SUPAC

&
BACPAC
11/15/2019 1
 SCALE UP
&
POST APPROVAL
CHANGES
11/15/2019 2
 SCALE UP & POST APPROVAL CHANGES

 WHAT IS SUPAC?
 TYPES OF SUPAC
 LEVEL OF CHANGES
1. In component or composition
2. The site of manufacture
3. The scale up of manufacture, and
4. The manufacturing(process and equipment)
PRESENTATION
OUTLINE BULK ACTIVE POST APPROVAL CHANGES
 INTRODUCTION
 BACKGROUND
 ASSESMENT OF CHANGES
 TYPES OF CHANGES
1. Site, Scale, And Equipment Changes
2. Specification Changes
11/15/2019 3. Manufacturing Process Changes 3
 1. In the process of developing the new product, the batch size
used in earliest human studies are small.
2. The sizes of the batch is gradually increased
WHAT IS (scale up).
SUPAC ? 3. The scale up 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 (supac)

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 o Supac- IR (immediate release solid oral dosage
form .
o Supac- MR (for modified release solid oral dosage
TYPES o
form)
Supac- SS (for non sterile semisolid dosage form
including creams, ointments, gels and lotions)

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 SUPAC GUIDELINES - DEFINE
• Minor changes
• Moderate changes
LEVEL OF • Major changes
CHANGES

• Annual report
• Changes being affected supplement
FILING • Prior approval supplement

• Application/compendial tests
• In-vitro dissolution/release
TESTS • In-vivo

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 Likelihood of impact on formulation qualityand performance

LEVEL  LEVEL 1:

Those changes that are unlikely to haveany detectable impact on formulation quality and performance.

OF
Example --Changes in the color,flavors, Changes In the excipient express as the percentage (w/w) of total formulation, less than or equal to the following range

CHANGES
LEVEL 2:

1) Changes are those that could havesignificant impact on the formulation quality and performance

2) Test & Filling documentation vary depending upon three factors

Solubility, Therapeutic range, & permeability.

3) Example –1) Changes in the technical grade of excipient (Avicel PH102 vs. Avicel PH200); 2) Changes expressed as percent (w/w of total formulation)

11/15/2019 7
LEVEL 3:
Changes are those that are likely to have significant impact on formulation
quality and performance. Example --Any qualitative or quantitative
excipient changes to a narrow therapeutic drug beyond the range for level 1 All
other drug not meeting the dissolution criteria as level 2.

These guidelines provide recommendation for post approval changes in

In component or composition
The site of manufacture
The scale up of manufacture, and
The manufacturing(process and equipment)

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COMPONENT 1)Focus on the changes in amount of
AND excipients in the drug product
COMPOSITION 2)Not focus on change in the amount of
the drug substance .

11/15/2019 9
 LEVEL 1 CHANGES
TEST DOCUMENTATION

1. CHEMISTRY DOCUMENTATION
Application/ compendial release requirements stability testing (One batch long term)
2. DISSOLUTION DOCUMENTATION
None beyond the compendial requirements
3. IN VIVO BIOEQUIVALENCE DOCUMENTATION:- None

FILLING DOCUMENTATION Annual report

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 LEVEL 2 CHANGES
TEST DOCUMENTATION

1. CHEMISTRY DOCUMENTATION
Level 1 + 1 batch with 3 month accelerated stability study

2. DISSOLUTION DOCUMENTATION
Case A – High permeability, High solubility
Case B – low permeability, High Solubility
Case C – High permeability, Low Solubility Drugs In vivo

3. BIOEQUIVALENCE DOCUMENTATION –None

FILING DOCUMENTATION – As level 1 + Accelerated stability study

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 LEVEL 3 CHANGES
TEST DOCUMENTATION
1. CHEMISTRY DOCUMENTATION – Level 1 + 1 month accelerated
stability of 1 batch (SBOIA) or 3 batches (SBOINA)
2. DISSOLUTION DOCUMENTATION– Case B
3. IN VIVO BIOEQUIVALENCE – Full bioequivalence study. Except IVIVC
verified.

FILING DOCUMENTATION
– prior approval supplement , annual report

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  It consist of changes in location of the site of
manufacture, packaging operations, and/or analytical
testing laboratory for both company owned and contract
manufacturing facilities.

 They do not include any scale up changes, changes in

manufacturing ( including process and/or
SITE equipment), or changes in components or composition.
CHANGES
 New manufacturing locations should have had a
satisfactory cGMP inspection.

