DEFECTS, QUALITY CONTROL

VARIATIONS, AND MATERIALS

CONTROL
DEFECTS AND QUALITY CONTROL
VARIATIONS
DEFECTS

 A DEFECT is an undesirable characteristic of a

product.
 It is defined as a failure to conform to
specifications.

 A unit of a product which contains one or more

defects is considered to be DEFECTIVE.
DEFECTS

→ QualityAssurance implements preventive

actions.
→ Corrective Action Preventive Action (CAPA)

→ Quality Control uses detection activities.

→ Initial QC activity is INSPECTION.
CLASSIFICATION
 Defects can be classified as follows:

1. According to measurability:
 Variable defect – a defect which can be measured directly by
instruments.
 Examples: Length, weight, height, thickness, concentration,
volume, viscosity, pH or size particles.

 Attribute defect – a defect which cannot be measured directly by

instruments. It shows mainly the conformance or nonconformance.
 Attribute defect can be counted.
 Examples: Functionality, Texture, presence of dents, cracks,
missing buttons, cracks
CLASSIFICATION
2. According to seriousness or gravity:
 Critical defect – a defect which may endanger life or
property and may render the product non – functional.
 Examples: Absence of a warning in a label for a potent drug
or disintegration time of one hour for an analgesic.

 Major defect – a defect which may affect the function of

the object and therefore, may render the product
useless or aesthetically objectionable
 Examples: Presence of a crack in a bottle, stains that may
appear
CLASSIFICATION

 Minor defect – a defect which does not

endanger life or property nor will it affect the
function but nevertheless remains a defect
since it is outside the prescribed limits.
 Examples: Slight deviation of the color of the label
from the color standards, scratches or dents
CLASSIFICATION
3. According to nature:
 Ocular defect - a defect that is visible.
 Example: foreign particulate contamination.

 Internal defect - a defect which is not seen although

present.
 Example: a sub – potent drug product.

 Performance defect - a defect in function.

 Example: suppository that does not melt at body
temperature.
PRODUCT RECALL
 Class I recall: a situation in which there is a reasonable
probability that the use of or exposure to a violative product
will cause serious adverse health consequences or death.

 Class II recall: a situation in which use of or exposure to a

violative product may cause temporary or medically
reversible adverse health consequences or where the
probability of serious adverse health consequences is
remote.

 Class III recall: a situation in which use of or exposure to a

violative product is not likely to cause adverse health
consequences
PRESENCE OF PATHOGENS

Pathogens:
I - Salmonella, Listeria monocytegenes, E. coli,
Clostridium
II – Shigella, Cyclospora, Cryptosporidium,
hepatitis A
III – Low levels of pesticide residue
EXAMPLES:

 a drug that is under-strength but that is not

used to treat life-threatening situations
 food found to contain botulinum toxin

 a minor container defect

 a label mix-up on a lifesaving drug

 a defective artificial heart valve

 Lots of injectable ketorolac with possibility of
tiny particles in the vials.
 A small number of patches were leaking
fentanyl gel
 Rofecoxib (Vioxx), which caused heart problems

 Cerivastatin (Baycol), which caused muscle

breakdown and death; trovafloxacin
(Trovan),which caused serious liver damage.
SOURCES AND CONTROL OF QUALITY VARIATION

 manufacturing processes become more

complex → The risk of errors increases

 material control, GMP, packaging control,

automation and statistical sampling plans are
employed → To minimize and eliminate the
sources of errors which can cause product
quality variation
SOURCES OF VARIATION

Men

Methods
DRUG Machines
PRODUCT

Materials
SOURCES OF VARIATION:

Materials
 Variation between suppliers of same
substance.

 Variation between batches from same supplier.

 Variation within a batch.

SOURCES OF VARIATION:

Machines
 Variation of equipment for the same process.

 Difference in adjustment of equipment.

 Aging and improper care.

SOURCES OF VARIATION:

Methods
 Inexact procedures.

 Inadequate procedures.

 Negligence by chance.
SOURCES OF VARIATION:

Men
 Improper working conditions.

 Inadequate training, and understanding.

 Dishonesty, fatigue and carelessness.

FISHBONE DIAGRAM

 A fishbone diagram, also called a cause and effect

diagram or Ishikawa diagram, is a visualization
tool for categorizing the potential causes of a
problem in order to identify its root causes.
 Dr. Kaoru Ishikawa, a Japanese quality
control expert, is credited with inventing the
fishbone diagram to help employees avoid
solutions that merely address the symptoms of a
much larger problem.
 Product
Registration with
FDA disapproved
MATERIALS CONTROL
MATERIALS CONTROL

 Raw material
 Packaging material
RECEIVING NUMBER

 Assigned to each batch received from the

supplier.
 Each container of raw materials is examined
visually for damage or contamination in transit,
including breakage of seals when indicated
 Receiving number – distinct

 Receiving Tally Report (RTR) is completed upon

receipt of material.
RECEIVING TALLY REPORT

 A document used to record the amount and

type of finished goods or raw materials when a
shipment has been accepted
 Completed upon receipt of material

 The receiving tally report is checked by a QC

inspector for accuracy.
RECEPTION
 The receiving tally report is checked by a QC inspector for
accuracy.
 Each container of raw materials is examined visually for
damage or contamination in transmit including breakage
of seals when indicated.
 Adequate number of samples are taken from a
representative number of containers.
 A sampling plan is used to determine the number of raw material
container to be sampled.
 Calculate for the total quantity of material required to determine
the amount of sample to be taken from each container.
 The composite sample should not be less than three times the
amount required for one complete test
RECEIVING NUMBER
 If the shipment consists of more than one
manufacturing lot number, a separate receiving
number is assigned to each lot.
 The RTR should be distributed to all groups
concerned:
 Quality
Control Department
 Warehouse Department
 Purchasing Department
 Accounting Department
PRE-PRINTED DATA

