WHO GMP update

Presented by Trevor Schoerie

29 June, 2016
How do the WHO GMPs fit in?

• World Health Organisation publishes TRS which stands for

Technical Report Series
• The latest is the TRS 992 – Forty-ninth report – May 2015
• Link is http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/trs_992/en/
• but
• All old TRS are still “active”
• There is no “one” WHO GMP
• Actually what is WHO GMP?

In spite of this “weaknesses” they

are still very helpful because of their
detail.

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Current version?

• 49th – WHO TRS 992 – 2015 (228 pages)

• 48th – WHO TRS 986 – 2014 (402 pages) Non sterile
• Hold times mentioned
• Annex 2 Non sterile GMPs
• 47th – WHO TRS 981 – 2013 (202 pages)
• Annex 2 QRM
• 46th – WHO TRS 970 – 2012 (250 pages)
• 45th – WHO TRS 961 – 2011 (pages) Sterile
• 44th – WHO TRS 957 – 2010 (292 pages)

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Who writes WHO GMP?

• By helping to promote and protect health and prevent and

control disease throughout the world, WHO’s books contribute
to achieving the Organization’s principal objective – the
attainment by all people of the highest possible level of
health.

• The WHO Technical Report Series makes available the findings

of various international groups of experts that provide WHO
with the latest scientific and technical advice on a broad range
of medical and public health subjects. Members of such expert
groups serve without remuneration in their personal
capacities rather than as representatives of governments or
other bodies; their views do not necessarily reflect the
decisions or the stated policy of WHO.

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The Global Fund

• US $14bn 2014 to 2016

• Targets 82% tuberculosis, 50% malaria, 21% HIV
• The Global Fund focuses on the countries with the highest
disease burden and the lowest ability to pay.

• More recently Ebola

• 1 child (most under 5) per minute dies from Malaria

• Traditional and complementary medicine – 11 expert reports

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TRS 992 – new items

• §6 Quality Assurance – Good Manufacturing Practices

• §6.1 Update on WHO GMP for Biologicals
• §6.2 Update on WHO GMP: Validation
• Supplement Appendix 7:non sterile process
validation
• §6.3 General guidance for hold time studies
• §6.5 Q&A for APIs
• §6.6 Proposal for new guidance on data management

• Annex 4 - General guidance on hold-time studies

• Annex 5 - Technical supplements to Model guidance for
the storage and transport of time and temperature-
sensitive pharmaceutical products (TTSPP)

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2011 – WHO TRS 961 Annex 9
16 technical supplements
1. Selecting sites for storage facilities
2. Design of storage facilities
3. Estimating the capacity of storage facilities
4. Security and fire protection in storage facilities
5. Maintenance of storage facilities
6. Temperature and humidity monitoring systems for fixed
storage areas
7. Qualification of temperature-controlled storage areas
8. Temperature mapping of storage areas

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2011 – WHO TRS 961 Annex 9
16 technical supplements
9. Maintenance of refrigeration equipment
10. Checking the accuracy of temperature control and
monitoring devices
11. Qualification of refrigerated road vehicles
12. Temperature-controlled transport operations by road and
by air
13. Qualification of shipping containers
14. Transport route profiling qualification
15. Temperature and humidity monitoring systems for
transport operations
16. Environmental management of refrigeration equipment

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TRS 992 – Annex 3
Guidelines on good manufacturing practices: validation,
Appendix 7: non-sterile process validation

The appendices of the Supplementary guidelines on good

manufacturing practices: validation currently comprise the
following:
Appendix 1. Validation of heating, ventilation and air-
conditioning systems
Appendix 2. Validation of water systems for pharmaceutical
use
Appendix 3. Cleaning validation
Appendix 4. Analytical method validation
Appendix 5. Validation of computerized systems
Appendix 6. Qualification of systems and equipment
Appendix 7. Non-sterile process validation – revised
text reproduced in this Annex
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TRS 992 – Annex 3
Guidelines on good manufacturing practices: validation,
Appendix 7: non-sterile process validation

• Control strategy
• Continued process verification
• SPC
• Critical Process Parameter
• Critical Quality Attribute
• Quality Target Product Profile (QTPP)
• Life cycle
• matrix approach or bracketing

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TRS 992 – Annex 3
Guidelines on good manufacturing practices: validation,
Appendix 7: non-sterile process validation

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TRS 992 - Annex 4
General guidance on hold-time studies
Does not prescribe a process for establishing hold times

• aspects that should be considered in the design of the

hold-time study.
• manufacturers should gather scientific and justifiable data
to demonstrate that the dispensed raw materials and
packaging materials, intermediate and bulk products:
• remain of appropriate quality before processing to the
next stage;
• meet the acceptance criteria.

The finished product should meet the release specifications

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TRS 961 – Sterile Pharmaceutical
Products

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TRS 961 – Sterile Pharmaceutical
Products
1. General considerations
2. Quality control
3. Sanitation
4. Manufacture of sterile preparations
5. Sterilization
6. Terminal sterilization
7. Aseptic processing and sterilization by fi ltration
8. Isolator technology
9. Blow/fill/seal technology
10. Personnel
11. Premises
12. Equipment
13. Finishing of sterile products
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May 2015 – Supplements

WHO Technical Report Series, No.961, 2011 - Annex 9 Model guidance for the storage and transport of time-
and temperature–sensitive pharmaceutical products

