 times with CO free water and fill with the
2
same to their filling volume.
 Also fill & Cover the vials and bottles and keep in autoclave.
 Heat to 100⁰C for 10min and allow the steam to issue from the vent cork.
 Rise the temp from 100⁰C to 121⁰C over 20min. Maintain the temp at 121⁰C to
122⁰C for 60min.
 Lower the temp from 121⁰C to 100C over 40min venting to prevent vacuum.
 Remove the container from autoclave, cool and combine the liquids being
examined.
 Measure the volume of test solution into a conical flask and titrate with 0.01M
HCl using methyl red as an indicator.
 Perform blank with water and the difference between the titration represents
the volume of HCl consumed by the test solution.
Nominal capacity of Number of containers to Volume of test solution
container (ml) at least be used to be used for titration
(ml)

5 or less At least 10 50.0

6 to 30 At least 5 50.0

More than 30 At least 3 100.0

4. THERMAL SHOCK TEST

 Place the samples in upright position in a tray.

 Immerse the tray into a hot water for a given time and transfers to cold water
bath, temp of both are closely controlled. Examine cracks or breaks before
and after the test.
 The amount of thermal shock a bottle can withstand depends on its size,
design and glass distribution.
 Small bottles withstand a temp differential of 60 to 80⁰C and 1 lit bottle 30
to 40⁰C.
 A typical test uses 450C temp difference between hot and cold water
5. LEAKAGE TEST

 Drug filled container is placed in a container filled with coloured solution

(due to the addition of dye)which is at high pressure compared to the
pressure inside the glass container so that the coloured solution enters the
container if any cracks or any breakage is present.
 Subject Name: Quality Assurance Module -IV
Subject Code: BP 606T

Objectives of the course



 Appreciate the importance of documentation, complaints, quality audit and quality

review according to regulatory agencies.

Learning outcomes

 Students learnt about the documentation, quality of product, various records, and
complaints in pharmaceutical industry.
 Structure of Module -4BP 606T
Learning Material

Complaints- Complaints and evaluation of complaints, Handling of return good, recalling

and waste disposal.

Document Maintenance in Pharmaceutical Industry- Batch Formula Record, Master

Formula Record, SOP, Quality audit, Quality Review and Quality documentation, Reports
and documents, distribution records.
 Complaint

COMPLAINT
• Reasons
• Types of Complaint
• Steps involved in Handling of complaints
• Product Complaint Data Sheet
• Complaint Record
• Regulatory Guidelines
• SOP on Complaint Handling
Complaint
Statement that is something wrong or not good enough, which shows
customer dissatisfaction about the company and the product
Example: Complaint about packaging materials, Concerning about the product
etc.
Reasons
 It gives the company an opportunity to improve the quality of the product
 It is helpful to maintain cGMP
 It maintains committed relationship between the customer and company
 It is the regulatory obligation.
 Aid in implementing solutions to these quality problems
 Reduce costs and improve production schedules
 Reduce employee confusion
 Improve the safety and performance of devices
 Identify poor performance in the overall quality system, particularly
faulty design of devices, and faulty manufacturing processes
 Verify confidence in, and improve the performance of the quality system
 Reduce medical device reporting
 Improve customer relations by reducing the frequency of problems,
complaints, and recalls; and,
 Assure compliance with device regulations and consensus standards.

Types of Complaint

Quality complaints: Originate at consumer level and concern with

physical, chemical and biological properties or condition of labeling and /or
 packaging of the product.
Adverse reaction complaints: Due to allergic reactions of any other untoward
reaction or fatal reaction or near fatal reaction.
Other medically related complaints: Include complaints such as lack of
efficacy or clinical response
PROCEDURE:
1. Market complaint may be received from any of the following sources:
Physicians , Pharmacist , Warehouse, Patients, Regional Offices, Hospitals
Regulatory affairs, Wholesale Traders, Actual users
2. Complaints shall be classified in following categories to facilitate
investigation:
- Product quality complaints (non therapeutic).
- Packaging complaints (shortages and packaging error).
- Medical complaints (therapeutic problems).
3. As a company policy even verbal complaints shall be formalized and
investigated.
4. All written and oral complaints to be forwarded to Head,
QA/QC/Regulatory or his nominee for investigation
5. All the Product Quality Complaints shall be investigated jointly with
QA/F and D/Manufacturing within 5 days of the receipt of the complaint.
6. Medical complaint investigations shall be carried out jointly by
Medical department, QA, Production, F and D and Marketing Department
within 3 days of receipt of complaint
7. Packaging complaints and Quality complaints shall be jointly
investigated by QA, F and D and Manufacturing department within 10 days
of receipt of complaint.
8. The investigator shall investigate the complaint by referring to the
Batch Manufacturing Record, SOP, machine log tables, retain samples,
reconciliation of materials, storage conditions used and prepare the
Product Complaint Report (PCR)
9. The PCR shall include the product details, details of the complainant,
quantity involved, enclosed complaint sample (if any), details of
investigation actions taken and recommended corrective actions to prevent such
recurrences in future. Each PCR shall be approved by
Head/QA/QC/Regulatory or his nominee
10. Incase of the Head/QA/QC/Regulatory finds that investigation is not
necessary, such written records shall be maintained including reasons for not
conducting the investigation.
11. Each report shall be assigned a specific PCR number, which will be a 3 digit
number starting with “001”in continuous sequence prefixed with “PCR” and
suffixed with the last two digits of the year. For example, the first market
complaint for 2006 shall have the number PCR/001/006
12. If product defect is established or suspended in a batch,
Head/QA/QC/Regulatory will decide for checking other batches in order to
determine weather they are also affected.
13. Incase of medical complaints, if Head, /QA /QC /Regulatory and
Medical Advisor feels that the product will put the public at risk, he shall advise
immediate recall of the batch. The depth of recall is dependent on the
seriousness of the complaint.
14. Complaint Record shall be maintained at least one year after
expiration date of medicine.
15. Complaint Record shall be reviewed and a monthly summary shall be
prepared for the management.
16. A Register is maintained having the complete details of complaint for future
reference.
 DOCUMENTATION IN PHARMACEUTICAL INDUSTRY
Method of preparing a written material, which describes the process in terms of
specifications and instructions etc. The D & C Act under conditions of granting
license and schedule M require manufacturer of drugs to maintain various
records.
Importance of documentation
Provides necessary working details
Reduces the risk of mistake
Helps in decreasing batch to batch variation
Considered as the history of batch operations
Types of documentation
 Commitment document: Relationship between industry and the regulatory
authorities.
 Directive document: Relationship between management and employee.
 Record document : Relationship between the employee and the work they
perform

.
 Master formula record (MFR):
Written procedure that give the complete description of all aspects of manufacture, packing
and control with an inspection to ensure purity, identity, quality and strength of each dosage
unit through its shelf life. Includes all the materials used in any batch manufacturing
and step by step process of manufacturing.
The master formula must include:
a) The name of the product together with product reference code relating to
its specifications.
b) The patent or proprietary name of the product along with the generic name,
a description of dosage form, strength, composition of the product and batch size
c) A statement of the processing location and the principal equipment to be
used.
d) Name , quantity and reference number of all starting materials to be used.
e) A statement of expected final yield with the acceptable limits and of relevant
intermediate yields, where applicable.
f) The methods or reference of the methods to be used for preparing the critical
equipment including cleaning, assembling, calibrating, sterilizing.
g) Detailed stepwise processing instructions and the time taken for each step.
Master production and control record
Detailed written instructions including all operations starting from dispensing of
raw materials till finishing of bulk products and packaging operation of the
particular product.
It includes batch size, date of manufacture and full signature by 1st person and
further independently checked, dated and signed by 2nd person.
Preparation of master formula
 Master formula can be prepared by competent technical staff.
 It should be reviewed by the head of production, QC department and R &
D department.

Drug master file Drug Master File (DMF):

Document prepared by a pharmaceutical manufacturer and submitted solely at its
description to the appropriate regulatory authority in the intended drug market.
There is no regulatory requirement to file a DMF.
The DMF provides confidential, detailed information about facilities, process or articles
used in the manufacturing, packaging, storing etc. to the regulatory authority.
DMF is filed when two or more firms work in a partnership or developing or
manufacturing a drug product.
Drug master file include ncludes:
A) General information
1. General properties.
2. Structure.
3. Nomenclature.
B) Manufacture
1. Manufactures.
2. Description of manufacturing process and process control.
a) Flow chart of manufacturing process,
b) Synthetic route of manufacturing process,
c) Manufacturing method,
Drug Master
3. Control of Material
1. List of materials
2. Specification and routine test of the raw material
4. Control of critical steps and intermediates
1. Critical steps,
2. Process validation,
5. Specifications and test method for the intermediates, 6.Manufacturing process
development
…..
C) Characterization
1.Elucidation of structure and other characteristics-
a) Elemental analysis
b) IR spectrum of drug substance
c) NMR spectrum of drug substance
d) Mass spectrum of drug substance
e) UV spectrum of drug substance
f) X-ray diffraction
g) Thermal analysis
h) Comprehensive illustration
Drug Master: Cont …..
2) Impurities
a) Sources of potential impurities
b) Types of impurities
c) Test procedure for determining impurities
D) Control of drug substances
a) Specifications
b) Analytical procedure
c) Validation of analytical procedure
d) Batch analysis
e) Justification of specification
Drug Master File (DMF) Includes: cont …..
E) Reference standards of material
F) Container closure system
G) Stability
H) Material data safety sheet

TYPES OF DRUG MASTER FILE e (

Type 1: Manufacturing site, facilities, operating procedures and personnel.
Type 2: Drug substance, drug substance intermediate and material used in their
production or drug product.
Type 3: Packaging material.
Type 4: Excipient, colorant, flavor.
Type 5: FDA accepted reference information.
Types of Drug Master File (DMFCont…
Type 1:
 Manufacturing site, facilities ,operating procedures and personnel
 No longer used, once used to describe facilities
 Recommended for a person outside of the United states to assist FDA in conducting
on site inspections of their manufacturing facilities
 Should describe manufacturing site, operational layout, equipment capabilities,
processing layout.
Type 2:
Drug substance ,drug substance intermediate and material used in their preparation or
drug product required for drug substance – active ingredient.
A separate DMF is filed for each active ingredient.
Brief description of the manufacturing facilities, the address, a contact, phone number
and fax number.
Manufacturing procedures and control for finished dosage forms submitted in an IND,
NDA, ANDA or export application.
Type 3:
Packaging material,
Its components and composition,
Packaging material intended for use,
Name of the suppliers or fabrications of the components used in preparing the
packaging material.
Acceptance specifications,
Eg: - Products that would be classified as type 3 DMFs include bottles, seals,
dispensers etc.
Type 4:
Excipient, colorant, flavor, essence used in their preparation.
Each additive should be identified by this method of manufacture, release
specification and testing methods.
Toxicological data would be included.
The official compendia and FDA regulation for color additives, direct food additives
and food substances may be used as sources for release tests and safety.
Type 5:
FDA accepted reference information.
FDA discourages the use of type 5 DMFs for miscellaneous information, duplicate
information.
 To submit the data which is not covered in type 1 to type 4 DMF
A holder must first submit a letter of intent to the drug master file staff.
FDA will contact the holder to discuss the proposed submission.
Distribution record
Written procedures shall be established and followed, describing the distribution of drug
products
Include:
1. A procedure where by the oldest approved stock of a drug product is distributed first
2. A system by which the distribution of each lot of drug product can be readily
determined to facilitate its recall if necessary.
3. Distribution records must be constructed and procedures established to facilitate
recall of defective product.
4. All records should be indexed by either the manufacturing batch-lot number of the
packaging control number as a means of accountability. It shall contains:
1. Description of dosage form
2. Name and address of the consigner
3. Date and qty shipped
4. Lot and control number of the drug
5. Name of drug and strength
WHO guidelines of Distribution records
Written instruments and records should be available.
Procedure should be established and maintained.
The title, name and purpose of each document should be clearly stated.
All documents should be completed, approved,signed ad dated by an appropriate
authorized persons.
In the case of temperature-sensitivity pharmaceutical products, records of
investigations and actions should be retained for at least one year after the expiry
date of the product.
 DOCUMENT MAINTENANCE IN PHARMACEUTICAL
INDUSTRY
Documentation is essential part of the quality assurance system and as such, should be related
to all aspect of GMP. Its aim is to define the specifications for all materials and the method of
manufacture and control, to ensure that all personnel concerned with manufacture have the
information necessary to decide whether or not to release a batch of a drug for sale, and to
provide an audit trail that will permit investigation of the history of any suspected defective
batch. The specifications should describe in detail the requirement with which the products or
materials used or obtained during manufacture have to conform. They serve as a basis for
quality evaluation. Documentation provides the route for auditors to assess the over all quality
of operations within a company and the final product.

