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Some Critical Aspects in the Scale

up of Pharmaceutical Dosage Forms

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 Disclaimer

Sidvim LifeSciences Private Ltd has taken due care and caution in developing this
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available in the public domain, its adequacy or accuracy or completeness cannot be
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accepted practices and standards consistent with the level of care and skill exercised
under similar circumstances by professional consultants or firms that perform the same
or similar services.
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Agenda
Basic definitions

Key elements of success

What is technology transfer strategy?

Oral Solid scale up and technology transfer principles

Scale up and technology transfer of Dermal Products

Parenteral Scale up Principles

Industry Academia Partnerships

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Basic Definitions

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 Definition
Scale up: the process of increasing the batch size. The process wherein the
product that is successfully developed in the lab is transferred to pilot scale and
then to commercial scale.
Scale down?
Technology Transfer: The goal of technology transfer activities is to transfer
product and process knowledge between development and manufacturing,
and within or between manufacturing sites to achieve product realization. This
knowledge forms the basis for the manufacturing process, control strategy,
process validation approach and ongoing continual improvement. (Ref.: ICH Q10
[1], paragraph 3.1.2)

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 WHO goes one step further to define as
follows
Transfer of technology is defined as “a logical procedure that controls the transfer of any process
together with its documentation and professional expertise between development and manufacture or
between manufacture sites”.

It is a systematic procedure that is followed in order to pass the documented knowledge and
experience gained during development and or commercialization to an appropriate, responsible and
authorized party. Technology transfer embodies both the transfer of documentation and the
demonstrated ability of the receiving unit (RU) to effectively perform the critical elements of the
transferred technology, to the satisfaction of all parties and any applicable regulatory bodies.

Transfer of technology requires a documented, planned approach using trained and knowledgeable
personnel working within a quality system, with documentation of data covering all aspects of
development, production and quality control. Usually there is a sending unit (SU), a receiving unit
and the unit managing the process, which may or may not be a separate entity.

Ref. : https://www.who.int/medicines/areas/quality_safety/quality_assurance/TransferTechnologyPharmaceuticalManufacturingTRS961Annex7.pdf?ua=1 7
 A typical product lifecycle involves the
following
Pharmaceutical Development:
Drug substance development;
Formulation development (including container/closure system);
Analytical method development.
Manufacture of investigational products;
Delivery system development (where relevant);

Manufacturing process development and scale-up;

Technology Transfer:
New product transfers during Development through Manufacturing;
Transfers within or between manufacturing and testing sites for
marketed products.
Ref: ICH Q 10 8
 Technology transfers occur at multiple stages
during development

Ref: https://store.pda.org/TableOfContents/Tech_Transfer_Ch01.pdf 9
 What is success defined as?
Technology transfer can be considered successful if there is documented
evidence that the RU can routinely reproduce the transferred product,
process or method against a predefined set of specifications as agreed with
the SU.

There are no deviations during routine manufacturing.

Slight variations which are within the acceptance criteria for equipments do
not lead to any OOT (Out of trend) or OOS (out of specification).

The product does not come back to the lab!

Robust formula/ process leads to successful transfer!

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Key Elements of
Success

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 Prerequisite for a successful scale up and technology
transfer is – successful product development.
Pharmaceutical Development Q8 (R2)

Describes science and risk-based approaches for pharmaceutical product and manufacturing process
development
Introduced concepts of design space and flexible regulatory approaches
Introduced concepts of Quality by Design (QbD) and provided examples of QbD development approaches and
design space.
The Pharmaceutical Development section should describe the knowledge that establishes that the type of
dosage form selected and the formulation proposed are suitable for the intended use. This section should
include sufficient information in each part to provide an understanding of the development of the drug product
and its manufacturing process. Summary tables and graphs are encouraged where they add clarity and
facilitate review.
At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing
processes that are critical to product quality should be determined and control strategies justified. Critical
formulation attributes and process parameters are generally identified through an assessment of the extent to
which their variation can have impact on the quality of the drug product.
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 First steps to Scale up and tech transfer
QbT versus QbD
Writing an effective technology
transfer protocol is very important
Documented data – intangible
experience based inputs- need to be
translated effectively
Visual observation – e.g. end points –
translated to values
Additional Sampling and testing to
ensure robustness– IPQC testing
Challenges of scale –API sifting
Identify potential causes for variability
Ref.: https://www.sciencedirect.com/science/article/pii/S1818087616300575 13
FDA Inspectional Observations

Do not directly refer to

technology transfer.

