Chem Draw
Chem Draw
Chem Draw
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INTRONON:
which intetes
hitity ant Manutacnuring unik
1e Nl ntant ix htN
which intes
ommevial prxducion svsem
pr
>Ani nlo Nao N efinnd as the volumes of new tochnoogr haNN
pNtN
hngy and poduces small
N
the same
l
increasing the batch size or apnvaure for ay»\ing
>SoaleSthe pves ot
volumes,
p t 0dierent output
> The Nl plant
studies must include:
Practices (cGMP)CHvinonnent,
CumentGood Manufacturing
stafts,
Highly trained and skilled
Equipment support, fomula,
Facilityof through andclosc examination of the
"
be determine for successful product scale u) are;
> The factors that must
e The requirements,
Training,
The reporting relationships,
Responsibility of personnel. and inali
proces8 control must be evaluated, validated
and
The pilot plant, production
tranxfer
during the scale up.
important role in the technology evaluation, scale u) and
> The pilot plantplays an
activities of new products.
Pilot plant scale up activities: scale up in carly development phase
are,
place during
> The major activities takes development,
" Technical aspects of process
Technical aspects of scale up.
Organisation responsibility
transfer team,
Determination of responsibility of technology
Technology transfer documentation,
preparation.
" FDA pre-approval inspection
Major technical aspects:
up of pilot plant includes major technical aspects that are,
> The scale
" Inearly development,
o ldentification of critical components,
Control of critical components,
o ldentification of formulation variables,
o Controlof formulation variables,
areas equipment.
Simulating the pilot plant equipment with manufacturing
ldentification of critical process parameters.
Identification of operating ranges for the pilot plant equipment
Collection of data of Product and process.
Objectives of Pilot plant scale up:
Avoidance of the problems associated with the scale-up.
Production and process controls guidelines preparation.
To identify the critical features of the process
manufacturing.
Preparation and providing of Master Manufacturing Formula for
Evaluation and Validation for process and equipment.
Examination of the formula to assess the batch stability.
Significance of Pilot Plant:
Standardization of formulae.
Review of range of relevant processing equipment.
Optimization and control of production rate.
Information on infrastructure of equipment during the scale up batches.
Information of batches physical space required for eqipment.
Identification of critical features to maintain quality of a product.
Appropriate records and reports to support GMP.
Key activities
Key groups Developaentmilestones
Pharmaceuticalformulaton arketingtorOutation defined Jdentify crntical process and pacKaging
parameters
Phamaoeuical fomulation Plot scale stability batch manufacture
Phamacautcal technology RrocassdaveBopmant
development
Pilot plant Phamaceutical formulation HDevelopment report
Pharmaceutcal technology Site selection
development
SetouStabiäitly Inlttai large scale process qualificaton studies
Ciniot suppty batches
Manutacturing
Validation Scale-up report
OAOC Addilional large scale process qualificatcn studies
A ADA Subission Produc transfer doCUment issued
Manutacturing Product acceptance ty manufactunng
Validaion Vahdation protocols written
Producion QAQC Manufactue validaion batches Pre-approval inspection task force initiated
Faciity Plarmaceutical technology Manufacturing site preparatan
develapment Pre-approval inspecion by FDA
NDA approval LValdation report
EFDAappraval to market product
Mannfactuing
QAQC
Phamaceutical techinology Productionstatu HProkuct launch
devalopment
2
technology transfers
relationship between different activities during
Fig 1.The layout of the
the pilot plant to the production
facility.
from
GENERAL CONSIDERATIONS:
a
Reporting Responsibility:
responsibility in Pilot plant is to facilitate the transfer of
reporting
> The objective of the production.
product from the laboratory into determined by the ease with which the
new product or
Pilot plant is
> The effectiveness of
process is brought into routine production. exists between the pilot plant group with other
relationship
> This could be possible if a good Packaging, Engineering, Quality Assurance,
Development, Processing,
groups (Research &
Quality Control, Regulatory and Packaging) of the company.
formulator who developed the product can take the product intothe production.
