The document provides guidance on the Plasma Master File (PMF) certification process and evaluation of transmissible spongiform encephalopathy (TSE) and bovine spongiform encephalopathy (BSE) risk. It outlines the PMF submission and evaluation procedure, including the use of an electronic common technical document format. It also describes TSE and BSE as rare brain diseases caused by prion proteins, and the regulatory compliance and risk assessment measures taken to prevent transmission through pharmaceutical and biological products derived from animal sources.

1. Plasma Master File
&
TSE/BSE
EVALUATION

2. Topic to be Covered
Plasma Master File
PMF submissions
Guideline on Requirements for PMF
Certification
Principle of the PMF Certification
Procedure
Initial Certification of a PMF
GUIDELINES ON THE USE OF THE eCTD
FORMAT FOR PMF HOLDERS
 Structure of the eCTD Dossier
 Envelope Elements and Metadata for the PMF
Certification/Recertification Dossiers
 File Formats
 File-naming
 Lifecycle and Sequencing
TSE/BSE EVALUATION
TSE
BSE
PRION- Causative Agent
Development
Regulatory Compliance
Risk aspects
EU inspection
2

3. “
”
It is a process on collecting all the required
scientific data on the quality and safety of
human plasma relevant to the medicines,
medical devices and investigational
products that use human plasma in their
manufacture.
3

4. Plasma Master File (PMF)
● These data cover all aspects of the use of
plasma, from collection to plasma pool.
● The concept of the PMF was established by
European legislation in June 2003.
● The PMF is a separate set of documentation
from the dossier for a medicine's marketing
authorization.
4

5. PMF submissions
When shall I submit my application?
What is the timetable for my procedure?
● The appropriate time and planning of submission and the timetable for
assessment of applications is important for applicants who is in the EMA,
CPMP members and experts for a better and efficient working plan.
● The submission deadlines and full procedural timetables are published as a
generic calendar and are for the information and use of Applicant/PMF
Holder, the EMA, CPMP members and assessment teams.
● The published timetables identify the submission, start and finish
dates of the procedures as well as other dates/milestones that
occur during the procedure.
5

6. CONT’D
● Timetables are classified under 90, 60 or 30 day evaluation procedure and
individual links are provided on this page.
● The initial PMF certification procedure is run on a 90 day evaluation
timetable.
● The timetable for annual update is 60 day (or 90 day) and is decided in
consultation with the coordinator. Depending on the extent of the
responses, their evaluation will follow a 30 or 60 day timetable.
● The submission/start/CPMP dates are generally fixed; other dates may be
subject to adjustments until the CPMP Scientific committee proceeds to
their adoption for every individual application.
6

7. 7

8. GUIDELINE ON
REQUIREMENTS FOR
PLASMA MASTER FILE (PMF)
CERTIFICATION
 Principle of the PMF Certification
 Initial Certification of a PMF

9. “
”
USE OF PMF CERTIFICATION
● Reducing the number of dossiers submissions
&
data evaluations carried out for the same plasma.
● Ensuring consistency throughout the European
Community.

10. “
”
10

11. Procedure
11
The first step of the PMF certification procedure is
similar to the marketing-authorization evaluation
procedure. Following the satisfactory outcome of an
evaluation, the Agency issues a PMF certificate of
compliance with European legislation. This
certificate is valid throughout the EU.
In the second step, after certification, it is the
responsibility of the marketing-authorization
holder to update its medicinal product
licenses and to incorporate the certified PMF
in its marketing authorizations.

