Sterile formulation basics Flashcards

Question

Process Simulations (Media Fills) – Validation of aseptic processing

Answer 1

Annex 1 and PIC/S (more detailed) guidance Should imitate as closely as possible the actual process, including set-up, and include all critical subsequent steps in your aseptic filling operation. Choose a suitable media (to represent your product). Take into account interventions known to occur during normal production, as well as worse-case situations. Must cover all shifts and operators. Operators only considered trained and qualified if they have taken part in a successful media fill. Must be performed as initial validation with 3 consecutive satisfactory simulations and after any significant modifications (e.g HVAC, equipment, water changes). Number of vials to be filled depends on validated batch size (Annex 1) Batch size <1,000 – perform media fill on full batch size. Batch size 3,000-100,000 – perform media fill on 3,000-10,000 units Batch size >100,000 units – perform media fill on 10,000 units New Annex 1: Batch sizes under 5,000 – no. containers for media fill should at least equal prodn batch size. For larger batches typically a min of 5,000 – 10,000 containers are filled. Vials should be filled with enough media that when rotated the media touches all of the inner surfaces of the vial. Risk assessment may be used to determine the worse case vial size for products with multiple vial sizes. Bigger, wide neck vials generally considered high risk, as easier for ‘things’ to get in the vial. Video and or have scribes during media simulations. This is helpful to look back at if failures occur. If failures occur, investigate, look back at all batches released since the last successful media fill. Performed at least every 6 months (per line & per shift), but based on the risk of your product/process (e.g. radiopharmaceuticals may be done more often due to RTRT used and reliance on QMS and processes).

Answer 2

Perform RA & review process, identify worst case parameters (e.g. longest fill duration, widest container opening, longest exposure time of open container). Document and execute under approved protocol. Protocol to include all aspects of media fill, including acceptance criteria. Interventions: Defined & classified regarding contamination risk, frequency etc. Covered during media fill Duration of media fill planned to allow performing all defined interventions Proper documentation of interventions required (batch records) Other points to consider: Shift patterns Fill level of units Max. holding time All integral units to be incubated Incubation / storage Different possibilities e.g.: 14 days at 20-25°C / 7 days at 20-25°C and 7 days at 30-35°C (Heat up period to be considered). Inspect after each incubation period. Evaluation/Examination To be performed or at least supervised by QC personnel Examination by educated, trained and experienced personnel Growth promotion to be demonstrated for medium

Answer 3

Media fill pass criteria The objective of the media fill is to produce zero contaminated units, irrespective of run size. Therefore the target involving such simulations should be zero positive units. New Annex 1: No set criteria – target zero growth. Any contaminated unit should result in failed process simulation and investigation performed. Sufficient no. of successful, consecutive repeat media fills performed to demonstrate process returned to state of control (normally min. 3) Discovery of any positive units, investigate with RA to assess any potential root causes, CAPAs and respective documentation. ID micro Find what batches have been manufactured since last successful media fill. Quarantine what’s in your control. Following any failures, it is critical to verify the robustness of CAPA, may need to perform multiple media fill runs to do so * Investigations which determine a definitive and readily identifiable root cause, might provide grounds for a reduced number of repeat run(s)  CAPAs should be put in place to avoid such issues and deviations to studies and processes from reoccurring. * Execution of media fills without investigation to identify and correct any potential root causes is not acceptable.

Answer 4

Determination of “Critical Zone” (Grade A) Environmental background, based on QRM. Terminally sterilised at least Grade D Aseptic, grade C with gowning as A/B Validation & reproducibility of CIP and SIP KEY! Eqp design & Qual Integrity testing of product pathways Duration of batch or filling campaigns Resin control Care with interventions into the critical zone BFS Forming, filling and sealing of container in a continuous process Liquid filled containers

Answer 5

Sublimation of ice to vapour at low pressure Tg – Glass transition temp – Critical temp for primary & secondary drying phases Shelf loading (High Risk as vials not completely sealed – Lyo caps) Load top down to avoid contamination into vials Validated loading pattern Shelf Freezing 5oC down to -60oC over 1-2 hours at 1 bar Primary Drying Sublimation of ice to vapour, 5oC Below Tg for 12- 72h 1-5mbar Secondary Drying De-sorption of bound water, >20oC Below Tg for 6 – 24h, 0.01mBar Container Sealing Typically 25oC, N2 1 bar or below Shelf moves up to push caps fully into vials Vial overseals completed after vials taken from chamber  vials kept under Grade A. Chamber must be SIP before use - 15 mins at 121oC. CIP after use  inside product contact Defrosting of condenser – must be cleaned regularly to avoid cross contamination N2 and air enter through Hydrophobic filters. Speed of freezing determines size of ice crystals  critical to structure of ‘cake’ and stability of product  slow freezing best, gives larger ice crystals Equipment exposed to extreme temperatures & pressures  leaks tests NB

Answer 6

Prepare stable products from materials unstable in soln / sensitive to heat, e.g. antibiotics, proteins