> The support to the other departments even after the
The formulator continues to provide the
transition into the production has been completed.
Personnel requirements:
> The Qualification required for a person to work
in pilot plant organization are;
Good theoretical knowledge on blending
Pharmaceutical industry experiences.
personnel.
Ability to develop good relationships with other
Good communication skill (Writing and speaking).
and equipment.
Practical Experiences in production areas about formulation, process
perspective of production
and
Should be able to understand the intent of the formulator
personnel.
Computer.
Must have minimum knowledge on Engineering, Electronic and Medical attributes of
Biochemical and
Must have knowledge on Physical,. Chemical,
dosage form.
Must be aware on the principle of GMP Practices.
by the individuals, which must be
The individual responsibilities should be clearly understood
recorded.
Space requirements:
that are as follows:
Thespace required in pilot plant is divided into 4 areas
> Administration and information area:
technicians.
Adequate office and desk space should be provided for both scientists and
The space should be adjacent to the working area.
> Physical testing area:
This area should provide permanent bench top space for routinely used physical- testing
equipment.
> Standard equipment and floor space:
The sufficient specified space must be there for free installation, operation and easy
maintenance of the equipment.
Storage area:
Storage area for in process materials, finished bulk products, retained samples,
experimental production batches, packaging materials (segregated into approved and
unapproved areas).
3
Controlled environment space allocated for storage of stability samples. approved and
segregated into
Separate provisions for API and excipients further
unapproved areas according to GMP.
Training:
> The various departments that are responsible for compliance of GMP are;
Engineering
Quality control
Material handling
Warehousing and distribution
Purchasing.
Depending on complexity of the job, each person involved in manufacturing, Processing,
packaging and holding of a drug product, must receive the GMP and other specific training.
The employee those need training are divided into the following categories;
New employees.
Those employees who are assigned with a new job.
Those employee whose performance a task falls below required standard.
are;
The employee get trained on following activities as per the GMP and FDA guidelines that
Technical environment
Dealing with potent or dangerous chemicals
Working with system of weights and measures
Checking of manufacturing steps, containers, equipment and drying racks.
Identification of packaging.
Proper stock rotation system.
Raw material inspection.
Quality validation.
Review of the Formula:
final product manufactured on
> The objective of each ingredient and its contribution to the
small scale equipment must be thoroughly understood.
phase III trial, so
> The modification in formulation during the scale up is possible to be done in
in
that sufficient time could be available for generation of meaningful long term stability data
support of a proposed New Drug Application (NDA).
Raw materials:
and excipient
> One major responsibility of a Pilot plant is the approval and validation of active
raw materials used in the Pharmaceutical products.
trials may not be
This is because the raw materials used during the small scale formulation
raw materials
representative of the large volume shipment of material due to change in
solubility,
properties like particle size, shape, morphology, bulk density, static charges, rate of
flow property and colour.
which must validate the batches for
> An alternative supplier must be arranged as stand by basis
manufactured products.
Relevant Processing Equipment:
product within the proposed
> The selection criteria for one equipment to produce effective handling, cleaning
specifications are equipment must be economic, simple (In installation,
producing a product.
and maintenance), efficient and most capable of consistently
4
should be such that experimental trials can be run that are
The size of the equipment
meaningful and relevant to the production sized batches.
Production Rate:
equipment required, the immediate and
For determination of production rate, size and type of
future market requirement must be considered.
at afrequency need following
The selection of process and equipment to produce batches
considerations that are;
The time required to clean the equipment between the batches.
The product loss in the equipment during the manufacture.
The number of batches that need to be tested before release of product.
Process Evaluation:
> Thingsthat should be critically examined during the Process Evaluation are;
Order of addition of the components including adjustment of their amount.
Mixing speed ant time.
Rate addition of granulating agent, solvents and rug solutions.
Heating and cooling rates.
Filter size for liquids.
Typeand nature of filter media used for liquids.
Screening size for solids.
Drying temperature and time.
Fan speed.
The basis for process optimization and validation is the knowledge on effect of above
mentioned parameters on the in process and finished product quality.