 A stand alone packaging operations site change and

laboratory changes, may be submitted as a Changes
11/15/2019 13
Being Effected Supplement
 LEVEL 1 CHANGES
Site change within a single facility where same equipment, SOP, Environment condition
and common 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. TEST DOCUMENTION
Chemistry, dissolution are according to compendial and
In vivo BE not required.
2. FILING DOCUMENTION
the annual report
LEVEL 2 CHANGES
Site change within a contiguous campus, or between facilities in adjacent city blocks.
o TEST DOCUMENTATION – level 1 + one batch long term stability in chemistry
documentation
o FILING DOCUMENTATION – annual report
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 LEVEL 3 CHANGES
• 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 qualify 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, where needed.

TEST DOCUMENTATION
1. CHEMISTRY DOCUMENTATION
Location of new site and updated batch records. Application/compendial release requirements
2. DISSOLUTION TESTING – Case B
3. NO BE REQUIRED

FILING DOCUMENTATION – annual reports

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 o Post approval changes in the size of a batch from the
pivotal/pilot scale bio batch material to larger or smaller
production .
CHANGE
o Scale down below 1,00,000 dosage units is not covered by
IN this guideline.
BATCH SIZE
o Scale up changes should be properly validated and if
needed, inspected by appropriate agency personnel.

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 LEVEL 1 CHANGES
o Changes in the batch size up to and including factor of 10 times the size of the pilot /
biobatch where
o The equipment is of same design and principle
o Batches are manufactured According to the CGMP compliance.
o Same SOP’s followed
o Test and filing documents are same as of the level 2 of the site changes requirement.

LEVEL 2 CHANGES
o Changes in the batch size beyond the factor of 10
TEST DOCUMENTATION
1. STABILITY TESTING
As per level 1 + one batch with three months accelerated stability + Case B dissolution
testing. (Other documents are same as above).
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 A. EQUIPMENT

LEVEL 1 CHANGE
o This consist of
MANUFACTURING 1) Change from non-automated to automated or vice versa to
CHANGES move ingredients
2) Change to alternative equipment of same design and the
operating principle of the same or different capacity

o TEST AND FILING DOCUMENTATION –

as per level 1 of batch size change

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 LEVEL 2 CHANGES
o Change in equipment to a different design

TEST AND FILING DOCUMENTATION

1. As per level 3 of the site change except
Case C dissolution instead of Case B.

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B. PROCESS CHANGES

LEVEL 1 CHANGES
o This changes includes process changes like mixing times and operating speed
within application/validation range
o TEST AND FILING DOCUMENT as per level 1 of site change

LEVEL 2 CHANGES

o This changes includes process changes like mixing times and operating speed
outside the application/validation range
o TEST AND FILING DOCUMENTATION – as per the level 2 changes in
site changes
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 LEVEL 3 CHANGES

o Change in the type of the process used in the manufacture of the product,
such as a change in from the wet granulation to the direct compression of
dry powder.

o DOCUMENTATION – As per the level 3 changes of components and

composition changes.

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 o COMPONENTS AND
COMPOSITION-
NONRELEASE CONTROLLING
EXCIPIENT
SUPAC - MR
 Focuses on changes to nonrelease controlling
excipients.

 Changes in components or composition that have the effect of

adding a new excipient or deleting an excipient are defined at
level 3.
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 LEVEL 1 CHANGES

TEST DOCUMENTATION

1. CHEMISTRY DOCUMENTATION
Application/compendial product release requirement
2. STABILITY: First production batch-Long term stability data
3. DISSOLUTION DOCUMENTATION: None
4. BIOEQUIVALENCE DOCUMENTATION: None
o FILING DOCUMENTATION
 Annual report- all information including long term stability data

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 LEVEL 2 CHANGES
o TEST DOCUMENTATION

1. CHEMISTRY DOCUMENTATION
Application/compendial product release requirements and updated executed batch
records.

2. STABILITY: One batch with three month accelerated stability data reported in prior
approval supplement and long term stability data of first production batch reported in
annual report.

3. DISSOLUTION DOCUMENTATION
Extended release
 Multipoint dissolution profile in 0.1N HCl and USP buffer media at pH 4.5 and 6.8
for the changed drug product and the bio batch or marketed batch (unchanged
drug product).
Delayed release
11/15/2019 24
 BIOEQUIVALENCE DOCUMENTATION: None

FILING DOCUMENTATION
 Prior approval supplement (accelerated stability data) annual report (long term stability

LEVEL 3 CHANGES
TEST DOCUMENTATION:
1. CHEMISTRY DOCUMENTATION:
Application/ compendial product release requirements and updated executed batch records.

