The document discusses perspectives on ICH Q7 and Q11 from scientific and regulatory viewpoints. It summarizes common GMP deficiencies observed during API inspections, including inadequate vendor audits that failed to properly evaluate supplier quality systems and cleaning procedures. Specific examples call out insufficient control of API starting materials due to unacceptable facility maintenance and lack of testing, as well as inadequate sampling and improper storage of materials.

1. Discussion Forum on ICH Q7 & Q11
Scientific & Regulatory Perspectives
Dr. Obaid Ali
Deputy Director, DRAP
Member ISPE, PDA
23 April 2017 (Program A)
21 May 2017 (Program B)

2. ICH Q7 & Q11
Scientific & Regulatory Perspectives

3. Starting Material
Handling Site

4. Starting Material
Handling Site
Cyanide compound also
handled there

5. Starting Material
Handling Site
Cyanide compound also
handled there
Risk of
Contamination
was not
discussed

6. Starting Material
Handling Site
Cyanide compound also
handled there
Risk of
Contamination
was not
discussed
What will be
your
judgment?

7. Outline of the Talk
1. GMP Compliance
 Background
 Starting Materials
 Change Control
2. Common GMP Deficiencies reported

8. Why API production should
comply with GMP?
Review of
some
concepts of
GMP for
APIs
Observed
trends &
deficiencies
during API
inspections

9. Why GMP in API production?
Ensuring the quality of the API greatly
contributes to achieving the objective of
building the quality, safety and efficacy into
the product.

10. Risk based approach in Inspection
(Parameters)
Polymorphism
Solubility in
water
Complexity of
route of Synthesis
Solvents used
Impurities –
genotoxic
Sterile API
Fermentation
Toxicity, Activity,
Potency
Particle size
Site compliance
information
Other properties to be
considered

11. GMP for APIs (ICH Q7): Starting Materials
From what point does GMP for APIs start to be applied ?
– For synthetic process, this corresponds to the
introduction of the API starting material into the
process;
– Stringency of GMP in API manufacturing increases
from early steps to final steps

12. GMP for APIs (ICH Q7): Starting Materials
Advanced intermediates and crude APIs outsourced should
be manufactured in compliance with GMP
– “late intermediate and crude API” manufacturers should
be considered as contract manufacturers
(WHO GMP for APIs chapter 16 applicable)

13. GMP for APIs (ICH Q7): Starting Materials
Sterilization and aseptic processing should be
performed according to GMP related to Sterile
pharmaceutical products.

14. APIs
Registered
Intermediates
Critical Raw
Materials
Non critical
Raw Materials
Quantity of
materials in each
category is likely
to decrease as the
criticality increases
as indicated in the
above triangle

15. GMP for APIs (Change Control)

16. RM, specifications, analytical methods, facilities,
support systems, equipment (including
computerized systems), processing steps,
labelling and packaging materials
That can impact the quality of the API
Proposal drafted, reviewed and approved
by the appropriate organisational unit

17. Change reviewed and approved by QU
Classification and impact assessment
Evaluation and monitoring Notification

18. Facilities, Equipment and Utilities System

19. Critical operation
with prolonged
exposure to the
environment
Non critical operation
with prolonged
exposure to the
environment
Non critical or
critical operation in a
closed equipment
Prevent mix-
ups
Precautions
implemented
Cleaning
methodology
& intervals
Contamination
Risk
assessment
(HVAC)
To prevent
build-up and
carry-over of
contaminants
(degradants)

20. Supplier Qualification for API Manufacturers

21. API manufacturer should have
supplier qualification
procedures in place for their
suppliers of critical and non-
critical raw materials, API
Starting Materials, Registered
Intermediates and APIs
(in the case of contract
manufacturers)
an evaluation that provides
adequate evidence that the
manufacturer can
consistently provide
material meeting
specifications
At least
identity testing
of each batch

22. Reduced testing for
approved/validated suppliers
Past quality
history
Full analysis at
least on three
batches before
starting reduced-
testing
Reliability of the
CoA checked at
regular intervals:
a full analysis and
compared with
the certificates of
analysis

23. Precaution for bulk
deliveries in non-
dedicated tankers.
Certificate of cleaning,
testing for trace
impurities, supplier audit.

