1. APPLICABILITA’ DEI CAPITOLI 3,5,6 E 8 DELLE EU-GMP ALLA PRODUZIONE DEGLI API Damiana Gentili Procos 19 aprile 2016

2. 19 th April 2016 – slide# 2 April 19 th, 2016 Applicabilità dei Capitoli 3, 5, 6, 8 delle EU-GMP alla produzione degli API D. Gentili – Qualified Person / Quality Unit Director

3. 19 th April 2016 – slide# 3 AgendaAgenda GMP in EU: Today overview A quick comparison Chapter 3 GMP part I – The areas o Production Areas o Storage Areas Chapter 5 GMP part I – Production o Starting materials o Prevention of cross contamination Chapter 6 GMP part I – Quality control Chapter 8 GMP part I – Complaints, quality defects, recalls Conclusion & Impacts

4. 19 th April 2016 – slide# 4 GMP in EU: today overview Principles and Guidelines of GMP Directives 2003/94/EC and 91/412/EEC DL 219/2006 EU GMP Guide Part I Detailed Guidelines for Medicinal Products EU GMP Guide Part II Detailed Guidelines for Active substances ICH Q7 Supplementary Guidelines Annexes 1 to 19 Good Distribution Practice EU GMP Guide Part III Miscellaneous GMP-related guidance

5. 19 th April 2016 – slide# 5 Chapter 3: Premises and equipment (new version in operation since March 2015) Chapter 5: Production (new version in operation since March 2015) 4 Buildings and facilities A quick comparison Part I 8 Production and In- process controls Chapter 6: Quality control (new version in operation since October 2014) 11 Laboratory controls Chapter 8: Complaints, quality defects and product recalls (new version in operation since March 2015) 15 Complaints and Recalls Part II

6. 19 th April 2016 – slide# 6 Chapter 3 GMP part I – The areas General principles of having premises and equipment suitable for cleaning and maintenance activities in order to avoid cross contamination are the same Smooth interior surfaces (walls, floors and ceilings) (3.9 GMP Part I) Forced ventilation (3.12 GMP Part I) Appropriate design of services to avoid creation of recesses (3.10 GMP Part I) Drains of adequate size, open channels avoided where possible (3.11 GMP Part I) PRODUCTION AREA

7. 19 th April 2016 – slide# 7 API manufacturers have:

8. 19 th April 2016 – slide# 8 STORAGE AREAS In GMP part I there are the following requirements: Storage areas with good conditions and temperature control (3.19 GMP part I) Material discharging protection (3.20 GMP part I) Segregated areas for rejected and claimed materials (3.23 GMP part I) Sampling area also for starting materials (3.22 GMP part I)

9. 19 th April 2016 – slide# 9 API manufacturers have:

10. 19 th April 2016 – slide# 10 Chapter 5 GMP part I– Production The quality system of the manufacturer has to cover from the API starting material to final API The quality system of the manufacturer has to cover from the API starting material to final API Level of supervision should be proportionate to the risk posed by the individual materials Level of supervision should be proportionate to the risk posed by the individual materials Supply chain traceability should be established from the API starting materials to the finished medicinal product Supply chain traceability should be established from the API starting materials to the finished medicinal product Audits should be carried out to assure that a clear assessment of the GMP is made STARTING MATERIALS: ACTIVE SUBSTANCES

11. 19 th April 2016 – slide# 11 EXAMPLE 1/2 The justification for the choice of …as a starting material is not acceptable Please note that statements from applicants such as “we commit to carrying out manufacture of starting materials to GMP and are willing to be inspected” and justification that manufacture of the starting material is subjected to strict control system of Procos SpA are not sufficient and cannot be accepted. It should be noted that it is the Marketing Authorisation Holder’s responsibility to ensure that the synthesis of API is covered by GMP and any changes in the full manufacturing process are assessed for impact on API quality and genotoxic risk assessment (Estonia, July 2014)

12. 19 th April 2016 – slide# 12 EXAMPLE 2/2 The suggested starting material ….cannot be accepted. In addition : the active substance should be manufactured under GMP conditions. GMP needs to be confirmed by the QP of the finished product manufacturer and /or manufacturer responsible for the batch release of the finished product. The active substance manufacturer is therefore requested to inform the Applicant of any new facility involved in the active substance manufacturing process as stated in the ASMF (Netherlands, March 2016)