 Name of report
 Name of drug/cosmetic company

 Address

 Receiving number
INFORMATION TO BE SUPPLIED BY

 Warehouse
 Name of the material
 Item code number

 Label claim

 Purchase order number

 Invoice number

 Vendor (Supplier/distributor)

 Unit of measure
INFORMATION TO BE SUPPLIED BY

 Warehouse
 Number of containers received
 Weight/volume/pieces contained each container

 Dare the report was prepared

 Date the shipment was received

 Name of the warehouse personnel receiving the

shipment
INFORMATION TO BE SUPPLIED BY

 Quality Control Department

 Inspector’s Report
 Analysis of the material

 Disposition

 Name of the person responsible for receiving the

report
 Date of review
INFORMATION TO BE SUPPLIED BY
 Inspector’s Report  Disposition
 Quantity of the sample  Reason, if rejected
 Comments, if any
 If approved
 Name of inspector  Re-assay date
 Date inspected  Release number

 Analysis
 Analyticalreference number
 Name of analyst
 Date of analyst
 Manufacturing firms may have different entries
but the basic information is quite similar.
 The RTR is prepared in the warehouse by the
warehouse personnel who is responsible for
assigning a receiving number to the material.
The shipmen is held in quarantine pending
quality control approval.
DECISION STICKERS

 If the test results indicate that the raw material

meets monograph specifications, the material
is approved for use; otherwise, it is rejected.
 Decision stickers are issued
DECISION STICKERS
1. No two stickers of different dispositions must be
present on the same container.

2. The decision stickers are either placed on top of

the quarantine sticker or the quarantine sticker is
first removed before the decision sticker is
pasted.

3. At this stage, the raw material is transferred to

either the rejected or approved materials area.
QUARANTINE

 The inspector checks that the raw material

container has a "Hold" or a quarantine sticker
pasted by the receiving warehouse personnel
to indicate that a decision to accept or reject is
yet to be made by quality control.
 Samples are submitted to the laboratory for
testing.
QUARANTINE

 The sample is subjected to tests such as:

 Physical and organoleptic examination
 Identification tests

 Limits of impurities and degradation products

 Potency or assay

 Microbiological tests
QUARANTINE

 If the test results indicate that the raw material

meets monograph specifications, the material
is approved for use; otherwise, it is rejected.
Decision stickers are then issued by quality
control.
QUARANTINE

 The decision stickers are either placed on top

of the quarantine sticker or the quarantine
sticker is first removed before the decision
sticker is pasted.
 No two stickers of different dispositions must
be present on the same container. At this
stage, the raw material is transferred to either
the rejected or approved materials area
REJECTED

 Held at a rejected materials area to prevent the

possibility of use in any manufacturing or
processing procedure

 Returned to the supplier

APPROVED
 Approved materials are brought to the approved
materials area.

 Approved materials are subject for re-assay

 Approved raw materials are audited to assure that

they are rotated in such a manner that the oldest
stock is used first. This is known as the FIFO (first
in, first out) policy.
REASSAY DATE
 Periodic testing is done to revalidate the material.

 The date of retest, given in terms of month and

year, determined from the last assay date.

 The finished product can only be as good as the

raw materials used in its manufacture.
 Monitoring of the quality of the raw materials during the
storage.
RE-ASSAY DATE

Based on the stability of raw materials, the re-

assay dates assigned are:

Monthly or prior to use – highly unstable

materials
6 months – vitamins, flavors
12 months – active ingredients, dyes
24 months – excipients
RE-ASSAY DATE

 Ascorbic acid powders – date released:

9/8/2021

 Lactose – date of release: 12/12/21

 FD & C Red No. 3: date released: 10/30/21

RE-TEST REQUIREMENTS
1. Appearance
2. Identification
3. Melting range
4. Specific gravity
5. Refractive index
6. pH
7. Loss on drying, moisture and water content
8. Acidity and alkalinity
9. Alcohol content
10. Disintegration and dissolution limits
11. Assay
12. Microbial tests
PACKAGING VS. PHARMACEUTICAL PACKAGING
 Packaging is the process by which the pharmaceuticals are
suitably placed so that they should retain their therapeutic
effectiveness from the time of their packaging till they are
consumed.
 Pharmaceutical packaging is the means of providing
protections, presentation, identification, information and
convenience to encourage compliance with a course of
therapy.
 Composition of package:
 Container
 Closure
 Carton or Outer
 Box
PRINTED AND PACKAGING MATERIALS
 Product containers, closures and other
component parts of a product package should
not be reactive, additive, or absorptive so as to
alter the safety, identity, strength, quality, and
purity of the product.
 These should be tested for suitability for its
intended use. Storage and handling are suited
to prevent them from contamination and to
avoid mixups
PRINTED AND PACKAGING MATERIALS

 Aspects considered in packaging:

 Functions of packaging
 Selection of packaging material

 Testing of the material selected

 Filling and assembly

 Sterilization

 Labeling

 Storage and stability

TYPES OF PACKAGING MATERIAL

 Primary packaging components – packaging

materials which come in direct contact with the
product itself
 Examples: Bottles, tubes, ampules, vials, carpules,
caps, stoppers, plungers, stripping materials, jar,
fillers, and seals
TYPES OF PACKAGING MATERIAL

 Secondary packaging components – packaging

materials which do not come in direct contact
with the product and serve as accessory to the
primary packaging component
 Examples: Labels, inserts, unit cartons, brochures,
pack boxes, and shippers
LABELING