The objective of process validation to ensure the selected process could be able to produce
quality products at various critical stages of production.
> This is possible by critically monitoring the within the batch variation of measurable
parameters like content uniformity, moisture contet and compressibility.
Some measurable change in the materials may take place during the processes like milling,
mixing, heating, cooling, drying, sterilizing, compacting and filling, should be evaluated.
> The process remains validated only if there is no change in the formula, quality of the
ingredients and equipment configuration.
> The manufacturing process and quality control information should be reviewed on an annual
basis and should be followed by re-validation to ensure that changes have not occurred.
Preparation of Master Manufacturing Procedure:
The Master Manufacturing Procedure includes followings;
> The Process or Manufacturing Direction.
Process direction should be precise and explicit.
" Must be written in a simple manner which should be easily understood by the operator.
The Chemical Weight Sheet.
Identification of chemical required.
Quantities of chemical to be added.
Order of chemicals to be added.
The name and Identification number of the ingredient must be mentioned.
> The Sampling Direction.
should be such th¡t experimental trials can be run that are
The sIze of the equipment
meaningful and relevant to the production sized batches.
Production Rate:
determination of production rate, size and type of equipment required, the immediate and
For
future market requirement must be considered.
batches at a frequency need following
The selection of process and equipment to produce
considerations that are;
The time required to clean the equipment between the batches.
The product loss in the equipment during the manufacture.
The number of batches that need to be tested before release of product.
Process Evaluation:
> Things that should be critically examined during the Process Evaluation are;
Order of addition of the components including adjustment of their amount.
Mixing speed ant time.
Rate addition of granulating agent, solvents and drug solutions.
Heating and cooling rates.
Filter size for liquids.
Type and nature of filter media used for liquids.
Screening size for solids.
Drying temperature and time.
Fan speed.
> The basis for process optimization and validation is the knowledge on effect of above
mentioned parameters on the in process and finished product quality.
The objective of process validation to ensure the selected process could be able to produce
quality products at various critical stages of production.
This is possible by critically monitoring the within the batch variation of measurable
parameters like content uniformity, moisture content and compressibility.
Some measurable change in the materials may take place during the processes like milling,
mixing, heating, cooling, drying, sterilizing, compacting and filling, should be evaluated.
> The process remains validated only if there is no change in the formula, quality of the
ingredients and equipment configuration.
The manufacturing process and quality control information should be reviewed on an annual
basis and should be followed by re-validation to ensure that changes have not occurred.
Preparation of Master Manufacturing Procedure:
The Master Manufacturing Procedure includes followings;
> The Process or Manufacturing Direction.
Process direction should be precise and explicit.
Must be written in a simple manner which should be easily understood by the
> The Chemical Weight Sheet.
operator.
Identification of chemical required.
Quantities of chemical to be added.
Order of chemicals to be added.
The name and Identification number of the ingredient must be mentioned.
> The Sampling Direction.
Time of sampling of finished product.
Manner of sampling of finished products.
The Batch record direction.
The batch record directions should include specification for addition rates, mixing times,
mixing speeds, heating and cooling rates and temperature.
The In-Process Specification.
Must mention a simple and easy access specification for easy understanding of operators.
The Finished Product Specification.
The drug in the dose specified.
The self-life of the product.
The capability of the process.
The reliability of the test methods.
The stability kinetics of the product.
The periodic revalidation, GMP and monitoring of finished product test results via control charts
are essential to maintaining consistent product quality.
GMP Consideration:
> The check list of the GMP items that should be a part of the scale-up or new product or
process introduction including following:
Equipment qualification.
Process Validation.
Regulatory schedule preventive maintenance.
Regular process review and revalidation.
Relevant writing standard operating procedures.
The use of competent, technically qualified personnel.
Adequate provision for training of personnel.
A well-defined technology transfer system.
Validated cleaning procedures.
Arrangement of material to avoid cross contamination.
Transfer of Analytical Methods to Quality Assurance:
> Analytical methods developed in research must be transferred to the QA department.
Transfer process includes the following aspects;
Review the process to make sure that the proper analytical instrument is available.