QAS/14.598 - Supplement 1 - Selecting sites for storage facilities

QAS/14.598 - Supplement 2 - Design and procurement of storage facilities
QAS/14.598 - Supplement 3 - Estimating the capacity of storage facilities
QAS/14.598 - Supplement 4 - Building security and fire protection
QAS/14.598 - Supplement 5 - Maintenance of storage facilities
QAS/14.598 - Supplement 6 - Temperature and humidity monitoring systems for fixed storage areas
QAS/14.598 - Supplement 7 - Qualification of temperature-controlled storage areas
QAS/14.598 - Supplement 8 - Temperature mapping of storage areas
QAS/14.598 - Supplement 9 - Maintenance of refrigeration equipment
QAS/14.598 - Supplement 10 - Checking the accuracy of temperature control and monitoring devices
QAS/14.598 - Supplement 11 - Qualification of refrigerated road vehicles
QAS/14.598 - Supplement 12 - Temperature-controlled transport operations by road and by air
QAS/14.598 - Supplement 13 - Qualification of shipping containers
QAS/14.598 - Supplement 14 - Transport route profiling qualification
QAS/14.598 - Supplement 15 - Temperature and humidity monitoring systems for transport operations
QAS/14.598 - Supplement 16 - Environmental management of refrigeration equipment

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Comparison of EU GMP guidelines with
WHO guidelines
EU - Chapter 1 Pharmaceutical Quality System (PQS) (Jan’13)
• Overview of the chapter to come
and divided into sections
PQS, GMP, QC, PQR, QRM
(BTW this is very different to current PIC/S)

WHO - TRS 961 Annex 3

Chapter 1, Quality Assurance
Chapter 2, GMP for pharmaceutical products
Chapter 17, 17.1, 17.3, Good Practices in QC.
Conclusion mostly similar, APR, QRM, cross
contamination and mix up’s
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 EU - Chapter 2 Personnel (Feb ‘14)
Overview of the chapter to come and divided into sections
Key Personnel, Personal Hygiene, Training + Consultants
(BTW this is different to current PIC/S)

WHO - TRS 961 Annex 3

• Chapter 9 (“Personnel”) - the WHO guidelines additionally describe
the qualification of key personnel responsible for production and quality control
• Chapter 10 (“Training”)
• Chapter 11 (“Personal hygiene”), Chapter 3 (“Sanitation
and hygiene”) the topic “Personnel Hygiene” is explained more explicitly in
the WHO guideline than in the EU guideline e.g. “used clothes, …, should be
stored in separate closed containers until properly laundered…”.
Conclusion mostly similar

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 EU - Chapter 4: Documentation (Jan ‘11)
More explicit in which docs are now GMP documents
Reinforces records “not written down, it never happened”
(same as current PIC/S)

WHO - TRS 961 Annex 3

• Chapter 15 (“Documentation”)
• Glossary, Point “Specification”

Conclusion the same and Manufacturing

Instruction requirements match FDA
requirements too

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 EU - Chapter 5: Production (Mar ‘15)
Detailed process description based on the respective
manufacturing, plus Annex 15 on Validation.
But new Contamination controls – Technical and Procedural
(NOT the same as current PIC/S)

WHO - TRS 961 Annex 3

• Chapter 14 (“Materials”)
• Chapter 16 (“Good practices in production”)
• Chapter 3 (“Sanitation and hygiene”)
• Chapter 15, Point 15.10 (“Documentation”)
• Chapter 4, Point 4.4, 4.8 (“Qualification and validation”)

Conclusion big differences

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 EU - Chapter 6: Quality Control (Oct ‘14)
The tasks of quality control are beside others:
• sampling,
• stating of specifications,
• execution of tests, as well as
• organisation and documentation of release methods.
(NOT the same as current PIC/S)

WHO - TRS 961 Annex 3

• Chapter 17 (“Good practices in quality control”)
• Chapter 14, Point 14.34, 14.35, 14.39, 14.42 (“Materials”)
• Chapter 9, Point 9.12 (“Personnel”)
• Chapter 10, Point 10.3 (“Personnel”)
• Chapter 7, Point 7.33 (“Materials management”)
Conclusion small differences
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 EU - Chapter 7: Outsourced Activities (Jan ‘13)
PIC/S “Contract Manufacture and Analysis”
The Contract Giver
The Contract Accepter
The Contract
(NOT the same as current PIC/S)

WHO - TRS 961 Annex 3

• Chapter 7 (“Contract production and analysis”)
e.g. that in case of contract analysis the Contract Acceptor
should understand that he is subject to inspection by the
competent Authorities.

Conclusion similar

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 EU - Chapter 8: Complaints, Quality Defects and Product
Recalls (Mar ‘15)
Personnel and Organisation
Procedures for handling and investigating complaints
including possible quality defects
Investigation and Decision-making
Root Cause Analysis and Corrective and Preventative Actions
Product Recalls and other potential risk-reducing actions
(NOT the same as current PIC/S)

WHO - TRS 961 Annex 3

• Chapter 5 (“Complaints”)
• Chapter 6 (“Product recalls”)
• Chapter 14, Point 14.32 (“Materials”)
Conclusion very different
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 EU - Chapter 9: Self Inspection (Mar ‘15)
3 points
(identical to current PIC/S)

WHO - TRS 961 Annex 3

• Chapter 8 (“Self-inspection, quality audits and supplier`s
audits and approval”)
• As the title implies, the WHO guidelines give some
additional information on the execution of “Suppliers’
audit”.
• Furthermore they list in more detail the “Items for self-
inspection”.

Conclusion similar to EU GMPs

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Thank you for your time.

Trevor Schoerie
Managing Director

trevor.schoerie@pharmout.net
www.pharmout.net

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