 Labeling includes all written, printed or graphic

materials accompanying a product.
 These are subjected to inspections by an
experienced proofreader for graphical errors,
compliance with specifications as to type and
grade of stock printing quality, and dimensional
tolerance.
CONTENTS OF THE LABEL
CONTENTS OF THE LABEL

1. Name of the drug product

2. List of active ingredients (If applicable, with
the International Non-Proprietary Names
(INN), showing the amount of each present,
and a statement of the net contents in terms
of number of dosage units, mass or volume)
3. Batch number assigned by the manufacturer
CONTENTS OF THE LABEL

4. Expiry date in an uncoded form

5. Any special storage conditions or handling
precautions that may be necessary
6. Directions for use, and any warnings and
precautions that may be necessary
7. The name and address of the manufacturer or
company responsible for placing the product
on the market
MINIMUM CRITERIA FOR ACCEPTANCE OF
PRINTED MATERIALS
 Text
 Color
 Size
 Thickness
 Grain direction
 Sealability
 Cleanliness
 Surface finish
 Adequate paste
 Shape
CONTAINERS

 Article which holds or is intended to contain

and protect a drug and is or may be in direct
contact with it.
 Physical and chemical evaluation of containers
like those made of glass, plastic, and metal
have been extensive.
CLASSES OF CONTAINERS

 According to material
 Glass

 Plastics

 According to capacity
 Single unit, multiple unit, single dose, multiple dose
 Ability to protect
 Well-closed, tight, hermetic, light-resistant, tamper-
proof, child-proof
GLASS CONTAINERS

 Type 1 – Highly Resistant Borosilicate

 Type 2 – Treated Soda Lime

 Type 3 – Soda Lime

 Type 4 – Non-Parenteral or General Purpose

Soda Lime
PLASTIC CONTAINERS

 Polyethylene (LDPE and HDPE) for dry oral

dosage forms
 Polyethylene terephthalate (PET, PETG) for oral
liquid dosage form
 Polypropylene – either for dry solid or oral
liquids Polyvinyl Chloride
RECYCLING SYMBOLS
RECYCLING SYMBOLS
RECYCLING SYMBOLS
ACCORDING TO CAPACITY
 Singe unit container - designed to hold a quantity of drug
intended for single administration as a single dose or dose of
the medication
 Multiple unit containers- contain more than a single unit or
dose of the medication
 Single dose container – in which the quantity of the sterile
drug contained is intended as single dose and which
cannot be resealed once opened
 Multiple dose container – a hermetic container which
permits withdrawal of successive portions of the contents
without changing the strength or endangering the quality
or purity of the remaining portions
ABILITY TO PROTECT
Well-closed protects against extraneous solids and loss of
container drug under ordinary conditions of handling,
shipment, storage and distribution
Tight container protects from extraneous solids, liquids or
vapors, from loss of drug and from
efflorescence, deliquescence or evaporation
Hermetic - impervious to air or any other gases under
container ordinary conditions of handling, shipment,
storage and distribution
- generally sterile
Light-resistant - protects the contents from photochemical
container deterioration
- amber, opaque, blue
ABILITY TO PROTECT
Child-resistant - one that is difficult for most children under 5 years of
container age to open or gain access to the contents or obtain a
harmful amount of the contents
- based on the principle that a young child is unlikely to
coordinate two or more separate actions to achieve a
successful opening
Tamper-resistant - uses an indication or barrier to entry that is distinctive
container by design, or must employ an identifying characteristic
which if breached or missing can reasonably be
expected to provide visible evidence to consumers that
tampering has occurred
- film wrappers, blister/strip packs, bubble packs,
shrink seals/bands, foil, paper or plastic pouches,
bottle seals, tape seals, breakable caps, sealed tubes,
sealed cartons, aerosol containers, cans
CONTAINER AND CLOSURES
 The integrity of the seal between the closure
and container depends on the geometry of the
two, the materials used in their construction,
the composition of the cap liner and the
tightness with which the cap has been applied.
 Geometry can be controlled by the mold of the
packaging components. A mold number is
assigned which is used as its identification
number.
BOTTLE CLOSURES AND FINISHES

 Closures are important in effecting the seal of

the container.
 Enhancing the seal or for prevention of leak is
the cap or closure liner which has the backing
or adhesive part and the facing that comes in
direct contact with the product.
TYPES OF BOTTLE CLOSURES AND FINISHES

 Friction Closure
 Threaded or Screw-on Closure

 Snap-on or Press-on Closure

 Lug Cap

 Crown Closure
TYPES OF BOTTLE CLOSURES

Threaded screw cap Dispensing Snap on

Friction fit Pilfer proof Lug cap

TYPES OF BOTTLE FINISHES
 Finishes of the bottles include the portion of the neck up
to the sealing surface, these may come in various
designs.
 Types:
 Crown
 Sprinkle top
 Lug-amerseal
 Shallow
 Brandy cork
 Pry off
 Pour out
 Pilfer-proof
 Biological
 Roll-on
BOTTLE CLOSURES AND FINISHES
 Closures should fit the thread of the container.
It should sit on a container without tilting,
produce no leaks, should not rotate
continuously, be reasonably tight and look
elegant.
 Controlling the cap tightness reduces the
problems on leak or seal of contents.
 Cap tightness may be determined by Torque
Test.
CONTAINERS TESTING

 <661> Containers, plastics

 <671> Container Permeation

 <87> <88> Biological Reactivity Test, In vivo

 <381> Elastomeric Closures for Injections

ANALYSIS FOR CONTAINERS

1. Physical Inspection
2. Physicochemical Tests
3. Water Vapor Permeation Test
4. Light Transmission Test
5. Thermal Analysis
ANALYSIS FOR CONTAINERS
 Physical Inspections generally include the
following criteria:
 Shape  Clarity