13. 19 th April 2016 – slide# 13 THE QP DECLARATION

14. 19 th April 2016 – slide# 14 THE QP DECLARATION

15. 19 th April 2016 – slide# 15 THE QP DECLARATION

16. 19 th April 2016 – slide# 16 CONSEQUENCES FOR API MANUFACTURER IN CASE OF REDEFINITION OF THE STARTING MATERIAL The Finished dosage manufacturer is directly involved in audit of this entity Very often, from the technical point, the GMP expectations of the finished dosage manufacturer are very far from the application of GMP of this early intermediate

17. 19 th April 2016 – slide# 17 Aren’t we the closest entity to the supply chain? Aren’t we the best to evaluate the risks that our suppliers could bring to us? Is it realistic having a conflict of interests? Why the GMP part II does not contemplate the suppliers audit? WHY FINISHED DOSAGE MANUFACTURER CANNOT RELY ON THE API MANUFACTURER AUDIT?

18. 19 th April 2016 – slide# 18 Chapter 5 GMP part 1– Production PREVENTION OF CROSS CONTAMINATION A quality risk management process is the base for determining the necessity and the extent to identify equipment and premises to a specific product or product family A quality risk management process is the base for determining the necessity and the extent to identify equipment and premises to a specific product or product familyBUT

19. 19 th April 2016 – slide# 19 DM 27/05/1999 API manufacturers have: A rigid classification of the manufacturing (even if some exceptions granted from AIFA are present) still exists

20. 19 th April 2016 – slide# 20 Chapter 6 GMP part I – Quality Control Quality control requirements in part I are aligned to the part II in terms of :   Responsibility   Documentation   Testing methods   Stability program   Sampling

21. 19 th April 2016 – slide# 21 ALMOST THE SAME WORDINGS The independence of qualiy control from production is considered fundamental (GMP part I Principles) The indipendent quality unit should have at its disposal adequate laboratory (GMP part II 11.10) Documentation (specifications, procedures describing sampling, calibration of equipment, records etc) should be available to the quality control department (GMP part I 6.7) All specifications, sampling plans and tests procedure should be available and scientifically sound (GMP part II 11.12) A procedure for investigation of OOS and OOT should be available (GMP part I 6.7) Any OOS should be investigated and documented according to written procedures (GMP part II 11.15) BUT

22. 19 th April 2016 – slide# 22 API manufacturers have * : Periodic evaluation of the water quality from analytical and microbial testings Periodic evaluation of the water quality from analytical and microbial testings Trend analysis of the data obtained Trend analysis of the data obtained Investigation in case of OOS and OOT Investigation in case of OOS and OOT …Many of us have almost the same level of data & trend for the clean areas of the finishing department *even for oral Even if data from enviromental (air, water and utilities) monitoring, should be available where required (GMP part I 6.7) and this section IS NOT CONTEMPLATED IN PART II

23. 19 th April 2016 – slide# 23 Chapter 8 GMP part I– Complaints, quality defects and product recalls GMP part I emphasizes the investigation in case of compliant & quality defects to be run according to the principles of the quality risk management Request to identify the root cause or the most likely root causes Specific mention is made to human errors Appropriate CAPA plan identification is requested Complaint & recall chapter of GMP part II remains very simple, no specific mention to investigations is made BUT…

24. 19 th April 2016 – slide# 24 API manufacturers have: A detailed investigation procedure Annexed to a CAPA plan that is periodically reviewed A recall procedure is in place and in most of the cases with a mock test In our recall procedure the address of the concerned HA is always present QP is always leading the activities Aren’t we as safe as Pharma colleagues?

25. 19 th April 2016 – slide# 25 Basic requirements for Active Substances used as Starting Material is historically originated after the part I so it contains already some important improvements During the course of this experience, the Basic requirements have increased mostly due to always stricter interpretation Reasons are due to local authority requests as well as intrinsic spirit of quality improvements also enforced by customer’s audit on site Up to date the «applicability» of Part II is comparable to Part I (at least in some portions) Conclusion & Impacts

26. 19 th April 2016 – slide# 26 No balance of these increased requirements will bring to extraordinary costs for APIs suppliers (competition risk) Formal recognition of these achieved standards could bring to API suppliers some benefits, in example: o o Manufacturing of mixtures under the umbrella of GMP part II o o New areas of development (eg co-crystals) covered under GMP part II Conclusion & Impacts

27. 19 th April 2016 – slide# 27 Thanks for your attention! gentili@procos.it Questions?