Personnel should be trained to perform the test.
Reliability of the test should be checked.
At last assay procedure should be reviewed before transfer.
PILOT PLANT SCALE UP CONSIDERATIONS FOR SOLIDS:
> The following points to be carefully consider during scaling up the solid dosage forms;
Batch size from intermediate to large scale production.
Each stage of operation.
Different types of equipment.
Use of sophisticated instruments with larger volume load.
Various sizes of equipment.
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and
Material Handling: and necessary to handle carefully in medium
is quite difterent
The handling of materials laboratory scale (Mostly poured by handor scooped).
the
large scale production frommaterials density, size, shape and static charge must be taken into
like
> The characteristics of like;
consideration while adopting the processing steps
Lifting and tilting of drums,
Vacuum loading system,
Screw feeding systems,
Metering pump systems.
must deliver the accurate amount of the ingredient to the
Any material handling system
destination.
prevented if a system uses transfer of materials for more
must be
> The cross contamination
than one product step. for the equipment.
validated cleaning procedure
> This is accomplished by use of
Chemical Weighing: and misbranded
incorrect ingredients and quantities may lead to cross contamination
> The
brand during chemical weighing. all the processing areas due to following
department should have for
A central weighing
advantages;
Centralization of responsibility,
Avoidance of duplicating weighing facility,
Lower labour cost.
checkers,
chemical weighing department should be designed to provide supervision,
A
> proper weighing equipment, supply of sink
lightening, dust collection, adequate sanitation, printing scale facility and meters for
and drain board, cabinets, vacuum supply system,
liquids.
separate room must be equipped.
> For weighing of dye and high potent drugs, a
Tablet blending and Granulation:
Blending and Granulation:
granulated must be well blended to ensure good
> Powders to be used for encapsulation or to be
drug distribution.
> Inadequate blending at this stage could result in
discrete portions of the batch being either
high or low in potency to avoid drug content variation.
of.
Steps should also be taken to ensure that all the ingredients are free
screening or milling of the ingredients
> The lumps and agglomerates can be removed by doing encapsulation
should be done to avoid flow problems, non-reproducible compression and
process, to facilitate content uniformity of the product.
which depends on particle size,
> In blending, segregation and mixing operation takes place
shape, hardness and density.
Dry Blending and Direct Compression:
double cone blender, Ribbon blender,
> Different blenders used in blending are V- blender,
horizontal high intensity
Slant coneblender, Bin blender, Orbiting screw blenders, vertical and
mixers.
7
blending operation of directly compressible materials
} The factors affect the optimization of
are;
to the blender.
Theorder of addition of components
Planetary type mixer, Tumbling Mixer, Cone Type Mixer.
The mixing speed - compressibility of Finished Material.
The mixing time -It affects Twin Shell
cquipment with the mixer - Use chopper cell in
dispersion
The use of auxiliary
Mixer.
by the Mechanics of the Mixer.
The mixing action - Determined
volume and normal working range.
The blender loads Optimum working
Slugging (Dry Granulation): properties.
compressed directly due to poor flow and compression
> The dry powder cannot be Tablet Press of 15 tonnes.
The slugging is done by using the by Hammer Mill with
suitable particle size
slugs are broken down
After compression,
two
achieved by passing powders between
distribution.
compaction can also be
The granulation by dry
per linear inch.
roller which put pressure of 10Tonnes
Wet Granulation:
to justify granulating are;
> The most common reasons given
the material,
To impart good flow properties to
powders,
To increase the apparent density of the
distribution,
To change the particle size
Uniform dispersion of active ingredients. Heavy-duty
wet granulation has been carried out using Sigma blade mixer and
Traditionally,
planetary mixer. high-speed
using tumble blenders equipped with
Wet granulation can also be prepared
chopper blades. performing all
More recently, the use of multifunctional "processors" that are capable of
> such as dry blending, wet granulation,
functions required to prepare a finished granulation,
process in a single equipment.
drying, sizing and lubrication in a continuous
Granulator are;
The factors that affecting the Fluidized Bed
Process Inlet Air Temperature,
Atomization Air Pressure,
Air Volume,
Liquid Spray Rate,
Nozzle Position and Number of Spray Heads,
Product and Exhaust Air Temperature,
Filter Porosity.