2. STABILITY:
Significant body of information available:
One batch with three months accelerated stability data reported in prior approval supplement
and long term stability data of first three production batches reported in annual report.
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o BIOEQUIVALENCE DOCUMENTATION:
 A single dose bioequivalence study. The bioequivalence study may be waived in presence of
an established in vitro/in vivo correlation.

FILING DOCUMENTATION:
Same as level 2 changes.

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 COMPONENTS AND COMPOSITION —
RELEASE CONTROLLING EXCIPIENT
• Focuses on changes in release controlling excipients in the drug product.

• For modified release solid oral dosage forms, consideration should be given as to whether
or not the excipient is critical to drug release.

• The sponsor should provide appropriate justifications for claiming any excipient(s) as a
release controlling excipient in the formulation of the modified release solid oral dosage
form. The functionality of each excipient should be identified.

11/15/2019 27
 LEVEL 1 CHANGES
TEST DOCUMENTATION

A. CHEMISTRY DOCUMENTATION Application/compendial product release requirements.

B. STABILITY: First production batch on long-term stability data reported in annual report.

C. DISSOLUTION DOCUMENTATION None beyond application/compendial requirements.

D. BIOEQUIVALENCE DOCUMENTATION-None.

FILING DOCUMENTATION
Annual report (all information including long-term stability data)

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 LEVEL 2 CHANGES
Are those that could have a significant impact on formulation quality and performance..

TEST DOCUMENTATION
a. CHEMISTRY DOCUMENTATION Application/compendial product release requirements
and updated executed batch records.
STABILITY: !
a. NON NARROW THERAPEUTIC RANGE DRUGS: One batch with three months'
accelerated stability data reported in prior approval supplement and long-term stability data
of first production batch reported in annual report. !
b. NARROW THERAPEUTIC RANGE DRUGS: Three batches with three months'
accelerated stability data reported in prior approval supplement and long-term stability data
of first three production batches reported in annual report

FILING DOCUMENTATION Prior approval supplement (all information including

accelerated stability data); annual report (long-term stability data
11/15/2019 29
 LEVEL 3 CHANGES
Are those that are likely to have a significant impact on formulation quality and performance
affecting all therapeutic ranges of the drug.
TEST DOCUMENTATION

1. CHEMISTRY DOCUMENTATION Application/compendial product release

requirements and updated executed batch records.
2. STABILITY: Three batches with three months' accelerated stability data reported in
prior approval supplement and long-term stability data of first three production
batches reported in annual report.
3. BIOEQUIVALENCE DOCUMENTATION A single-dose bioequivalence study . The
bioequivalence study may be waived in the presence of an established in vitro/in vivo
correlation . Changes in release controlling excipients in the formulation should be
within the range of release controlling excipients of the established correlation.

FILING DOCUMENTATION
Prior approval supplement (all information including accelerated stability data);
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annual report (long-term stability data).
 BULK ACTIVE
POST APPROVAL
CHANGES
11/15/2019 31
 This guidence provide recommendation to holders of
NADAs (New animal drug application), ANADAs
(Abbreviated new animal drug application),
VMFs(Veterinary master files)

POST APPROVAL CHANGES INCLUDE

INTRODUCTION
 Site of Manufacture
 Scale of Manufature
 Equipment
 Specification
 Manufacturing process of intermediates in synthetic
pathway leading to drug substance
32
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 Under section 506A of federal Food, drug and cosmetic act, the
holder of an NADA or ANADA must notify FDA about each
change in each condition established in an approved application
beyond the variation already provided for in theapplication

BACKGROUND THE ACT PROVIDES 4 REPORTING

CATEGORIES
 PRIOR APPROVAL SUPPLEMENT
 SUPPLEMENT- CHANGES BEING EFFECTED IN 30 DAYS
 SUPPLEMENT-CHANGES BEING EFFECTED
 ANNUAL REPORT

33
11/15/2019
The reporting category for a change is based on the potential for the change to
have an adverse effect on the identity, strength, quality, purity, or potency of
the drug product as these factors may relate to the safety or effectiveness of the
drug product.

The guidance applies to synthetic drug substances and the synthetic steps involved
in the preparation of semisynthetic drug substances.

 It is limited to structurally well-characterized drug substances for which

impurities can be monitored at the levels recommended.