However product
failure investigations
are referred back to
the PDR and the
development process
itself.

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What is technology
transfer strategy?

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 Technology transfer is managed at multiple
levels
Management Level

Portfolio Revenue
Regulatory Filing
Management identification Generation
/ Litigation / Launch Planning
priorities across different Targets and
licensing
therapeutic areas Budgets

Project Governance Level

Successful
Completion of Technology Execution of Exhibit Batch
demonstratio
Development Transfer Plan Trials Execution
n TTR

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 Technology transfer strategy encompasses
many aspects
Define the scope of transfer- new product / new dosage form / additional
strengths / new site
Document the activity step wise and with timelines - granularity
Identify critical and supportive stakeholders and their priorities – decision
makers
Get stakeholder buy in – align cross functional priorities
Provide sufficient time for digestion of information prior to expecting a response
Follow up
Start with a kick off meeting
Ref: http://www.pharmtech.com/keys-executing-successful-technology-transfer?pageID=2
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 What does a successful scale up and
technology transfer have?
The project plan should encompass the quality aspects of the project and be based
upon the principles of quality risk management;
The capabilities of the SU and at the RU should be similar, but not necessarily
identical, and facilities and equipment should operate according to similar operating
principles;
A comprehensive technical gap analysis between the SU and RU including technical
risk assessment and potential regulatory gaps, should be performed as needed;
Adequately trained staff should be available or should be trained at the RU:
regulatory requirements in the countries of the SU and the RU, and in any countries where the product
is intended to be supplied, should be taken into account and interpreted consistently throughout any
transfer programme project; and
there should be effective process and product knowledge transfer
Ref. : https://www.who.int/medicines/areas/quality_safety/quality_assurance/TransferTechnologyPharmaceuticalManufacturingTRS961Annex7.pdf?ua=1 18
 Key elements for successful technology transfer
generally include the following
Direct involvement and engagement among technical staff on both sides throughout
the course of transfer activities
Well-defined leadership and governance and competent project management
Multifunctional involvement (cross functional or matrixed teams) with appropriate
competencies on both the transferring and receiving ends
Meaningful demonstration of success –repeatable independently (e.g., a successful
good manufacturing practice [GMP] manufacturing campaign resulting in comparable
material)
Good documentation of what is transferred, how it is to be transferred, and the
results of that transfer.
Agreement on the outcome with formal sign off
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 Kick off meeting is key!
Clearly state the agenda & state the expected goals
Alignment -Management  Business Unit  Department(s)  Group Leads  ME
Share a detailed presentation upfront (at least 48 hours prior to kick off)- covering product
data and desired timelines along with expected roles and responsibilities
Ask for all inputs on possible road blocks –LISTEN with an open mind!
Obtain stakeholder commitment on dates
Learn from others experience- shop floor personnel (Experience speaks)
Seek help to address the potential road blocks proactively
Red flagged issues to be followed up during the entire project
Identify gaps and provide mitigation plan based on the gap analysis
Minute the meeting and share and follow up on the agreements reached
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 Gap Analysis – identify gaps across the whole
process
API lot differences- stage of API development (process / solvents / purity)
Raw material vendors- critical versus standard – cost / vendor qualification
Procurement lead times – API/ RM /PM/ change parts
Equipment availability -types / size/ scale
Instrumentation for sampling & testing
Storage requirements –cold storage?
Hold time impact
Risk assessment
Risk mitigation plan
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 Effective stake holder management is needed to
Facilitate Technology Transfer
Project Plan – management buy in across levels
Project Management team – knowledgeable and proactive
Timelines / Gantt chart management – with a constant eye to improve the same
Task force- core team – scientific issues
Stage Gate reviews – frequency based on priority
Budget & Cost control – additional batches / contingency
Communicate – effectively. Extent of data sharing depends on need for the
same. More rather than less.
Work as a team – common goals!
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 Cross functional team may consist of the
following departments
PD (FD and AD) Production QC Engineeri QA/ Project Core Task
ng & Regulatory management force
maintena
nce
i. Selection of raw i. Provide facility i. Quality Calibration Preparation and Timeline and Execution of
materials, API, PM- and equipments testing of API/ and review of cost tech transfer,
for performing
formula process, RM/ PM, in- maintenan documentation management. conflict
operation. Ensure
methods. process ce of (protocol and resolution and
suitably trained
ii. Design and personnel are material equipment reports) for all Stakeholder responsibility
development of available. ii. Quality s. processes of management. for success
manufacturing ii. Perform testing of technology
process operation with full finished Support transfer. Effective
iii. Identification of understanding of product for trouble communication
critical process criticalities. iii. Preparation shooting For any
parameters Provide feedback of certificate of during deviation or
iv. Establishing on possible analysis (CoA) process. OOS provide
specifications and improvements iv. Stability necessary
from efficiency
validation of testing support.
perspective.
analytical test
iii. Record results
methods. of operation and
controls
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 Analytical Method Transfer is critical to
Success
Testing to meet the specification of raw material, intermediate, and/or ingredient and
product is critical in establishing the quality of a finished dosage form.