Drying:
the
> The most common conventional method of drying a granulation continues to be
circulating hot air oven, which is heated by either steam or electricity.
> The important factors to consider as part of scale-up of an oven drying operation are airflow,
air temperature, and the depth of the granulation on the trays.
> If the granulation bed is too deep or too dense, the drying process will be inefficient, and if
soluble dyes are involved, migration of the dye to the surface of the granules.
8
temperatures and airflow rates must be establishcd for cach product,
> Dryng times at specificd
and for each particular oven load. air ovens.
Fluidized bed dryers are an attractive alternative to the ciroulating hot are optimum loads,
> part of scale up fluidized bed dryer
considered as
> The important factors humidity.
rate of airflow, inlet air temperature and proOcess
up areAir
by using Tray Dryer for scale process
considered for drying
The parameters to be granulation on the trays, Monitoring of the drying
ow, Air temperature, Depth of the temperatures and
moisture and temperature probes and Drying times at specificd
by the use of
air flow rates for cach product. drying process by using a Fluid Bed Dryer for
scale
considered for the
The Paranmeters to be Temperature and Humidity of the incoming
air.
Rate, Inlet Air
up are Optimumload, Air Flow
Reduction of Particle size: are flowability,
factors that may be affected by the particle size distribution
> Compression
tablet weight, content uniformity, tablet hardness, and tablet
compressibility, uniformity of
color uniformity. using a
this process is to determine the particle size distribution of granulation
First step in
series of "stacked" sieves of decreasing mesh openings. production size batches can be carried out
reduction of the dried granulation of
Particle size granulator, a hammer mill, a mechanical
all the material through an oscillating
by passing screning device.
sieving device, or in some cases, a
scale-up of a milling or sieving operation, the lubricants and glidants, which in
As part of the added to the dried
laboratory are usually added directly to the final blend, are usually
the
granulation during the sizing operation. stearate, tend to
additives, especially magnesium
This is done because some of these
granulation in a blender.
agglomerate when added in large quantities to the
Facilities:
to facilitate the cleaning of equipment
> To avoid cross contamination in scale up and
effectively, following facilities must be available that are;
Presence of separate room with availability of more space,
Must have granulation as unit operation,
Must have washing and drainage facilitics,
Must have cold, hot water and steam supply system,
Platform should be with stainless steel or non-dust material system,
must be screened,
Air condition system is encouraging but if absent, window
" Use of a multifunctional processing system.
Granulation Handling and Feed System:
area is either by Hand scooping
> The handling of the finished granulation in the compression mechanical
with vacuum or
for small scale or by sophisticated automated handling system
system for large scale.
flow property affects the tablet
The properties of material like size, size distribution and
hardness.
properties like drug content uniformity, tablet weight, thickness and
>For efficient cleaning, sophisticated material
handling systems like long lengths transfer
tubes, valves, vacuum and pneumatic pumps should be used.
Tablet Compression:
9
tablet press performs following functions during the compression are;
> The
Filling of an empty die cavity with granulation.
Pre-compression of granulation.
Compression of granules.
from the die cavity and take-off of the compressed tablet.
Ejection of the tablet generally adopted to find out the
potential
runs at press speeds is
The prolonged trial punch surface, tablet hardness, capping,
and weight
compression problems like sticking to the
variation detected.
depends on the ability of the press to interact with granulation.
> High-speed tablet compression criteria that should be considered are;
> During selection of high speed press
Granulation feed rate.
size distribution.
Delivery system should not change the particle
particles.
System should not cause segregation of coarse and fine
should induce static charges. of time
The die feed system must be able to fill the die cavities adequately in the short period
>
that the die is passing under the feed frame.
uniform to fill high press speeds.