34
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 THE GUIDANCE COVERS – TYPES OF CHANGES

1. SITE, SCALE, AND EQUIPMENT CHANGES

Involving the synthetic steps up to and including the step that produces the final
intermediate,

2. SPECIFICATION CHANGES
For raw materials, starting materials, and intermediates, except the final intermediate,
and

3. MANUFACTURING PROCESS CHANGES

Changes involving the synthetic steps up to and including the final intermediate.

4. MULTIPLE CHANGES
Combination of all above changes
35
11/15/2019
 THE FOLLOWING CHANGES ARE EXCLUDED FROM THE BACPAC 1

 Any specification change for a raw material, starting material, or intermediate derived
from a biotechnology process .

 Changes related to testing for viruses or adventitious agents:

(1) Relaxing an acceptance criterion,
(2) deleting a test, or
(3) A change in the analytical procedure that does not provide the same or increased assurance
of the identity, strength, quality, purity, or potencyof the material being tested as the analytical
procedure previously described

36
11/15/2019
 Changes in virus or adventitious agent removal or inactivation methods

 Changes in source material (e.g., Plant species, geographic location of plant harvesting,
microorganism) or supplier ofsubstances derived from natural sources that are the
intermediates that begin the synthetic part of a semi synthetic process.

 The final intermediate was chosen as the break point in this attempt to categorize risk
because
(1) it is typically the most well characterized material in the synthetic scheme, except for
the drug substance itself, and
(2) physical properties of the drug substance usually will not be affected by changes
made up to that point.

37
11/15/2019
ASESSMENT OF CHANGES
A HOLDER OF AN APPROVED APPLICATION must assess the effects of the changes
before distributing a drug product made with the manufacturing change (according to
section 506a of the act).

A central tenet is that a given change in drug manufacturing process can be adequately assessed
by comparing pre and post change materials(i.e. Of same or better quality).

When equivalence can't be demonstrated, applicants should submit a PRIOR APPROVAL

SUPPLEMENT ,and

Should consider appropriate tests for qualification of impurity, demonstration of

bioequivalence, assessmentof stability.

Two major factors for determining equivalence in drug substance are the:-
 Impurity profile
38
11/15/2019
 Physical property
A. EQUIVALENCE OF IMPURITY PROFILES

 It is important to determine the STAGE in the manufacturing process at which

impurities should be evaluated and to establish the ADEQUACY OF THE ANALYTICAL
PROCEDURES used for this purpose.

 Ideally, impurities should be evaluated in ISOLATED INTERMEDIATES immediately

following the process step in which the manufacturing modification is made

 When it is not feasible to evaluate impurities in intermediates, or when equivalence

cannot be demonstrated at these stages, the testing can be carried out on the DRUG
SUBSTANCE ITSELF

 The analytical procedures used to evaluate the change should be adequate for
quantitating both existing and new impurities at the recommended levels. Development
of new analytical procedures may be called for.
11/15/2019 39
When new analytical procedures are developed for this purpose, a summary of validation
data should be provided. The same analytical procedure should be used when comparing
impurity levels in Pre- And Post Modification Batches.

The impurity profile will be considered equivalent after a given change if three consecutive
post modification batches of either an isolated intermediate or the drug substance are
evaluated and the test data for each batch demonstrate that

For evaluation of an intermediate, no new impurity is observed above 0.1 % ( or above

0.2 % in an intermediate with only veterinary use).

Each existing impurity is within its stated limit or, if not stated, is at or below the upper
statistical limit of historical data.

Total impurities are within the stated limit or, if not stated, are at or below the upper
statistical limit of historical data.
40
11/15/2019
Each existing Residual solvent is within its stated limit or, if not stated, is at or
below the upper statistical limit of historicaldata.

Equivalence of the impurity profile can be established by testing any isolated

intermediate following the change, including the final intermediate or the drug
substance. Equivalence should not be established by combining results from
multiple intermediates.

In situ intermediates are generally not appropriate for demonstrating

equivalence.

The batches of the intermediate or drug substance used for testing should be
synthesized using exclusively the material that has been subjected to the
change(s)(i.e., without blending with pre-change material)
41
11/15/2019
 When a manufacturing change is made to an outsourced
intermediate, either the vendor or the customer can establish
equivalence. However, in addition to assessing equivalence of the
impurity profile, release testing by the vendor or acceptance testing
by the customer, as appropriate, should be conducted.

