1. Sampling, Identification and Testing (S.I.T.)

2. IntroductionIntroduction Define basic principles for applying sampling, identification and testing requirements 1)Systems and procedures  ensuring that samples are representative of the batch when sampled  Correctly identified  Tested 2)Systems and Procedures in accordance with regulatory and Safety requirements Define basic principles for applying sampling, identification and testing requirements 1)Systems and procedures  ensuring that samples are representative of the batch when sampled  Correctly identified  Tested 2)Systems and Procedures in accordance with regulatory and Safety requirements

3. ScopeScope Applies to all manufacturing sites Applies to all sub-contractors Applies to all Affiliates Applies to Raw-materials, isolated intermediates, APIs, excipients, medical devices, packaging materials, inprocess materials, bulk and packaged drug products Does not apply to environmental samples and Reference and Retention samples Applies to all manufacturing sites Applies to all sub-contractors Applies to all Affiliates Applies to Raw-materials, isolated intermediates, APIs, excipients, medical devices, packaging materials, inprocess materials, bulk and packaged drug products Does not apply to environmental samples and Reference and Retention samples

4. Reference Documents ICH Q7 : Good Manufacturing Practice for Active Pharmaceutical Ingredients EU GMP Part I Chapter 6 : Quality Control EU GMP Annex 8 : Sampling of Starting and Packaging Materials US CFR : Subpart E-Control of Components and Drug Product Containers and Closures : §211.80 : General requirements ; §211.84 Testing and approval or rejection of components, drug product containers, and closures ; §211.110 Sampling and testing of in-process materials and drug products, Subpart G-Packaging and Labelling Control : §211.122 Materials examination and usage criteria ICH Q7 : Good Manufacturing Practice for Active Pharmaceutical Ingredients EU GMP Part I Chapter 6 : Quality Control EU GMP Annex 8 : Sampling of Starting and Packaging Materials US CFR : Subpart E-Control of Components and Drug Product Containers and Closures : §211.80 : General requirements ; §211.84 Testing and approval or rejection of components, drug product containers, and closures ; §211.110 Sampling and testing of in-process materials and drug products, Subpart G-Packaging and Labelling Control : §211.122 Materials examination and usage criteria

5. Sampling General Requirements (1) Composite sample : justify the number of individual samples Sampling operations recorded with specific items. Records available for evaluation as condition of batch release Additional sampling may be considered in case of OOS/OOT - Based on approved re-sampling protocol Sterile materials sampled aseptically in environmental zone A. Composite sample : justify the number of individual samples Sampling operations recorded with specific items. Records available for evaluation as condition of batch release Additional sampling may be considered in case of OOS/OOT - Based on approved re-sampling protocol Sterile materials sampled aseptically in environmental zone A.

6. Sampling General Requirements (2) Sampling personnel initially trained and retrained on regular basis Only qualified and authorised personnel can sample Any anomaly/irregularity during sampling has to be notified and recorded. Sampling personnel initially trained and retrained on regular basis Only qualified and authorised personnel can sample Any anomaly/irregularity during sampling has to be notified and recorded.

7. Sampling General Requirements (3) Sampling areas designed to protect product from environment and cross contamination and protect personnel from the product Appropriate areas in case of high potency, sensitizing material, antibiotic, etc Gowning instructions and personnel protective equipment must be available Material Safety Data Sheet (MSDS) available before sampling. Sampling areas designed to protect product from environment and cross contamination and protect personnel from the product Appropriate areas in case of high potency, sensitizing material, antibiotic, etc Gowning instructions and personnel protective equipment must be available Material Safety Data Sheet (MSDS) available before sampling.

