Manufacturing process of ZFill Zimmer Aesthetic Division exportzimmer

Manufacturing process of Z-Fill Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Hyaluronic acid (sodium salt) – native HA From non animal orgigin (biofermentative) Sensitive to heat (storage, sterilisation!) Enzymatic degradation by hyaluronidase Soluble in water Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Hyaluronic acid – stabilised HA Stabilization with hydrogen bonds, e. g. with glycerol (Z-Fill refresh²) Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Hyaluronic acid – crosslinked HA Crosslinking by covalent bonding, e. g. with 1, 4 -butanedioldiglycidylether (BDDE) – Z-Fill contour² & deep². Covalent modification of HA molecule (reticulation=crosslinking). Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Manufacturing process crosslinked HA (1) o. Preparation cross-linked phase 1. Alignment of HA chains: high p. H value prepares HA for crosslinking process, dry HA is slightly hydrated; 2. Addition of BDDE (bulk), stirring under vacuum; 3. Cross-linking reaction: it depends on the duration of process, the temperature and the concentration. In the case of Princess products, the temperature and duration are the same for Filler and Volume, the only difference is in the concentration (9% for Filler and 14% for Volume) 4. Crosslinked bulk is neutralised, diluted (swelling phase) 5. Purification cross-linked phase: removal of free BDDE, swelling by dialysis in specially designed container; o. Preparation non-crosslinked phase Mixing of buffer and high molecular weight HA in bulk Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Preparation crosslinked phase Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Purification crosslinked phase Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Manufacturing process crosslinked HA (2) o. Mixing crosslinked & non-crosslinked phase Viscoelastic optimisation and homogenisation in one step (new!) under vacuum. This allows to obtain a homogenous and smooth gel. o. Evacuation Removal of oxygen prior to filling (bubble free, better stability) o. Filling & closing of syringes under vacuum o 100% visual control (fibers, particles, …) o. Assembly of plunger rod & backstop Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Z Cryo Z Wave Z Fill Quality for lasting effects 1. Cross-linking: BDDE is added to create the cross-links between the hyaluronic acid chains 2. Cross-linking: BDDE is added to create the crosslinks between the hyaluronic acid chains Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de 3. The product is then homogenised. The gel is now viscous and also very soft and elastic: ideal to be injected smoothly and evenly through thin

Z Cryo Z Wave Z Fill Quality for lasting effects 4. Cleaning Process: All surplus and harmful elements (unbound BDDE, proteins and endotoxins) are carefully removed. 5. The gel then has its oxygen removed, resulting in even higher stability and a much longer shelf life. Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de 6. Finally the filled gel syrings are sterilised in a steam autoclave.

Mixing of phases - homogenisation Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Manufacturing process crosslinked HA (3) o. Terminal sterilisation Syringes are sterilised in pouches of 10 syringes Inner sterility of product Parameters (temperature, time, load) determine product characteristics o. Labelling and packaging in blister o. Secondary packaging Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Output process 10 liters Old process (contract manuf. ): 800 syringes/batch Process 5 liters: appr. 4000 syringes / batch Process 10 liters: 8. 500 syringes / batch Filler 7. 400 syringes / batch Volume Duration of process: 1 week (5 working days) (Wo)man power: 4 people (manufacturing Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Advantages of 10 liter process o. Increased batch size o. Reduction of sources of error (higher degree of automatisation) o. Higher reproducibility o. Improvement of product characteristics - higher elasticity - better injectability - decreased degradation of product during sterilisation - decrease of air bubbles in product Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Advantages Z-Fill filler o. Well-established and safe crosslinking technology o. Highly automated manufacturing process improved reproducibility and homogeinity o. Proprietary purification process high level of purity (BDDE, endotoxines, proteins) o. Z-Fill deep²: innovative formulation, exceptional high cohesion o. Easy injection of both contour² & deep² with 27 g thin wall intradermal needle Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de

Thank you very much for your attention! Zimmer Aesthetic. Division export@zimmer. de www. zimmer. de