 Changes can be evaluated using data from pilot scale batches. If

equivalence is demonstrated by using pilot batches, the first production
batch should also be evaluated for equivalence. The production batch
equivalence data should be kept on file at the manufacturing site.

42
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EQUIVALENCE OF PHYSICAL PROPERTIES
Two physical properties of the drugsubstance,
1. Morphic Form
2. Particle Size,

 The physical properties of the drug substance will be considered equivalent after a given
change if three consecutive post-modification batches of thefinished drug substance are
compared to three or more consecutive representative pre-modification batches and the test
data for each batch demonstrate

 Conformance to established acceptancecriteria for Morphic form or, where acceptance criteria
do not exist, the isolation of the same form or mixture of forms within the range of historical
data

11/15/2019
Conformance to historical particle sizedistribution profile 43
 A. SITE, SCALE, AND EQUIPMENT CHANGES
The manufacturing site, scale of manufacture, and
manufacturing equipment changes discussed inthis
section do not include any modifications to the
TYPES synthetic pathway (i.e., the samestarting
materials, intermediates, solvents, and reagentsare
involved).
OF
CHANGE

11/15/2019 44
1. SITE CHANGES

I. Changes to a different manufacturing site should be reported. Changes within the

same manufacturing site need not be submitted to the Agency, and equivalence
testing as described in this document need not be carried out.

II. TEST DOCUMENTATION (submitted as amendments to master files and/or

in annual reports or supplements to the applications, as appropriate) should include:

1) The Name And Address Of The New Facility

2) A Concise Description Of The Manufacturing Steps Being Transferred, a

summary of any variation in equipment or operating conditions, and a statement
that the Synthetic Pathway Is Identical At The New Site.
11/15/2019
45
1) Evaluation of the impurity profile and physical properties. This evaluation
should include
 A report on changes in impurities with a description of analytical procedures.
Data on three consecutive batches made at the new site.
 Historical data for comparison.
 A description of the source of the historical data.

REPORTING CATEGORY:
Annual Report if the site change does not involve the final intermediate
Supplement :Changes Being Effected if the site change involves the final
intermediate

11/15/2019 46
 2. SCALE CHANGES
 Scale changes include increases and decreases in the batch size of
intermediates,including the final intermediate, beyond those approved in the
original application

3. EQUIPMENT CHANGES
 A change to new equipment need not be submitted to the Agency, even where
equipment is specified in the approved application.

47
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 B) SPECIFICATION CHANGES

Specification changes for the final intermediate are not included in this guidance, nor are
certain specification changes for raw materials, starting materials, and intermediates
derived from natural sources or biotechnology.

1. SPECIFICATION CHANGES MADE TO COMPLYWITH COMPENDIAL

CHANGES
Test documentation (submitted in amendmentsto master files and/or in annual reports
to the applications, as appropriate) should include:
A description of thechange
Updated specifications
Reporting Category: Annual report.
Annual Report.
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2. SPECIFICATION CHANGES THAT PROVIDE GREATER ASSURANCE OF
QUALITY
Examples:
 Tightening of acceptance criteria
 Replacing an existing analytical procedure with an improved procedure

Test documentation
1. Rationale for the proposed change and a brief description of any newanalytical
procedures, including a discussion of improvements over existing procedures.
2. Updated specifications.

 Reporting Category:
• Annual Report.

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3. OTHER SPECIFICATION CHANGES EXAMPLES:

Deleting a test
Replacing an existing analytical procedure with a new procedure that does not qualify
as an improvement
Revised specifications associated with changes in supplier/grade of starting
materials, reagents, or solvents

Some SPECIFICATION CHANGES THAT DO NOT AFFECT the quality of

downstream intermediates or the drug substance and therefore no evaluation of
equivalence would be needed. Examples include:

 Elimination of a redundant test (e.g., deletion of a boiling point test for a solvent
where a chromatographic assay test is routinely performed)

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 Elimination of a test that is no longer necessary (e.g., testing for an impurity that is no
longer present due to a change in the supplier of a starting material)

TEST DOCUMENTATION should include-

1. Rationale for the proposed change and a brief description of any new analyticalprocedures

2. Evaluation of the Impurity profile and physical properties, if appropriate. This

evaluation should include: (SAME AS ABOVE)

3. CERTIFICATE OF ANAALYSIS of Raw Materials and Batch Release data for

Intermediates.