The transfer of analytical procedures (TAP), also referred to as method transfer, is the
documented process that qualifies a laboratory (the receiving unit) to use an analytical
test procedure that originated in another laboratory (the transferring unit), thus ensuring
that the receiving unit has the procedural knowledge and ability to perform the transferred
analytical procedure as intended.

When appropriate and as a part of pretransfer activities, the transferring unit should
provide training to the receiving unit, or the receiving unit should run the procedures
and identify any issues that may need to be resolved before the transfer protocol is
signed. Training should be documented.
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Ref. : USP Chapter <1224>
 Technology transfer from one organization to
another may have more hurdles
Contract – legal document
Licensing agreement / Master Services agreement
Supply clauses – meeting specification / yields
Data sharing and Gap analysis – multiple differences possible
Align the QMS – collaborate to avoid conflict
Minimum batch – MOQ or sudden increase in demand – prepare contingency
Define Roles and responsibilities
Define resolution process
Document everything – MOM / data e-rooms / decisions
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 Oral Solid Scale up &
Technology Transfer Principles

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 Critical Planning Aspects that impact Scale up
& TT for OSD
Typically 1/10th of commercial batch size
Orphan drugs – smaller batches
Expensive API – smaller batches – justification needed. Cap on maximum commercial batches
Raw Materials – free samples or vendor qualified by QA?
Manufacturing Procedures and Equipment details – screens / tooling availability & lead times
Blend / Granulation / Mix Analysis – justification of specifications
In-Process Controls and specifications – with suitable justification
Test Results with Validated Methods – for development batches including stability data
Investigations/Product Failures – sharing the data from development
Paper Based Site Review of equipments & Instruments– for identifying mis-match / gap
Well written Technology Transfer Protocol
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 Bio batch at development scale is manufactured with
excessive care
Executed by : the development scientist
Batch size is usually small – sufficient for pilot BE and some stability
Tested at multiple intervals
All parameters are strictly adhered to
Batch is closely monitored
RM/API/ CC: are all as used in development trials
Batch size being small – enables quick completion
Documentation is per GMP & DQA controlled

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 Common issues that are many a times faced
in scaling up
API vendor change – do we know what parameters are important?
Raw material source differences
Equipment differences – type, speed and efficiency
Equipment principle- SUPAC
Modification in process due to operating principle differences
Batch run time – maybe over multiple shifts
Validation by sampling at multiple intervals
Temperature / RH impact
Trained personnel – especially for new technologies
Hold time impact