8. Sampling General Requirements (4) Sampling equipment and tools : specified, stored appropriately protected from contamination, cleaned after use and cleaning validation performed Cleanliness status of equipment identifiable Containers carefully opened and closed Containers marked when sample taken Identification of person who performs sampling Date of sampling recorded. Sampling equipment and tools : specified, stored appropriately protected from contamination, cleaned after use and cleaning validation performed Cleanliness status of equipment identifiable Containers carefully opened and closed Containers marked when sample taken Identification of person who performs sampling Date of sampling recorded.

9. Sampling General Requirements (5) Sampling General Requirements (5) Containers in which samples are placed must be clean and clearly labelled Sampled samples must not be returned to the batch Containers in which samples are placed must be clean and clearly labelled Sampled samples must not be returned to the batch

10. Identification General Requirements Identification method : described in the current locally applicable Pharmacopoeia (e.g. USP, EP, JP) or approved Regulatory File For material identification, a NIR validated method can be applied even if not registered in the Regulatory File; for countries where the practice is allowed. Identification method : described in the current locally applicable Pharmacopoeia (e.g. USP, EP, JP) or approved Regulatory File For material identification, a NIR validated method can be applied even if not registered in the Regulatory File; for countries where the practice is allowed.

11. Sampling and Identification Operations (1) Samples must be representative of the batch of materials or products from which they are taken Pre-samples allowed only from approved or certified suppliers with written agreement on sampling delegation Place(s) where samples need to be taken or identification : detailed in SOP Sampling must not be the cause of contamination or cross-contamination Cleaning operation in case of outer dirty container. Samples must be representative of the batch of materials or products from which they are taken Pre-samples allowed only from approved or certified suppliers with written agreement on sampling delegation Place(s) where samples need to be taken or identification : detailed in SOP Sampling must not be the cause of contamination or cross-contamination Cleaning operation in case of outer dirty container.

12. Sampling and Identification Operations (2) Sampling and Identification Operations (2) Hazardous or highly toxic materials, processing aids (solvents) or other special material may not be sampled or tested CoA needed from supplier : results conform to established specifications Practice to be justified and approved. Hazardous or highly toxic materials, processing aids (solvents) or other special material may not be sampled or tested CoA needed from supplier : results conform to established specifications Practice to be justified and approved.

13. Sampling and Identification Operations (3) Sampling and Identification Operations (3) Each batch of incoming material for API product : subject for identity, except in case of risk for health and safety  Such kind of materials to be listed  CoA obtained from supplier for each batch. Each batch of incoming material for API product : subject for identity, except in case of risk for health and safety  Such kind of materials to be listed  CoA obtained from supplier for each batch.

14. Sampling and Identification Operations (4) Sampling and Identification Operations (4) Sampling plans or procedures minimum information  Version, approver’s name, date of approval  Name of material, amount to be sampled  Sample packaging and labelling, storage conditions  Sampling equipment, safety/handling precautions : sterile, noxious product, pyrogens. Sampling plans or procedures minimum information  Version, approver’s name, date of approval  Name of material, amount to be sampled  Sample packaging and labelling, storage conditions  Sampling equipment, safety/handling precautions : sterile, noxious product, pyrogens.

15. Sampling and Identification Operations (5) Sampling and Identification Operations (5) Sampling plans or procedures minimum information (cont.)  Number of containers to be sampled  Number of samples to be taken  Sampling/Identification location within the container : Supplier pre-samples or identification location when direct NIR identification  Measurement units : quantity (g, ml, mg,…) Sampling plans or procedures minimum information (cont.)  Number of containers to be sampled  Number of samples to be taken  Sampling/Identification location within the container : Supplier pre-samples or identification location when direct NIR identification  Measurement units : quantity (g, ml, mg,…)

16. Sampling and Identification Operations (6) Sampling plans or procedures minimum information (cont.)  Composite sample (number of sample for a composite)  Sub-division of sample  Department/person - the sample is to be sent  Instructions for cleaning and storage of sampling equipment. Sampling plans or procedures minimum information (cont.)  Composite sample (number of sample for a composite)  Sub-division of sample  Department/person - the sample is to be sent  Instructions for cleaning and storage of sampling equipment.