REPORTING CATEGORY:
1. Annual Report.
2. Supplement C
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 C) MANUFACTURING PROCESS CHANGES
This category encompasses a wide range of process- related changes. New specifications may be
called for when different solvents, reagents, starting materials, or intermediates are involved

1. CHANGES THAT DO NOT INVOLVE NEW STARTING MATERIALS OR

INTERMEDIATES

EXAMPLES- changes made in one/more synthetic/ purification processes.

1. Changes in unit operations (e.g., addition, deletion, change in theorder, repetition of an
existing unit operation on a routine basis)
2. Addition or deletion of rawmaterials (e.g., solvents, reagents) or ancillarymaterials (e.g.,
resins, processing aids)
3. Changes in solvent composition (other than for an analytical procedure, which would be
coveredunder Specification Changes)
4. Operating conditions (e.g., temperature, pH, reagent stoichiometry, time). 52
11/15/2019
TEST DOCUMENTATION should include:
1. Description of change
2. Specifications for new reagents and solvents and Certificates of Analysis from the
suppliers, if applicable
3. Evaluation of the impurity profile and physical properties.

REPORTING CATEGORY:
1. Annual Report if equivalence is demonstrated priorto the final intermediate.
2. Supplement: Changes Being Effected if equivalence is demonstrated at the final
intermediate or drug substance.

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 2. CHANGES IN THE ROUTE OF SYNTHESIS IN ONE OR MORE
STEPS INVOLVING DIFFERENT STARTING MATERIALSAND/OR
INTERMEDIATES (EXCEPT THE FINAL INTERMEDIATE)
TEST DOCUMENTATION
1. Description of the change with details of the new synthetic procedure, the operating
conditions,and controls of critical steps andintermediates
2. Appropriate structural characterization data for new intermediate
3. Specifications for any new starting materials and/or intermediates
4. Evaluation of the Impurity profile and physical properties.

REPORTING CATEGORY:
1. Supplement: Changes Being Effected in 30 Days if equivalence is demonstrated prior to the
final intermediate.
2. Prior approval supplement if equivalence is demonstrated at the final intermediate or drug
54
substance.
11/15/2019
3.CHANGES IN WHICH AN INTERMEDIATE IS REDEFINED AS
A STARTING MATERIAL
This change is often in response to an increase in commercial availability of the proposed
starting material. In general, the specification for the proposed starting material should be
more comprehensive than the intermidiates.

TEST DOCUMENTATION
1. Rationale for the proposed change and overview of current synthetic procedure

2. Evidence that the intermediate complies with the current definition and/or expected
characteristics of a starting material.

3. A new or revised specification, a description of new or revised analytical procedures for

the redefined starting material, and, if appropriate, additional tests and/or tightened
acceptance criteria for downstream intermediates
11/15/2019
55
• A list of sources of the redefined starting material.

• A description of how the suitability of a new supplier or revised process from an existing
supplier will be assessed.

• Evaluation of the Impurity Profile and Physical Properties.

REPORTING CATEGORY:
• Supplement: Changes Being Effected in 30 Days

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 D) MULTIPLE CHANGES
Multiple changes are those that involve various combinations of the changes described insections
V.A, B, and C.

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 BACPAC
 CDER: http://www.fda.gov/cder/guidance/index.htm
 CVM: http://www.fda.gov/cvm/fda/TOCs/guideline.html
FDA Guidance Documents Specifically Referenced In BACPAC I:
1) Submitting Supporting Documentation in Drug Applications for
the Manufacture of Drug Substances, CDER, February 1987.
2) Changes to an Approved NDA or ANDA, CDER, November 1999.
REFERENCES 3) Changes to an Approved Application for Specified Biotechnology
and Specified Synthetic Biological Products, Center for Biologics
Evaluation and Research (CBER) and CDER, July 1997.
ICH GUIDELINS
1. ICH Q3A Impurities in New Drug Substances, January 1996.
2. ICH Q3C Impurities: Residual Solvents, Federal Register,
December 1997.

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3. VICH GL10 Impurities in New Veterinary Drug Substances, May 58
2000
 SUPAC
1. ICH HARMONISED TRIPARTITIE GUIDELINES www.ich.org
2. USP 2000
3. Encyclopedia of Pharmaceutical technology, Vol-19, pg. 227-235.
4. Drug Stability: Principles and Practices, 3rd Edition, edited by Jens T. Carstensen and C.
T. Rhodes
5. www.who.int/medicines
6. Expert Consultation for 2nd Addendum to the 3rd Edition of the Guidelines for Drinking-
water Quality, Geneva, 15–19 May 2006
7. Pharmainfo.net
8. www.fda.gov

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