QA Hand Book Part-3
QA Hand Book Part-3
HAND
BOOK
A Compendium of Guidelines and Related
Materials
EDITION – I
(PART-3)
PHARMACEUTICAL
FORMULATIONS
Ajay Thakur
QA HAND BOOK
Basic Concepts
&
Their
Questions& Answers
Which information should master document carry on every page not just one of
the pages to meet GMP?
Page Number.
Document Reference Number.
Authorizing signatures.
Schedule M
Grade A.
Grade B.
Grade C.
Grade D.
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USFDA (US 209E)
Class 1.
Class 10.
Class 100.
Class 1000.
Class 10000.
Class 100,000.
WHO 2002
Grade A.
Grade B.
Grade C.
Grade D.
EU GMP
Grade A.
Grade B.
Grade C.
Grade D.
ISO 14644-1
ISO-3.
ISO-4.
ISO-5.
ISO-6.
ISO-7.
ISO-8.
ISO-9.
0.035.
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0.35.
3.5.
35.
350.
3500.
1
2
3
4
5
6
GMP is the part of Quality assurance which ensures that products are consistently produced
and controlled to the quality standards appropriate to their intended use and as required by
the marketing authorization. GMP is aimed primarily at diminishing the risks inherent in any
pharmaceutical production.
Cross Contamination.
Mix-ups.
CGMP
Current Good Manufacturing Practices. This means any procedure/ system adopted by the
manufacturer which proves to be necessary and important for identity, strength and purity of
a product.
What do you mean by validation protocol and its contents of process validation?
A written plan stating, how validation will be conducted and defining acceptance criteria e.g.
The protocol for manufacturing process identifies process equipment’s, critical process
parameters and / or operating range, product characteristics, sampling, test data to be
collected, number of validation runs and acceptance test results.
Contents
Protocol Approval.
Table of Contents.
Objective.
Scope.
Responsibility.
Accountability.
Validation Team.
Brief Manufacturing Process (Description, Flow Chart, Reaction scheme).
Selection of batches.
List of equipment’s used in the manufacturing process.
Critical operations with justification.
In-process controls with acceptance criteria.
Sampling & testing plan with frequency.
Stability program.
Data to be compiled.
Acceptance criteria.
Intermediate & Final Products Quality & Yield.
Stability Specification.
Document Review.
Training Record.
Conclusion.
Revalidation Criteria.
Class I
Solvents to be avoided.
Class II
Solvents to be limited.
Class III
What is MSDS and how many contents are mentioned & what are those?
Product Identification.
Composition/ Information on Ingredients.
Hazards Identification.
First Aid Measures.
Fire Fighting Measures.
Accidental Release Measures.
Handling & Storage.
Exposure Controls / Personal Protection.
Physical & Chemical Properties.
Stability & Reactivity.
Toxicological information.
Ecological Information.
Disposal Consideration.
Transport Information.
Regulatory Information.
Other Information.
Design Qualification.
Installation Qualification.
Operational Qualification.
Performance Qualification.
Swab Sampling
Areas which are reasonably accessible & hardest to clean can be evaluated, leading to level of
contamination or residue per gives surface area.
Rinse Sampling
Large areas or parts of equipment’s which could not be swabbed should be rinse sampled or
directly extracted by solvent. Tubes, nozzles, pipes or containers with surface those are not
reasonably accessible for direct surface sampling have to be rinsed with solvent.
Typical users include military, nuclear, pharmaceutical, electronics, biological and medical
facilities.
To qualify as a Type A HEPA filter, the filter must capture at least 99.97% (9,997 out of 10,000)
of particles 0.3 microns in size-about 300 times smaller than the diameter of a Human hair,
and 25 to 50 times smaller than we can see.
In fact, the dirtier a HEPA filter gets, the more efficient it can become.
What is RLAF?
RLAF stands for “Reverse Laminar Air Flow”, CRESCENDDO make RLAF Bench finds a major
application in sampling and dispensing. Majorly used for mixed airflow stream to control the
hazardous emission of dust powder during dispensing or sampling process.
Or
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RLAF is a purifying apparatus fitted with a high efficiency HEPA filter to ensure maximum
protection from airborne contaminants produced at the time of powder handling operations
such as sampling and dispensing.
Where,
As mm of WC = millimeter of water columns
What is QMS?
It is the quality management system to direct and control an organization with regard to
quality.
CAP.
PVAP.