 Volume  Leak

 Finish  Torque

 Opening  Print

 Diameter  Peeling

 Height  Cleanliness

 Thickness  LightTransmission
 Color  Stress crack resistance
ANALYSIS FOR CONTAINERS
 Physicochemical Tests include:
 Identification
 Infraredproperties
 Thermal analysis
 Extractable substance
 Non-volatile residue
 Water vapor permeation/transmission
 Moisture
 Resistance to water attack
TORQUE TEST
 Tightness of closure is maintained
at all times. To check tightness, a
torque tester is used.
 Torque
 The rotational movement used
during application or removal
of a continuous thread closure
from a container.
 The unit of force is in terms of
inch pound
 Sample size is 10 bottles.
TORQUE TEST
 Torque Tester is used as a quality control device to
test or calibrate torque controlled tools
 Closure torque can be related to three measurements:
 Application torque – the torque used to apply
pressure to effect a peal.
 Removal torque - the maximum torque required to
remove a closure.
 Stripping torque - the torque necessary to strip or
override threads while applying a closure.
SPECIFICATIONS
CONTROL OF THE CAP

 The following considerations are very important

in this connection:
A minimum tightness is essential to avoid
evaporation or leakage of the product.
 Excessive torque may break molded closures.

 Caps applied too tightly may be difficult to remove.

BOTTLE RESISTANCE TEST
 Powdered Glass Test
 Water Attack Test
 Uses autoclave at 121 deg C, hardened steel mortar
and pestle (crushing 6 more containers), titration set-
up, 0.02 N H2SO4 and 5 drops Methyl Red Solution
GLASS TYPES AND TEST LIMITS
Type General Type of Limit Size, ml of
Description Test ml 0.020 N
H2SO4
Type I Highly Powdered All 1.0
resistant glass test
borosilicate
Type II Treated soda Water 100 or less 0.7
lime attack test Over 100 0.2
Type III Soda lime Powdered All 8.5
glass test
NP General Powdered All 15.0
purpose soda glass test
lime
LIGHT TRANSMISSION TEST

 Applicable for transparent and opaque

containers
 Uses spectrophotometer (290-450 nm)

 Limits depend on type of containers

SPECIFICATION
 Any container of a size intermediate to those listed
above exhibits a transmission not greater than that of
the next larger size container listed in the table. For
containers larger than 50 mL, the limits for 50 mL
apply.]
 The observed light transmission for plastic containers
for between 290 and 450 nm products intended for
oral or topical administration does not exceed 10% at
any wavelength in the range from 290 to 450 nm.
WATER VAPOR PERMEATION TEST

 12 containers, 2 as controls
 Filled with dessicant, glass beads
 Within 13 mm = 20 ml or more
 2/3 of the capacity = less than 20 ml

 Weighed and stored under 23+/-2°C and RH

75+/-3% (35 g of NaCl in 100 ml of water)
 Test is run for 14 days.
SPECIFICATION
 For containers used for drugs being dispensed on
prescription, the containers so tested are tight containers
if not more than 1 of the 10 test containers exceeds 100
mg per day per L in moisture permeability, and none
exceeds 200 mg per day per L.
 For containers used for drugs being dispensed on
prescription, the containers are well-closed containers if
not more than 1 of the 10 test containers exceeds 2000
mg per day per L in moisture permeability, and none
exceeds 3000 mg per day per L.
THERMAL ANALYSIS

 Thermal analysis is a technique in which a

physical property of a substance is
monitored as a function of controlled
temperature increase.
ASSIGNMENT

 Topic: Manufacturing Control

 General tests for In-process Quality Control.
Discuss.
 Discuss the specific tests for the following dosage
forms:
 Tablets

 Parenteral/ Sterile Drug Products

 Non-Parenteral / Non-Sterile Drug Products
MANUFACTURING CONTROL AND
QUALITY CONTROL TESTS FOR
DOSAGE FORMS

96
 Standard
Quality Control
Operating
Monograph
Procedures

Batch
Manufacturing
Production
Monograph
Record
DRUG
PRODUCT
Manufacturing monograph
The basic document from where the master formula
and batch production records are based.
Quality Control Monographs
The document which provides the basis for accepting the
quality of each and every component used in the
manufacture of the product in accordance with the
specifications and methods

99
Standard operating procedures (SOPs)
The document generated to explain in detail the reason
behind a procedure and proper sequence of steps to be
done, and how equipment are to be operated for
maximum performance.

Batch Production Record

A document that accompanies a pharmaceutical product
as it is made
MASTER FORMULA RECORD

o The original document used as the key in the

manufacture of products.
o Being the prototype, it is kept in a secured
documentation room, duplicated or photocopied
only whenever a job order is issued.

o It assures identical reproduction of the product

document.

101
BATCH PRODUCTION RECORD
oA batch production record is an accurate
reproduction of the master formula record.
After being used as the guide to production and
actual data of what has been done are recorded
therein

102
IMPORTANCE
 The completed document permits reconstruction
of the history of the product formula,
manufacturing procedures, production record
(processing batch records, processing control
records, packaging records), raw material
records, packaging materials records and
product experience reports.

 Differences in format and content of batch

production records from product to product are
to be expected
BATCH, LOT OR CONTROL CODES

o The batch means a specific amount produced

in a unit time or according to a single
manufacturing order during the same cycle of
manufacture.
o The lot means a batch, a portion of a batch, or
a combination of batches.

104
BATCH NUMBER, LOT NUMBER, OR
CONTROL NUMBER
 A unique combination of numbers, letters,
and/or symbols that identifies a batch (or lot)
and from which the production and distribution
history can be determined.
NATIONAL DRUG CODE (NDC)

 a unique 10-digit, 3-segment number. It is a

universal product identifier for human drugs in
the United States. The code is present on all
nonprescription (OTC) and
prescription medication packages and inserts
in the US.
o Control codes should be identified as such on
the label.
o .