12. General principles of a PMF
12

13. Trigger for submission of a PMF
application
Trigger 1
In the framework of a
new MAA via the
centralized
procedure.
Trigger 2
In the framework of a
new MAA via Mutual
Recognition (MR)
procedure.
Trigger 3
In the framework of a new
purely national MAA,
provided the PMF
corresponds to
blood/plasma-derived
medicinal products with
marketing authorizations
in more than one MS.
13

14. Trigger 4 & 5
The data submitted for
certification are identical to the
corresponding data approved in
all proposed linked MAs, and no
changes are proposed during the
certification,
A change (variation) to the data
approved in all linked MAs is
proposed by the Applicant
Annual update is due.
14
Trigger 5
a new PMF can be submitted for certification separately, at anytime in advance of any application
for a MA, or for a consultation on a blood derivative incorporated in a medical device.
PMF certification application may be initiated at any time, e.g.
when:

15. 15
SUBMISSION

16. Pre submission activities
16
Letter of intent to
EMEA
Applicants should ideally inform
the EMEA of their intention to
submit PMF applications
approximately 2-3 months
before submission, specifying
the intended submission date
and the appropriate trigger for
submission.
Submission and
Validation
All documentation requirements for
the EMEA, co-ordinators will be
published on the EMEA website. The
validation of the submission will be
performed by the EMEA and the
outcome communicated to the
Applicant together with the
evaluation timetable.
Appointment of
coordinators
Two co-ordinators will be
appointed by the CPMP in
consultation with the BWP; the
appointment will be notified to the
Applicant and where appropriate to
the Mutual Recognition Facilitation
Group (MRFG) and the National
Authority.
01 02
04 03
Evaluation
An evaluation report will be prepared
by the appointed co-ordinator(s) and
circulated for review by the BWP. The
BWP will then make
recommendations on the outcome of
the evaluation, to the CPMP.

17. 17
Evaluation

18. Certification
● An inspection(s) may be
requested by the CPMP.
Inspection(s) requested must
be carried out and the final
report(s) sent to the EMEA
and submitted to the CPMP
in accordance with the 90-
day time limit for the
evaluation of the PMF.
● Within 5 working days of
the adoption of a positive
evaluation report by the
CPMP, the EMEA will
issue a PMF certificate.
The evaluation report will
accompany the certificate.
18
Inspection

19. 19
GUIDELINES ON THE USE OF
THE eCTD FORMAT FOR PMF
HOLDERS
 Structure of the eCTD Dossier
 Envelope Elements and Metadata
for the PMF
Certification/Recertification
Dossiers
 File Formats
 File-naming
 Lifecycle and Sequencing

20. ● The complete PMF scientific data
package is made up of multiple files.
The PMF data should be placed in
module 3 under 3-2-s-2-3 control-
of-materials within the eCTD
structure.
● Documentation should be included
as per the CPMP guideline on the
scientific requirements for the PMF.
20
1) Structure of the eCTD Dossier for the PMF

21. Structure of the eCTD Dossier for
the PMF
21
Re-use of Content
Example
File/Directory Structure vs. XML Backbone and
Stylesheet/eCTD Review Tool
Node Extensions
Applicable/Non-Applicable Documents
Granularity

22. MODULES
Module 1 EU
● Cover Letter
● Application Form
● Product Information
● Information about the Experts
● Specific Requirements for Different
Types of Applications
● Environmental Risk Assessment
● Orphan Market Exclusivity
● Pharmacovigilance
● Information relating to Clinical Trials
● Information relating to Pediatrics
Module 2
● Quality overall
summary
Module 3
● Quality
● body-of-data
● Drug substance
● Manufacture
● Control-of-
materials
● PMF Annual
update module
● PMF Dossier
Integrated
22

23. 23

24. 2) Envelope Elements and Metadata for the PMF
Certification/Recertification Dossiers
● <Submission Type>
● <Submission Description>
● <Application Number>
● <ATC>
● <Invented Name>
● <INN>
24

25. <Submission Type>
25

26. ● <Submission Description>: The contents should be short but clearly indicative of
the exact content of the submission. The submission description should not exceed
200 characters.
● <Application Number>: The <Application Number> should follow this convention:
<EMEA>/<H>/<PMF holder ref. number>/<initial submission year18>/<type of change
for variations or transfers>/<procedure number (if applicable)>, all separated by
slashes
● e.g.: EMEA/H/PMF/000123/08
EMEA/H/PMF/000123/08/I/01
● <ATC>: This envelope element is not applicable for the PMF dossier. Where an
envelope element is not applicable, please indicate ‘Not Applicable’ rather than
leaving the element blank.
● <Invented Name>: This envelope element is not applicable for the PMF dossier.
● <INN>: This envelope element is not applicable for the PMF dossier.
26

27. Typical envelope for a PMF submission
27

28. 28

29. 5) Lifecycle and Sequencing
eCTD Baseline Submission
● The baseline eCTD
submission should be
sequence 0000
29
Updates to the PMF Dossier
Sections
● When there is any change
to the PMF data, in line with
general eCTD principles,
only changed sections
should be submitted.