GENERAL REQUIREMENT:
 Good documentation constitutes an essential part of the quality assurance system.
Clearly written procedures prevent errors resulting from spoken communication, and
dear documentation permits tracing of activities performed.
 Documents must be designed, prepared, reviewed, and distributed with care.
 Documents must be approved, signed, and dated by the appropriate competent and
authorized persons.
 Documents must have unambiguous contents. The title, nature, and purpose should be
clearly stated. They must be laid out in an orderly fashion and be easy to check.
‘Reproduced documents must be clear and legible.
 Documents must be regularly reviewed and kept up-to-date. When a document has been
revised, systems must be operated to prevent inadvertent use of superseded document:
(e.g., only current documentation should be available for use).
 Documents must not be handwritten; however, where documents require the entry of
date, these entries may be made in clear legible handwriting using a suitable indelible
medium (i.e., not a pencil). Sufficient space must be provided for such entries.
 Any correction made to a document or record must be signed or initialled and dated,
the correction must permit the reading of the original information. Where appropriate,
the reason for the correction must be recorded
All documents related to the manufacture of intermediates, even pharmaceutical ingredients
(API), and the finished products should be prepared, reviewed, approved and distributed
according to written procedures. Such documents can be paper based or in electronic form.
Documents should be approved, signed and dated by the appropriate responsible persons. No
document should be changed without authorization and approval. Each specification for raw
materials. Intermediates, final products, and packing materials should be approved and
maintained by the quality control department. Periodic revisions of the specifications must be
carried out whenever changes are necessary.
The issuance, revision, superseding, and withdrawal of all documents should be controlled with
maintenance of revision histories. When a document has been revised, systems should be
operated to prevent inadvertent use of superseded documents. Superseded documents should
be retained for a specific period of time. Periodic revisions of the specifications may be
necessary to comply with new edition of the national pharmacopoeia or other official
compendia. Documents should have unambiguous contents: the title, nature and purpose
should be clearly stated. They should be laid out in an orderly fashion and be easy to check.
Reproduced documents should be clear and legible. The process of reproduction of working
documents from master documents must not allow any error to be introduced through the
reproduction process.
A procedure should be established for retaining all appropriate documents (e.g. development
history reports, sale up reports, technical transfer reports, process validation reports, training
records, production records, control records, and distribution records). The retention periods
for these documents should be specified.
All production, control, and distribution methods should be retained for at least 1 year after the
expiry date of the batch. For APIs with retest dates, records should be retained for at least 3
years after the batch is completely distributed.
Documents should not be handwritten; however, where documents require the entry of data,
these entries may be made in clear, legible, indelible handwriting. Sufficient space should be
provided for such entries. Any alteration made to the entry on a document should be signed
and dated; the alteration should permit the reading of the original information. Where
appropriate, the reason for the alteration should be recorded.
During the retention period, originals or copies of records should be readily available at the
establishment where the activities described in such records occurred. Records that can be
promptly retrieved from another location by electronic or other means are acceptable. Data
may be recorded by electronic data processing systems or photographic or other reliable means,
but detailed procedures relating to the system in use should be available and the accuracy of
the records should be checked. If documentation is handled by electronic data processing
methods, only authorized persons should be able to enter or modify data in the computer, and
there should be a record of changes and deletions. Access should be restricted by passwords or
other means and the result of entry of critical data should be independently checked. Batch
records that are electronically stored should be produced by back up transfer onto magnetic
tape, microfilm, paper or other means.
Specifications should be established and documented for raw materials, intermediates and API
/formulations, as well as labelling and packaging materials. In addition, specifications may be
appropriate for certain other materials, such as process aids, gaskets or other materials used
during the production of intermediate API/ formulation that could critically impact on quality.
Acceptance criteria could be established and documented for in- process control. Master
production instructions/Master production and control record ( MPCR) / Master formula
card(MFC) to ensure uniformity from batch to batch, master production instruments for each
intermediate or API /finished product should be prepared, date, and signed by one person and
independently checked, date, and signed by a second person in the quality unit(s)
Competent persons experienced in production and quality control should be responsible for
content and distribution within the firm of instructions and master formulae. This should be
duly signed and date, outdated master formulae should be withdrawn but returned for reference.
Copies of the master formula should be prepared in a manner that will eliminate any possibility
of transcription error in certain circumstances, for e.g., in the one production runs following
pilot development, the master formula might need to be amended, any amendment must be
formally authorised and signed by component person(s). The amended document should be
replaced at the earliest opportunity by a newly prepared master formula. Processing should be
carried out accordance with the master formula.

TYPES OF DOCUMENT
There are various types of procedures that a GMP facility follows. Given below is a list of the
common types of documents.
1. Quality manual: A global company document that describes, in paragraph form, the
regulations and /or parts of the regulations that the company is required to follow.
2. Policies: Documents that describe in general terms, and not with step-by-step
instructions, how specific GMP aspects (such as security, documentation, health, and
responsibilities) will be implemented.
3. Standard operating procedures (SOPS): Step-by-step instructions for performing
operational tasks or activities.
4. Batch records: These documents are typically used and completed by the manufacturing
department. Batch records provide step-by-step instructions for production-related tasks
and activities, besides including areas on the batch record itself for documenting such
tasks.
5. Test methods: These documents are typically used and completed by the quality control
(QC) department. Test methods provide step-by-step instructions for testing supplies,
materials, products, and other production-related tasks and activities, e.g., environmental
monitoring of the GMP facility. Test methods typically contain forms that have to be
filled in at the end of the procedure; this is for documenting the testing and the results of
the testing.
6. Specifications: Documents that list the requirements that a supply, material, or product
must meet before being released for use or sale. The QC department will compare their
test results to specifications to determine if they pass the test.
7. Logbooks: Bound collection of forms used to document activities. Typically logbooks
are used for documenting the operation, maintenance, and calibration of apiece of
equipment. Logbooks are also used to record critical activities, e.g.; monitoring of clean
rooms, solution preparation, recording of deviation, change controls and its corrective
action assignment.
BATCH PROPUCTION RECORDS/BATCH PRODUCTION ANDCONTROL,
RECORDS (BPCR)/BATCH MANUFACTURING RECORD (BMR)
Definition: Batch manufacturing record is a written document of the batch, prepared during
pharmaceutical manufacturing process. It contains actual data and step by step process for
manufacturing each batch. Batch manufacturing record is like a proof that batches were
properly made and checked by quality control personnel.
Batch production records should be prepared for each intermediate and API/formulation and
should include complete information relating to the production and control of each batch. The
batch production record should be checked before issuance to assure that it is the correct
version and a legible accurate reproduction of the appropriate master production instruction. If
the batch production record is produced from a separate part of the master document, that
document should include a reference to the current master production instruction being used.
Before any processing begins, a check should be performed and recorded to ensure that the
equipment and workstation are clear of previous products, documents, or materials not required
for the planned process and that the equipment is clean and suitable for use.
These records should be numbered with unique batch or identification number and dated and
signed when issued. In continuous production, the product code together with the date and time
can serve as the unique identifier until the final number is allocated.
The batch number should be immediately recorded in a logbook or by electronic data
processing system. The record should include date of allocation, product identity, and size of
batch.
Documentation of completion of each significant step in the batch production records (batch
production and control records) should include:
 Dates and, when appropriate, times.
 Identity of major equipment used (e. g, reactors, driers, mills, etc.)
 Specific identification of each batch, including weights, measures, and batch numbers
of raw materials, intermediates, or by reprocessed materials used during manufacturing.
 Actual results recorded for critical process parameters.
 Any sampling performed.
 Signatures of the persons performing and directly supervising or checking each critical
step in the operation.
 In-process and laboratory test results.
 Actual yield at appropriate phases or times.
 Description Of packaging and label.
 Representative label (commercial supply).
 Any deviation noted, its evaluation, and investigation conducted (if appropriate) or
reference to that investigation (if stored separately).
 Results of release testing.
 All analytical records relating to the batch, or a reference that will permit their retrieval.
 A decision for the release or rejection of the batch, with the date and signature of the
person responsible for the decision.
 The production record review.
Production and quality control records should be reviewed as part of the approval process of
batch release. Any divergence or failure of a batch to meet its specifications should be
thoroughly investigated. The investigation should, if necessary, extend to other batches of the
same product and other products that may have been associated with the specific failure or
discrepancy. A written record of the investigation should be made and should include the
conclusion and follow-up action
The following information should be recorded at the time each action is taken (the date must
be noted and the person responsible should be clearly identified by signature or electronic
password):
  The name of the product, the batch number and the quantity of product to be packed,
as well as the quantity actually obtained and its reconciliation.
 The date(s) and time(s) of the packaging operations.
 The name of the responsible person carrying out the packaging operation.
 The initials of the operators of the different significant steps.
 The checks made for identity and conformity with the packaging instructions, including
the results of in-process controls.
 Details of the packaging operations carried out, including references to equipment and
the packaging lines used and, when necessary, instructions for keeping the product
unpacked or a record of returning product that has not been packaged to the storage
area.
 Whenever possible, the regular check for correctness of printing (e.g. batch number
expiry date and other additional overprinting) and specimen samples collected.
 Notes on any special problems, including details of any deviation from the packaging
instructions, with written authorization by an appropriate person.
 The quantities and reference number or identification of all printed packaging materials
and bulk product issued, used, destroyed, or returned to stock and the quantities of
product obtained; this is necessary to permit an adequate reconciliation

MASTER FORMULA RECORD

Definition: A document or set of documents specifying the starting material with their
quantities and the packaging materials, together With a description of the procedure and
precautions required to produce a specified quantity of a finished product as well as the
processing instructions, including the in-process controls."
Master production instructions should include:
 The name of the intermediate/AP/ formulation being manufactured and an identifying
document reference code, if applicable
 A complete list of raw materials and intermediates (designated by names or
code497sufficiently specific to identify any special quality characteristic)
 An accurate statement of the quantity or ratio of each raw material or intermediate to
be used, including the unit of measure. Where the quantity is not fixed, the calculation
for each batch size or rate of production should be included. Variations to quantities
should be included wherever justified.
 The production location and major production equipment to be used
 Detailed production instructions, including the:
i. Sequences to be followed
ii. Ranges Of process parameters to be used
iii. The methods, or reference to the methods, to be used for preparing the critical
equipment (e.g., cleaning, assembling)
iv. Sampling instructions and in-process controls, with their acceptance criteria where
appropriate
v. Time limits for completion of individual processing steps and/or the total process,
Where appropriate
vi. Expected yield ranges at appropriate phases of processing or time
  Where appropriate, special notations and precautions to be followed, or Cross
references to these
 Instructions for storage of the intermediate or API/semi-finished formulations to assure
its suitability for use; instructions should cover the labeling (specimen label sand
packaging materials and special storage conditions with time limits, where appropriate).
Master Formula Record is also called MFR, Master Production Record. MFR is used as
reference standard for preparing batch manufacturing record (BMR) by manufacturing units.
It is prepared by the research and development team of the company. It contains all Information
about the manufacturing process for the product. Master Formula Record (MFN) is a master
document for any pharmaceutical product. MFR plays an important. Inconsistency for each
batch manufacturing. There shall be Master Formula records relating to all manufacturing
procedures for each product and batch size to be manufactured. These shall be prepared and
endorsed by the competent technical staff i.e., head of production and quality control. A Master
Formula Record is ether prepared based upon experience of impotent qualified staff like
manufacturing chemist or analytical chemist or prepared based upon batch manufacturing
record of a batch size.
MFR includes-
 Product Details : Name, logo and address of the manufacturing company
 Dosage form name. Brand name, Generic name.
 Product code and Label claim of all ingredients
 Product description : Batch size, Pack size and packing style
 Shelf life and Storage conditions
 MFR number and date: Supersede MFR number and date
 Effective batch number
 Authorization by the production and quality assurance head
 Equipment: A list of all required equipment and machines required in the
Manufacturing process with their capacity
 Special instructions: The precautions and special instructions to be followed during the
product manufacturing and packing
 Calculations: Include the calculation steps of all active materials to get the 100% of the
active material. The calculation is done using water or LOD to get 100% potency
 Manufacturing Process: All steps in all stages of the manufacturing process are written.
All process steps like shifting, milling, lubricating, granulation, compression and
coating are written in detail including the process time and yield. It also include
atmospheric conditions as temperature, humidity, and storage conditions for every step
 Packing Process: List of all packing materials with their quantity is written. Line
clearance, reconciliation of printed and unprinted packing materials should be included
in details
 Yield: Include the theoretical, actual yield and acceptance limit of the batch.
Primary Responsibility is of FD and Production Department and secondary responsibility is of
Quality Assurance Department. Accountability lies with Head-Quality Assurance for
Implementation of SOP.
Steps in preparation of MFR:
Production Department in association with PD prepares MFR. It is divided into two sections;
1) Manufacturing 2) Packaging
The first page of both the sections shall have following details: Name, address and logo of the
company, Dosage form, Brand name Generic name Product code Label claim include all
ingredients and text included in product permission. Product Description, Shelf Life, Pack Size,
Batch Size and Storage conditions.
The secondary page of manufacturing section shall include-Processes to monitor. Subsequent
pages shall include the processes to be monitored. The list of equipment machines, utensils to
be used, shall be described. The subsequent page shall include any Special precautions to be
taken for the product during manufacturing and packing. The same should also include Batch
Manufacturing formula
At the end of every important stage, include a statement of the yield with the acceptable Limits.
In-process quality checks during and at the end of important steps and stages with their limits
are included. The process shall include the equipment to be used. The methods or the reference
of the methods/procedures to employed for preparing, cleaning assembling, operating the
various equipments are given. Detailed stepwise processing instructions (example: checks on
materials, pretreatments, sequence for adding materials, mixing times, temperatures, humidity
etc.) is included. The requirements for storage conditions of the products is also present.
The secondary page of packaging section of MFR should include complete list of all then
packaging materials required for a standard batch size including quantities sizes and types
Include line clearance checking during batch cording and batch packaging operations. Includes
reconciliation of printed and unprinted packaging materials with acceptable limits. Includes
destruction of excess or rejected printed packaging materials Includes description of packaging
Operation including any significant subsidiary operations and equipments to be used.
SOP:
A Standard Operating Procedure (SOP) is a set of written instructions that document a routine
or repetitive activity which is followed by employees in an organization. The development and
use of SOPs are an integral part of a successful quality system. It provides information to
perform a job properly, and consistently in order to achieve pre-determined specification and
quality end result. SOs should allow for the continual improvement of standards of service, and
provide evidence of commitment towards protecting patients.
BENEFITS OF SOP
1. Standard Operating Procedure (SOP is a set of written instructions that document
routine or repetitive activity which is followed by employees in an organization
2. To ensure that processes continue uninterrupted and are completed on a Described
schedule. Ensure against process shut-downs caused by equipment failure or other
facility damage.
3. To ensure that no failures occur in manufacturing and other processes that would harm
anyone in the surrounding community. Following health and environmental Steps in
SOPs ensures against spills and emissions that threaten plant neighbours and create
community outrage
 4. To ensure that approved procedures are followed in compliance with company and
Government regulations. Well-written SOPs help ensure that government regulations
are satisfied. They also demonstrate a company good-faith intention to operate properly.
5. To serve as a training document for teaching users about the process for which the SOP
was written. Thorough SOPs are used as the basis for providing standardized Training
for employees who are new to a particular job and for those who need retraining
6. To serve as a checklist for co-workers who observe job performance to reinforce proper
performance. The process of actively caring about fellow workers involves one worker
coaching another in all aspects of proper job performance. When the proper procedures
are outlined in a good SOP, any co-worker can coach another to help improve work
skills.
7. To serve as a checklist for auditors. Auditing job performance is a process similar to
Observation mentioned in the previous item only it usually involves record keeping.
SOPs should serve as a strong basis when detailed audit checklists are developed.
8. To serve as an historical record of the how, why and when of steps in an existing process
so thee is a factual basis for revising those steps when a process or equipment are
changed. As people move from job to job within and between companies, unwritten
knowledge and skills disappear from the workplace. Properly maintained written SOPs
can chronicle the best knowledge that can serve new workers when older ones move on
9. To serve as an explanation of steps in a process so they can be reviewed in accident
investigations. Although accidents are unfortunate, view them as opportunities to learn
how to improve conditions. A good SOP gives you a basis from which to being
investigating accidents

