Materials Rutendo Kuwana Technical Officer, WHO, Geneva Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 2 |2 | Basic Principles of GMP Materials 14

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 3 |3 | Materials Objectives To review specific requirements for each type of material: äStarting materials äPackaging materials äIntermediate and bulk products äFinished products äRejected and recovered materials äRecalled products äReturned goods äReagents and culture media äReference standards äWaste materials äMiscellaneous materials

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 4 |4 | Materials Principle Objective of the pharmaceutical manufacturer äproduce finished products for patient's use from a combination of materials Materials combined äActive pharmaceutical ingredients and äExcipients (auxiliary materials) äPackaging materials Materials include also äGases, solvents, reagents, process aids, etc. äSpecial attention 14.1, 14.2

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 5 |5 | 14.3–14.6 Materials General requirements for materials Materials for cleaning, lubrication, and pest control äNot in direct contact with product äSuitable grade, e.g. food grade if possible All incoming materials and finished products äquarantined after receipt or processing –until released for use or distribution ästored –under appropriate conditions –orderly fashion (batch segregation) –materials management –stock rotation (FEFO) Water – suitable for use

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 6 |6 | 14.7 – Materials Starting Materials – I Purchasing – important operation From approved suppliers – if possible, direct from the manufacturer Specifications for materials Consignment checks äIntegrity of package äSeal intact äCorresponds with the purchase order äDelivery note äSupplier’s labels Cleaned and labelled with information

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 7 |7 | Supplier Evaluation Historical experience Questionnaire – including reputation within industry, availability of certificates e.g. ISO 9000 certificates, GMP Check/compare own analytical results e.g. three batches/shipments with suppliers CoA Site audit of supplier (case by case basis) Name and address of manufacturer of critical material must always be known Changes in source (manufacturer or supplier) of critical material should be handled according to Change Control procedure

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 8 |8 | – Materials Starting Materials – II Different batches in one delivery/consignment Starting materials labelled äname and internal code äSupplier's batch number(s) and manufacturer's on receipt äStatus (e.g. quarantine, on test, etc.) äexpiry date or retest date Role of validated computer systems "Sampled" containers identified

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 9 |9 | Basic Principles of GMP

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 10 | Sampling and Testing Sampling plans should be scientifically sound (not just statistically based) and appropriate for material being sampled. They must also be practical/easy to use - obtain a representative sample Should be based on Risk Assessment Criticality of the material Manufacturers/suppliers quality system and manufacturing process Historical data Homogeneity

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 11 | Basic Principles of GMP Damage to and problems with containers äRecorded and reported to QC äInvestigated

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 12 | Materials Examples of Labelling of Starting Materials

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 13 | – Materials Starting Materials – III Use only QC released material if within shelf-life Dispensing ädesignated persons äwritten procedure äCorrect materials accurately weighed äclean, properly labelled containers Independent checks and record ämaterial and weight or volume Dispensed material äkept together and labelled

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 14 | Basic Principles of GMP

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 15 | 14.25–14.20 Materials Packaging materials - I Primary and printed packaging materials äpurchasing, handling and control –as for starting materials Printed packaging materials: particular attention äStored in secure conditions with authorized access äRoll labels where possible in place of cut labels äLoose materials stored and transported in separate, closed containers - to avoid mix-ups äIssued by designated personnel äSOP for issue and returns

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 16 | Basic Principles of GMP

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 17 | – Materials Printed and primary packaging materials - II Each delivery or batch: specific reference number or identification mark Delivery to packaging department äCheck quantity, identity and conformity to packaging instructions Outdated or obsolete material äDestroyed äDisposal record

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 18 | Basic Principles of GMP Intermediate and bulk products Kept under appropriate conditions If purchased as such äHandled on receipt as though these are starting materials – 14.25

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 19 | Basic Principles of GMP Finished products Held in quarantine until their final release Then stored as usable stock under suitable storage conditions Evaluation and documentation necessary for release äProduct release procedure äBatch record review and related procedure – 14.27

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 20 | Materials Rejected, reworked and recovered materials Rejected materials and products äClearly marked äStored separately in restricted areas äAction – returned to supplier/destroyed, etc. in timely manner äAction approved by authorized personnel – records maintained

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 21 | – Materials Rejected, reworked and recovered materials Rework and recovery äShould be exceptional cases äOnly if: –Risks involved have been evaluated and the quality of final product will not be affected –Specifications are met –Defined procedure –Records maintained –New batch number äadditional testing to be considered by QC

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 22 | – Materials Recalled products and returned goods Recalled products äIdentified äStored separately äSecure area - access controlled äDecision taken on their fate Returned goods äDestroyed unless suitable quality äSOP: decision regarding their fate (relabelling, resale, etc.) –Consider: nature of product, special storage conditions, condition, history, time elapsed since issue äAction taken to be recorded

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 23 | – Materials Reagents and culture media Records for receipt or preparation Reagents äPreparation in accordance with SOP äAppropriately labelled: –concentration, standardization factor, shelf-life, date that restandardization is due, storage conditions –signed and dated Culture media äpositive and negative controls each time prepared and used äInoculum size appropriate

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 24 | – 14.40, Materials Reference standards - I Official reference standards äUse preferable whenever these exist äOnly for the purpose as per monograph äStorage conditions Reference standards prepared by the producer äTested, released and stored in the same way as official standards äIn a secure area äA responsible person Secondary or working standards äAppropriate checks and tests at regular intervals äStandardized against official reference standards – initially and at regular intervals

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 25 | 14.41, Materials Reference standards - II Reference standards labelled with information including äName äBatch, lot or control number äDate of preparation äShelf-life äPotency äStorage conditions Stored and used in an appropriate manner

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 26 | Materials Waste materials äproper and safe storage when awaiting disposal ätoxic substances and flammable materials: –in suitably designed, separate, enclosed areas as per national legislation änot to be allowed to accumulate –collected in suitable containers for removal to collection points –safe and sanitary disposal –regular and frequent intervals

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 27 | Materials Miscellaneous materials Miscellaneous äRodenticides, insecticides, fumigating agents äSanitizing material äNo contamination risk to equipment, starting materials, packaging materials, in-process materials, finished products

Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 28 | Materials Group session List specific aspects of GMP requirements, in relation to the groups of materials listed below, that you would assess when inspecting a manufacturer äPrinted packaging materials äThermolabile materials äWater äSterile materials Identify three materials that present problems in your experience What are some of the problems that you have experienced before and during inspection of materials?