30. 30
TSE/BSE
EVALUATION
TSE- Transmissible
Spongiform
Encephalopathy
BSE-Bovine Spongiform
Encephalopathy

31. TSE
In general, it is a disease. Scrapie is a TSE in small ruminants (sheep and
goats). It is a rare disease occurs in Humans and animals.
● TSE = A disease capable of being transmitted by infection and gives
the appearance of sponge like tiny holes in the brain.
● Transmissible = Capable of being transmitted(spread) by infection
1.Spongiform = Sponge like
2.Encephalopathy = Brain Disease
Creutzfeldt-Jakob disease:
if it is transmitted to humans.
31

32. BSE
● It is a brain disease that occurs in bovines; generally known
as “Mad Cow Disease”
● It is a rare disease occurs in human & animals; for example,
cow/cattle.
● BSE = A disease capable of transmitted by infection and
gives a appearance of sponge like tiny holes in the brain of
bovines.
● Bovine = Characteristic of or resembling cows, sheep or
cattle.
32

33. BSE, CLASSIFICATION
33
Two forms of BSE
Atypical BSE
Classical BSE
Which is
transmitted via the
feed and was the
cause of the BSE
epidemics in the
80s, 90s and 2000s
A spontaneous and sporadic
disease, not linked to the feed
given the animals, occurring at
a very low prevalence rate in
old bovine animals.

34. 34
Prion = proteinaceous infectious particle,
named as Prion Proteins
Prion, usually present in the body cells of
Human and Animals.
 Normal Form -A harmless protein
found in the body's cells which is
unfolded in structure which does
not cause TSE
 Abnormal Form -The protein which
is in folded structure and can cause
TSE
The accumulation of an abnormal isoform of the prion protein
in the CNS causes the diseases. After the name of the
causative agent the disease is also named as prion diseases.
Prion- Causative Agent

35. 35

36. 36
DEVELOPMENT

37. “
”
According to European Pharmacopeia,
“The complete elimination of risk at source is rarely
possible, appropriate measures and considerations should
be taken to manage the risk of transmitting animal TSEs
via medicinal products represent the risk minimization
rather than the risk elimination.”
Regulatory Compliance

38. RISK of TSE/BSE in Pharmaceuticals
There is a possible risk
of contamination of
infected animal derived
products in the
pharmaceutical
finished dosage form
for human
consumption leads to
transmission of
TSE/BSE to
human beings.
The primary
packaging materials
like gelatins capsules
derived from the fat of
animals also increases
the possibilities of
transmission of
TSE/BSE.
There is a high risk in
the case of
biotechnological
products like serums,
blood products and
vaccines where the
source material is
derived from animals
and animal derived
products.
38

39. “
”
Inspections, Controls & Registration
● The Directorate General for Health and Food Safety of the
European Commission carries out audits in the Member
States to verify the correct implementation, enforcement
and control of EU legislation by the national authorities
● TSEs are laid down in Annex IX to the TSE Regulation, status
of third countries or regions thereof, as laid down in
Commission Decision 2007/453/EC.
39

40. Short Summary
40
1 3 5
6
4
2
PMF
eCTD
DOSSIER DEVELOPMENT
GUIDELINES FOR PMF
CERTIFICATION
TSE/BSE RISK FACTOR

41. Reference
https://www.ema.europa.eu/en/glossary/plasma-
master-file
https://www.ema.europa.eu/en/human-
regulatory/overview/plasma-master-file-pmf-
certification
https://www.ema.europa.eu/en/minimising-risk-
transmitting-animal-spongiform-encephalopathy-
agents-human-veterinary-medicinal

42. Thanks!
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