Kollicoat (Methacrylic acid Ethyl Acrylate Copolymer (1:1)).
Diluent.
Binder and adhesive.
Disintegrants.
Lubricants & Glidants.
Coloring Agents.
Flavoring Agents.
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Sweetening Agents.
Requirements outlined in the URS are usually tested in the PQ. 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 requirement outlined in the URS.
Why water for pharmaceutical use is always kept in close loop in continuous
circulation?
Water is best medium for many microorganism can be a highly pathogenic which causes
serious diseases (many disease are water born), these pathogens infect after consumption of
contaminated water, microorganism tend to settle on a surface if water is allowed to stand in
a stagnant position for few hours, these settled microorganism form a film over the surface of
vessel and piping, such film formed by microorganisms is also called as biofilm, biofilms are
very difficult of remove, once a biofilm is formed at a particular point then that point may
form a biofilm again even after cleaning very easily as seed from this point is may not
completely get removed effectively.
Anions like chloride are highly active they participate in nucliophylic substitution reactions,
where in they break a double bond between –C=C- in to a single bond as CL-CH-CH2-, which a
reason why we observe that colors dies tend to fed in presence of chlorine as most of the dies
used are diazo compound which has plenty of places for nucliophylic substitution reactions,
which is also a reason why stability of drug is drastically affected in presence of cations and
anions from mineral origin present in water.
Phase 1.
Phase 2.
Phase 3.
Phase 1
A test period of 2 to 4 weeks should be spent for monitoring the system intensively. During
this period the system should operate continuously without failure of performance deviation.
Phase2
A further test period of 2 to 4 weeks. Sampling scheme will be same as Phase 1. Water can be
used for manufacturing process in this phase. Approach should also
Phase 3
Phase 3 runs for one year after satisfactory completion of phase 2. Water can be used for
manufacturing process during this process.
Briefly explain about ICH climatic zones for stability testing &long term storage
conditions?
ICH stability zones:
Zone IVb:
MINIMUM DURATION
Zone I Zone II Zone III Zone Iva Zone IVb
21°C ± 2°C. 25°C ± 2°C. 30°C ± 2°C. 30°C ± 2°C. 30°C ± 2°C.
45% RH ± 60% RH ± 35% RH ± 65% RH ± 65% RH ±
5% RH. 5% RH. 5% RH. 5% RH. 5% RH.
12 12 12 12 12
Months. Months. Months. Months. Months.
Refrigerated
5°C ± 3°C.
No
Humidity
12
Months.
Frozen
-15°C ±
3°C.
No
Humidity
12
Months.
What is the selection criteria of type of filters for required ambient quality air, air
change rates and return air quality during design and qualification stages of
clean area classification?
The type of filters required for different applications depends on levels of protection that is
briefing in below table
Note
The filter classifications referred to above relate to the EN1822 and EN779 test standards
(EN779 relates to filter classes G1 to F9 and EN1822 relates to filter classes H10 to U16).
Level 1 Area
General area with normal, housekeeping and maintenance, e.g. warehousing, secondary
packing.
Level 2 Area
Protected area in which steps are taken to protect the exposed pharmaceutical starting
material or product from contamination or degradation, e.g. manufacturing, primary packing,
dispensing.
Level 3 Area
Controlled area in which specific environmental conditions are defined, controlled and
monitored to prevent contamination or degradation of the pharmaceutical starting material or
product.
Note
Contaminants may result from inappropriate premises (e.g. poor design, layout or
finishing), poor cleaning procedures, contaminants brought in by personnel and a poor
HVAC system.
Airborne contaminants should be controlled through effective ventilation.
External contaminants should be removed by effective filtration of the supply air.
Internal contaminants should be controlled by dilution and flushing of contaminants in
the room, or by displacements airflow.
Sampling of materials, primary packaging materials and products, should be carried out in the
unidirectional airflow environmental conditions that are required for the further processing of
the product in a dispensing booth situation.
Dispensing booth should be provided with unidirectional airflow for protection of the product
and operator.
Where facilities are to be maintained at negative pressures relative to the ambient pressure to
prevent the escape of harmful products to the outside.
Negative pressure zones should, as far as possible, be encapsulated by surrounding areas with
clean air supplies, so that only clean area can infiltrate into the controlled zone.
The first segment the labeler code is assigned by the FDA. A labeler is any firm that
manufacturers (including repackers or relabelers) or distribute (under its own name) the
drug.