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Critical steps in OSD scale up include the
below
Particle size distribution of the active(s)
Sequence of addition
Blending time for the powder mix prior to granulation
Granulating time and speed; amount of granulating fluid and binder
concentration. Rate of addition. End point identification.
Wet milling – need, impact on drying
Drying time – final moisture content, granule particle size distribution
Granule active content and homogeneity, blending time of external
phase
Coating issues – percentage coat, efficiency of coater
Environmental controls / light sensitivity
In roller compaction – impact of change in roller size
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 Case Study: Blend uniformity (BU) failure at
scale up
Blending and Mixing: The reorientation of particles relative to one
another in order to achieve uniformity.
Operating Principles:
Diffusion blending (Tumble)
V-blenders
Double Cone Blenders
Slant Cone Blenders
Cube Blenders
Bin Blenders
Convection Mixing
Ribbon Blenders
Orbiting Screw Blenders
Planetary Blenders
Pneumatic Mixing
no pneumatic mixer subclasses have been identified
Ref: https://www.fda.gov/media/85681/download
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 FDAs stand on Blend Uniformity
The CGMPs require that all sampling plans be scientifically sound and representative of the batch under test
(see 21 CFR 211.160(b)). Further, in-process testing of powder blends to demonstrate adequacy
of mixing is a CGMP requirement (21 CFR 211.110). Between- and within-location variability in the
powder blend is a critical component of finished product quality and therefore should be evaluated. Drug
product manufacturers need to use a science- and risk-based sampling approach to ensure
(a) adequacy of blend mixing and
(b) that sampling of the blend is done at a suitable juncture in the manufacturing process.

The sampling and analysis needs to ensure that no differences exist between locations in a blend
that could adversely affect finished product quality. Traditional sampling using a powder-thief may
have drawbacks and limitations, such as causing disturbance to the powder bed, powder segregation, or
other sampling errors. However, powder-thief sampling remains widely used and provides reliable results in
many cases. The Agency encourages firms to adopt more innovative approaches to ensuring adequacy of
mixing (see, e.g., the guidance for industry PAT—A Framework for Innovative Pharmaceutical Development,
Manufacturing, and Quality Assurance). If a manufacturer proposes to use a thief sampling method, the
reliability of the method should be evaluated as part of analytical methods development
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 Case Study: BU acceptance criteria
BU Criteria: Individual values Not less than 90.0 % and not more than 110.0% of
label claim; Mean Value of the test results should not be less than 95.0% and not more than
105.0 % of label claim.
Blend Sample Criteria: RSD is ≤ 5.0% and all individuals are within +/- 10% of absolute
mean. The RSD value should be used to classify the testing results as either readily pass (RSD ≤
4.0%), marginally pass (RSD ≤ 6.0%) or inappropriate for demonstration of batch homogeneity
(RSD > 6.0%)
Absolute as used to define the acceptable range (+/- 10%) in which individual blend sample
values must fall and which is independent of the value of the mean. For example, if the mean of
all blend samples is 95.0%, the absolute range is 85.0% to105.0%, (not 95.0% +/- 9.5%).
In case of very low dose products – with adequate justification:
Individual assays: 85.0-105.0% of the label claim/mean value, RSD: NMT 5.0%
May be acceptable provided that uniformity of dosage units is satisfactorily demonstrated on tablets/capsules manufactured from blend
lot with close to limit blend uniformity results
Ref: http://academy.gmp-compliance.org/guidemgr/files/5831DFT.PDF
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 Case Study : BU failure on scale up
Importance of sampling and specification setting:

Sampling location -usually predetermined as part of qualification of the mixer (i.e. mostly GMP issue)
But, in the dossier, we at least check if periphery, center positions and various other positions are considered
Dead spots included?
Samples from each location are usually taken in triplicate

Samples should also be taken from the blend container (Drum)- to evaluate impact of transfer
important for low dose products and particularly for DC processed blend

at least 3 replicate samples be taken from at least 10 locations in the powder blender -all replicate samples taken from various
locations in the blender be evaluated to perform a statistically valid analysis

Sampling should be done consistently and in away that does not disturb the bulk blend state – such
aspects (e.g. type of sampling thief used) are better addressed at the time of inspection

Sample size should be justified: 1x to 3 x, 5x to 10x?

Ref.: https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practices-production-and-process-
controls#:~:text=Section%20V%20(Exhibit%2FValidation%20Batch,to%20assess%20powder%20blend%20uniformity. 34
 Case Study : BU failure
Capsule dosage form with BCS class I drug

Development equipment and scale up equipment follow same operating principle – 5 kg to 50 kg scale up (1x to 10x)

API is crystalline and forms 25% w/w of the fill weight. Fill weight 100 mg / size 2 capsule.

Formula and process are replica of RLD- process is simple sifting / blending / lubrication followed by capsule filling.

Issue: Basis the equipment qualification protocol – the blending time and speed were set for the first scale up batch-
BU failed, CU was passing.