SOP REQUIREMENTS
The data generated through these procedures should be maintained to show compliance with
the above mentioned requirements.
 Prepare apex documents like Quality Policy, Quality Manual, Site Master File,
Validation Master Plan, etc. to describe the quality commitments of the management
 Define the roles and responsibilities of all personnel working in the organization
 Prepare policy for periodic review of documents. Ensure that the current industrial
practices and Pharmacopoeial requirements are fulfilled by the current versions of
documents
 SOP for document (SOPS, MPCR, BPCR, validation/qualification protocols,
formats)preparation, review, approval, training, distribution, control, and its retention
 Procedure for maintaining revision history
 Management, control, and retention of superseded or obsolete documents
 Document archival and retrieval procedure
 Handling, archival, retrieval, and retention of electronic records/documents
 Procedure for control of electronic signatures
 Equipment cleaning and sanitation procedure
  Issuance and control of equipment logs
 Document describing measures taken for avoidance of cross contamination and it's
training records
 Cleaning validation master plan
 Procedure for batch-to-batch and product-to-product cleaning and its verification to
ensure removal of residue of previous batch/product
 Records for incoming raw materials and packaging materials
 SOP for preparation of process validation protocol and reports
 SOP for preparation of master production control records
 SOP for preparation of batch manufacturing and control records
 SOP for allocation of batch number
 Calibration master plan and calibration reports
 Batch release procedures
 SOP for preparation and control of QC data sheet
 SOP for allocation of analytical control number
 Procedure for review of analytical data
 SOP for investigation of OOS results
 SOP for change control, revision of any process or documents, or upgradation of facility
or equipment should be routed through impact assessment and change control
procedure
FORMAT OF TECHNICAL SOP
In general, technical SOPS will consist of five elements:
 Title page:
 Table of Contents
 Procedures
 Quality Assurance/Quality Control
 References
1. Title Page.
2. Table of Contents
3. Procedures - The following are topics that may be appropriate for inclusion in technical
SOPS. Not all will apply to every procedure or work process being detailed.
a. Scope end Applicability (describing the purpose of the process or procedure and any
organization or regulatory requirements, as well as any limits to the use of the
procedure),
b. Summary of Method (briefly summarizing the procedure),
c. Definitions (identifying any acronyms, abbreviations, or specialized terms used),
Health & Safety Warnings (indicating operations that could result in personal injury or
loss of life and explaining what will happen if the procedure is not followed or is
followed incorrectly; listed here and at the critical steps in the procedure
d. Cautions (indicating activities that could result in equipment damage, degradation of
sample, or possible invalidation of results; listed here and at the critical steps in the
procedure)
e. Interferences (describing any component of the process that may interfere with the
accuracy of the final product),
 f. Personnel Qualifications/Responsibilities (denoting the minimal experience the user
should have to complete the task satisfactorily, and citing any applicable requirements,
like certification or "inherently governmental function"),
g. Equipment and Supplies (listing and specifying, where necessary, equipment,
materials, reagents, chemical standards, and biological specimens
h. Procedure (identifying all pertinent steps, in order, and the materials needed to
accomplish the procedure such as:
 Instrument or Method Calibration and Standardization
 Sample Collection
 Sample Handling and Preservation
 Sample Preparation and Analysis (such as extraction, digestion, analysis,
identification, and counting procedures)
 Troubleshooting
 Data Acquisition, Calculations & Data Reduction Requirements (such as listing any
mathematical steps to be followed)
 Computer Hardware & Software (used to store field sampling records, manipulate
analytical results, and/or report data)
 Data and Records Management (e.g., identifying any calculations to be performed,
forms to be used, reports to be written, and data and record storage information).
4 Quality Control and Quality Assurance Section -QC activities are designed to allow self-
verification of the quality and consistency of the work. Describe the preparation of
appropriate QC procedures (self-checks, such as calibrations, recounting, reidentification)
and QC material (such as blanks - rinsate, trip, field, or method; replicates; splits; spikes;
and performance evaluation samples) that are required to demonstrate successful
performance of the method. Specific criteria for each should be included. Describe the
frequency of required calibration and QC checks and discuss the rationale for decisions.
Describe the limits/criteria for QC data/results and actions required when QC data exceed
QC limits or appear in the warning zone. Describe the procedures for reporting QC data
and results.
5 Reference Section - Documents or procedures that interface with the SOP should be fully
referenced (including version), such as related SOPS, published literature, or methods
manuals. Citations cannot substitute for the description of the method being followed in the
organization. Attach any that are not readily available.

QUALITY AUDIT:
A systematic and independent examination to determine quality activities and related results
comply with the planned arrangements and whether these arrangements are implemented
effectively and are suitable to achieve objectives
Quality audit are typically performed at defined intervals. Any failure in their proper
implementation may be published publicly and may lead to revocation of quality certification
TYPES OF AUDIT:
 A first is an audit performed by an organization on itself i.e. an internal audit
  A Second party audit performed by one organization on its own behalf on another
usually on a supplier by a customer
 A third party audit is an audit by an independent organization other than the customer
on a supplier

PHASES OF AUDIT:
 Phase-01 Preparation: this phase precedes the actual review meeting it is the
responsibility of the chairman and presenter to organize the quality review and notify
all that invited
 Phase-02 The review meeting: the central phase of quality review process is the review
meeting itself during the review meeting the emphasis should be on error detection, in
line with the criteria, and only limited discussion of corrective action should occur
 Phase-03 The follow-up: following the quality review meeting there should be a follow
up period during which the error identification at the review that were committed to
follow-up action list are rectified and signed

OBJECTIVES OF QUALITY AUDIT:

Pharmaceutical manufacturer audit as an effective mechanism to verily comply with GMP
regulation. The general objectives of quality audit are as follows:
 To determine conformity or non conformity of the quality system elements with
specified requirements
 To determine the effectiveness of the implemented system in meeting specific quality
objectives
 To afford an opportunity to improve the quality system
 To provide managers with information

PRINCIPLES OF AUDITING:
 Ethical conduct : the foundation of professionalism, trust, integrity, confidentiality and
discretion are essential to auditing
 Fair presentation: the obligation to report truthfully and accurately
 Due professional care: the application of diligence and judgment in auditing
 Independence: the bases for the impartiality of the audit and objectives of the audit
conclusions. Evidence based approach: the rational method for reaching reliable and
reproducible audit

TYPES OF QUALITY AUDIT:

 Adequacy audit/ document audit:
 This is also known as system or management audit and is normally documented system
represented by the quality manual and the associated procedures adequately meets the
need of the application standard
 Compliance audit/ on-site audit:
This is the audit which seeks to establish the extent to which the documented system
is implemented and observed by the workforce, .i.e. are the people complying with the
system
 External audit:
This is the most important type of audits, which requires the company to look into its
own suppliers or subcontractors. Purpose of external audit is to gain confidence in the
partnership arrangement. This ensures that requirements are understood. There is a
reduction of in-house Q.C testing of starting materials and reduces the risk of failure
 Internal audit:
This is the most important types of audits, which requires the company to look into its
own systems, procedures and activities in order to ascertain whether they are adequate
and being complied with. It provides the management with the information on whether
or not their policies are being met, if the system is an efficient and as effective as it
should be and whether any changes are needed. It can provide a line of communication
throughout the company and be a great motivator
 Product/ process audit:
Product review refers to an in-depth examination of a particular product/service to
evaluate whether it conforms to product specifications, performance standards and
customer requirements. Process audit refers to an analysis of elements of process and
appraisal of completeness, correctness of conditions and probable effectiveness.

 THE AUDIT LIFE CYCLE:

AUDIT METHODS AND TECHNIQUIES:
Audit methods and techniques are categorized based on the purpose of audit.
 Horizontal auditing:
It involves examination of each functional area of an organization to verily adequacy
and implementation of quality. Used for internal system auditing and second and third
party assessment when it is necessary to establish if a basic QMS has been installed
and is being implemented and maintained. Each functional area is checked for
conformance with quality system requirements, applicable to that area
 Vertical auditing:
It involves examining functional areas of an organization that are actively contributing
to a specific work package or contractual requirement
 Random auditing:
It examines the various aspects of an organization’s operation as determined by auditor
and due to the need to closely examine a particular actively or generally probe the
system in a random manner

ROLE OF GMP AUDITS IN Q.A AND PROGRAMMES

 Auditor's review on sops employees' practices and behaviour.
 Compare master specifications against compendia & regulatory requirements.
 Verify the test data and validation testing.
 Validation test reports are compared against raw data.
 Verify corrective actions taken in reaction to audit finding.
GMP Regulation Format
The basic elements are derived from the following subparts of regulations:
 Organization and personnel
 building and facilities
 Equipments Production and Processing controls
 Production and packaging control
 Holding and distribution
 Lab controls
 Records and reports
 Returned and salvaged drug
Written Criteria & SOP has to be established defining which audit data or elements are to be
considered in the assessment of program performance. Formal Witten SOPs should fully
describe the details for carrying out the various audit functions like: The responsibility for audit
data review Personnel responsible for recommendation Decisions concerning corrective
actions Effective use of written criteria to ensure that conditions and practices remain under
suitable state of control. SOPs should be established.
Planned periodic frequency
Each firm must establish the optimum time interval between audits based on several important
factors like: -intended purpose -objectives, scope and depth -prior history of and it finding Two
types of Visits can be done depending on the type of audit: Announced Visit Un-announced
Visit.
Personnel: The following personnel factors deserve systemic attention.
• Defining audit or Qualification: Auditors ate selected based on their knowledge in
manufacture and QC as well as years of first hand dealing with GMP matters. Essential
Auditor skill includes awareness Of firm's SOP Sknowledge about its various
departments
• Documentation training skills & Experience: There are usually 2 formats
(1)principles, training under chemistry, engineering, statistics and (2)GMP training
may include the cumulative knowledge from reasonable years of experience. This
knowledge comes from; daily activities and formal training sessions.
• Audit teams: The personnel in the audit team are selected based on their and
knowledge. The team is required to cover many different systems and large amount
of data. Composition of team will vary depending upon the nature and scope of the
audit. Leader is usually a senior auditor who has extensive knowledge of the firm's
operations & has strong leadership qualities. Tem size depends upon: Firm size
Total number of products manufactured & control systems.
REPORTING AUDIT FINDING
Audit reports should contain complete details of the program detected. Corrective action
is taken to eliminate problems and to measure the overall adequacy of the audit program.
There are two important reporting reports during the audit (2)Final report to the
management
BENEFITS DERIVED FROM AUDITS
The major benefits that are derived from Audits are as follows:
• Assuring GMP compliance
• Detecting potential problems
• Effecting programmed improvement
• Increasing management awareness
AUDIT CHECK
• Documentation work.
• QA/QC Issues.
• SOP Manuals.
• Building and Facilities.
• Failure Investigation.
• Process Validation Program
• Master Records.
• Production and In-Process controls.
• Packaging and labelling of API's and Intermediates.
 • Equipment Processing.
• Storage and Distribution.
• Material Management.
• House keeping facilities

QUALITY REVIEW
Quality review is an evaluation conducted at regular periodic or rolling registered
medicinal reviews of standard of each drug product With the view to verify the consistency
of existing process and to check the appropriateness of current specifications and to
highlight any tends in order to determine the need to change any drug product
specifications or the or control procedures. It is an effective quality improvement tool to
the consistency of manufacturing process and overall quality of the product. A Good
Manufacturing Practice ensures that the products are consistently produced and controlled
according to quality standards.
Annual Product Quality Reviews (APQR) not only are required by GMP but also required
for robust quality improvement for manufacturing the pharmaceutical product. It is a
written report that is required for every drug product, based on data collected at least
annually. It is designed to minimize the risks involved in any pharmaceutical production
that cannot be eliminated through testing the final product. It is universally accepted by
the industry and contents must specify a list of manufactured batches, release data and
reviews of deviations, complaints, recall and returned goods.

HISTORY OF PRODUCT QUALITY REVIEW

The US Food and Drug Administration proposed a necessity to prepare written summary
for each product in its February 13, 1976 by rewriting the good manufacturing practices
(GMP) for drug products. The purpose of this proposed GMP requirement was to provide
reliable procedures for a drug manufacturer to review the quality standards for each drug
product. After numerous comments from industry objecting to the preparation of written
summaries, US FDA revised the proposal to allow each company to establish its own
procedures foe evaluation of product quality standards, by reviewing the records required
by the GMPs on annual basis. This requirement was published as final current good
manufacturing practice (CGMP) regulations for drug products (21 CFR 211.180(e)). Since
its publication, 21 CFR 211.180(e) has been commonly referred by FDA and the
pharmaceutical industry is the "Product Annual Review" (PAR) or the "Annual product
review” (APR). In august: 2001. FDA also adopted and published the guidance for industry
ICHQ7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.
This guidance was developed within the expert Working Group of the International
Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use. This guidance was then incorporated as Part II of the
European Community Guide to GMP (EU Guide) in October 2005.

