scale up andpost approval changes and post marketing surveillance

1. SUPAC AND POST MARKETING
SURVeILLANCE
1
Prepared by:
Mr. Bhavya Jivrajani
M.Pharm 1st sem
(Pharmaceutics)
Guided By:
Dr. Dhaval D. mori
Senior lecturer
BKMGPC

2. CONTENTS
SUPAC
• Introduction
• Purpose of guidelines
• Components and composition
• Site changes
• Changes in batch size
• Manufacturing process/ equipment
Post marketing surveillance
• Introduction
• Safety Monitoring during the Post-Approval Phase of a Drug Product’s Life Cycle
• Types of Post-Marketing Adverse Event Data
• Post-marketing Adverse Event Reporting and MedWatch
• Post-marketing safety reporting requirements
• Serious Adverse Experience
2

3. 3
SUPAC

4. WHAT IS SUPAC ?
• Scale up post approval changes
• 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.
• SUPAC-IR (immediate release solid oral dosage form)
• SUPAC-MR (modified release solid oral dosage form)
• SUPAC-SS (semi solid dosage form including cream,
ointment, gels, and lotion)
4

5. Purpose of guidelines:-
Provides recommendation to sponsor of NDA,ANDA,
AADA’s who intend, during the post approval period,
to changes:
5
The components or composition
The site of manufacturing
The scale-up/scale-down of manufacturing
The manufacturing process/Equipments

6. The guidance defines:
I. Levels of change;
II. Recommended chemistry manufacturing and control
tests for each level of change;
III. In vitro dissolution tests and/or in vivo bioequivalence
tests for each level of change; and
IV.Documentation that should support the change.
6

7. Level of
changes
• Minor changes
• Moderate changes
• Major changes
filing
• Annual report
• Changes being affected supplement
• Prior approval supplement
tests
• Application/ compendial test
• In-vitro Dissolution/release
• In-vivo Bioequivalence
7

8. 8
DissolutionTesting
Case A: Dissolution of Q = 85% in 15 minutes in 900 milliliters
(mL) of 0.1N hydrochloride (HCl), using the United States
Pharmacopeia (USP) <711>Apparatus 1 at 100 revolutions per
minute (rpm) or Apparatus 2 at 50 rpm.
Case B: Multi-point dissolution profile in the
application/compendial medium at 15, 30, 45, 60, and 120
minutes or until an asymptote is reached for the proposed and
currently accepted formulation.
Case C: Multi-point dissolution profiles 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 currently accepted
formulations. Adequate sampling should be performed at 15,
30, 45, 60, and 120 minutes until either 90% of drug from the
drug prod is dissolved or an asymptote is reached. A surfactant
may be used with appropriate justification.

9. 9
SUPAC-IR (immediate release
solid oral dosage form)

10. I. COMPONENTS AND COMPOSITION:-
This section of the guidance focuses on changes
in excipients in the drug product. Changes in the
amount of drug substance are not addressed by
this guidance. Changes in components or
composition that have the effect of adding a new
excipient or deleting an excipient are defined at
Level 3 (defined below), except as described
below.
10

11. 11
Level 1 Level 2 Level 3
Components
and
composition
Test
documents
-CMC
Stability
testing:
-Unlikely to have any
detectable impact on
formulation quality and
performance
-Application/
compendial release
requirements and
stability testing.
-one batch on long-
term stability data
reported in annual
report.
-Significant impact on
formulation quality and
performance.
-vary depending upon three
factor
1.therapeutic range
2.solubility
3.permiability
-1 batch with 3 months
accelerated stability data in
supplement and 1 batch on
long-term stability data
reported in annual report.
-
-Likely to have a
significant impact on
formulation quality and
performance.
-vary depending on the
following three factors:
1.therapeutic range
2.solubility, and
3.Permeability
-1 batch with 3 months
accelerated stability data
reported in supplement; 1
batch on long-term
stability data reported in
annual report.

12. 12
Level 1 Level 2 Level 3
-Dissolution
Documentati
on
-InVivo
Bioequivalen
ce
-Filing
Documentati
on
-None beyond
application/
compendial
requirements.
-None.
-Annual report (all
information including
long-term stability
data).
Case A-high perm., high
solubility.
Case B-low perm., high
solubility.
Case C-high perm., low
solubility.
Case D-low perm., low
solubility.
-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
(including accelerated
stability data); annual
report (long-term stability
-Case B
Full bioequivalence study.
Prior approval supplement
(including accelerated
stability data); annual
report (long-term stability
data).

13. II.SITE CHANGES:-
It changes in location of the site of manufacture for both
company-owned and contract manufacturing facilities
and do not include any scale-up changes, changes in
manufacturing (including process and/or equipment), or
changes in components or composition.
13

14. 14
Level 1 Level 2 Level 3
SITE CHANGES
Test
documents
-CMC
Documents
Stability
testing:
site changes within a
single facility where the
same equipment,
standard operating
procedures (SOP's),
environmental
conditions (where no
changes are made to
the manufacturing
batch records)
None beyond
application/compendia
l release requirements.
Site changes within a
contiguous campus, or
between facilities in
adjacent city blocks.
Location of new site and
updated batch records.
None beyond application/
compendial release
requirements. One batch
on long-term stability data
reported in annual report.
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.
-Location of new site and
updated batch records.
- One batch with three
months accelerated
stability data reported in
supplement; one batch
on long-term stability
data reported in annual
report.