107
PRODUCT FORMULA

1. The product name and/or unique identification

such as:
a. Batch size

b. Dosage form and strength

c. Formula code number and date

d. Batch of lot number

PRODUCT FORMULA

2. An authorizing signature and date by a

competent and responsible individual.
3. A complete list of raw materials designated
by whole names and codes sufficiently
specific to indicate any characteristic.
4. The theoretical weight, measure, or percent
of each raw material regardless of whether it
appears in the finished product or not.
PRODUCT FORMULA

5. The standards or specifications of each ingredient

used in the product.
6. An appropriate statement concerning any
calculated excess of an ingredient, reasonable
variations, and adjustments.
7. A statement of total weight, measure or percent.
8. Appropriate statements of theoretical yield at
various stages and the termination of the
product.

110
PRODUCT FORMULA
9. The actual weight, measure or percent of each
raw material allocated or dispensed for the
batch.
10. The receiving number of the raw material
dispensed.
11. The signature of competent individuals
responsible for measuring and dispensing the
raw materials, duly endorsed by another
competent and responsible individual.
Signatures should be dated.

111
MANUFACTURING PROCESS

1. Product name and/or unique identification.

2. An authorizing signature and date by a
competent and responsible individual duly
endorsed by another competent and
responsible individual.
3. A step by step description of all significant
aspect of the process including, where
necessary:

112
MANUFACTURING PROCESS
a. Means of raw material measurement
b. Order of addition and point of addition of raw
materials
c. List of major equipment
d. Temperature
e. Mixing Speeds
f. Mixing times

113
MANUFACTURING PROCESS

4. Signature of the individual performing and

endorsement of the individual supervising
each step. Both should be dated.
5. Intermediate and finished product
specifications, test methods and sampling
instructions.
MANUFACTURING PROCESS

7. Special notations and precautions including,

where necessary:
a. Cleaning procedures

b. Storage conditions

c. Filling temperatures

d. Remedial measures

e. Special safety and health measures

115
PRODUCT SPECIFICATIONS

1. The finished product name/or unique

identification
2. Physical, chemical and microbiological
specification, where necessary, for the
acceptance of each lot in-process samples
and finished products and a description of
the sampling and test procedures.
3. The result of control tests

116
PRODUCT SPECIFICATIONS

4. Samples retained
5. Endorsement and date of the authorized
individual performing the test
6. Disposition of the batch or lot endorsed by
an authorized individual
IN-PROCESS CONTROL
 During processing, the quality of the product at
various stages of production is audited by quality
control.
 Basic Activities
 Area (line) clearance

 Yield control

 Reconciliation

 Use of GMP status

 IPQC of various dosage forms

118
LINE CLEARANCE
 Done before start of a process
 Ensure identification, correct materials and
equipment used
 Check on setting of critical parameters
 Absence of ‘foreign’ matter
 Hygiene, cleanliness and GMP compliance
 Suitable environmental parameters
 Avoid potential parameters
 Avoid potential risk of mis-labeling and mix-up
EXAMPLE
2.0 Line clearance prior to sifting / granulation / blending / compression /
capsule Filling/ tablet inspection/ tablet coating / capsule/ Inspection and
polishing
2.1 Check the areas for the following:
2.2 All materials and residues from previous operations have
been removed.
2.3 Utensils and accessories from previous operations have been
removed.
2.4 Containers used for previous operations have been removed.
2.5 Paperwork from previous operations has been removed.
2.6 Status labels form previous operations have been removed.
2.7 All equipment is clean and labeled as such.
2.8 Areas are clean and status is displayed.
YIELD CONTROL

 Done at end of a stage/process

 Check on yields, reconciliation on quantities to
be carried out
 Require control limits based on previous record
and/or validation
 Theoretical target is 100% yield
YIELD CONTROL
 Target for yield depends on dosage form and difficulty of
processing
 For dry products, usually 95.-100%
 For liquids, 95 - 102.5%
 For capsules, 90 - 100%
 For herbal capsules, 85 - 100%

 Out Of Specifications (OOS) value warrant investigation:

 Fear of mix- up or sabotage
 Possible pilferage by internal staff
 Check for unusual wastages
SAMPLE PROBLEM 1

A 50-L batch size was filled into 50-ml vials with

an average filling volumes of 52 ml

A total of 950 vials were produced. Determine

the % wastage if the theoretical yield is 50L. Is
the filling run within the specification?
SAMPLE PROBLEM 1

 Given: 950 vials x 52 ml = 49,400 ml

𝐴𝑐𝑡𝑢𝑎𝑙 𝑌𝑖𝑒𝑙𝑑
 % 𝑦𝑖𝑒𝑙𝑑 = 𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑌𝑖𝑒𝑙𝑑
𝑥 100
49,400 𝑚𝑙
 % 𝑦𝑖𝑒𝑙𝑑 = 50,000 𝑚𝑙
𝑥 100 = 98.8%

 Passed the specifications of 95% - 100.5%

SAMPLE PROBLEM 2
Reconcile the bulk of a liquid preparation given the
following data:
Theoretical yield 100L