The NDC Code will be in one of the following configurations: 4-4-2, 5-3-2 or 5-4-1.
The Bolar amendment to the Drug Price Competition and Patent Term Restoration Act allows a
pharmaceutical manufacturer (sponsor) to seek approval from FDA to market a generic drug
before the expiration of a patent relating to the brand name drug upon which the generic
based.
As part of the ANDA, the sponsor must consider the pertinent patents and provide the results
to the FDA. The Act requires patent information to be cled with all newly submitted section
505 drug applications and that no NDA may be approved after September 24, 1984, without
the submission of pertinent patent information to the FDA. The ANDA sponsor must provide a
certification that, in the opinion of the sponsor and to the best of the sponsor’s knowledge
with respect to each patent that claims the listed drug, some or all of the following
certification may be submitted:
A certification under paragraph III indicates that the ANDA may be approved on the patent
expiration date.
If the Orange Book lists one or more unexpired patents, the sponsor of the ANDA who seeks
effective approval prior to the patent’s expiration must either:
Challenge the listing of the patent (e.g., file a Paragraph IV Certification that the patent
is invalid or will not be infringed by the manufacture, use or sale of the drug product).
File a statement that the application for use is not claimed in the listed patent.
What is Dissolution?
Dissolution rate may be defined as amount of drug substance that goes in the solution per unit
time under standard condition of liquid/solid interface, temperature and solvent composition.
It can be considered as a specific type of certain heterogeneous reaction in which a mass
transfer results as a net effect between escape and deposition of solute molecules at a solid
surface.
Result from in-vitro dissolution rate experiments can be used to explain the observed
differences in in-vivo availability.
Dissolution testing provides the means to evaluate critical parameters such as adequate
bioavailability and provide information necessary to formulator in development of more
efficacious and therapeutically optimal dosage forms.
Most sensitive and reliable predictors of in-vivo availability.
Dissolution analysis of pharmaceutical dosage forms has emerged as single most
important test that will ensure quality of product.
It can ensure bioavailability of product between batches that meet dissolution criteria.
Physicochemical properties of model can be understood needed to mimic in in-vivo
environment.
An IR product is considered very rapidly dissolving when a means of 85 percent or more of the
labeled amount of the drug substance dissolves within 15 minutes, using the above mentioned
conditions.
An airlock is produced by creating differential pressure between two areas and differential
pressure is produced by HVAC. According to WHO a differential pressure of 10 to 15 Pascal’s
should be maintained. To produce a higher differential pressure cost of the system is also
increased.
In most of the pharmaceutical industries, a common airlock system is used for the entry of
men and materials it is wrong practice.
The airlocks which are used for the entry of personnel into the cleanroom is called personnel
airlock (PAL).
The airlock which is used for transferring of materials is called Material Air lock (MAL).
Air lock is usually with two doors one door open in one clean room like in class C and other
door opens in another class area like in class D. So if we want to enter from Class D to Class C,
first of all, we will enter from Class D into Airlock and then the airlock to Class C.
Both doors of airlock should not be opened simultaneously. First of all open and enter into
airlock from Class D then close that door and open other door to enter into Class C.
Interlocking system should be installed in airlocks to prevent the opening of both door at the
same time. An alarm system should be installed which give an alert if both doors are opened
at the same time.
The doors of airlock should be opened towards higher pressure side so that it can easily be
closed by air pressure. The airlock should always be free from any furniture, chairs, table, shoe
covers etc.
Bubble Airlock.
Sink Airlock.
Cascade Airlock.
Bubble Airlock
In bubble airlock pressure inside the airlock is high or positive and in adjacent sides, the
pressure is less or negative.
For example, in airlock pressure is 20 Pa and in both the sides, the pressure is 10 PA so air
moves form 20 Pa to 10 Pa in adjacent sides. Mean air moves from the airlock to the primary
manufacturing area and in the same way from the airlock to the corridor. Higher air changes
are produced in the airlock. It is called bubble because it pushes air outside from the airlock.
Sink Airlock
In sink airlock, the pressure inside airlock is negative and in adjacent areas pressure is positive
so air moves from higher pressure area to lower pressure mean from adjacent rooms to the
airlock.
For example, in airlock pressure is 10Pa and in both sides, the air pressure is 20 Pa so air
moves from adjacent to 10Pa in airlock. Mean air moves from adjacent areas to airlock e.g.
from the primary manufacturing area to airlock and in the same way from the corridor the
airlock. It is called sink because the air from both sides come into the airlock.