15. 15
Level 1 Level 2 Level 3
-Dissolution
Documentati
on
-InVivo
Bioequivalen
ce
-Filing
Documentati
on
None beyond
application/compendia
l release requirements.
None
Annual report
None beyond application/
compendial release
requirements.
None
Annual report (long-term
stability test data).
-Case-B.
The dissolution profile of
the drug product at the
current and proposed site
should be similar.
None
Annual report (long-term
stability test data).

16. III. CHANGES IN BATCH SIZE (SCALE-UP/SCALE-
DOWN)
Post approval changes in the size of a batch from the
pivotal/pilot scale bio batch material to larger or smaller
production.
Scale-down below 100,000 dosage units is not covered
by this guidance.
scale-up changes should be properly validated and,
where needed, inspected by appropriate agency
personnel.
16

17. 17
Level 1 Level 2 Level 3
CHANGES IN
BATCH SIZE
(SCALE-
UP/SCALE-
DOWN)
Change in batch size, up to
and including a factor of
10 times the size of the
pilot/bio batch.
1) The equipment used
to produce the test
batch( es) is of the
same design and
operating principles;
2) The batch( es) is (are)
manufactured in full
compliance with
cGMP's
3) Same SOP’s,
controls,
formulation,
manufacturing
procedure followed
Changes in batch size beyond
a factor of ten times the size
of the pilot/bio batch.
-

18. 18
Level 1 Level 2 Level 3
CMC
documents
(stability
testing)
-Dissolution
Documenta
tion
-InVivo
Bioequivale
nce
-Filing
Documenta
tion
One batch on long-term
stability reported in
annual report.
None
None
Annual report (long-
term stability data).
One batch with three
months accelerated
stability data and one
batch on long-term
stability.
-Case : B
None
Changes being effected
supplement; annual report
(long-term stability data).

19. IV. MANUFACTURING:-
Manufacturing changes may affect both
equipment used in the manufacturing process
and the process itself.
Equipment
Process
19

20. 20
Level 1 Level 2 Level 3
Manufacturing
equipment
Manufacturing
process
1. Change from non-
automated or non-
mechanical equipment to
automated or
mechanical equipment to
move ingredients.
2. Change to alternative
equipment of the same
design and operating
principles of the same or
of a different capacity.
This category includes
process changes
including changes such
as mixing times and
operating speeds within
application/validation
ranges.
Change in equipment to a
different design and different
operating principles.
This category includes process
changes including changes
such as mixing times and
operating speeds outside of
application/validation ranges.
-
This category includes
change in the type of
process used in the
manufacture of the product,
such as a change from wet
granulation to direct
compression of dry powder.

21. 21
Level 1 Level 2 Level 3
CMC
documents
(stability
testing)
-Dissolution
Documenta
tion
-InVivo
Bioequivale
nce
-Filing
Documenta
tion
For
Process
One batch on long-
term stability
reported in annual
report.
-None beyond
application/
compendial release
requirements.
-None
Annual report (long-
term stability data).
As per level 1 of site
change
As per level 3 of the site
change
Case: C
-None
As per level 2 of site
change
As per level 3 of changes
of components and
composition changes.

22. 22
Post marketing
surveillance

23. 23
Practolol syndrome:- Practolol, a drug used to treat
cardiovascular disease, was eventually found to cause
skin rashes, eye lesions, hearing impairment, and
sclerosing peritonitis , with deaths occurring in about 2
percent of reported cases.
The drug thalidomide,
taken worldwide, led to
limb deformities
(phocomelia) in the
newborns of those
mothers who took the
drug while pregnant.
HISTORY:

24. • Introduction :-
Safety concerns
Strategies and Actions to Minimize Risk
24
• Preclinical
• Safety and biological activity
Preclinical
• Phase 1
• Safety and dosage
Phase 1
• Phase 2
• Safety and efficacy
Phase 2
• Phase 3
• Safety and efficacy
Phase 3
• Post marketing
• Safety and surveillance
Post marketing
Approval

25. Safety Monitoring during the Post-
Approval Phase of a Drug Product’s Life
Cycle:-
• Less frequent adverse drug experiences (ADEs)
• Patients with higher risk for ADEs
• Chronic and long term use
• Drug-drug interactions
• Drug-food interactions
• Expected ADEs
– Increased severity or frequency
• Misuse or abuse of drug product
• Medication errors
– Product packaging, labelling, other characteristics
25

26. Types of Post-Marketing Adverse Event
Data:-
• Spontaneous/voluntary reporting of cases
• National (FDA MedWatch)
• Local or Regional (Joint Commission Requirement)
• Scientific literature publications
• Post-marketing studies (voluntary or required)
• Observational studies (including automated healthcare
databases)
• Randomized clinical trials
• Active surveillance
• Drug-Induced Liver Injury Network (DILIN) – Sentinel
initiative
26