24. Blending Operations: only
batches meeting established
specifications

25. • Blending Operations
– Expiry or retest date of the
blended batch based on the
manufacturing date of the
oldest batch included.
– Should be controlled and
documented – traceability
1. Blending small
batches to ↑se batch size
2. Blending tailings

26. • Blending Operations
– Validation for homogeneity
following blending
APIs for OSDs/Suspensions
1. Particle size distribution
2. Bulk density
3. Tap density

27. Rejection & Re-use of Materials

28. Re-process
Rework

29. Back into the process
Reprocessing by
repeating any step
(crystallization)
Physical or Chemical
Manipulation steps
(Filtration, chromatography,
distillation)
R
E
P
R
O
C
E
S
S
Such reprocessing is not
allowed in majority of the
batches
If so add in Standard Mfg Process

30. Continuation of a process
step after an in-process
control test has shown
that the step is
incomplete.
R
E
P
R
O
C
E
S
S
It is considered a
normal process,
not re-processing

31. Repeating a chemical reaction
and
Introducing untreated material
back into process is re-
processing
However, if it is part of
established process, it is ok
R
E
P
R
O
C
E
S
S
Be careful of
potential
formation of by-
products & over
reacted materials

32. Investigation & reason
of non-conformance
before going for
rework
R
E
W
O
R
K
I
N
G
Careful evaluation, testing
& stability testing,
additional testing
Prove equivalent quality with the
original process

33. • Recovery of Materials and solvents
– Reactants, intermediates or APIs may
be recovered from mother liquor or
filtrates.
– Must use approved procedures and
specifications.
– Recovered solvents may be reused in
same process or in different process if
confirmed to meet appropriate
standards.
– Fresh and recovered solvents and
reagents can be combined if confirmed
their adequacy
1. Approved procedures
2. Suitable specs
3. Adequate testing
5. Use documented
1. No approved procedures
2. Specs – carry over
impurities
3. Not adequately tested
4. Use not documented

34. Very careful while
reprocessing or reworking or
even destroying
R
E
T
U
R
N
Document
Document &
Document

35. Common GMP deficiencies reported
API manufacturers

36. • Inadequate vendor audit and approval:
– A contractor audit established that the cleaning procedures were
inadequate and the deficiency was classified as critical. As
compliance mechanism, it was decided that the API
manufacturer shall supply organic solvents for cleaning,
however, the solvents were not identified and criteria for their
selected was not high lighted given that the report did not list
the other materials handled on the site.

37. • Inadequate vendor audit and approval:
– The suppliers of key starting materials had not been evaluated
to establish their quality system with respect to the handling of
respective material.
• Furthermore, these materials were accepted based on the
sole supplier's certificate of analysis and there was no
system in place to periodically and independently evaluate
the accuracy of these certificates.

38. • Inadequate control of API starting material (API-SM):
– Block A, where the API-SM was manufactured, was
unacceptable in that,
• Standards of maintenance and house-keeping were unacceptable
including the fabrication of building
– There were many examples of leaks in pipework and process equipment
– The equipment used was unacceptable, both in design and standards of housekeeping
and maintenance.
– No utility or process pipework were labelled
– No QC testing was done on API-SM.
– Specifications for API-SM were due for review July 2010 but
this was never conducted.

39. • Inadequate sampling and storage of materials
– The number of drums sampled for a consignment of 340 drums
of ABC B. No. 123 as recorded on the sampling sheet (5) was
less than that required by the sampling procedure (√N+1 = 19).
– ABC BN 123 was stored in an uncontrolled T° storage area
(same warehouse where staff bus was parked). The
recommended storage condition for this material is below 150C
– API XYZ B. No. 1111 had a release status label dated
09.02.2008 although its manufacturing date was 10.02.2008