Regulatory Approvals for In Vivo Testing, Scale-Up Processes and Post-Approval Changes

05-04-2022 © R R INSTITUTIONS , BANGALORE 1
Regulatory affairs(1 SESSIONAL)
IN VIVO AND SCALE-UP PROCESS APPROVAL
CHANGES
R.R. COLLEGE OF PHARMACY
Submitted to: Prof. SRILATA
Presented by: PUSHPA SAHANI
YEAR: 1Sem M.Pharm.

 Introduction
 In vivo
 SUPAC guidelines
 Level of changes
 Current requirements for post approval
1)Component and composition and their levels
2) Site changes and their levels
3)Batch size changes and their levels
4) Manufacturing changes and their levels
1.Equipment changes
2. Process changes
© R R INSTITUTIONS , BANGALORE

 In vivo ,is a latin word which means within the living
 It is the experiment or observation done in the living tissue
of the whole living organism in a controlled environment.
 It is done on living organism not in a dead or partial one.
 It is found to be more suited on experiment done on
organism that are alive .
 For example clinical testing or a clinical trials which can be
controlled testing of new drug on human subject.
 Another example is animal testing which is an experiment
done on animals usually rats ,mice , rabbits, apes etc. where
the drugs are directly injected into body .so in vivo
experiments ,conditons are not manipulated or controlled .

 It is a guideline for scale up batches with recommendation to
industry in the form of guidance given by regulatory agency.
 The scale-up process and the changes made after
approval in the composition, manufacturing process,
manufacturing equipment, and change of site have
become known as SCALE-UP and POST APPROVAL
CHANGES, or SUPAC.

The FDA has issued various guidance for SUPAC changes
designated as:-
A. SUPAC-IR (for immediate-release solid oral dosage forms)
B. SUPAC-MR (for modified-release solid oral dosage forms)
C. SUPAC-SS (for non-sterile semisolid dosage forms
including creams, ointments, gels and lotions).

level of changes Minor changes
Major changes
Moderate changes
Filling Annual report
Changes being affected supplement
Prior approval supplement
Tests Application/Compendial tests
In-vitro dissolution/release
In-vivo

The guidance describe the following areas where change is
likely:
 Components and composition of the drug product
 Manufacturing site change
 Scale-up of the drug product
 Manufacturing equipment
 Packaging
The SUPAC guidance describes three levels and the
recommended chemistry, Manufacturing and controls
tests, In vitro dissolution tests and bioequivalence tests for
each level and also the documents to support the change.

Likelihood of impact on formulation quality and
performance
Level 1: Those changes that are unlikely to have any
detectable impact on formulation quality and
performance.
example: 1)Changes in the colour, flavours
2)Changes in the excipient express as the
percentage (W/W) of total formulation, less than or equal
to the following range.

LEVEL 2: Changes are those that could have significant
impact on the formulation quality and performance.
example: Changes in the technical grade of excipient
(Avicel PH102 vs Avicel PH200)
Changes expressed as percent
(w/w of total formulation)

LEVEL 3: Level 3 changes are those that are likely to have
significant impact on formulation quality and
performance.
Example: Any quantitative or qualitative excipient
changes to a narrow therapeutic drug beyond the range
for level 1 All other drug not meeting the dissolution
criteria as level 2.

Current requirements for post-approval
Component and composition changes
 In general, changes to the qualitative and quantitative
composition of the formulation are considered major
changes. Therefore, these changes must be considered
carefully before implementation.
 In this changes may be done in the composition and
component like excipents or other materials used in the
formulation.

LEVEL 1 CHANGES
TEST DOCUMENTATION
 Application/compendial release requirements
and stability testing.
 Stability testing: One batch on long-term
stability data reported in annual report.
FILLING DOCUMENTATION
 Annual report( all information including long term
stability data)

Level 2 changes
test documentation
1)Chemistry documentation
 Application/compendial release requirements
and batch records.
 Stability testing: 1batch with 3months
accelerated stability data in supplement and
1 batch on long-term stability.

Dissolution documentation
Case A: HIGH PERMEABILITY, HIGH SOLUBILITY DRUGS
Dissolution of 85% in 15minutes in 900ml of 0.1N HCl.
If a drug product fails to meet this criteria, the applicant should
perform the tests described for case B or C (below).
Case B: low PERMEABILITY, HIGH SOLUBILITY DRUGS
Multi-point dissolution profile should be performed in the
application/compendial medium at 15,30,45,60,120 minutes or
until an asymptote is reached. The dissolution profile of the
proposed and currently used product formulations should be
similar.