> The smaller the tablet, the more difficult it is to get a
systems with a variety of feed paddles and
> For high-speed machines, induced die feed
variable speed capabilities, are necessary.
the heads of the punches
Compression of the granulation usually occurs as a single event as
pass over the lower and under the upper pressure rollers.
compacting the granulation to
This causes the punches to penetrate the die to a pre-set depth,
the thickness of the gap set between the punches.
by the speed at
The rapidity and dwell time in between this press event occurs is determined
which the press is rotating and by the size of compression rollers.
is applied and released.
> Larger the compressions roller, the more gradually compression force
reduce capping in
> Slowing down the press speed or using larger compression rollers can often
a formulation.
The final event is the ejection of compressed tablets from the die cavity.
During compression, the granulation is cOmpacted to form tablet, bonds within compressible
material must be formed which results in sticking.
> High levels of lubricant or over blending can result in a soft tablet, decrease in wettability of
the powder and an extension of the dissolution time.
> Binding to die walls can also be overcome by designing the die to be 0.001 to 0.005 inch
wider at the upper portion than at the centre in order to relieve pressure during ejection.
Tablet Coating:
Many changes in Sugar coating (Carried in conventional coating pans), due to new
developments in coating technology (Conventional sugar coating pan changed to perforated
pans or fluidizd-bed coating columas), changes in safety and environmental regulations.
> The development of new polymeric materials has resulted in a change from aqueous sugar
coating to aqueous film coating.
> The tablets must be sufficiently hard towithstand the tumbling to which they are subjected in
either the coating pan or the coating column.
10
coating with an
materials are naturally bydrophobic, and in these cases, film solution.
> Some tablet core formulation of the tablet core and/or the coating
aqueous system may require specialbeen found to work well with a particular tablet in a small
may haye
> A flm coating solution unacceptable on a production scale.
lab coating pan but may be totally the tablet should not be designed as flat surface or sharpe
coating
> To facilitate the efficient
cdges.
Encapsulation of Hard Gelatin Capsules: powder
Speed equipment is used to prepare the capsule by using the processed density,
> The High characteristics like particle size distribution,
bulk
blend with following particle
compressibility to promote good flow property. cohesiveness to be
facilitates the formation of compacts of the right size and of sufficient
> This
filled into capsule shells.
Filling of capsule is done by two filling systems;
Zanasi or Martelli form slugs in a dosator.
Hofliger-Karg Machine lubrication
Weight variation in capsules may come due to poor flow characteristics, improper
>
and plug sticking to the dosator plunger surface. dissolution and
variation, disintegration,
> Overlay lubrication may create problems in weight
Bioavailability.
influenced by the type
The characteristics of granulation and the finished products are greatly
lubrication.
and size of equipment used for blending, granulating, drying, sizing and
conditions that are Controlled
> For better encapsulation, need of controlled environmental
room and
humidity (RH 4S to 55 %) system in processing and encapsulation (RH 35 to 65 %)
appropriate temperature condition of 15 to 25 °C.
PILOT PLANT SCALE UP CONSIDERATIONS FOR LIQUID ORALS:
> The physical form of a drug product that can be incorporated demonstrates Newtonian or
Pseudoplasticflow behaviour.
> Itconforms to its container at room temperature.
> Liquid dosage forms may be dispersed systems or solutions.
> In dispersed systems there are two or more phases, where one phase is distributed in another.
> A solution refers to two or more substances mixed homogeneously.
Steps of liquid manufacturing process:
Planning of material requiremets.
Liquid preparation.
Filling and Packing.
Quality assurance.
Critical aspects of liquid manufacturing
" Physical Plant.
Heating,ventilation and air controlling system.
> The effect of long processing times at suboptimal temperatures should be considered in terms
of consequences on the physical or chemical stability of ingredients as well as product.
Solution:
The parameters to be considered are for scale up of solutions are;
11
Impeller diameter.
. Tank size (diameter).
Numberof impellers.
Impeller type.
Mixing capability of impeller.
Rotational speed of the impeller.
Height of the filled volume in the tank.
Number of bafles.
Transfer system.
of the nmixing tank.
Clearance between lmpeller Blades and wall materials but should not remove active or
Filtration equipment(should remove desired
adjuvant ingredients).