17. Sampling and Identification Specific Rules (1) Materials used for Manufacture of APIs: Starting Materials, Raw Materials and Synthesis Intermediates  Manufacturers of SM, RM, SI must be identified  If Manufacturer is certified, reduced testing is allowed  Reduced testing on hold in case of investigation and return to reduced testing only if supported by conclusion of investigation and approval from Quality operations. Materials used for Manufacture of APIs: Starting Materials, Raw Materials and Synthesis Intermediates  Manufacturers of SM, RM, SI must be identified  If Manufacturer is certified, reduced testing is allowed  Reduced testing on hold in case of investigation and return to reduced testing only if supported by conclusion of investigation and approval from Quality operations.

18. Sampling and Identification Specific Rules (2) Materials used for Manufacture of APIs (cont.)  Starting Materials, Raw Materials 1) Manufacturer within « ICH » Region*: A justified sampling and identification plan based on criteria such as : – Criticality of material – Material variability – Supplier past quality history – Manufacturing factory dedication – Certification of Supplier At least one test for Identity of each batch (except in case of health and safety risk sample each container) * « ICH » = European Union, North America, Japan + EFTA: Switzerland, Norway, Iceland and Liechtenstein. Materials used for Manufacture of APIs (cont.)  Starting Materials, Raw Materials 1) Manufacturer within « ICH » Region*: A justified sampling and identification plan based on criteria such as : – Criticality of material – Material variability – Supplier past quality history – Manufacturing factory dedication – Certification of Supplier At least one test for Identity of each batch (except in case of health and safety risk sample each container) * « ICH » = European Union, North America, Japan + EFTA: Switzerland, Norway, Iceland and Liechtenstein.

19. Sampling and Identification Specific Rules (3) Materials used for Manufacture of APIs (cont.)  Starting Materials, Raw Materials 2) Manufacturer outside « ICH » Region: Sampling of each container, identification on composite sample and full testing (Identification on each container not required, in case of deviation/OOT: investigation to be performed and concluded). Materials used for Manufacture of APIs (cont.)  Starting Materials, Raw Materials 2) Manufacturer outside « ICH » Region: Sampling of each container, identification on composite sample and full testing (Identification on each container not required, in case of deviation/OOT: investigation to be performed and concluded).

20. Sampling and Identification Specific Rules (4) Materials used for Manufacture of APIs (cont.)  Intermediates Synthesis – external manufacturer 3) Regardless of geographical origin: Sampling on each container to make a composite sample – For identification – For full testing (Identification on each container not required, in case of deviation/OOT : investigation to be performed and concluded). Materials used for Manufacture of APIs (cont.)  Intermediates Synthesis – external manufacturer 3) Regardless of geographical origin: Sampling on each container to make a composite sample – For identification – For full testing (Identification on each container not required, in case of deviation/OOT : investigation to be performed and concluded).

21. Sampling and Identification Specific Rules (5) APIs and Excipients  API produced within company: sampling and identification limited to one container (process validation demonstrates homogeneity, container integrity)  API not produced within company and excipients with origin outside the ICH region – Identification of material on each container – Composite sample for later full testing. APIs and Excipients  API produced within company: sampling and identification limited to one container (process validation demonstrates homogeneity, container integrity)  API not produced within company and excipients with origin outside the ICH region – Identification of material on each container – Composite sample for later full testing.

22. Sampling and Identification Specific Rules (6) APIs and Excipients  API not produced at company manufacturing site and excipients with origin from the ICH Region: sampling and identification depend upon following parameters: – Supplier nature and status : when supplier is certified – Supplier quality assurance system – Manufacturing and control conditions – Nature of API, excipient and drug product in which they are used. APIs and Excipients  API not produced at company manufacturing site and excipients with origin from the ICH Region: sampling and identification depend upon following parameters: – Supplier nature and status : when supplier is certified – Supplier quality assurance system – Manufacturing and control conditions – Nature of API, excipient and drug product in which they are used.