Case c: high permeability, low solubility drugs
 Multi-point dissolution profiles should be performed in
water, 0.1N HCl, and USP buffer media at Ph 4.5, 6.5,
and 7.5 (five separate profiles) for the proposed and
currency accepted formulation.

In-vivo bioequivalence documentation
None: If the situation does not meet the description in
Case A, Case B or Case C, refer to level 3 changes.
Prior approval supplement(all information
including accelerated stability data); annual report
(long-term stability data).

Level 3 change
test documentation
1)Chemistry documentation
 Application/compendial release requirements and batch
records.
SIGNIFICANT BODY OF INFORMATION AVAILABLE
One batch with three months accelerated stability data
reported in supplement; one batch on long-term stability
data reported in annual report.
SIGNIFICANT BODY OF INFORMATION NOT AVAILABLE
Up to three batches with three months accelerated
stability date reported in supplement; one batch on long-
term stability date reported in annual report.

Dissolution documentation
Full bioequivalence study. The bioequivalence study
may be waived with an acceptable in in vivo/in vitro
correlation has been verified.
prior approval supplement( all information including
accelerated stability data) annual report has been
verified.

Site changes
 The sponsor of an ANDA must include in its application the
site of manufacture, Where the drug product will be
produced, Tested, Packaged and labelled.
 A change in any of these sites can adversely affect the
identity, strength, quality, purity/potency of the finished
product. Therefore ,any site change under SUPAC-IR calls
for the new site to be in compliance with current good
manufacturing practices (cGMP)

Different levels and the regulatory requirements for site
changes are discussed.

Level 1(site change)
1.definition of level
 Level 1 changes consist of site changes within a single facility
 where the same equipment, standard operating procedures
(SOP’s),environmental conditions (e.g., temperature and
humidity) and controls, and personnel common to both
manufacturing sites are used

LEVEL 2
1)DEFINITION OF LEVEL
 Level 2 changes consist of site changes within a
contiguous campus, or between facilities in adjacent city
blocks, where the same equipment, SOP’s, environmental
conditions.
 e.g.( Temperature and humidity) and controls, and
personnel common to both manufacturing sites are used,
and where no changes are made to the manufacturing
batch records, except for administrative information and
the location of the facility.

1)Definition of level
 Level 3 changes consist of a change in manufacturing site
to a different campus.
 A different campus is defined as one that is not on the
same original contiguous site or where the facilities are not
in adjacent city blocks.
 To quality as a level 3 change, the same equipment, SOP’s,
environmental conditions, and controls should be used in
the manufacturing process at the new site
 And no changes may be made to the manufacturing batch
records except for administrative information, location and
language translation.

 Change in batch size from the pivotal/pilot scale bio-batch
material to larger or smaller production batches tends to
change the operating parameter.
 Therefore all the parameters are adjusted according to the
equipment(large or small) used in process call for submission
of additional information in the application.
 Any change in the production batch for which the operating
parameter falls with the range established for the ANDA
batch and validation batches will be regarded as a level 1
change.

 Changes in the batch size up to and including factor of
10times the size of the pilot/bio batch where
 The equipment is of same design and principle.
 Both manufacturer. According to the CGMP compliance.
 Same SOP’s followed
 Test and filling documents are same as of the level 2 of the
site changes requirement.

 Changes in the batch size beyond the factor of 10
 Test documentation.
 As per level 1+one batch with three months accelerated
stability+ case B dissolution testing.

This includes any change Made in equipment and the
process used in manufacturing a drug product
1)EQUIPMENT CHANGE
 It requires appropriate validation studies to demonstrate
that the new equipment is similar to the original
equipment.
 Equipment within the same class and subclass would be
considered to have the same design and operating
principal under SUPAC-IR.

LEVEL 1 CHANge
 Change to alternative equipment of same design and the
operating principle of the same or different capacity.
 Test and filling documentation- as peer level 1 of batch size
change 22 SUPAC.

 Change in equipment to a different design.
 Test and filling documentation.
 As per level 3 of the site change except case C dissolution
instead of case B.

2)PROCESS CHANGE
 Change in manufacturing process/Technology from that
currently used by the applicant may have the potential for
adverse effects on the identity, strength, quality,
purity/potency of a drug product.
 The safety/effectiveness of the product depends on the type
of the manufacturing process and the changes being
instituted for the drug substance or drug product.
 Any fundamental change in the manufacturing process

1.Generic Drug product development solid oral
dosage forms by Leon Shargel.
2. www.slideshare.com
3. www.google.com
4. Industrial pharmacy 2 (8th sem book ) by Dr
A.A. Hajare

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