Root cause: Segregation of blend during sampling, inadequate replicates, less that ideal sample size (1x to 3X),
difference in API particle size distribution between development and scale up

Resolution: Increase sample size to 3x to 5x, justify with CU data of failed BU batch, re-define API PSD , use personnel
trained in sampling, revise blending time.
2 more batches were repeated and both BU and CU were satisfactory. (BU samples at blending and lubrication). All locations
tested.
FDA DRL (Discipline Review Letter) pinpointed this issue and discussed it further- validation batches commitment to sampling

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Case Study: Environmental Impact
Antimalarial product: High dose API; FC IR tablet; wet granulated product
% Moisture Content (MC) in the granules prior to tableting: 1-2.5 % w/w in development
No capping observed; no friability issues
Batch size maximum- 2.5 kgs in development
Scaled up to: 200 kgs
Issue: Capping of tablets in scale up batch
Root cause: Loss of moisture from granules on running the compression over long
periods- bulk granules exposed to controlled temperature and humidity.
Resolution: Revise the LOD limits of granules marginally- more stringent limits; Load
the hopper minimally, keep the granules well covered in drums- avoid too many transfers.
Between shifts – remove granules from turret and discard.

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Case Study: Equipment size /scale impact
Equipment Size impacts process
API-Anti emetic; low dose API, BCS Class I, Degrades on aqueous processing
Lab scale compactor- small auger and rolls- water jacket circulation; good compacts;
desirable flow, dissolution and stability. Output 750 gms to 3 kg/hour
Plant scale: 400 kg/ hour output
Issue: jamming of rollers; formation of flakes
Root Cause: Heat generation; material fuses to form flakes; lumps formed due to
intense heat in the process of compaction. Yield, dissolution and stability affected
adversely – specification failure.
Resolution: Replace partially water insoluble components with soluble ones –
formula change (!); ensure cold water circulation jacket; slow down Auger speed.
Additional In process test – added granule dissolution.
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 Case Study : API properties impact in an Antiepileptic
Capsule dosage form
Drug – ~50 % w/w
API characterized for:
Capsule size 2
Percentage w/w of API Lab trials with API from small scale manufacture of API
Particle size and Pivotal trials with bulk manufactured API
distribution Issue- final blend low BD and TD – does not fill capsules

Bulk and tapped density Root cause - API form- amorphous versus crystalline

Form- crystalline / Specs set during development inadequate

amorphous Resolution:

Flow ability API re-crystallized

API spec revised – test added

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Manufacturing Process changed
 Case Study: Granulation Process failure
Granulation principle : Excess shear has potentially detrimental effect. Over granulation / under granulation
impact differs from smaller to larger equipment.
Scale of operation:
Lab scale RMG  Pilot Scale RMG  Production scale RMG
3 kgs  25 kgs  110 kgs
12 litres  125 litres  600 litres
Product: Antiepileptic Dosage form: FC tablet
High dose API- about 66%w/w of product, BCS Class II moiety- in vitro dissolution indicates probable in vivo
performance
Dissolution profile matched from lab pilot bio batch to manufacturing level pilot plant batch.
Pivotal batch dissolution failed- slower by more than 30% from initial data
Granules PSD similar, Bulk density higher for pivotal batch granules
Opening pattern in the dissolution bath different
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Granulation process failure: Root cause
analysis
Investigation performed at each stage of operation
Dry blend; granules (un-milled & milled), lubricated blend, core and coated
tablets subjected to dissolution.
Issue: Drop in dissolution observed post granulation
Granules PSD comparable; bulk density higher- forms a heap at the bottom of
dissolution vessel
Root cause: MCC behaviour – Hypothesized that MCC tends to undergo plastic
deformation and form a pseudo –plastic mass on over kneading.
This leads to lower compressibility of granules, higher binding and harder
granules and therefore decreased solubility of the API
Resolution: Granulation optimized to obtain light granules , dissolution at
granulation stage introduced as an additional test till validation and
commercialization.
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Scale up & Technology transfer
of Topical Products
Unit operations in Topical Products
Unit operations involved in the manufacturing of Topical products varies depending on
the nature of the product.
Ointment / gel/ cream / lotion etc.
Typical unit operations :
Mixing
Heating and Melting
Homogenization
Cooling and deaeration
Filling
Critical quality attributes affected include description, assay, uniformity, related
substances, globule size, viscosity, specific gravity etc.