23. Sampling and Identification Specific Rules (7) APIs and Excipients (cont.) – API or excipient coming from single product manufacturer or plant – API, excipient coming directly from manufacturer in sealed containers and manufacturer regularly audited In such case : Sampling and Identification performed on a reduced number of containers according to justified sampling plan If previous conditions not fulfilled : identification on each container APIs and Excipients used for Parenterals : EACH container must be identified. APIs and Excipients (cont.) – API or excipient coming from single product manufacturer or plant – API, excipient coming directly from manufacturer in sealed containers and manufacturer regularly audited In such case : Sampling and Identification performed on a reduced number of containers according to justified sampling plan If previous conditions not fulfilled : identification on each container APIs and Excipients used for Parenterals : EACH container must be identified.

24. Sampling and Identification Specific Rules (8) Packaging Materials  Sampling plan based on quantity received and required, nature and criticality of material (geographical origin, primary packaging, printed packaging), production methods, quality assurance of manufacturer  Sampling place/location is dependant on supplier status : – Approved or certified supplier > sampling possible by supplier : written sampling delegation and justified sampling plan are mandatory – Supplier with no quality agreement > sampling by own company manufacturing site : justified sampling plan. Packaging Materials  Sampling plan based on quantity received and required, nature and criticality of material (geographical origin, primary packaging, printed packaging), production methods, quality assurance of manufacturer  Sampling place/location is dependant on supplier status : – Approved or certified supplier > sampling possible by supplier : written sampling delegation and justified sampling plan are mandatory – Supplier with no quality agreement > sampling by own company manufacturing site : justified sampling plan.

25. Sampling and Identification Specific Rules (9) Intermediates for Drug Product, Bulk Drug Products, In-Process Materials and Drug Products  Intermediates and Bulk drug product produced by same company and received at another site : – sampling and identification limited to one container (due to homogeneity demonstrated by process validation and by transport validation) – Each container perfectly sealed at receipt  Intermediates and Bulk drug product not produced by same company: – Sampling depending upon parameters : criticality of product, manufacturing in a dedicated facility, quality of sealing, experience with sub-contractor – Each individual container sampled and tested for identity. Intermediates for Drug Product, Bulk Drug Products, In-Process Materials and Drug Products  Intermediates and Bulk drug product produced by same company and received at another site : – sampling and identification limited to one container (due to homogeneity demonstrated by process validation and by transport validation) – Each container perfectly sealed at receipt  Intermediates and Bulk drug product not produced by same company: – Sampling depending upon parameters : criticality of product, manufacturing in a dedicated facility, quality of sealing, experience with sub-contractor – Each individual container sampled and tested for identity.

26. Sampling and Identification Specific Rules (10) Intermediates for Drug Product, Bulk Drug Products, In-Process Materials and Drug Products (cont.)  Intermediates and Bulk drug product not produced by same company: – Tests other than identity, sampling can be reduced or performed on each container, based on justified sampling plan  In-Process Materials and Drug Products : – If relevant, sampling and identification performed according to marketing autorisation requirements or site sampling plan. Intermediates for Drug Product, Bulk Drug Products, In-Process Materials and Drug Products (cont.)  Intermediates and Bulk drug product not produced by same company: – Tests other than identity, sampling can be reduced or performed on each container, based on justified sampling plan  In-Process Materials and Drug Products : – If relevant, sampling and identification performed according to marketing autorisation requirements or site sampling plan.

27. Testing Operations Requirements (1) Control operations of received goods - for each container check/perform and document  Container status and cleanliness  Correct storage conditions  Damages, closures integrity, potential tempering, homogeneity of containers  Labelling in comparison with delivery documentation  Number of containers  Materials reconciliation and weight discrepancies  1 lot per pallet. Control operations of received goods - for each container check/perform and document  Container status and cleanliness  Correct storage conditions  Damages, closures integrity, potential tempering, homogeneity of containers  Labelling in comparison with delivery documentation  Number of containers  Materials reconciliation and weight discrepancies  1 lot per pallet.