Pack size Filling volume Filled bottles

30 mL 31.8 ml 580
60 ml 61.5 ml 580
120 ml 122.4 ml 370

Determine the % yield and % loss

SAMPLE PROBLEM 2
 Theoretical Yield – 100,000 ml
 Actual Yield:
 31.8 ml x 580 bottles = 18,444 ml
 61.5 ml x 580 bottles = 35,670 ml
 122.4 ml x 370 bottles = 45,288 ml
 Total Actual Yield = 99,402 ml
99,402 𝑚𝑙
 % 𝑦𝑖𝑒𝑙𝑑 = 𝑥 100 = 99.40%
100,000 𝑚𝑙
 % 𝑙𝑜𝑠𝑠 = 100% − 99.40% = 0.6% 𝑙𝑜𝑠𝑠
SAMPLE PROBLEM 3
Production of Syrup
Batch Size 3000 L
Packaging Breakdown 25,000 x 15 ml
15,000 x 60ml
14,375 x 120 ml
Limits: Manufacturing 99% yield or NMT 1% loss
Packaging 98%yield or NMT 2% loss

Finished Product
Filled volume (ml) Net yield bottles QC Samples
14.98 24850 24 bottles
60.25 14390 12 bottles
120.15 14286 10 bottles
SAMPLE PROBLEM 3
 Theoretical Yield: 3,000,000 ml
 Actual Yield (include QC Samples)
 24, 850 bottles + 24 bottles = 24, 874 bottles

 14, 390 + 12 bottles = 14, 402 bottles

 14, 286 bottles + 10 bottles = 14, 296 bottles

 Filled volume per bottle

 24, 874 bottles x 14.98 ml = 372, 612.52 ml

 14, 402 bottles x 60.25 ml = 867, 720.50 ml

 14, 296 bottles x 120. 15 ml = 1,717,664.40 ml

 Total = 2,957,997.42 ml
SAMPLE PROBLEM 3
𝐴𝑐𝑡𝑢𝑎𝑙 𝑌𝑖𝑒𝑙𝑑
% 𝑦𝑖𝑒𝑙𝑑 = 𝑥 100
𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑌𝑖𝑒𝑙𝑑

2,957,997.42 𝑚𝑙
% 𝑦𝑖𝑒𝑙𝑑 = 𝑥 100 = 98.60%
3,000,000 𝑚𝑙
RECONCILIATION

A comparison, making due allowance

for normal variation, between the
amount or materials theoretically and
actually produced or used.
CROSS CONTAMINATION

 Cross contamination is the contamination of a

starting material, intermediate product or
finished product with another starting material
or product during manufacture.
US FDA REQUIREMENTS

 Critical Area: Zone or area where filling of

sterile products or other sterile processes take
place.
 Controlled Area: Zone or area where the
product is formulated, filled, and sealed.
EU-GMP/WHO REQUIREMENTS

 Class A
 Preparation of solutions for aseptic filling
 Provided by a laminar air flow work station with a
HEPA
 Depyrogenization of containers

 Filling of aseptic process

 Class B
 For aseptic preparation and filling
EU-GMP/WHO REQUIREMENTS
 Class C
 Clean areas for less critical activities of solution for
terminal sterilization and filling of terminal sterilization
 Hair and where relevant body hairs should be covered

 A single or two-piece suit gathered at the wrist and with

high neck and appropriate shoes or overshoes should
be worn should shed virtually no fibers or particulate
matter
 Class D
 Clean areas for less critical activities
 Washing of containers, for example
CLEAN ROOMS
 Clean rooms are defined as specially
constructed, environmentally controlled
enclosed spaces with respect to airborne
particulates, temperature, humidity, air
pressure, airflow patterns, air motion, vibration,
noise, viable (living) organisms, and lighting
 Clean room as a room in which the
concentration of airborne particles is controlled
to specified limits.
US-FDA CLEAN ROOM
TYPES OF CLEAN ROOM AIR FILTERS

• High efficiency particulate air (HEPA):

- minimum particle collective efficiency of
99.97 to 99.997% for a 0.3 micron particle.

• Ultra low penetration air (ULPA):

- minimum particle collection efficiency of
99.9997 % efficient for particles greater than
or equal to 0.12-micron in size.
DOP TEST

 Di-octyl phthalate
AIR FLOW DIRECTION
 Unidirectional
 entire body of air within a confined area moves with uniform
velocity and in single direction with generally parallel
airstreams.
 Clean rooms; class 100 and below have unidirectional
airflow pattern.

 Non-unidirectional
 airflow is not unidirectional by having a varying velocity,
multiple pass circulation or nonparallel flow direction.
 Conventional flow clean rooms (class 1000 & 10000) have
non-unidirectional or mixed air flow patterns.
IPQC TESTS

 In-Process Quality Control Tests are performed

to determine if the product meets
specifications throughout the entire processing
period and particularly during critical stages of
manufacturing.
IN-PROCESS CONTROL

 Any out of range measurement can thus be

corrected before further processing is
continued.
 The audit also fulfills the primary objective of
the IPQC which is to monitor all features of a
product.
CONTROL TESTS
 In order to satisfy product identity, purity, safety,
quality and strength, products must be
subjected to certain specific tests.
 Individual company monographs and published
compendia provide these.
 Minimum attributes common to general
categories of products are enumerated below.
Where necessary, some of these tests are
performed during processing (IPQC) of the
product and repeated in the final product.
QC TESTS FOR PHARMACEUTICAL DOSAGE
FORMS
1. Packaging Test
 Determines the material type, assembly, special
properties and integrity
2. Identification Test
 Determines the physical and chemical reactions
particular for the drug, gives the gross physical
appearance
3. Limit Test
 Determines presence of impurities, either gross,
chemical and biological
QC TESTS FOR PHARMACEUTICAL DOSAGE
FORMS
4. Assay
 Determines conformance of dosage form when
compared to label claim; this may be instrumental,
chemical or biological
5. Dosage-specific Tests
 Tests of properties, functionalities of particular
dosage forms
QUALITY CONTROL TESTS FOR TABLETS

 Tablet Hardness
 Tablet Friability

 Disintegration

 Dissolution

 Weight Variation
TABLET HARDNESS
 Determine resistance to chipping, abrasion or
breakage under storage, transportation, handling
before usage
 To determine the need for possible adjustments
on tableting machine