SIGNIFICANCE OF ANNUAL PRODUCT QUALITY REVIEW (APQR)

 1. Verify the consistency of the existing manufacturing process and minimize the risk to
pharmaceutical products which will be helpful for the pharmaceutical companies to
develop their products consistently of best quality on yearly basis.
2. It determines the quality and process defects of the products.
3. It also determines possible improvements of the analytical methods and manufacturing
process.
4. Trend of yield, analytical results, manufacturing parameters of the product are also
highlighted.
5. It is helpful to identify the process and product defects.
6. It reviews the quality of the raw material and packaging material which is used for the
product
7. Mainly it indicates the quality of material.
8. Verifies the appropriateness of current specifications for both starting materials and
finished product to highlight any trends and to identify product and process
improvements.
9. Out of Specification parameter helps to determine the product defects and the
prospective actions are defending the product from possible risks.
10. If any of the batches is failed, then it is also included in the Annual Product Quality
Review to determine reasons for the batch rejection
11. The review of the stability study results of any long term and on-going stability of the
bulk product and the marketed product should be done.
PROPUCT QUALITY REVIEW ACCORDING TO VARIOUS REGUATORY
AGENCIES
 European Commission
Regular quality reviews of APIs should be conducted with the objective of verifying the
consistency of the process. Such reviews should normally be conducted and documented
annually and should include at least:
 A review of critical in-process control and critical API test results.
 A review of all batches that failed to meet established specification(s).
 A review of all critical deviations or non-conformances and related Investigations
 A review of any changes carried out to the processes or analytical methods review of
results of the stability monitoring program
 A review of all quality-related returns, complaints and recalls
 A review adequacy of corrective actions
The results of this review should be evaluated and an assessment made of whether corrective
action or any revalidation should be undertaken. Reasons for such corrective action should be
documented. Agreed corrective actions should be completed in a timely and effective manner
Periodic Review of Validated Systems System and processes should periodically evaluated to
verify that they are still operating in a valid manner. Where no significant changes have been
made to the system or process, and a quality review confirms that the system or process is
consistently producing material meting its specifications, there is normally no need for
revalidation.

 United states
21 CFR Part 211 Sec 211.115 states about reprocessing one that falls to confirm with all
established standards, and characteristics. Reprocessing shall not be reformed without the
review and approval the quality control unit. See 211.180 states about general requirements for
any production, control, or distribution record shall be retained for at least 1 year after the
expiration date of the batch and in case of OTC drug products lacking the expiration dating
because they meet the criteria for exemption under 21.137, 3 years after distribution of the
batch. The quality standards of each drug product to determine the need for changes in drug
product specifications or manufacturing or control procedure. Written procedures shall be
established and followed for such evaluation and include provisions for:
1) A review representative number of batches, whether approved or rejected, and, where
applicable retorts associated with the batch.
2) A review of complaints, recalls, returned or salvaged drug products, and investigations
conducted for than 211.192 for each drug product, Procedures shall be established to assure
that the responsible officials of the firm if they are not personally involved in or immediately
aware of such actions, are notified in writing of any investigations conducted under 211.198,
21204 or 211.203 of these regulations, any recalls, reports Of inspectional observations issued
by FDA. Sec 2l1.192 states about production Record review, Sec 211.198 states about the all
the complaint files related to the product, and then 211.204 are about the returned Drug
Products etc. Just because of this, it is not always clear exactly what is expected by the
regulatory authority. So it presently a standard FDA practice to make additional and quite
reasonable demands that make is possible to improve the evaluation possibilities for products,
This development is then consistent of with the requirement s of the Guidance for industry
Quality Systems Approach to Pharmaceutical CGMP Regulations Published in Sep 2006. The
US FDA regulations describe very limited the contents for the review and evaluation of the
product but as per EUROPE the contents for the preparation of the APOR are well described.
QUALITY DOCUMENATTON
Documentation plays a key role in the Quality Management System. Documentation are define
the manufacturers system of information & control to minimize the risk of t misinterpretation
& errors inherent in oral or casually written communication, to provide unambiguous
procedures to be followed to provide confirmation of performance, to allow calculations to be
checked & to allow tracing of batch history.
Documents are a mirror to show actual image of any pharmaceutical company. Documents and
products are produced t in pharmaceuticals but regulatory bodies are interested to see
documents
First. Different documents can describe the different activity in pharma and its actual image.
Document is any written statement or proof. Documentation is an essential part of Quality
Assurance and Quality Control system and it is related to all aspects of Good Manufacturing
Practices (GMP). It is mainly defines the specification for all materials, method of
manufacturing and control. It also ensures that personnel concerned with manufacturing should
know information to decide whether to release the batch or not for sale it also provides an audit
trail which also allows the investigation of history of any suspected defective batch. These
documents should be approved, signed, dated by appropriate and authorized person. These
documents shall specify their title, purpose and nature, they should be regularly reviewed and
kept up to date and if any alterations are made in their entry shall be signed with date. Good
documentation encompasses practically all the aspect of pharmaceutical production.
QUALITY DOCUMENTATION HIERARCHY
The 4-tiered hierarchy has been established as a best practice for your quality Documentation
System.

 Quality manual:
The top tier in the hierarchy is the Quality Manual. This is the guiding document that's authored
and approved by upper management and it outlines the company’s goals, mission and vision.
It should outline what the company stands for and why they exist. It fully describes the scope
of QMS i.e. what should be included in the Quality system. It completely explains each and
every requirement of the ISO 9001 std. It contains complete detail and explanation of
exclusions i.e. what should be eliminated in the Quality system.
It contains references for the quality procedures used to describe all the QMS process.
A flow chart representating the series and interaction of the key business processes. The
organisation's quality policies which shows that the organisation is strictly committed to
quality. The quality policy and the objectives can be part of the manual as well.
The quality manual should include most of the following elements:
* Title and table of contents
* Scope of the QMS.
*Exclusions from ISO 9001.
*Versioning info and approval.
* Quality Polity and objectives.
*QMS description.
The business process model of the organisation.
*Definition of responsibilities of all personnel.
*Reference to relevant documents and relevant appendices.
It can be used for the following purposes.
'' To communicate management’s expectations for quality to the organisation.
* To reveal the organisation confirmity with ISO 9001 requirements.
*To serve as a measure for compliance to management's expectations for: internal audits; ISO
registrar audits; Customer audits.

 Quality policy:
A policy represents a declarative statement by an organisation to Quality and continuous
improvement. Usually, the Policy is used for promotional purposes and should be displayed in
the organisations premises and posted on websites, so clear and shot Quality policy is
convenient and is the general practice. The Quality policy defines the Quality objectives to
which the organisation strives. The Quality goals of organisations are defined bye quantifying
the Quality objectives. It should provide an outline for creating, stating and measuring your
performance of the Quality objectives formatting Example: We will consistently provide
products and services that meet or exceed the requirements and expectations of our customers.
We will actively pursue ever improving quality through programs that enable each employee
to do their job right the first time and every time.

 Quality procedures:
Quality procedures can have different formats and structures. They can be narrative i.e.
described through text; they can be more structured using tables; they can be more illustrative
i.e., flowcharts; or they can be any combination of the above.
Quality procedures should include the following elements:
* Title - for identification of the procedure.
*Purpose - describing the rationale behind the procedure;
* Scope - to explain what aspects will be covered in the procedure, and which aspects will not
be covered.
*Responsibilities and authorities of all people / functions included in any part of the procedures.
*Records the result from the activities described in the procedure should be defined and listed.
*Document control - identification of changes, date of review, approval and version of the
document should be included in accordance with the established practice for document control.
*Description of activities - this is the main section of the procedure, it relates all the other
elements of the procedure and describes what should be done, by whom and how, when and
where. In some cases, “why” should be clarified as well. Additionally, the input and the outputs
of the activities should be explained, including the needed resources.
*Appendices may be included, if needed.
  work instructions:
Work instructions can be part of a procedure. Or they can be required in a Procedure.
Generally, work instructions have a similar structure to the procedure; and cover the same
elements; however, the work instructions include details of activities that need to be realized,
focusing on the sequencing of the steps, tools and methods to be required and accuracy.
Training of personal and use of competent personnel decreases the need for highly detailed
work instructions. Work Instructions may cover many of the following details:
*The manner in which the work will be done.
*The equipment and tools that will be used.
* The environment or location associated with the work
*Material handling requirements. *Safety alerts for the employees. *Across-reference to any
other required processes or work instructions.
*The critical process parameters to be monitored and the instructions on how to monitor.
* Equipment maintenance procedures.
* Methods for verifying that the product meets specification.
*Other non-product related criteria for the final product.
 Records:
This Final tier in the Quality Documentation System. All the data, information, records, forms,
etc. are archived. Quality records are the objective evidence to prove that the Quality System
is being executed per procedure. Quality Records also describe how the quality of the end
product was verified to have met the specifications and then meet the customer's needs &
expectations. Records include the following sources:
*Non-Conformance Investigations.
*CAPA’s
*Audit Results
*Supplier Documentation
*Calibration Results
*Maintenance Records
THE ‘DOCUMENTS' MODEL
The “DOCUMENTS" model which lists out the areas required for -GMP document for
implementation:
D- Design, development, deviation, dossiers and Drug Master Files for regulated markets
distribution record.
0- Operational procedures/ techniques/methods, out 0f Specifications (00S). Out of Trend
(00T).
C- Cleaning, calibration, controls, complaints, container and closures, contamination and
change control.
U- User requirement specifications, utilities like water systems, HVAC, AHU etc.
M- Man, materials, machines, methods, maintenance. Manufacturing operations and controls,
monitoring, master formula, manuals (quality, safety and environment), medical records
E- Engineering control and practices, Environmental control, Equipment qualification
documents.
N- Non routine activities, new products and substances.
T-Technology transfer, training, testing. Trend analysis, Technical dossiers.
S- SOPs, safety practices, sanitation, storage, self-inspection, standardization, supplier
qualification, specifications and standard test procedures and site master file.

DOCUMENTS AND RECORDS:

Documentation and records are used throughout the manufacturing process, as well as
Supporting processes (e.g. Quality Control or Quality Assurance), must meet the basic
Requirements of Good Documentation Process. These include (but are not limited to):
1. Batch Record Forms
2. Bills of Materials (BOMs)
3. Specifications
4. Policies
5. Protocols
6. Standard Operating Procedures (SOPs)
7. Work Instructions (WIs)
8. Checklists
9. Forms/Log sheets
10. Certificate of Analyses or Certificate of Compliance
11. Technical transfer reports
12. Technical agreements
13. Technical reports
14. Test Methods
15. Training Assessments
16. Records
17. Worksheets, note books, and log books
18. Validation documentation
19. Manufacturing and packaging instructions
20. Confidentiality agreements
21. Change control
22. Quality system related documents
23. Quality manual
24. Validation protocols and report
25. Deviation reports
26. Audit plans
 27. Electronic and hard-copy Quality records (e.g. non-conformance, corrective and
Preventative actions, internal inspection, change control, training records etc.)
28. Validation Master Plans and validation documents including URS, DO, FAT, 1Q, 0Q,
PQ, and Validation reports.
29. Test material related documents including product specification, test material receipt
and Reports.
30. Personnel related documents including training records.
31. Facility related documents including floor plans, HVAC plans, and environmental
Specifications.
32. Deviation forms including unplanned deviations and system failure investigation

Laboratory control records

Laboratory control records should include complete data derived in all tests conducted to
ensure compliance with established specifications and standards, including examinations
and assays, as follows:
 A description of samples received for testing, including the material name or source
Batch number and, where appropriate, the manufacturer and/or supplier, Alternatively,
other distinctive code, date of sample taken and, where appropriate The quantity of the
sample and date the sample was received for testing
 A statement of, or reference to, each test method used
 A statement of the weight or measure of sample used for each test as described by The
method; data on, or cross-reference to, the preparation and testing of reference
Standards, reagents, and standard solutions
 A complete record of all raw data generated during each test, in addition to graphs,
Charts, and spectra from laboratory instrumentation, all properly identified to show the
specific material and the batch tested
 A record. Of all calculations performed in connection with the test including for
Example, units of measure, conversion factors, and equivalency factors
 A statement of the test results and how they compare with established acceptance
Criteria
 The signature of the person who performed each test and the date(s) on which the Tests
were performed
 The date and signature of a second person, showing that the original records were
reviewed for accuracy, completeness, and compliance with established standards.

Complete records should also be maintained for:

 Modifications to an established analytical method
 Periodic calibration of laboratory instruments, apparatus, gauges, and recording
Devices
 All stability testing performed on APls/formulations
 Out-of-specification (OOs) investigations
Complete records should be maintained of any testing and standardization of laboratory
Reference standards, reagents, and standard solutions; record should also be maintained of
Periodic calibration of laboratory instruments, apparatus, gauges, and recording devices.
Batch production record review
Written procedures should be established and followed for the review and approval of batch
Production and laboratory control records, including packaging and labeling, to determine
Compliance of the intermediate or API with established specifications before a batch is
Released or distributed.
Batch production and laboratory control records of critical process steps should be reviewed
and approved by the quality unit(s) before an APl batch is released or distributed. Production
and Laboratory control records of non-critical process steps can be’ reviewed by Qualified
production personnel or other units, following procedures approved by the quality Unit(s).
All Deviation, Investigation, and O0S reports should be reviewed as part of the batch record
review before the batch is released.
The quality Unit(s) can delegate to the production unit the responsibility and authority for
release of intermediates, except for those shipped outside the control of the manufacturing
Company.
Distribution record should be maintained and must include the batch number; quantity
produced; name, address, and contact details of customer; quantity supplied; and date of
Supply.

DISTRIBUTION RECORD
 Maintenance of records of finished product is essential to facilitate complete recall of
Batch if necessary. Distribution13 records are written data related to distribution of
Drug products from the manufacturer to the distributors. The complete data regarding
all batches of drug products should be maintained.