(Pre-reacting the SS with acetic acid or nitric acid solution
Passivation of Stainless Steel Stainless Steel).
the
to remove. the surface alkalinity of
Suspension:
are for scale up of suspension are;
> The parameters to be considered
Versator (To avoid air entrapment).
Wetting of suspending agent.
Addition and dispersion of suspending agents.
size.
Selection of the equipment according to batch
of the suspending agent.
Time and temperature required for hydration
as it leads to air entrapment).
Mixing speeds (High speed should not be used particulates and sieve selected based on
foreign
Mesh size (Must be able to remove the
production batch size trials).
Emulsion:
scale up of emulsion are:
The parameters to be considered are for
Homogenizing equipment.
Temperature.
Mixing equipment.
Phase densities.
In-process or final product filters.
Phase volumes.
Screens, pumps and flling equipment.
" Phase viscosities.
SEMl SOLIDS:
PILOT PLANT SCALE UP CONSIDERATIONS FOR
up of semisolid products;
> The following parameters are to be considered during the scale
" Mixing speed.
outside walls to the
Mixing equipment (Could be able to move semisolid mass from
centre and from bottom to top of the kettle).
viscous stage).
Motors (Drive mixing system with appropriate handling system at its most
Heating and cooling process.
Component homogenization.
12
Product transfer.
Addition of active ingredients.
Working temperature range. manufacturing to holding tank tofilling lines.
transfer from shear and
Shear during handling and viscous material without applying excessive
move
Transfer pumps (Easily must
free of entrapped air). and type of pump,
parameters must be consider during choosing the size
> Following
o Pumping rate.
should be considered.
o Pumping pressure required
Product compatibility with the pump surface.
o Product viscosity.
POSTAPPROVAL CHANGES)GUIDELINES:
SUPAC (SCALE UP AND of scale up or
recommended by the US FDA at the time
> SUPAC represents the changes
approval of NDA lANDA. product, the batch sizes used in the earliest
human
a new drug
Inthe process of developing batches is gradually increased (Scale-up). manufacturing
studies are small and the size of the composition,
changes made after approval in the
The scale-up process and the change of site have become known as
Scale-Up and
equipment, and
process, manufacturing
Post approval Changes, or SUPAC.
TheSUPAC Guidelines define; and Major Changes.
The level of changes - Minor, Moderate
vitro dissolution and in vivo
> Test - Application test, in supplement and Prior Approval Supplement.
being effected
> Filing- Annual report, changes formulation and quality performance in following levels;
> The level of changes may impact on
Impact.
Level 1: unlikely to have detectable
Level 2: could have significant impact.
Level 3: likely to have significant impact.
for post approval changes in;
These guidelines provide recommendations
The components or composition change,
The site of manufacture change,
The scale-up of manufacture change
The manufacturing (process and equipment) change.
A) The components or composition changes:
the drug product.
> This section focuses on changes in excipients in
non-critical to the Modified drug release.
> SUPAC-MR - Excipient critical or
Changes in non-release and release controlling excipients.
formulations.
> SUPAC-SS - Changes in preservative in semisolid
dosage forms.
> SUPAC-IR Changes for immediate-release solid oral
B) The site changes of manufacture:
> Changes in location of the site of manufacture,
packaging operations and/or analytical testing
laboratory. (including process and/or
in manufacturing
Do not include any scale-up changes, changes
equipment), or changes in components or composition.
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> Current Good Manufacturing Practice (CGMP) inspection.
Level I Changes -
procedures (SOP's),
Classiication-Single facility where the same equipment, standard operating personnel common.
controls, and
envinonmental conditions (e.g.,Temperature and humidity) and chemistry, dissolution and in
requirements in
lest Documentation - Application/ compendia
vivoBioequivalence - None.
Filing Documentation- Annual report.
Level II Changes -
Classiication-Same continuous campus, Common personnel, No other changes.