 Rule of thumb – crude method

 Tablet is of proper hardness if it was firm enough to
break with a sharp snap when held between 2nd and 3rd
finger, using thumb as fulcrum.
TABLET HARDNESS

 Too hard – MAY NOT DISINTEGRATE

 Too soft – ADD BINDERS, WILL NOT
WITHSTAND HANDLING
TABLET HARDNESS
 Sample Size
 Ordinary uncoated tablets – 4-10 kg
 Sublingual, chewable tablets – 2-3 kg
 Buccal tablets – 8-10 kg

 Tablet Hardness Tester Models

 Strong Cobb
 Stokes Monsanto
 Pfizer
 Erweka
STRONG COBB
 Measures the applied force in
kg required to break the
tablet across its diameter.
 The force produced by a
manually or pressure
operated air pump
 As the pressure increases, a
plunger is forced against the
tablet set on the edge. A dial
indicator records the final
breaking force.
STOKES MONSANTO
 Consist of a barred
containing a compressed
top spring held between
two plungers
 The lower plunger is in
contact with the tablet, the
upper plunge is forced
against the tablet.
 A pointer rides along the
gauge in the barrel
indicates the pressure by
which the tablet breaks.
ERWEKA
 A beam fastened to one end to a pivot applies the
breaking force.
 A motor moves a weight along the beam at
constant speed and increase the force against the
tail, in which the other end of the beam rests.
PFIZER

 Operates with the same

principle as a pair of pliers.
 The tablet is crushed in
between jaws of the device.
 The force is indicated on the
dial indicator.
TABLET THICKNESS AND DIAMETER

 May be measured by micrometer or vernier

calipher
 Thickness is an important criteria in tablet
packaging, inconsistent blocks the channel
of tablet counting machines.
SPECIFICATION

 Criteria: +5% of the specifications

 Example: 1.0 mm +/-5% of the average

 Lower Limit (LL): 1.0 mm – (1.0 x 0.05) = 0.95 mm
 Upper Limit (UL): 1.0 mm – (1.0 x 0.05) = 1.05 mm
FRIABILITY

 This test induces self-abrasion of the tablets as

the cylinder section rotates
 The tablets undergo shock as they fall 6 inches on
each turn. After 100 revolutions equivalent to 5
minutes, the tablets are weighed and compared to
initial weight.
 The loss due to abrasion or fracture is measured
to tablet friability which expressed in percentage.
The weight loss should not be more than 0.8%.
TABLET FRIABILATOR
DISINTEGRATION TIME

 It refers to the time it takes

for a tablet to reach a state
in which any residue of the
tablet (except fragments of
insoluble tablet coating
remains on the screen
resulting to a soft mass with
no palpably firm core.
PREPARATION

 Basket Rack Assembly

 6 cylindrical tubes

 10 mesh wire

 Temperature: 37+/-2 deg C

 Media: Purified water, Stimulated Gastric Fluid,

Intestinal Fluid
SPECIFICATIONS

 Immediate-release: 30 Stage Sample Criteria

minutes 1 6 Should
disintegrate
 Buccal: 4 hours
2 +12 16/18 should
 Sublingual: 2-3 minutes disintegrate
 Enteric-coated: 5 minutes
in water, 1 hour in
stimulated gastric fluid
and intestinal fluid
DISSOLUTION RATE

 Determines the length

of time by which 50%
and 90% of the tablet’s
active ingredient has
dissolved in the media
of 0.1 N HCl or buffer
water at 37 degrees
Celsius.
USP DISSOLUTION APPARATUS
SPECIFICATION

Stage Sample Acceptance Criteria

1 6 Each unit is NLT Q + 5%
2 12 Average of 12 is equal to or
greater than Q
No unit is less than Q – 15%
3 24 Average of 24 is equal to or
greater than Q
NMT 2 units are less than Q -15%
No unit is less than Q - 25%
WEIGHT VARIATION

 %Weight Variation = Actual weight per

sample/Average weight x 100

 Take 20 tablets and weighed individually

 Calculate average weight and compare
individual tablet to the average
SPECIFICATION

 NMT 2 tablets differ by more than %Weight

Variation
 No tablet differs by more than double than
%Weight Variation

Average Tablet Weight % Variation

<130 10
130-324 7.5
>324 5
CONTENT UNIFORMITY

 It is determined on each of the 10 tablets to

detect the homogeneity of distribution of the
drug’s active ingredients.
 The USP specifications is NLT 85% and NMT
115%
QUALITY TESTS FOR CAPSULES

 Identification
 Assay

 Disintegration

 Dissolution

 Uniformity of Dosage Units

QUALITY TESTS FOR SEMI-SOLID DOSAGE
FORMS
 Identification
 Assay
 Consistency/Viscosity
 Penetrometer: consistency
 Brookfield viscometer: viscosity

 pH
 Spatula feel
 Spreadability
 Melting range
QUALITY TESTS FOR SEMI-SOLID DOSAGE
FORMS
 Minimum Fill
 Ensures correctness of net weight/volume of the
contents of filled containers compared with the
labeled amount
 Specification: NMT 150 g or 150 ml
 Average net content is NLT the labeled amount
 If the labeled amount is </=60 g or 60 ml, the %LC of
any single container is NLT 90%
 Sample size: Initial – 10 containers, Retest - +20
containers
QUALITY TESTS FOR SEMI-SOLID DOSAGE
FORMS
 Metal Particles in Ophthalmic Ointments
 Microscopic examination of a heat-melted
ophthalmic ointment for presence of metal
particles
 Acceptance Specifications: The total number of
metal particles (>50 um) in all 10 tubes is NMT 50;
NMT 1 tube contains >8 particles
QUALITY TESTS FOR SEMI-SOLID DOSAGE
FORMS
 Microbial Content
 Topical: P. aeruginosa, S. aureus
 Ophthalmic: P. aeruginosa, B. subtilis