Distribution procedure: It shall include the following:-

 A procedure whereby the oldest approved stock of a drug product is distributed first.
Deviation from this requirement is permitted if such deviation is temporary and
appropriate.
 A system by which the distribution of each lot of drug product can be readily
Determined to facilitate its recall if necessary
 The manufacturer must maintain records of all distribution transactions involving in
Process or finished goods
 A variety of distribution recording system must be utilize
 Computerized tracking systems are most common but paper systems Such as Recording
the lot or control number on the retained copies of the shipping invoices or Recording
the dates on which each lot commenced distribution also use

Particulars in Distribution records

 Name
 Dosage Form and Strength of the Consignment 14(or delivery)
  The quantity of a pharmaceutical(s), made by one manufacturer and supplied at one
Time in response to a particular request or order. A consignment may comprise or More
packages or containers and may include material belonging to more than Batch.
 Name And Address Of Consignee
 Date And Quantity Shipped
 Name, Address And Number Of The Customer That The Product Is Shipped To
 Delivery Order Delivered Date And Number
 Quantity
 Product Batch Number
 Expiry Date
 Date of dispatch
 Quantity of the products, i.e. Number of containers and quantity per container
 Special Storage Requirement or Precautionary Measures to Handle the Product.
 A unique number to allow identification of the delivery order.

REFERENCES
1. A Textbook of Pharmaceutical Quality assurance by Mr. Sanjay A. Nagdev, Mr.
Mayur R. Bhurat, Dr. Md. Rageeb Md. Usman Dr. Krishna R. Gupta, Dr. Upendra
B. Gandagule
 UNIT – IV
Complaints: Complaints and evaluation of complaints, Handling of return good, recalling and
waste disposal.

Complaints
 All complaints and other information concerning potentially defective products should be
carefully reviewed according to written procedures and the corrective action should be
taken.
 A person responsible for handling the complaints and deciding the measures to be taken
should be designated, together with sufficient supporting staff to assist him or her. If this
person is different from the authorized person, the latter should be made aware of any
complaint, investigation or recall.
 There should be written procedures describing the action to be taken, including the need
to consider a recall, in the case of a complaint concerning a possible product defect.
 Special attention should be given to establishing whether a complaint was caused because
of counterfeiting.
 Any complaint concerning a product defect should be recorded with all the original
details and thoroughly investigated. The person responsible for quality control should
normally be involved in the review of such investigations.
 If a product defect is discovered or suspected in a batch, consideration should be given to
whether other batches should be checked in order to determine whether they are also
affected. In particular, other batches that may contain reprocessed product from the
defective batch should be investigated.
 Where necessary, appropriate follow-up action, possibly including product recall, should
be taken after investigation and evaluation of the complaint.
 All decisions made and measures taken as a result of a complaint should be recorded and
referenced to the corresponding batch records.
 Complaints records should be regularly reviewed for any indication of specific or
recurring problems that require attention and might justify the recall of marketed
products.
 The competent authorities should be informed if a manufacturer is considering action
following possibly faulty manufacture, product deterioration, counterfeiting or any other
serious quality problems with a product.

Complaints and Adverse Reactions

All complaints thereof concerning product quality shall be carefully reviewed and recorded
according to written procedures. Each complaint shall be investigated /evaluated by the
designated personnel of the company and records of investigation and remedial action taken
thereof shall be maintained.
Reports of serious adverse drug reactions resulting from the use of a drug along with comments
and documents shall be forthwith reported to the concerned licensing authority.
There shall be written procedure describing the action to be taken, recall to be made of the
defective product.

Product recalls

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  There should be a system to recall from the market, promptly and effectively, products
known or suspected to be defective.
 The authorized person should be responsible for the execution and coordination of
recalls. He/she should have sufficient staff to handle all aspects of the recalls with the
appropriate degree of urgency.
 There should be established written procedures, which are regularly reviewed and
updated, for the organization of any recall activity. Recall operations should be capable
of being initiated promptly down to the required level in the distribution chain.
 An instruction should be included in the written procedures to store recalled products in a
secure segregated area while their fate is decided.
 All competent authorities of all countries to which a given product has been distributed
should be promptly informed of any intention to recall the product because it is, or is
suspected of being, defective.
 The distribution records should be readily available to the authorized person, and they
should contain sufficient information on wholesalers and directly supplied customers
(including, for exported products, those who have received samples for clinical tests and
medical samples) to permit an effective recall.
 The progress of the recall process should be monitored and recorded. Records should
include the disposition of the product. A final report should be issued, including
reconciliation between the delivered and recovered quantities of the products.
 The effectiveness of the arrangements for recalls should be tested and evaluated from
time to time.

Recalled products
Recalled products should be identified and stored separately in a secure area until a decision is
taken on their fate. The decision should be made as soon as possible.

Returned goods
Products returned from the market should be destroyed unless it is certain that their quality is
satisfactory; in such cases they may be considered for resale or re-labelling, or alternative action
taken only after they have been critically assessed by the quality control function in accordance
with a written procedure. The nature of the product, any special storage conditions it requires, its
condition and history, and the time elapsed since it was issued should all be taken into account in
this assessment. Where any doubt arises over the quality of the product, it should not be
considered suitable for reissue or reuse. Any action taken should be appropriately recorded.

Waste materials
Provision should be made for the proper and safe storage of waste materials awaiting disposal.
Toxic substances and flammable materials should be stored in suitably designed, separate,
enclosed cupboards, as required by national legislation.
Waste material should not be allowed to accumulate. It should be collected in suitable
receptacles for removal to collection points outside the buildings and disposed of safely and in a
sanitary manner at regular and frequent intervals.

2
Batch processing records
A batch processing record should be kept for each batch processed. It should be based on the
relevant parts of the currently approved specifications on the record. The method of preparation
of such records should be designed to avoid errors. (Copying or validated computer programmes
are recommended. Transcribing from approved documents should be avoided.)
Before any processing begins, a check should be made that the equipment and work station are
clear of previous products, documents, or materials not required for the planned process, and that
the equipment is clean and suitable for use. This check should be recorded.
During processing, the following information should be recorded at the time each action is taken,
and after completion the record should be dated and signed by the person responsible for the
processing operations:
a) the name of the product;
b) the number of the batch being manufactured;
c) dates and times of commencement, of significant intermediate stages, and of
completion of production;
d) the name of the person responsible for each stage of production;
e) the initials of the operator(s) of different significant steps of production and, where
appropriate, of the person(s) who checked each of these operations (e.g. weighing);
f) the batch number and/or analytical control number and the quantity of each starting
material actually weighed (including the batch number and amount of any recovered
or reprocessed material added);
g) any relevant processing operation or event and the major equipment used;
h) the in-process controls performed, the initials of the person(s) carrying them out, and
the results obtained;
i) the amount of product obtained at different and pertinent stages of manufacture
(yield), together with comments or explanations for significant deviations from the
expected yield;
j) notes on special problems including details, with signed authorization for any
deviation from the master formula.
Batch packaging records
A batch packaging record should be kept for each batch or part batch processed. It should be
based on the relevant parts of the approved packaging instructions, and the method of preparing
such records should be designed to avoid errors. (Copying or validated computer programmes
are recommended. Transcribing from approved documents should be avoided.)
Before any packaging operation begins, checks should be made that the equipment and work
station are clear of previous products, documents or materials not required for the planned
packaging operations, and that equipment is
clean and suitable for use. These checks should be recorded.
The following information should be recorded at the time each action is taken, and the date and
the person responsible should be clearly identified by signature or electronic password:
a) the name of the product, the batch number and the quantity of bulk product to be packed,
as well as the batch number and the planned quantity of finished product that will be
obtained, the quantity actually obtained and the reconciliation;
b) the date(s) and time(s) of the packaging operations;
c) the name of the responsible person carrying out the packaging operation;
d) the initials of the operators of the different significant steps;

3
 e) the checks made for identity and conformity with the packaging instructions, including
the results of in-process controls;
f) details of the packaging operations carried out, including references to equipment and the
packaging lines used, and, when necessary, the instructions for keeping the product
unpacked or a record of returning product that has not been packaged to the storage area;
g) whenever possible, samples of the printed packaging materials used, including specimens
bearing the approval for the printing of and regular check (where appropriate) of the
batch number, expiry date, and any additionaloverprinting;
h) notes on any special problems, including details of any deviation from the packaging
instructions, with written authorization by an appropriate person;
i) the quantities and reference number or identification of all printed pack aging materials
and bulk product issued, used, destroyed or returned to stock and the quantities of product
obtained to permit an adequate reconciliation.
Master formulae Record
A formally authorized master formula should exist for each product and batch size to be
manufactured. The master formula should include:
[1] the name of the product, with a product reference code relating to its specification;
[2] a description of the dosage form, strength of the product and batch size;
[3] a list of all starting materials to be used (if applicable, with the INNs), with the
amount of each, described using the designated name and a reference that is unique
to that material (mention should be made of any substance that may disappear in the
course of processing);
[4] a statement of the expected final yield with the acceptable limits, and of relevant
intermediate yields, where applicable;
[5] a statement of the processing location and the principal equipment to be used;
[6] the methods, or reference to the methods, to be used for preparing and operating the
critical equipment, e.g. cleaning (especially after a change in product), assembling,
calibrating, sterilizing, use;
[7] detailed step-wise processing instructions (e.g. checks on materials, pretreatments,
sequence for adding materials, mixing times, temperatures);
[8] the instructions for any in-process controls with their limits;
[9] where necessary, the requirements for storage of the products, including the
container, the labelling, and any special storage conditions;
[10] any special precautions to be observed.

Standard Operating Procedures (SOPs) and Records

Standard operating procedures and associated records of actions taken or, where appropriate,
conclusions reached should be available for:
(a) equipment assembly and validation;
(b) analytical apparatus and calibration;
(c) maintenance, cleaning and sanitization;
(d) personnel matters including qualification, training, clothing and hygiene;
(e) environmental monitoring;
(f ) pest control;
(g) complaints;
(h) recalls;
(i) returns.

4
There should be standard operating procedures and records for the receipt of each delivery of
starting material and primary and printed packaging material. The records of the receipts should
include:
(a) the name of the material on the delivery note and the containers;
(b) the “in-house” name and/or code of the material if different from (a);
(c) the date of receipt;
(d) the supplier’s name and, if possible, manufacturer’s name;
(e) the manufacturer’s batch or reference number;
(f ) the total quantity, and number of containers received;
(g) the batch number assigned after receipt;
(h) any relevant comment (e.g. state of the containers).
There should be standard operating procedures for the internal labelling, quarantine and storage
of starting materials, packaging materials and other materials, as appropriate.

Standard operating procedures should be available for each instrument and piece of equipment
(e.g. use, calibration, cleaning, maintenance) and placed in close proximity to the equipment.
There should be standard operating procedures for sampling, which specify the person(s)
authorized to take samples.
The sampling instructions should include:
(a) the method of sampling and the sampling plan;
(b) the equipment to be used;
(c) any precautions to be observed to avoid contamination of the material or any
deterioration in its quality;
(d) the amount(s) of sample(s) to be taken;
(e) instructions for any required subdivision of the sample;
(f ) the type of sample container(s) to be used, and whether they are for aseptic sampling or
for normal sampling, and labelling;
(g) any specific precautions to be observed, especially in regard to the sampling of sterile
or noxious material.
There should be a standard operating procedure describing the details of the batch (lot)
numbering system, with the objective of ensuring that each batch of intermediate, bulk or
finished product is identified with a specific batch number. The standard operating procedures
for batch numbering that are applied to the processing stage and to the respective packaging
stage should be related to each other.
The standard operating procedure for batch numbering should ensure that the same batch
numbers will not be used repeatedly; this applies also to reprocessing.
Batch-number allocation should be immediately recorded, e.g. in a logbook. The record should
include at least the date of allocation, product identity and size of batch.

There should be written procedures for testing materials and products at different stages of
manufacture, describing the methods and equipment to be used. The tests performed should be
recorded.

Analysis records should include at least the following data:

(a) the name of the material or product and, where applicable, dosage form;
(b) the batch number and, where appropriate, the manufacturer and/or supplier;

5
 (c) references to the relevant specifications and testing procedures;
(d) test results, including observations and calculations, and reference to any specifications
(limits);
(e) date(s) and reference number(s) of testing;
(f ) the initials of the persons who performed the testing;

(g) the date and initials of the persons who verified the testing and the calculations,
where appropriate;
(h) a clear statement of release or rejection (or other status decision) and the dated signature
of the designated responsible person.

Written release and rejection procedures should be available for materials and products, and in
particular for the release for sale of the finished product by an authorized person.
Records should be maintained of the distribution of each batch of a product in order, e.g. to
facilitate the recall of the batch if necessary.
Records should be kept for major and critical equipment, as appropriate, of any validations,
calibrations, maintenance, cleaning, or repair operations, including dates and the identity of the
people who carried these operations out.
The use of major and critical equipment and the areas where products have been processed
should be appropriately recorded in chronological order.
There should be written procedures assigning responsibility for cleaning and sanitation and
describing in sufficient detail the cleaning schedules, methods, equipment and materials to be
used and facilities and equipment to be cleaned. Such written procedures should be followed.

Quality audit
It may be useful to supplement self-inspections with a quality audit. A quality audit consists of
an examination and assessment of all or part of a quality system with the specific purpose of
improving it. A quality audit is usually conducted by outside or independent specialists or a team
designated by the management for this purpose.
Quality audit may include questionnaires on GMP requirements covering at least the following
items:
(a) personnel;
(b) premises including personnel facilities;
(c) maintenance of buildings and equipment;
(d) storage of starting materials and finished products;
(e) equipment;
(f ) production and in-process controls;
(g) quality control;
(h) documentation;
(i) sanitation and hygiene;
(j) validation and revalidation programmes;
(k) calibration of instruments or measurement systems;
(l) recall procedures;
(m) complaints management;
(n) labels control;
(o) results of previous self-inspections and any corrective steps taken.