27. Post-marketing Adverse Event Reporting and
MedWatch:-
• How Post-marketing Reports Get to FDA
voluntary voluntary
regulatory requirement
FDA
5% of all reports 95% of all reports 27
Patients, Caregivers, and Healthcare
Professionals
FDA Med Watch Manufacture
Database
FAERS

28. Post-marketing safety reporting
requirements:-
Under 21 CFR 314.80 post-marketing safety
reports must be submitted to the agency for the
following:
• 15-day Alert reports: Serious and unexpected adverse
experience from all sources (domestic and foreign).
• Periodic Adverse Events Reports: Domestic
spontaneous adverse events that are:
• Serious and expected
• Non-serious and unexpected
• Non-serious and expected
• Quarterly for the first 3 years then annually
28

29. Serious Adverse Experience:-
Results in any of these outcomes:
Death
Life-threatening adverse experience
Inpatient hospitalization – new or prolonged
Persistent/significant disability/incapacity
Congenital birth defect
Other serious: based upon appropriate medical
judgment, they may jeopardize the patient and
require intervention to prevent a serious outcome.
29

30. Spontaneous reports:-
A communication from an individual (e.g.,
health care professional, consumer) to a
company or regulatory authority
Describes a suspected adverse event(s)
Passive and voluntary reports
30

31. Spontaneous Reporting System
Strengths:-
• Relatively affordable system to monitor all drugs
• Can report even if causality is uncertain
• Less restrictive than clinical trials
• Reports can be submitted for any drug, old and new
• Entire US population is “eligible”
• Reports emerge from usual healthcare settings:
i. Patient and prescriber population more heterogeneous
ii. All stages of treated disease
iii. Longer duration of use
iv. Captures “off-label” use, including diagnosis and dose
31

32. Factors Affecting Reporting:-
• Media attention
• Nature of the adverse event
• Type of drug product and indication
• Length of time on market
• Extent and quality of manufacturer’s surveillance
system
• Prescription or over-the counter (OTC) product status
• Reporting regulations
32

33. FDA Adverse Event Reporting System:-
• Fully automated computerized database
• Spontaneous reports
• Contains human drug and therapeutic biologic
reports
• 13 million reports since 1969
• Over 71 new reports in 2018
33

34. 34

35. Best Applications of FAERS(FDA Adverse
Events Reporting System)
• Events that are linked to specific diagnoses
• Events with a serious outcome that rarely
occur in an untreated population
• Events with a short-to-moderate period
following exposure
• “Safety signal” generation and descriptive
case series
35

36. Components of a Good post-marketing
Report
• Description of adverse event
• Suspected and concomitant product therapy details (e.g.,
dose, dates of therapy)
• Patient characteristics (e.g., age, sex), baseline medical
condition, family history, other risk factors
• Documentation of the diagnosis
• Clinical course and outcomes
• Relevant therapeutic measures and laboratory data
• Dechallenge and rechallenge information
• Reporter contact information
• Any other relevant information
36

37. Evaluation of Case Reports
• Adverse event occurrence in expected time
• Absence of symptoms prior to exposure
• Positive dechallenge or rechallenge
• Consistent with pharmacologic effects
• Consistent with known effects in the class
• Support from pre-clinical studies, clinical trials
• Absence of alternative explanations
37

38. How to Report to MedWatch
38
How to Report:
• Online (www.fda.gov/medwatch)
• Download the form
• Mail
• Fax 1–800–332–0178
• For questions about the form:
1–800–332–1088

39. Development of a Case Series
• Identify a well-documented case (or
cases) in FAERS, published
literature or other source that
supports a safety signal
Step-1
• Formulate a case definition
Step-2
• Search for additional cases using:
• FAERS
• Published literature
• ClinicalTrial Adverse Event Data
• Other databases
Step-3
39

40. Regulatory Actions:-
• Product information changes –Warnings,
Precautions, Adverse Reactions
• Pharmacovigilance activities - enhanced surveillance
(e.g., expedited reporting), registry, epidemiology
studies
• Risk Evaluation and Mitigation Strategy (REMS) –
Communication plan, restricted use
• Drug Safety Communication (DSC)
• Market withdrawal
40

41. Communicating Safety Issues to the
Public and Internationally
• MedWatch Safety Alerts
• Postmarket Drug and Biologic Safety
Evaluations (FDAAA 915)
• Potential Signals of Serious Risks/New Safety
Information Identified from FAERS (FDAAA 921)
• Published literature and scientific meetings
• Video and teleconferences with foreign
regulatory agencies: – EMA: European Medicines
Agency – 4-Way: Canada, Australia, New
Zealand, (Singapore in writing) 41

42. References:-
42
-https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/supac-ir-immediate-
release-sol
-https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/supac-mr-modified-rele
-https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/supac-ss-nonsterile-semi
-www.fda.gov
-https://www.fda.gov/media/79333/download
-www.fda.gov/medwatch

43. 43