 Rectal, vaginal and urethral: Yeasts and molds

QUALITY TESTS FOR SUSPENSIONS
 Sedimentation Volume
 Vs = Vu / Vo

 Where Vu is settled volume, Vo is volume of

suspension
 Ideal SV = 1, if closer to 1 = better suspension

 Degree of Flocculation - β is more useful and

fundamental parameter for flocculation, as it relates
the volume of flocculated sediment to that in
deflocculated system.
QUALITY TESTS FOR SUSPENSIONS

 Redispersibility - the amount of the force

necessary to redisperse particles, product is
subject to shaking for minimum of 10 spm
 Acceptance criteria: 100% redispersable with
minimum agitation
 Particle Size Distribution

 Optical Microscopy – counts and measures

size of particles
 Sedimentation rate – Stoke’s Law
QUALITY TESTS FOR SUSPENSIONS

 Zeta Potential – determines the repulsive

forces between particles
 Increased Zeta potential = Slower settling of
particles
 Rheological properties – Brookfield Viscometer

 Temperature and Gravitational Stress Tests

 Test for crystal growth at 40 degrees C

QUALITY TESTS FOR EMULSIONS

 Tests for creaming, cracking, phase inversion,

phase separation
 Dye Solubility Test
 UV Fluorescence Test

 Conductivity Test

 Cobalt Chloride in Filter Paper Test

 Dilute Test
DILUTION TEST

 Emulsion is diluted with water

 If homogenous (O/W)

 If separated (W/O)
DYE SOLUBILITY TEST

 Uses amaranth green and sudan red

 Sudanred (+) – W/O
 Amaranth green -(+) – O/W
CONDUCTIVITY TEST
QUALITY TESTS FOR STERILE DOSAGE FORMS

 Leakers Test
 Apparatus: autoclave or
vacuum chamber
(negative pressure)
 Reagent: 1% Methylene
blue
 All leakers are discarded.
All are subjected to
leakers test (100%
inspection)
QUALITY TESTS FOR STERILE DOSAGE FORMS
 Clarity Test
 Used to check for the presence of particulate
matter
 Done by swirling the solution and visually
inspecting against both light and dark backgrounds,
using a clarity testing lamp
 100% inspection
QUALITY TESTS FOR STERILE DOSAGE FORMS
 STERILITY TEST
 Ensures that the process used to sterilize the product
was successful
 Methods and time of incubation
 Membrane filtration – 7 days
 Direct Inoculation – 7-14 days

 Nutrient Medium
 Soybean-Casein Digest Medium – for aerobic bacteria
and fungi (B. subtilis, C. albicans, A. niger); 20-25 deg C
 Fluid Thioglycolate Medium – for anaerobic bacteria (P.
aeruginosa and S. aureus); 30-35 deg C
QUALITY TESTS FOR STERILE DOSAGE FORMS
 PYROGEN TEST
 QUANTITATIVE FEVER RESPONSE TEST
 Qualitative biological test based on the fever
response of rabbits (ear vein)
 Sample size: Initial – 3 rabbits; Retest - +5 rabbits

 Acceptance specification:
 Initial: Temperature rise for any single rabbit is NMT 0.5
deg C
 Retest: If a single rabbit has a temperature rise greater
than or equal to 0.5 deg C
QUALITY TESTS FOR STERILE DOSAGE FORMS
 PYROGEN TEST
 QUANTITATIVE FEVER RESPONSE TEST

 Dose: 10 ml/kg unless otherwise specified

 Received 10mL/kg in marginal ear vein,

completing injection w/in 10 mins after start
of admin
 Rectal temp recorded at 1,2,3 hrs after
injection or 30mins interval 1 hr after injection
QUALITY TESTS FOR STERILE DOSAGE FORMS
 PYROGEN TEST
 BACTERIAL ENDOTOXIN TEST USING LAL
REAGENT
 Limulus
Amoebecyte Lysate Reagent, Limulus
polyphemus or Tachypleus tridentatus
 Methods:
 Gel-clot formation – If a gel is formed via a clotting
reaction, endotoxin is present and the sample fails
the test
 Turbidimetric method - Turbidity testing determines
the cloudiness of a solution by measuring the loss of
intensity in a light beam passing through that
solution
LIMULUS AMEBOCYTE LYSATE
QUALITY TESTS FOR STERILE DOSAGE FORMS
 Particulate Matter in Injections
 Limitsthe presence of microscopic extraneous
undissolved particles
 Causes emboli and phlebitis

 Methods:
 Method I – Light Obscuration Particle Count Test
 Method II – Microscopic Particle Count Test
LIGHT OBSCURATION PARTICLE COUNT TEST

 Electronic particle counters

 Constant in-process measurement
 Quickly, identify, size and count the particles
 Provides trend analysis to identify the problem
 Applicable for clear solutions

 Disadvantage: Requires more preventive

maintenance and calibration
MICROSCOPIC PARTICLE COUNT TEST

 Membrane filtration allows collection of the

particles larger than rate pore size
 Microscopic identification of particle types and
materials
 Disadvantage: Slow counting and sizing on
membrane surface; requires top and bottom
lighting to distinguish all particles
SPECIFICATIONS
Type of Limits per container
Methods
Parenterals ≥ 10 um ≥ 25 um
Small Light
6000 600
Volume obscuration
Parenterals
(SVP) Microscopic 3000 300
Large Light
25 3
Volume obscuration
Parenterals
(LVP) Microscopic 12 2