Iest Documentation
o Application' compendial requirements
Notification of Location of newsite
o Updated batch records
profiles(15,30,45,60 and 120 min)USP buffer media
o SUPAC- MR - Multi-point dissolution (e.g., Water, 0.1N HCI, andUSP
at pH 4.5-7.5 forextended release). Three differentMedia
buffer media at pH 4.5and 6.8for delayed release)until 80% ofDrug Released.
Filing Documentation- Annual report.
Level Il Changes -
Classifñcation- Different campus, Different personnel.
Test Documentation -
o Application/compendial requirements.
o Notification of Location of new site.
o Updated batch record. application/compendial medium.
o SUPAC- IR: Multi-point dissolution profile in the
30, 45, 60 and 120 min) USP buffer
o SUPAC - MR: Multi-point dissolution profiles (15, Media (e.g., Water, 0. IN HCI, and
media at pH 4.5-7.5 for extended release). Three different
of Drug Released.
USP buffer media at pH 4.5 and 6.8 for delayed release) until 80%
Filing Documentation- Annual report prior approval of supplement.
C)Changes in Batch Size (Scale-Up/Scale-Down): pivotal/pilot scale bio batch material to
the
> Post-approval changes in the size of a batch from
submission of additional information in the
larger or smaller production batches call for
application.
by this guidance.
> Scale-down below 100,000 dosage units is not covered
Level IChanges - times the size of the
Classification- Change in batch size, up to and including a factor of 10
pilotbiobatch.
requirements stability.
Test Documentation-Updated batch records application/compendial
Filing Documentation- Annual report (long term stability data).
Level II Changes -
the pilot or biobatch,
Classification- Changes in batch size beyonda factor often times the size of
No other changes.
Test Documentation -
Chemistry Documentation Application compendial release requirements. Notification of
o records. Stability testing: One batch with three
change and submission of updated batch
stability.
months accelerated stability data and one batch on long-term
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o Dissolution Documentation-Case B testing.
o In Vivo Bioequivalence - None.
(long-term stability
En Deocumentation- Changes being effected supplement; annual report
data).
D)Manufacturing Changes:
Nlanutacturing changes may affect both equipment used in the manufacturing process and the
process itself.
DEquipment -
Level I Changes:
Classiication- Altemate equipment of the same design and principles as automated equipment.
Iest Documentation -Updated batch records, Appication/compendial requirements and stability.
Fling Documentation- Prior approval supplement with justification for change, annual report
(long-tem stability data).
Level II Changes:
Classifcation- Change to equipment of different design and principle.
Test Documentation-Updated batch records, Application/compendial requirements and stability.
o SUPAC - IR - Multi-point dissoBution profiles in multiple media.
o SUPAC- MR - Multi-point dissolution profiles in multiple media.
Filing Documentation-Annual report and changes being Efected Supplement.
nProcess
Level I Changes:
Classification- Alternate equipment of the same design and principles as automated equipment.
Test Documentation -Updated batch records, Application/compendial requirements and stability.
Filing Documentation- Annual report.
Level II Changes:
Classification- This category includes process changes including changes such as mixing times
and operating speeds outside of application/ validation ranges.
Iest Documentation -Updated batch records, Application/compendial requirements and
o SUPAC- IR - Multi-point dissoBution profle. stability.
o SUPAC- MR - Multi-point dissolution profiles in
o SUPAC - SS - In vitro release test
multiple media.
Documentation.
Filing Documentation- Changes being effected supplement; annual report
data). (long term stability
Level III Changes:
Classification- Changes in the type of process used (e.g. wet granulation to direct
Test compression).
Documentation - Updated batch records, Application compendial requirements, stability ,
bio-study and IVIVC.
o SUPAC - IR - Multi-point
o SUPAC- MR - Multi-point
dissolution profle.
dissoBution profiles in
Filing Documentation- Prior approval multiple media.
stability data). supplement with justification, annual report (long-term
INTRODUCTION TO PLATFORM TECHNOLOGY:
Platform technologies:
15
levels of
technologies are systems that distribute the system out into different
> Platfom between core - platform functions, and the
abstraction. This is done in order to differentiate
these underlying common services.
application layer that sits on top of, and draws upon,
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