6
Documentation & Records
Documentation is an essential part of the Quality assurance system and, as such, shall be related
to all aspects Good Manufacturing Practices (GMP). Its aim is to define the specifications for all
materials, method of manufacture and control, to ensure that all personnel concerned with
manufacture know the information necessary to decide whether or not to release a bath of drug
for sale and to provide an audit trail that shall permit investigation of the history of any suspected
defective batch
Good documentation is an essential part of the quality assurance system and, as such, should
exist for all aspects of GMP. Its aims are to define the specifications and procedures for all
materials and methods of manufacture and control; to ensure that all personnel concerned with
manufacture know what to do and when to do it; to ensure that authorized persons have all the
information necessary to decide whether or not to release a batch of a drug for sale, to ensure the
existence of documented evidence, traceability, and to provide records and an audit trail that will
permit investigation. It ensures the availability of the data needed for validation, review and
statistical analysis. The design and use of documents depend upon the manufacturer. In some
cases some or all of the documents described below may be brought together, but they will
usually be separate.
General
 Documents should be designed, prepared, reviewed and distributed with care. They
should comply with the relevant parts of the manufacturing and marketing authorizations.
 Documents should be approved, signed and dated by the appropriate responsible persons.
No document should be changed without authorization and approval.
 Documents should have unambiguous contents: the title, nature and purpose should be
clearly stated. They should be laid out in an orderly fashion and be easy to check.
Reproduced documents should be clear and legible. The reproduction of working
documents from master documents must not allow any error to be introduced through the
reproduction process.
 Documents should be regularly reviewed and kept up to date. When a document has been
revised, a system should exist to prevent inadvertent use of the superseded version.
Superseded documents should be retained for a specific period of time.
 Where documents require the entry of data, these entries should be clear, legible and
indelible. Sufficient space should be provided for such entries.
 Any alteration made to a document should be signed and dated; the alteration should
permit the reading of the original information. Where appropriate, the reason for the
alteration should be recorded.
 Records should be made or completed when any action is taken and in such a way that all
significant activities concerning the manufacture of pharmaceutical products are
traceable. Records should be retained for at least one year after the expiry date of the
finished product.
 Data (and records for storage) may be recorded by electronic data-processing systems or
by photographic or other reliable means. Master formulae and detailed standard operating
procedures relating to the system in use should be available and the accuracy of the
records should be checked. If documentation is handled by electronic data-processing
methods, only authorized persons should be able to enter or modify data in the computer,
and there should be a record of changes and deletions; access should be restricted by
passwords or other means and the entry of critical data should be independently checked.

7
 Batch records stored electronically should be protected by back-up transfer on magnetic
tape, microfilm, paper print-outs or other means. It is particularly important that, during
the period of retention, the data are readily available.

Documents required
Labels
Labels applied to containers, equipment or premises should be clear, unambiguous and in the
company’s agreed format. It is often helpful in addition to the wording on the labels to use
colours to indicate status (e.g. quarantined, accepted, rejected, clean).
All finished drug products should be identified by labelling, as required by the national
legislation, bearing at least the following information:
(a) the name of the drug product;
(b) a list of the active ingredients (if applicable, with the INNs), showing the amount of
each present and a statement of the net contents (e.g. number of dosage units, weight,
volume);
(c) the batch number assigned by the manufacturer;
(d) the expiry date in an uncoded form;
(e) any special storage conditions or handling precautions that may be necessary;
(f ) directions for use, and warnings and precautions that may be necessary;
(g) the name and address of the manufacturer or the company or the person responsible
for placing the product on the market.

For reference standards, the label and/or accompanying document should indicate potency or
concentration, date of manufacture, expiry date, date the closure is first opened, storage
conditions and control number, as appropriate.
Specifications and testing procedures
Testing procedures described in documents should be validated in the context of available
facilities and equipment before they are adopted for routine testing.
There should be appropriately authorized and dated specifications, including tests on identity,
content, purity and quality, for starting and packaging materials and for finished products; where
appropriate, they should also be available for intermediate or bulk products. Specifications for
water, solvents and reagents (e.g. acids and bases) used in production should be included.
Each specification should be approved, signed and dated, and maintained by quality control,
quality assurance unit or documentation centre. Specifications for starting materials,
intermediates, and bulk, finished products and packaging materials are referred to the following
sections.
Periodic revisions of the specifications may be necessary to comply with new editions of the
national pharmacopoeia or other official compendia.
Pharmacopoeias, reference standards, reference spectra and other reference materials should be
available in the quality control laboratory.
Specifications for starting and packaging materials
Specifications for starting, primary and printed packaging materials should provide, if applicable,
a description of the materials, including:
(a) the designated name (if applicable, the INN) and internal code reference;
(b) the reference, if any, to a pharmacopoeial monograph;
(c) qualitative and quantitative requirements with acceptance limits.

8
Depending on the company’s practice other data may be added to the specification, such as:
(a) the supplier and the original producer of the materials;
(b) a specimen of printed materials;
(c) directions for sampling and testing, or a reference to procedures;
(d) storage conditions and precautions;
(e) the maximum period of storage before re-examination.
Packaging material should conform to specifications, and should be compatible with the material
and/or with the drug product it contains. The material should be examined for compliance with
the specification, and for defects as well as for the correctness of identity markings.
Documents describing testing procedures should state the required frequency for re-assaying
each starting material, as determined by its stability.
Specifications for intermediate and bulk products
Specifications for intermediate and bulk products should be available. The specifications should
be similar to specifications for starting materials or for finished products, as appropriate.
Specifications for finished products
Specifications for finished products should include:
(a) the designated name of the product and the code reference, where applicable;
(b) the designated name(s) of the active ingredient(s) (if applicable, with the INN(s));
(c) the formula or a reference to the formula;
(d) a description of the dosage form and package details;
(e) directions for sampling and testing or a reference to procedures;
(f ) the qualitative and quantitative requirements, with acceptance limits;
(g) the storage conditions and precautions, where applicable;
(h) the shelf-life.

Distribution Records
 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 for distribution shall be maintained in a manner such that finished batch of a
drug can be traced to the retain level to facilitate prompt and complete recall of the batch,
if and when necessary.
Reference:
https://www.who.int/medicines/areas/quality_safety/quality_assurance/QualityAssurancePharmVol2.p
df

9
 Subject Name: Quality Assurance Module -V
Subject Code: BP 606T

Objectives of the course

➢ Understand the scope of quality certifications applicable to pharmaceutical industries

Learning outcomes
➢ Students learnt about the calibration and validation and good warehousing and distribution
practices.
 Structure of Module -5BP 606T
Learning Material

➢ Calibration and Validation- Introduction, definition and general principles of calibration,

qualification and validation, importance and scope of validation, types of validation, validation
master plan.
➢ Calibration of pH meter, Qualification of UV-Visible spectrophotometer, General principles of
Analytical method Validation.
➢ Warehousing- Good warehousing practice, materials management.
 TABLE OF CONTENTS
Calibration
Qualification
o Design Qualification [Dq]
o Installation Qualification [Iq]
o Operational Qualification [Oq]
o Performance Qualification [Pq]
Validation
Organization For Validation
Validation Master Plan
Validation Protocol
Types Of Validation
o Prospective Validation
o Concurrent Validation
o Retrospective Validation
o Re- Validation
Streamlining Validation Operations
Calibration v/s Validation
User Requirement Specifications
Acceptance Testing
o Factory Acceptance Test
o Site Acceptance Test
Calibration And Preventive Maintenance
Calibration OfAnalytical Balance
○ CALIBRATION
• “Calibration of an instrument is the process of determining its accuracy.
The process involves obtaining a reading from the instrument and
measuring its variation from the reading obtained from a standard
instrument.”
• Calibration of an instrument also involves adjusting its precision and
accuracy so that its readings come in accordance with the established
standard.
• This is important for justifying the processes ofQualificationand
Validation.
• The instrument or equipment with the known accuracy is known as
standards. All the other instruments are measured against this standard.
It is important to know that the standards vary from one country to the
other depending upon the type of industry.
• Calibration Achieves 2 Main Objectives —
a) It checks the accuracy of an instrument
b) It determines the traceability of the measurement
 Scope/Purpose of Calibration
Calibration is primarily done to achieve 5 main purposes which are:
To make sure that the readings of equipment or instruments are consistent
with other measurements and display the correct readings every single time
To determine the accuracy, precision, reliability and deviation of the
measurements produced by all the instruments
To establish the reliability of the instrument being used and whether it can
be trusted to deliver repeatable results each time
To map the ‘drift’ as documented. Instruments have a tendency to produce
inaccurate measurements over a period of time, following repeated use.
Ensuring that the industry standards, quality assurance benchmarks such
as and government
regulations are adhered to.
• What Is Instrument Calibration?
can be defined as the process of
comparing the measurements made by the instrument to be
calibrated against a known measurement of either standards
or an instrument known to be making measurements that
exceed the acceptable limits of accuracy and precision.

o Usually, calibration labs prefer a standard with 10 times the

accuracy; however, most regulating organizations and
authorities also accept a 3:1 accuracy ratio.
 Frequency Of Instrument Calibration
• How often you conduct instrument calibration mainly depends
upon its tendency to drift from the true measurement and how
it impacts the quality of the end product. Examine each
instrument being used and study its behavior. Based on this
information, you can design a for each
instrument. The interval between calibrations can vary as:
Weekly
Monthly or bi-monthly
Quarterly, semi-annually or annually
After every heavy usage of the instrument
When Should The Measuring Instruments Be Calibrated?
The frequency of calibrating the measuring instruments depends on a number of
different factors. The following is a guide outlining when instruments need to be
calibrated as a part of GMP:
As soon as you bring in a new instrument, you should calibrate it before you
test it out.
Before and after you take critical measurements
After any instance of electrical or mechanical shock or a similar event that
includes a fall, bump, etc.
When you suspect that the accuracy of measurements being produced is
questionable
If there were any repairs or re-qualifications of the instrument
As per included as part of a calibration schedule
Depending on the task and processes as some require calibration to be
conducted before the work starts
According to the manufacturer’s recommendation
• Commonly Used Calibration Methods and Procedures:
There are different ways that are used to . These
methods are chosen based on the desired results of the calibration and
regulatory authorities’ requirements, like . Let us look at three
such procedures:
• Standard Calibration:This method is mostly preferred for calibrating
instruments that are non-critical to quality or are not required for accreditation
and license purposes. Use traceable standards and document its performance.
• Calibration with Data:Procedures for calibrations with data are similar to
that of accredited calibration. The only exception being that these procedures
are not accredited to the ISO standard. Moreover, they are not accompanied by
data on measurement uncertainties.
• ISO 17025 Accredited Calibration:This has to be the strictest method of
calibration. Generally, it requires a measurement report which has the details
of the measurements that are made against a standard of ‘as found’ (before
calibration is started) and ‘as left’ (once the calibration is completed). If the
calibration is done by a calibration service provider, they must issue a
certificate of the same.
 Importance of Regular Calibration:
is responsible for defining the accuracy of any measurement
and its quality that is recorded by any instrument.
When you start working with any instrument, it must be calibrated
well, thus assuring you of accurate results. However, over a period of
time you will start observing a ‘drift’. Calibration minimizes such
uncertainties by assuring the accuracy of the test equipment.
• When you regularly calibrate your equipment, you can eliminate the drift
at its budding stage instead of allowing it to grow till it affects the
measurements in significant ways.
• Calibration helps in quantifying and controlling errors and uncertainties
within various measurement processes to an acceptable level.
• Further, it helps in improving the accuracy of the measuring device,
which in turn improves the quality of the end product.
• In short, regular calibration allows pharmaceutical companies to have
confidence in their results which they can record, monitor and control.
 QUALIFICATION
• It refers to activities undertaken to demonstrate that utilities
and equipment are suitable for their intended use and
perform properly.
• It is the action ofproving that any equipment or process
works correctly and consistently and produces the expected
results.
• “It is the action of proving and documenting that
equipment or ancillary systems are properly installed, work
correctly, and actually lead to the expected results.”
• Qualification is part of validation, but the individual
qualification steps alone do not constitute process
validation.
• Qualification of analytical instrumentation is essential for
accurate and precise measurement of analytical data. If the
instrumentation is not qualified, ensuring that the results
indicated are trustworthy, all other work based upon the use
of that instrumentation is suspect.
• Qualification of instruments is not a single, continuous
process but instead results from many discrete activities. For
convenience, these activities have been grouped into 4 phases
of qualification. These phases are described below:
Design Qualification (DQ)
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)
 Design Qualification (DQ):
• It is the documented verification that the proposed design of
the facilities, systems and equipment is suitable for the
intended purpose.
• DQ should be performed when new equipment is being
purchased, or when existing equipment is being used for a
new application. DQ serves as the precursor to defining the
equipment Installation Qualification (IQ) and OQ protocols.
• The purpose is to ensure that all the requirements for the final
systems have been clearly defined at the start.

In other words,
“Has it been designed and selected correctly?”
• DQ check items:
GMPs and regulatory requirements
Performance criteria
efficiency and Reliability
requirements Commissioning
Construct ability and installation of equipment
Safety and environment impact
Description of the intended use of the equipment
supplier the of selection Preliminary
Final selection of the equipment
 Installation Qualification (IQ):
• It is documented evidence that the premises, supporting utilities, the
equipment have been built and installed in compliance with design
specifications
• It verifies that the equipment has been installed in accordance with
manufacturers recommendation in a proper manner and placed in an
environment suitable for its intended purpose.
• It involves the co-ordinate efforts of the vendor, the operating department
and the project team.
• The purpose ofI.Q is to check the installation site/environment, confirms
equipment specifications and verifies the condition of installed equipment;
and also to ensure that all aspects (static attributes) of the facility or
equipment are installed correctly and comply with the original design.
In other words,
“Has it been built or installed correctly?”
• In I.Q, connect each unit (Electrical system, Flow line system) and confirm
that the connections are correct.
• IQ check items:
Equipment design features (i.e. material of construction cleanability,
etc.)
Installation conditions (wiring, utility, functionality, etc.)
Calibration, preventative maintenance, cleaning schedules.
Safety features.
Supplier documentation, prints, drawings and manuals.
Software documented.
Spare parts list.
Environmental conditions (such as clean room requirements,
temperature, and humidity).
• Any problems identified in I.Q must be investigated and appropriate
actions must be taken. All such actions must be documented and
approved by higher authority.
 Operational Qualification (OQ):
• It refers to establishing by objective evidence process control limits
and action levels which result in product that all predetermined
requirements.
• OQ is the process of demonstrating that an instrument will function
according to its operational specification in the selected environment.
• The purpose is to ensure that all the dynamic attributes comply with
the original design.
In other words,
“Does it work correctly?”
• Prior to implementing O.Q, check the system configuration, determine
the items to be evaluated and record them in O.Q record and have
them approved.
• OQ check items:
Process control limits (time, temperature, pressure, line speed, setup
conditions, etc.)
Software parameters.
Raw material specifications
Process operating procedures.
requirements. handling Material
control. change Process
Training.
Potential failure modes, action levels and worst-case conditions.
The use ofstatistically valid techniques such as screening experiments to
optimize the process can be used during this phase.

