WHO GMP update

Presented by Trevor Schoerie29 June, 2016

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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 theirdetail.

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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 facilities2. Design of storage facilities3. Estimating the capacity of storage facilities4. Security and fire protection in storage facilities5. Maintenance of storage facilities6. Temperature and humidity monitoring systems for fixed

storage areas7. Qualification of temperature-controlled storage areas8. Temperature mapping of storage areas

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2011 – WHO TRS 961 Annex 9 16 technical supplements

9. Maintenance of refrigeration equipment10. Checking the accuracy of temperature control and

monitoring devices11. Qualification of refrigerated road vehicles12. Temperature-controlled transport operations by road and

by air13. Qualification of shipping containers14. Transport route profiling qualification15. Temperature and humidity monitoring systems for

transport operations16. Environmental management of refrigeration equipment

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TRS 992 – Annex 3Guidelines 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 3Guidelines 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 3Guidelines 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 considerations2. Quality control3. Sanitation4. Manufacture of sterile preparations5. Sterilization6. Terminal sterilization7. Aseptic processing and sterilization by fi ltration8. Isolator technology9. Blow/fill/seal technology10. Personnel11. Premises12. Equipment13. 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 sectionsPQS, 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 sectionsKey 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 GiverThe Contract AccepterThe 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 OrganisationProcedures for handling and investigating complaints including possible quality defectsInvestigation and Decision-makingRoot Cause Analysis and Corrective and Preventative ActionsProduct 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

trevor.schoerie@pharmout.net

www.pharmout.net

Managing Director

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