28. Testing Operations Requirements (2) Analytical Methods validated Results obtained recorded and checked, calculation critically examined Tests performed must be recorded with following data:  Material name, dosage form  Batch number, Manufacturer/Supplier if appropriate  References of specifications and testing procedures  Results, calculations, Supplier’s CoA  Testing date(s)  Initials of personnel who performed testing and verification  Release or rejection decision and signature of manager  Tests records and raw data archived All IPC must be performed and recorded with QC approval Raw materials tested in accordance with written procedures and specifications in respect with current pharmacopeias and/or approved dossiers. Analytical Methods validated Results obtained recorded and checked, calculation critically examined Tests performed must be recorded with following data:  Material name, dosage form  Batch number, Manufacturer/Supplier if appropriate  References of specifications and testing procedures  Results, calculations, Supplier’s CoA  Testing date(s)  Initials of personnel who performed testing and verification  Release or rejection decision and signature of manager  Tests records and raw data archived All IPC must be performed and recorded with QC approval Raw materials tested in accordance with written procedures and specifications in respect with current pharmacopeias and/or approved dossiers.

29. Testing Operations Requirements (3) Packaging Materials  most frequent defects and degree of criticality listed Tests reduced  if certified supplier  raw materials, intermediates, synthesis intermediates and drug products manufactured within company regardless of origin Reduced testing not allowed  raw materials used in manufacture of parenterals products  raw materials, intermediates, synthesis intermediates and drug products with origin outside ICH region. Packaging Materials  most frequent defects and degree of criticality listed Tests reduced  if certified supplier  raw materials, intermediates, synthesis intermediates and drug products manufactured within company regardless of origin Reduced testing not allowed  raw materials used in manufacture of parenterals products  raw materials, intermediates, synthesis intermediates and drug products with origin outside ICH region.

30. Testing Operations Requirements (4) GLYCEROL and Diethyleneglycol testing sites are required to:  Evaluate traceability of manufacturers/distributors  Define manufacturer’s location : ICH or not ICH  Declare manufacturer’s status certified or not certified  Evaluate the risk and decide on the need for DEG testing on each container taking into account the following: – Regular audits, no critical observation, no major related to traceability – Manufacturing & packaging conditions – Traceable distribution channels – Transportation – Good quality history – Containers sealing integrity – Containers aspect/integrity and labelling – Use for parenteral (note : If yes, then high risk) – Good service history  Evaluate the risk of fraud  Decide on the DEG testing. GLYCEROL and Diethyleneglycol testing sites are required to:  Evaluate traceability of manufacturers/distributors  Define manufacturer’s location : ICH or not ICH  Declare manufacturer’s status certified or not certified  Evaluate the risk and decide on the need for DEG testing on each container taking into account the following: – Regular audits, no critical observation, no major related to traceability – Manufacturing & packaging conditions – Traceable distribution channels – Transportation – Good quality history – Containers sealing integrity – Containers aspect/integrity and labelling – Use for parenteral (note : If yes, then high risk) – Good service history  Evaluate the risk of fraud  Decide on the DEG testing.

31. Testing Operations Requirements (5) The decision tree diagram below determines the extent of DEG testing required: * Composite sample size: 1 composite sample derived from no more than 5 individual samples The decision tree diagram below determines the extent of DEG testing required: * Composite sample size: 1 composite sample derived from no more than 5 individual samples Glycerol Directly Supplied by Manufacturer Supplied from ICH Location Certified Supplier? Risk Assessment DEG Testing on Composite Samples* DEG Testing on Each Container YES NO HIGH RISK LOW RISK

32. Thank You Any Questions Thank You Any Questions