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Key considerations for Scale up
Apply the principles of QbD and Risk assessment to identify potential CPPs ,
and the CQAs they are likely to impact. Establish acceptable range of
CQAs, which will not affect product quality.
Establish a range of scale independent parameters at lab scale via a DoE or
OFAT experiments.
Challenge scale dependent parameters thoroughly at lab scale to
understand the nature and level of their impact on CQAs, even though the
range at lab scale might not be valid at higher scale.
Opt for equipments of similar geometry and design, and apply
engineering principles like tip speed calculation to minimize scale up failures.
Don’t forget the CMAs : API PSD, Melting point of excipients etc
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 Critical aspects of Topical product
manufacturing
Mixing : The reorientation of particles relative to one another to achieve uniformity or
randomness. This process can include wetting of solids by a liquid phase, dispersion of discrete
particles, or deagglomeration into a continuous phase. Heating and cooling via indirect
conduction may be used in this operation to facilitate phase mixing or stabilization
Potential CPPs :
Type and geometry of mixing apparatus : Propeller, Anchor, etc
Mixing time and Speed : Tip Speed
Occupancy of mixing vessel
Order of Addition of ingredients
Application of heat / rate of application

Affected CQAs :
Assay, uniformity, related substances

Ref. : https://www.fda.gov/media/85681/download
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 Critical aspects of Topical product
manufacturing
Heating and melting.

Potential CPPs :
Type and geometry of mixing apparatus : Propeller, Anchor, etc
Heating temperature
Order of Addition of ingredients

Affected CQAs :
Description, Related substances, viscosity

Ref. : https://www.fda.gov/media/85681/download
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 Critical aspects of Topical product
manufacturing
Homogenization / Emulsification: The application of physical energy to a liquid
system consisting of at least two immiscible phases, causing one phase to be
dispersed into the other
Potential CPPs :
Type and geometry of homogenizer
Order of Addition of ingredients
Speed and time of homogenization : Tip speed
Temperature of homogenization
Number of cycles

Affected CQAs :
Assay, uniformity, related substances, Viscosity, globule size etc

Ref. : https://www.fda.gov/media/85681/download
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 Critical aspects of Topical product
manufacturing
Deaeration and Cooling: The elimination of trapped gases to provide more
accurate volumetric measurements and remove potentially reactive gases

Potential CPPs :
Cooling rate
Shear during cooling : cooling under mixing vs cooling under homogenization
Application of vacuum
Temperature of cooling

Affected CQAs :
Viscosity, Specific Gravity etc

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 Application of QbD and Risk assessment for
manufacturing of Topical products
Typical example of risk matrix of unit operations Vs Critical quality attributes

Process Step Process Scale Affected CQA Risk Justification and

parameters dependent/ Ranking Mitigation strategy
Independent
Homogenization Homogenizer Independent Assay, uniformity, Low Same make and geometry
type and viscosity, Globule as lab scale. No mitigation
Geometry size strategy required.
Order of Independent Related Low Studied and established in
addition substances, lab scale. No mitigation
Viscosity strategy required.
Speed and Time Scale dependent Viscosity, Globule High Speed and time to be
and number of size, Assay, optimized based on tip
cycles Uniformity speed

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 Tips for successful scale up of topicals
Expect increase in mixing times, even though the composition is exactly the same as
that of lab scale. For e.g., a dispersion of Carbopol or even solubilization of some APIs.

Expect overall increase in processing time, consider API exposure to different phases
and temperatures during scale up.

Typically higher scale equipments produce more shear even if tip speed calculation is
maintained. Consider impact on viscosity, globule size etc.

At times, process efficiency might increase during scale up, like cooling rate can be
faster or vacuum applied can be stronger. Consider impact on viscosity, specific gravity etc.

Develop tools like IVRT (in vitro release testing) during development to understand
impact of CPPs better

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Parenteral Scale up
Principles

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 Parenteral Preparations
Definition:Parenteral preparations are defined as solutions, suspensions,
emulsions for injection or infusion, powders for injection or infusion, gels for
injection and implants. They are sterile preparations intended to be
administrated directly into the systemic circulation in human or animal body.