Cascade Airlock
Example
Take the example of a simple layout; we have one primary room where we want to
manufacture the product for example granulation area of tablet manufacturing section.
Outside the primary room is a corridor and on other side of the corridor is compression room
so we want to prevent cross-contamination of granulation area to compression room or from
compression room to granulation room. We will build an airlock room between granulation
room and corridor and in the same way between corridor and compression room.
To prevent cross contamination by Bubble airlock for granulation area, build an airlock
room between granulation area and corridor and create positive in airlock pressure by
supplying more air through HVAC say it is 20Pa.
In granulation room produce 10Pa so when we will open the door, clean air will move
from airlock to granulation area and powders from granulation will not enter to airlock
because of differential pressure.
In the same way in corridor create 10Pa so when we will enter from corridor the clean
air from airlock will move into the corridor.If inside granulation room is positive e.g.
20Pas and in the lock is 10Pa the powder from granulation area will enter in the airlock
and if in the corridor is 8Pa then this powder will move from airlock to corridor and will
contaminate other areas.
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For Cascade Airlock
For cascade airlock inside of granulation area is maintained negative for example at
10Pa and airlock is maintained at 30Pa means highly positive.
According to principle air will move higher pressure to lower pressure so air will move
from corridor to airlock and from airlock to manufacturing area. In this case, the
corridor will be cleaned corridor having high air changes.
In oral solid dosage form areas, we keep inside of the manufacturing area at negative pressure
to prevent our flow of powders.
So critical monitoring of air pressure maintenance is required in all areas because any drop or
increase in the pressure of any area may result in cross contamination.
This enables smooth operation and long life of the equipment. It also avoids major breakdown
of the equipment during manufacturing of the product.
Maintenance was done after stopping machine breakdown weekly, Monthly, Quarterly, Half
yearly and Yearly preventive maintenance.
What is HVAC?
HVAC system function is to condition (heating & cooling), replace (makeup, fresh air, oxygen
replacement), and pressurize (contaminant) and clean (filter) the air in the environment to
meet the required operational conditions.
To achieve this objective, electrical, mechanical & electronic components are arranged in
several configurations such that they produce the expected results.
Where the same piece of equipment is utilized for a range of products formulations. To
prevent the cross-contamination between products becomes the main objective in the
cleaning validation effort. Clearly, cleaning non-dedicated equipment’s represents a more
significant obstacle to overcome.
If one batch is failed during the validation, then what will you do for completion
of validation?
When a quality parameter fails with respect to the specification, a deviation report shall
be raised and the investigation shall be conducted immediately for the identification of
failure.
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If the reason for failure is identified, one more consecutive batch shall be considered
for the validation run by taking preventive actions to avoid those failures.
If the reason is unidentified, another three consecutive batches shall be taken for
Validation.
Why blending validation is required? What quality parameters of product are
considered for validation and what parameters of equipment are to be
considered during validation?
Because of to provide sufficient documented evidence to assure that the blending operation
of product is capable of repeatedly and reliably producing a homogeneous material to meet
established specifications when operated under defined standard conditions.
The following Quality parameters are to be considered, but not limited:
Loss on Drying / Water content.
Bulk density / tapped density.
Residual solvent.
Particle size.
The following parameters are to be considered for the equipment during validation, but not
limited:
Blender capacity.
RPM of the blender.
Occupancy of the blender.
Number of individual batches to be taken for each blend.
Mixing time.
Clean-in-Place
The cleaning of large pieces of equipment may be performed in the equipment’s permanent
location. Generally, in a configuration very similar to that in which it is utilized for production.
This procedure widely known as Clean-in-Place (CIP)
Clean-out-Place
A condition or set of conditions encompassing upper and lower processing limit and
circumstances, within standard operating procedures, which poses the greatest chance of
product or process failure when compared to ideal conditions. Such conditions do not
necessarily induce product or process failure.
Specification
A document giving a description of a starting material, packaging material, intermediate, bulk
or finished product in terms of its chemical, physical & possibly biological characteristics. A
specification normally includes description clauses & numerical clauses, the latter stating
standards & permitted tolerances.
Or
Lists of detailed requirements with which the products/ materials used or obtained during
manufacture have to conform. They serve as a basis for quality evaluation.
Limit
The point, edge or lines beyond which something cannot or may not be proceed. The
boundary surrounding a specific area, bounds.