• Any problems identified in O.Q must be investigated and

appropriate actions must be taken. All such actions must be
documented and approved by higher authority.
 Performance qualification:
• After the IQ and OQ have been performed, the instrument’s continued
suitability for its intended use is proved through performance
qualification.
• It refers to establishing by objective evidence that the process, under
anticipated conditions, consistently produces a product which meets all
predetermined requirements.
• PQ should always be performed under conditions that are similar to
routine sample analysis. PQ should be performed on a daily basis or
whenever the equipment is being used.
• PQ considerations include:
Actual product and process parameters and procedures established in OQ.
Acceptability of the product.
Assurance ofprocess capability as established in OQ.
Process repeatability, long term process stability.
• Theobjectiveis to ensure that the instrument is performing within
specified limits. The PQ represents the final qualification of equipment
or system.

• It is used to establish and or confirm;

1. Definition ofperformance criteria and test procedures.
2. Selection of critical parameters, with predefined specifications.
3. Determination of the test intervals, e.g.,
(a) - Everyday.
(b) - Every time the system is used.
(c) - Before, between and after a series of runs.
4. Define corrective actions on what to do if the system does not meet
the established criteria.
 Re – Qualification:
• Modification to, or relocation of equipment should follow satisfactory
review and authorization of the documented change proposal through
the change control procedure. This formal review should include
consideration of re-qualification of the equipment.

• Minor changes or changes having no direct impact on final or in-

process product quality should be handled through the documentation
system of the preventive maintenance program.
 Scope of Performance Qualification.
• According to regulatory documents, like FDA guidelines, the scope ofPQ
is somewhat limited. While equipment validation tests the ability
individually for each piece of equipment, PQ verifies the performance of
equipment, systems and facilities as a whole.
• It represents the final qualification, including any requalification of the
system and equipment that you use in your business.
• Typically, the scope ofPQ extends to include the following scenarios:
New systems being delivered and operated for the first time
Existing systems in use (as part of a regular maintenance schedule)
Systems that have been modified to any degree
Equipment/systems which have been used more than they normally
would be
After a system has been expanded in order to increase its capacity
 Frequency of Performing Performance
Qualification
• The objective ofPQ is to provide quality assurance that the system is
capable of being subsequently validated. GMP and other such
guidelines might not specify the frequency ofperforming PQ,
so the schedule or frequency you choose depends on a lot offactors.
• This will typically be one or more of the following:
• Everyday
• Each time the equipment or system is used
• Before, after, or even during, a series of operations
• Other periodic schedule, or as needed
 VALIDATION:
• Validation is an integral part of quality assurance; it involves the
systematic study ofsystems, facilities and processes aimed at
determining whether they perform their intended functions
adequately and consistently as specified.

• A validated process is one which has been demonstrated to provide

a high degree of assurance that uniform batches will be produced
that meet the required specifications and has therefore been
formally approved.

• Validation in itself does not improve processes but confirms that

the processes have been properly developed and are under control.
• Definitions :
• According toISO:
“Validation is the confirmation by examination and the provision of
objective evidence that the particular requirements for a specific intended
use are fulfilled.”

• According to the US Food and Drug Administration (FDA), the goal of

validation is to:
“Establish documented evidence which provides a high degree of
assurance that a specific process will consistently produce a product
meeting its predetermined specifications and quality attributes.”

• According toEuropean commission:

“Action providing in accordance with the principles of GMP, that any
procedure, process, equipment, material, activity or system actually lead
to the expected results.”
 Adequate validation is beneficial to the manufacturer in many ways:
• It deepens the understanding ofprocesses; decreases the risk of
preventing problems and thus assures the smooth running of the process.
• It decreases the risk of defect costs.
• It decreases the risk of regulatory noncompliance.
• A fully validated process may require less in-process controls and end
product testing.

Validation should thus be considered in the following situations:

• Totally new process;
• New equipment;
• Process and equipment which have been altered to suit changing
priorities; and
• Process where the end-product test is poor and an unreliable indicator of
product quality.
 Scope of validation
• Validation requires an appropriate and sufficient infrastructure including:
– organization, documentation, personnel and finances
• Involvement of management and quality assurance personnel
• Personnel with appropriate qualifications and experience
• Extensive preparation and planning before validation is performed
• Validation should be performed:
– for new premises, equipment, utilities and systems, and processes and procedures;
– at periodic intervals; and
– when major changes have been made.
• Validation in accordance with written protocols.
• Validation over a period of time, e.g. at least three consecutive batches (full
production scale) to demonstrate consistency. (Worst case situations should be
considered.)
• Significant changes (facilities, equipment, processes) - should be validated
• Risk assessment approach used to determine the scope and extent of validation
needed
 Importance of Validation
1. Assurance of quality
2. Time bound
3. Process optimization
4. Reduction of quality cost.
5. Minimal batch failures, improved efficiently and productivity.
6. Reduction in rejections.
7. Increased output.
8. Fewer complaints about process related failures.
9. Reduced testing in process and in finished goods.
10. More rapid and reliable start-up of new equipments
11. Easier maintenance of equipment.
12. Improved employee awareness ofprocesses.
13. More rapid automation.
14. Government regulation (Compliance with validation requirements is
necessary for obtaining approval to manufacture and to introduce new
products)
 ORGANIZATION FOR VALIDATION
Validation organization can be divided into three basic areas;
1. Establishing the organization.
2. Operating itfrom a quality and cost effectiveness basis.
3. Maintaining afunctioning organization.

• Establishing the organization

Formulating a department mission is necessary so that, not
only process validation staff members understand the breadth
of their job, but also the other corporate groups with whom
there is interaction, can also understand.
• Departments responsible
oSite validation committee:- Develop site master validation plan.
oManufacturing department:- Prepares the batches as though their
routine production batches.
o Quality assurance:- Ensure compliance and that documentation,
procedures are in place. Approves protocols and reports.
o Quality controls:- Perform testing contracts validation testing and
reviews protocol and report as needed.
oResearch and development:- Deals with product design.
oEngineering department:- Installation, quality and certify plant,
facilities, equipment and support systems.
• Validation team
A multidisciplinary team is primarily responsible for conducting and
supervising validation studies. Personnel qualified by training and
experience in a relevant discipline may conduct such studies.
• Responsibilities of validation team
Creates updates and reviews/approves individual project validation
plans and validation deliverables.
Ensures validation compliance with the company validation master plan
and project validation plan.
Coordinates, implements, verify elements of VMP.
Consults on, evaluates and approves changes.
Reviews and approves IQ/OQ/PQ procedures and plans.
Reviews test results and makes recommendations regarding release.
Assess risks and develops contingency plan.
ORGANIZATION FOR VALIDATION
• Department interaction:
Once the validation team has been constituted and mission
have been formalized, the team will interact with different
departments which are :
Research and development department
Engineering department,
Production department,
Maintenance department,
Quality control department,
Quality assurance department.
 VALIDATION MASTER PLAN
• The validation master plan should provide an overview of the entire
validation operation, its organizational structure, its content and
planning.
• The main elements of it being them list/inventory of the items to be
validated and the planning schedule.
• All validation activities relating to critical technical operations, relevant
to product and process controls within a firm should be included in the
validation master plan.
It should comprise all prospective, concurrent and retrospective
validations as well as revalidation.
• The Validation Master Plan should be a summary document and should
therefore be brief, concise and clear.
• It should not repeat information documented elsewhere but should refer
to existing documents such as policy documents, SOP’s and validation
protocols and reports.
• The format and content should include:
Introduction: validation policy, scope, location and schedule.
Organizational structure: personnel responsibilities.
Plant/process/product description: rational for inclusions or
exclusions and extent of validation.
Specific process considerations that are critical and those
requiring extra attention.
Key acceptance criteria.
Documentation format.
Reference to the required SOPs.
Time plans of each validation project and sub-project.
List ofproducts/ processes/ systems to be validated, summarized
in a matrix format, validation approach.
Re-validation activities, actual status and future planning
 VALIDATION PROTOCOL
• A written plan stating how validation will be conducted, including test
parameters, product characteristics, production and packaging
equipment, and decision points on what constitutes acceptable test
results.
• This document should give details of critical steps of the manufacturing
process that should be measured, the allowable range of variability and
the manner in which the system will be tested.
• The validation protocol provides a synopsis of what is hoped to be
accomplished.
• The protocol should list the selected process and control parameters,
state the number of batches to be included in the study, and specify how
the data, once assembled, will be treated for relevance. The date of
approval by the validation team should also be noted.
• In the case where a protocol is altered or modified after its approval,
appropriate reasoning for such a change must be documented.
• The validation protocol should be numbered, signed and
dated, and should contain as a minimum the following
information:
objectives, scope of coverage of the validation study
validation team membership, their qualifications and
responsibilities
type of validation: prospective, concurrent, retrospective, re-
validation
number and selection of batches to be on the validation study
a list of all equipment to be used; their normal and worst case
operating parameters
outcome ofIQ, OQ for critical equipment
requirements for calibration of all measuring devices
critical process parameters and their respective tolerances
description of the processing steps: copy of the master
documents for the product
sampling points, stages ofsampling, methods of sampling,
sampling plans
statistical tools to be used in the analysis of data
training requirements for the processing operators
validated test methods to be used in in-process testing and for
the finished product
specifications for raw and packaging materials and test
methods forms and charts to be used for documenting results
 TYPES OF VALIDATION
Prospective validation
• It is defined as the established documented evidence that a system does
what it purports to do based on a pre-planned protocol.
• This validation usually carried out prior to distribution either of a new
product or a product made under a revised manufacturing process.
• Performed on at least three successive production-size (Consecutive
batches).
• The objective of the prospective validation is to prove or demonstrate that
the process will work in accordance with validation protocol prepared
for the pilot production trials. Prospective validation should normally be
completed prior to the distribution and sale of the medicinal product.
• In Prospective Validation, the validation protocol is executed before the
process is put into commercial use.
 Concurrent validation
• It is a process where current production batches are used to monitor
processing parameters.
• Concurrent Validation means establishing documented evidence a
process does what it is supposed to based on data generated during
actual implementation of the process.
• It is important in these cases when the systems and equipment to be
used have been fully validated previously.
• It is similar to prospective, except the operating firm will sell the
product during the qualification runs, to the public at its market price,
and also similar to retrospective validation.
• This validation involves in-process monitoring of critical processing
steps and product testing. This helps to generate and documented
evidence to show that the production process is in a state of control.
 Retrospective validation
• It is defined as the established documented evidence that a system
does what it purports to do on the review and analysis of
historical information. This type of validation of a process is for a
product already in distribution.
• Retrospective validation is only acceptable for well-established
processes and will be inappropriate where there have been recent
changes in the composition of the product, operating procedures
or equipment.
• Validation of such processes should be based on historical data.
• For retrospective validation, generally data from ten to thirty
consecutive batches should be examined to access process
consistency, but fewer batches may be examined ifjustified.
 Revalidation
• Re-validation provides the evidence that changes in a process and /or the
process environment that are introduced do not adversely affect process
characteristics and product quality. Documentation requirements will be the
same as for the initial validation of the process.
• Re-validation becomes necessary in certain situations. Some of the changes
that require validation are as follows:
Changes in raw materials (physical properties such as density, viscosity,
particle size distribution etc., that may affect the process or product).
Changes in the source of active raw material manufacturer.
Changes in packaging material (primary container/closure system)
Changes in the process (e.g., mixing time, drying temperatures and
batch size)
Changes in the equipment (e.g., addition of automatic detection system).
Changes in the plant/facility.
 CALIBRATION v/s VALIDATION
• Calibration and validation are two processes in manufacturing to
guarantee the quality of the product or related apparatus.

• With the calibration, the measurements are compared with an accepted

reference measurement, to assure the considered measurements
comply with the requirements.