Main challenge for clear solution sterile parenteral products is mixing time
and equipment.

For suspensions: particle size post homogenization

For emulsions: distribution of phases

Ref: https://gmpua.com/Process/ProcessScale-Up.pdf 51
 Properties of Parenteral preparations
They must meet the following minimum compendia criteria:
Must be sterile and pyrogen-free
Must be clear or practically exempt of visible particle and to be free from sub-
visible particles as required by pharmacopeias EP, USP and JP;
There should be no evidence of phase separation for the emulsions, or
aggregates formation for aqueous dispersion such as injectable Mab (monoclonal
antibody) preparations; and
In the case of suspensions, the use of appropriate particle size and any sediment
should be readily dispersed upon shaking to give stable formulations and
ensure the correct dose to be withdrawn and injected.

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 Importance of Container Closure Systems
CDER and CBER approve a container closure system
to be used in the packaging of a human drug or
biologic as part of the application (NDA, ANDA or
BLA) for the drug or biologic.

Table 1 illustrates the correlation between the

degree of concern regarding the route of
administration with the likelihood of
packaging component-dosage form
interactions for different classes of drug products.

For the purposes of this table, the term suspension

is used to mean a mixture of two immiscible phases
(e.g., solid in liquid or liquid in liquid).
As such, it encompasses a wide variety of dosage
forms such as creams, ointments, gels, and
emulsions, as well as suspensions in the
pharmaceutical sense.

Ref.: https://www.fda.gov/media/70788/download 53
 Important aspects related to manufacture of
parenteral products include
Process Tests Critical parameter
Mixing Description Order of addition of
components, including
Homogenization Potency & Purity
adjustments of their amounts.
Preservative content
Filtration Mixing speed and mixing time.
Volume/Dose Uniformity Rate of addition of drugs and
Filling & sealing
Bacterial endotoxin buffers
Sterilization - Heating and cooling rates.
Sterility
terminal sterilization Filter sizes for sterile
or aseptic fill pH
manufacturing
Redispersion - suspensions Lyo cycles and temperatures
Reconstitution - Lyo 54
Additional specifications
Absence of Particulate matter (all solutions)
Dissolution rate (implant, suspensions)
Particle size distribution (suspension /emulsion)
Osmolarity
Preservative content
Antioxidant content
Resuspendability
Extractables and Leachables

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 Critical steps & In-process controls to be monitored
during scale up and technology transfer
Sterilization/depyrogenation processes – with justification
Sterilization parameters for the product and all items in contact with the sterile
product
Validation reports (heat penetration and performance validation):
Results for three consecutive runs
Loading chart(s)

Filter validation report – Bacterial retention, chemical compatibility,

extractables, absorption – Flush volume – Filter integrity testing
Environmental controls – no sterility failures
Media fill studies and process validation runs
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 Example of failed technology transfer
Product needs lyophilization so as to maintain stability
Successfully developed in lab- two process cycles established
API is poorly soluble and needs solubility enhancers- is high dose
Formula without ethanol meets Q1/Q2
Formula with ethanol is also stable – needs regulatory justification
CC (Controlled correspondence ) with FDA signals use of formula without ethanol

Issue: Batch transfer to manufacturing site – first batch is successful- meets AQL though not ideal
(acceptable quality limits)
Second, third and fourth batch – collapse
Root cause analysis: risk assessment due to manufacturing equipment and lyophilization
conditions not established appropriately
Resolution: Not achieved yet. Equipment parameters for lyo cycles are suspected.

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Industry Academia Collaborations –
my personal view

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 Asking the right questions

Trust – respecting the CDA

Scoping of the project – with details

Full understanding of timelines and future course for the company

Academia should have access to industry trained personnel to assist / advice

Access to right quality of API / RM/ PM

Autonomy – ability to take decisions independently

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 Equipment sizes and types and likely gaps
between academia and industry
Transparent Information exchange prior to project start

Understanding the gaps – and partnering effectively to close the same

Documentation standards / Calibration of equipment / adherence to

timelines

Identifying possible additional actions at the time of scale up & technology

transfer- additional timeline and budget

My view: success is possible with collaboration:

• Abbess Healthcare in Bharati Vidyapeeth

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Thank You!

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