In 2 batches we cannot assure the reproducibility of data, 4 batches can be taken but the time
and cost are involved.
Why nitrogen gas used in the manufacturing area at room temperature and why
not other gas?
Because of nitrogen is chemically less reactive and does not react with other elements at
ordinary temperature. It is due to strong bonding in its molecule.
The date place on the container / labels of an API designated the time during which the API is
expected to remain within established shelf life specifications if stored under defined
conditions and after which it should not be used.
Re-test date
The date when a material should be re-examined to ensure that it is still suitable for use. The
period of time during which the drug substance is expected to remain within its specifications
and therefore, can be used in the manufacturing of the drug product, provided that drug
substance has been stored under the defined conditions.
A unique combination of numbers, letters, and/or symbols which identifies a batch (or lot) and
from which the production and distribution history can be determined
Batch
What is quarantine?
The status of materials isolated physically or by other effective means pending a decision on
their subsequent approval or rejection.
The quantity that would be produced at any appropriate phase of production, based upon the
quantity of material to be used, in the absence of any loss or error in actual production.
Expected yield
The quantity of material or the percentage of theoretical yield anticipated at any appropriate
phase of production based on previous laboratory, pilot scale, or manufacturing data.
A device that takes a physical measurement and displays a value or has no control or analytical
functions.
Equipment
It is used solely for the production of a single product or product line. Concerns over cross-
contamination with other products are markedly reduced. Dedicated equipment’s must be
clearly identified with the restrictions of use in order to prevent potential errors during
cleaning and preparation.
Non-dedicated equipment
The same piece of equipment is utilized for a range of products formulations. The prevent of
cross-contamination between products becomes the main objective in the cleaning validation
effort. Clearly, cleaning non-dedicated equipment’s represents a more significant obstacle to
overcome.
If one batch is failed during the validation, then what will you do for completion
of validation?
When a quality parameter fails with respect to the specification, a deviation report shall
be raised and the investigation shall be conducted immediately for the identification of
failure.
If the reason for failure is identified, one more consecutive batch shall be considered for
the validation run by taking preventive actions to avoid those failures (If necessary
revise the BMR and BPR).
If the reason is unidentified, another three consecutive batches shall be taken for
Validation.
What are ISO 9001, ISO 14001, ISO 18001, and ISO 22001?
ISO 9001:Quality Standard Management.
Physical
Chemical
Biologic
Energy
A substance that has been shown by an extensive set of analytical tests to be authentic
material that should be of high purity. This standard may be obtained from an officially
Working Standard
Management attitude.
Ineffective documentation.
Lack of trained personnel.
Lack of co-ordination / co-operation within or among departments.
A defined space in which the concentration of air borne particles is controlled to meet a
specified air borne particulate cleanliness class.
A room in which the concentration of air borne particles is controlled and contains one or
more clean zone.
Airflow having generally parallel steam lines, operating in a single direction, and with uniform
velocity over its cross section; previously referred to as “laminar” air flow
Air flow which does not meet the definition of unidirectional air flow, previously referred as
“Turbulent or Non-Laminar” air flow.
Review Period
Storage Period
Perpetual
In any product, presence of a substance other than product manufacturing formula is called
Contamination.
Cross Contamination
For Material transfer from unclassified area to classified area. This Pass box having HEPA filter
and UV Light. Frequency of Validation is every six month
Test
Air Velocity
Filter Integrity
Particle count
Water Content
Water Content determined by the Karl Fischer method and it consists of only i.e. water
content. The result does not contain other volatile matter.
LOD is determined by heating the sample below its melting point in an oven and it includes all
volatile matter including water content and solvent.
Loss on Drying is an unspecific analytical technique removing not only water but all other
volatile impurities like alcoholetc. From a sample.
Temperature
Drying time
LOD or water content of pharmaceutical products can include both bound (e.g. water of
hydration) and free water. In case there are additional traces of other volatile impurities
present, like alcohol: LOD ma be higher than water content. In other cases, LOD may be lower
than water content, as bound crystal water may not be removed by heating
What is Commissioning?
Commissioning is the documented process of verifying that the equipment and systems are
installed according to specifications, placing the equipment into active service and verifying its
proper action. Commissioning takes place at the conclusion of project construction but prior to
validation.
THANKS
“AND GO CHALLENGE THOSE
WHO SAY’S YOU DIDN’T
HAVE KNOWLEDGE”
AJAY KUMAR
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