• With the validation, the performance, quality, and other operating

parameters of a system are tested to verify that they comply with the
requirements.
 CALIBRATION v/s VALIDATION

CALIBRATION VALIDATION
• Calibration is a demonstration • Validation is a documented
that, a particular Instrument or program that provides high degree
device produces results within of assurance that a specific
specified limits by comparisons process, equipment, method or
with those produced by a reference
system consistently produces a
or traceable standard over an
appropriate range of result meeting pre-determined
measurements. acceptance criteria.
• In calibration performance of an • No such reference standards are
instrument or device is comparing using in validation program.
against a reference standard.
 CALIBRATION
VALIDATION
• Calibration ensures that instrument
or measuring devices producing • Validation provides documented
accurate results. evidence that a process, equipment,
method or system produces consistent
• Shall be performed periodically, to results (in other words, it ensures that
identify the ‘drift’ of the measuring uniforms batches are produced).
device or equipment and make them • No such requirements. Shall be
accurate. performed when changes or
• Shall be performed as per calibration modifications happen to the existing
SOP. system or once revalidation period is
reached.
• Shall be performed as per validation
protocol.
 User Requirements Specification (URS).
• The User Requirements Specification describes the business needs for what
users require from the system.
• User Requirements Specifications are written early in the validation process,
typically before the system is created. They are written by the system owner and
end-users, with input from Quality Assurance.
• Requirements outlined in the URS are usually tested in the Performance
Qualification or User Acceptance Testing.
• User Requirements Specifications are not intended to be a technical document;
readers with only a general knowledge of the system should be able to
understand the requirements outlined in the URS.
• A URS defines clearly and precisely, what the customer (i.e. you) wants the
system to do, and should be understood by both the customer and the
instrument vendor.
• The URS is a living document, and must be kept updated, via a change control
procedure.
• This focuses on the ‘‘what’’ rather than the ‘‘how.’’
• A well-written URS provides several specific benefits, as it:
Serves as a reference against which off-the-shelf commercial products are selected,
evaluated in detail, and any enhancements are defined.
Reduces the total system effort and costs, since careful review of the document
should reveal omissions, misunderstandings and/or inconsistencies in the
specification and this means that they can be corrected easily before you purchase
the system.
Provides the input to user acceptance test specifications and/or qualification of the
system.
• The URS should include:
o Introduction – including the scope of the system, key objectives for the project, and
the applicable regulatory concerns
o Program Requirements – the functions and workflow that the system must be able
to perform
o Data Requirements – the type of information that a system must be able to process
o Life Cycle Requirements – including how the system will be maintain and users
trained
• General Guidance for Writing the Requirements
The following guidelines should be followed during the production of the
specification:
Each requirement statement should be uniquely referenced and no longer than
250 words.
The URS should be consistent and requirement statements should not be
duplicated or contradicted.
Specify requirements and not design solutions. The focus should be on what is
required, but not how it is to be achieved.
Each requirement should be testable. This allows the tests to be designed as soon
as the URS is finalised.
Both the customer and the vendor must understand the document. Therefore,
jargon should be avoided wherever possible and key words are defined in a
specific section in the document.
Requirements should be prioritised as mandatory or desirable.
The URS should be modifiable but changes should be under aformal control
procedure.
A URS is correct if every stated requirement has only one interpretation and is
met by the system. Unfortunately, this is very rare.
 ACCEPTANCE TESTING
• The question of what USER ACCEPTANCE TESTING (UAT) is, becomes very
important as you reach a state of having equipment /systems delivered to a
facility.
• The system/equipment is claimed to be constructed in a manner that has been
defined by a User Requirement, and constructed or fabricated in a manner that
meets the requirements of the industry and ofyour company specifically.You
can ill afford to accept a system or piece of equipment that does not meet these
requirements.

• What is Acceptance Testing?

User Acceptance Testing defines precisely and clearly what the user expects
the system to do. UAT documents contain information about the operating
environment, the required data for processing, and the functionality that the
system should carry out.
Completed during a FAT and a SAT
What is a FAT?
AFATorFactory Acceptance Testis usually preformed at the vendor prior to
shipping to a client. The vendor tests the system in accordance with the clients
approved test plans and specifications to show that system is at a point to be
installed and tested on site.
It’s an essential aspect of the whole system lifecycle and should be performed
by experienced personnel. Time spent doing a proper FAT will lead to fewer
problems when the equipment is installed.
Summary - It is the partial commissioning and qualification of equipment
and/or systems prior to their shipment from the fabricator’s site.
The FAT protocol is an inspection that includes both static and dynamic
exhaustive testing ofsystems or major system components to support the
qualification of equipment or a system. The tests must verify that all
functionality detailed in the User Requirements Specification (URS) is
embodied and performs as specified. It is written by the manufacturers and
executed by the client or client representative.
What is a SAT?
SATisSite Acceptance Testof a system to ensure it is tested in
accordance to client approved test plans and specifications & to show
the system is installed properly and interfaces with other systems and
peripherals in its working environment.
Summary - Inspection and /or dynamic testing of the systems or major
system components to support the qualification of an equipment
system conducted and documented at the manufacturing site.
The SAT is related to the FAT and also entails inspection and dynamic
testing ofsystems or major system components to support the
qualification of equipment. This is written by the client and verifies that
the installed functionality of the equipment meets or exceeds the
operational requirements as specified in the equipment
The SAT is executed on completion of all commissioning tasks; but prior
to the start ofInstallation Qualification execution.
 CALIBRATION AND PREVENTIVE
MAINTENANCE
• Regulations of the regulatory authorities like FDA and EU require that
all the firms have program for calibration and preventive maintenance
for test as well as measurement equipments.
• Preventive maintenance program is one of the most importance aspects
for GMP inspection as it ensures the efficient GMP operations.
• Any equipments either it is automatic or manually operated will
perform its functions properly and are used for manufacturing,
processing, packaging, labeling or holding of drug products; it is
mandatory that it will be timely calibrated, inspected and checked for
errors according to the written program which is specially designed to
assure the best performance of the equipments.
INTRODUCTION
• Definition of Calibration:- "It is a set of operation that performs
under specific conditions to verify the values/data obtained by
comparison of two instruments or measuring devices one of which is a
standard of known accuracy (Traceable to national standards). It is used
to detect, correlate, report or eliminate any of the discrepancy in
accuracy of instruments or measuring devices when being compared to
the standard."
• Calibration is one type of comparison but it is not an adjustments.

• Definition of Preventive Maintenance: "It is a care or service

provided by personnel to maintain the equipment or facility in
satisfactorily working conditions by providing inspections, detection and
correction offailures before they occur. Basically they are
conducted to keep the instrument in working conditions and to extend the
life of the instrument."
Main advantages of PM are:
Improvement in the reliability ofsystem,
Decrease in replacement cost and time,
improved. also is system management Inventory

Requirements of Regulatory Authorities

Calibration program is required by the regulatory authority (FDA)
under section 21 CFR part 211.68 and Preventive maintenance and
calibration program is required by FDA under section 21 CFR part
211.67.
Calibration requirements for Lab instruments under section 21
CFR part 211.67 are: specific directions, schedule, limit of
accuracy and precision remedial action and system to prevent
usage of instrument which are failed to calibrate.
Calibration and maintenance procedure (SOP)
There should be a documented SOP for conducting the
calibration and preventive maintenance for each type of
instrumentation.
The SOP for calibration must includes accuracy and precision
limits and what are the remedial actions should be taken if this
limits do not meet with each other. There should be an
authorized department to perform and monitor calibration and
maintenance.
The SOP must contain the step by step calibration instructions,
instrumentation manual, proper calibration procedures,
provisions for adjustments, provisions for record and
document the actual measurement reading before and after
doing adjustment.
○ Software used for calibration and PM
• Lots of software are used for calibration and PM at industrial scale. This
computerized system has more efficiency and guaranteed the best results.
○ Calibration software
• Quality Calibration Management system (QCMS) is complete instrument
and designed according to the requirements of 21 CFR part 11. This
software ensures regulatory compliance and also traceability. It will help
to improve the reliability ofplant and optimize the administrative
costs. It will help to increase in the productivity as well as efficiency.
○ Preventive maintenance software
• RCM turbo is very popular PM software. Traditional approach took
years to complete just one PM but by using this RCM turbo, anyone can
quickly go for PM. This software directs us through EMEA process. But
the thing is it will go through quickly and efficiently. It is 100 % reliable
and will allow you do risk assessment.
 CALIBRATION OF ANALYTICAL BALANCE
Measure the pan position error of the balance
calibration Daily
The maximum and minimum weight limits of the balance are taken
and divided into four to five parts and single standard weight is
selected in those four or five different regions for the purpose of
daily calibration.
The variation allowed from the standard weight used for measuring
is NMT ±0.1% ofstandard weight.
Drift check from day to day is carried out using any particular
weight and the deviation allowed should not be more than ±1% of
that weight.
 Monthly calibration
• All the standard weights in the maximum and minimum weighing
limits are used in monthly calibration and the deviation allowed
should not be more than ±0.1% of standard weight used. (The
standard weights that are used are E1 and E2 weights)

Measurement of uncertainty
• For measurement of uncertainty any single standard weight is
taken and is weighed for 10 times the readings are noted and the
standard deviation for all the readings is calculated. And
measurement of uncertainty can be measured using the formula:

• Measurement of uncertainty =
GOOD WAREHOUSING PRACTICES
Agenda
Warehouse Design and Construction
Warehouse Maintenance and Sanitation
Good Warehousing practice
Introduction
Warehouse is a suitable place where raw materials or
finished products may be stored before their
distribution.
Proper storage is vital to ensure quality, safety and
efficacy of the pharmaceutical products.
Warehouse Design and Construction
Warehouse must be located, designed, constructed
and maintained to suit the operations and to
minimize risk of cross-contamination.
The layout and design of warehouse should be such
that it avoids build-up of dust or dirt in the
warehouse and permits its effective cleaning and
maintenance.
Lighting and ventilation in warehouse should be
appropriate.
Warehouse Design and Construction
There should be proper controls for temperature and
humidity, so that the quality of pharmaceutical
products should not be adversely affected during
storage.
Measures should also be taken to avoid the entry of
insects, birds, or other animals inside the warehouse.
SOPs should be laid down for prevention for rodents
and for the pest control.
Warehouse Design and Construction
The layout of warehouse shall permit adequate space for
different areas like receiving area, sampling area, dispensing
area, quarantine area etc.
While designing and construction of warehouse, sufficient
space should be provided for orderly warehousing of various
categories of materials and products including raw materials;
in-process and finished products; packaging materials;
released; rejected; returned or recalled products; spare parts
for machine and equipment etc.
Warehouse Design and Construction
Areas inside the warehouse shall be designed
to ensure adequate facilities like racks, bins
and platforms for proper storage of materials
and products.
Warehouse Maintenance and Sanitation
Warehouse should be cleaned, dried and sanitized
regularly.
Where special storage conditions like temperature,
humidity etc. are required, they shall be recorded
and monitored properly.
Written procedure for maintenance and sanitation
should available.
Warehouse Maintenance and Sanitation
These include validated cleaning procedure for
warehouse and equipment; instructions relating to
the health, hygienic practices and clothing of
warehouse personnel; disposal procedures for waste
materials and unusable residues.
Eating, smoking and unhygienic practices shall not be
permitted inside the warehouse.
Written procedures should be laid down for the use
of insecticides, fungicides, rodenticides, and
cleaning, sanitizing and fumigating agents.
Good Warehousing Practices
Stock in the warehouse should be received with
proper documents with details of product name,
batch number, quantity received, the date of
dispatch and the quality control status of batches
received.
The inventory control department are only issued for
market distribution.
Stock should be stored in a manner which allows
quick identification and efficient control over the
stock movement.
Good Warehousing Practices
Stock should be located shelves at convenient
heights with proper labeling for easy
identification of the products.
Good Warehousing Practices
Highly hazardous, poisonous and explosive materials
and substances presenting potential risks of abuse
such as narcotics and psychotropic drugs should be
stored in safe and secure areas.
The entry to those areas should be restricted to the
authorized persons only.
Adequate measures shall be provided for fire
protection in conformity with the government rules.
Good Warehousing Practices
Separate sampling and dispensing areas for APIs and
excipients shall be provided in the warehouse.
Sampling should be performed in such away as to
prevent contamination, cross-contamination and
mix-ups.
Vehicles to carry the stocks should be clean, dry and
sufficiently protected from rain and other weather
factors. They should of suitable construction to
withstand the weight of the load they carry and
should be free from any infestation.
Characteristics of good warehousing
Systematic storage of various categories of materials
or products.
Storage of each material or product at one specific
place.
Proper cleaning and sanitation.
Safety measures for warehouse staff and stocked
goods.
Protection against pests and rodents.
Clear labeling of products stored on the shelves.
Characteristics of good warehousing
Separate stoke card for each material or product.
Storage of hazardous, poisonous and flammable or
explosive materials in separate places.
Warehouse staff
In warehouse of pharmaceutical products, pharmacist is
responsible for proper stock management, and safety and
prevention of stock in the warehouse.
The warehouse workers are responsible for handling
operations including carrying and moving of stock for storage,
shipment and sale.
They also help in receiving, issue and management of
inventory in the warehouse.
Security staff is responsible for supervision and security of
the warehouse.
Warehouse of raw and packaging materials
The purchase of raw materials is an important
operation that should involve staff who has
thorough knowledge of the products and the
suppliers.
Raw materials should purchased only from the
approved suppliers and if possible directly from the
manufacture of the material.
Appropriate storage conditions like controlled
temperature and humidity should be ensured for
storage of raw materials.
Warehouse of raw and packaging materials
Measures should be taken to prevent cross
contamination during the storage and issue of raw
materials.
Warehouse of raw and packaging materials
Packaging materials like bottles, vials, ampoules,
tins, tubes etc. should be stored in a manner that
they are not contaminated by any extraneous
matter.
Printed packaging materials such as labels, printed
films, foils, laminates, cartons etc. should be
stored properly.
Printed and non-printed packaging materials
should be kept in separate storage cupboards to
prevent any mix-ups.
Warehouse of intermediate and bulk
products
Intermediate and bulk products should be kept in separate
storage area under appropriate conditions.
If any intermediate or bulk products are purchased, then
they should be handled as through they were raw
materials.
Warehouse of finished products
Proper warehousing of finished products is
utmost necessary to avoid deterioration or
spoilage of the products.
Finished products should be held in
quarantine until their final release.
The testing data and all documentation
necessary for the release of finished
products for sale should be properly
maintained.
Warehouse of finished products
Some key requirements of the warehousing of finished
products are:
Adequate number of qualified and trained
personnel.
Regular cleaning and sanitation of the warehouse
area.
Storage area of sufficient capacity to allow orderly
storage of quarantine, released, rejected, returned
and recalled products.
Warehouse of finished products
Efficient temperature and relative humidity control.
Clear labeling marking over the storage containers
for quick identification and controlled stock
movement.
Effective pests and rodents control.
Store rotation based on first in first out (FIFO)
basis.
Proper documentation for storage, handling and
transportation of stock.