ANNEX IVSupplementary provisions
ANNEX IV Scope 1. This Annex applies to substances, combinations of substances, or items intended to be used for facial or other dermal or mucous membrane filling by subcutaneous, submucous or intradermal injection or other introduction, excluding those for tattooing, listed in Section 3 of Annex XVI to Regulation (EU) 2017/745. This Annex only applies to the means for introduction into the body, for example syringes and dermarollers, where they are prefilled with the substances, combinations of substances or other items listed in Section 3 of Annex XVI to Regulation (EU) 2017/745. This Annex does not apply to active devices. Risk management 2. When carrying out the risk management process provided for in Annex I to this Regulation, as part of the analysis of risks associated with the device, manufacturers shall consider the specific risks listed in Section 3 of this Annex and, where relevant to the device, adopt the specific risk control measures listed in Section 4 of this Annex. 3. Specific risks 3.1. Manufacturers shall take into account the following aspects and related risks: (a) physical and chemical characteristics of the device; (b) the selection of raw materials in view of biological safety, biocompatibility and chemical and biological additives or contaminants; (c) biological safety and biocompatibility of the final product, including consideration of at least the aspects of cytotoxicity, sensitisation, irritation, material mediated pyrogenicity, acute systemic toxicity, subacute toxicity, subchronic toxicity, chronic toxicity, genotoxicity, carcinogenicity, implantation, sterilisation residues and degradation products, extractable and leachable substances; (d) resorption and life-time in the body, indicating the half-life and the end of the resorption, including the possibility of metabolisation (for example enzymatic degradation of the filler material such as hyaluronidase for hyaluronic acid fillers); (e) microbiological properties, bioburden, microbiological contamination of the final device, residual bacterial endotoxins and sterility; (f) the specific anatomical location of injection or introduction; (g) consumer specific factors (for example previous and current treatments (medical and surgical), age restrictions, pregnancy, breast-feeding); (h) if applicable, risks related to the use of local anaesthetic, either as part of the product or stand-alone; (i) for non-resorbable devices, the risk associated with the removal of the device; (j) aspects associated with the use of the device, including: — injection technique; — means of injection (for example rollers, catheters or needles); — maximum quantity injected depending on location and applied technique; — possible repeated injections; — force required to administer the product; — product temperature; — transfer of the product (for example from a vial to a syringe). 3.2. Where appropriate, manufacturers shall analyse, eliminate or reduce as far as possible risks related to the following hazards or harms: (a) microbiological contamination; (b) presence of manufacturing debris; (c) hazards associated with the procedure to inject or otherwise introduce the device (including use errors); (d) migration of the device; (e) device visibility through the skin; (f) unintended local inflammation and swelling; (g) regional swelling or lymphadenopathy; (h) capsule formation and contracture; (i) discomfort or pain; (j) hematoma; (k) infection and inflammation; (l) superficial wound; (m) interruption of wound healing; (n) scarring and scar hyperpigmentation and hypertrophy; (o) nerve injury; (p) seroma; (q) compartment pressure problems and compartment syndrome; (r) granuloma, including siliconoma where applicable; (s) edema; (t) vascular damage; (u) severe allergic reactions; (v) blindness; (w) necrosis. 4. Specific risk control measures (a) Devices shall be sterile non-pyrogenic and intended for single use. (b) The safe use of the device shall be supported by clinical and other data considering the anatomical location. (c) Long-term data shall be collected to evaluate the presence of non-degradable substances originating from the devices. (d) Manufacturers shall provide training on the administration and safe use of the device. That training shall be accessible to users. (e) Presence of substances referred to in Section 10.4.1, points (a) and (b), of Annex I to Regulation (EU) 2017/745 shall be evaluated independently of their concentration. Information for safety 5. Label 5.1. The label shall contain: (a) in bold fonts of largest used size on the label the text: “Only to be administered by appropriately trained healthcare professionals who are qualified or accredited in accordance with national law”. (b) a clear indication that devices are not to be used in persons who are less than 18 years old. 6. Instructions for use 6.1. The instructions for use shall contain: (a) on top in bold font of largest used size in the instructions for use the text: “Only to be administered by appropriately trained healthcare professionals who are qualified or accredited in accordance with national law.”; (b) a clear indication that devices are not to be used in persons who are less than 18 years old; (c) precise and detailed technical information for a good administering practice; (d) description of treatment of the most common side-effects, such as overdosing, swelling, hardening, nodules and immune responses, with the instruction to consult a medical professional if needed; (e) instructions for users as to how and when new injections can be placed at previously injected locations; (f) a list of constituents, which specifies: — all constituents responsible for the intended action with specification of their concentration and, where applicable, their molecular weight range, their particle size and their degree of cross-linking, together with the method used for its determination; — other constituents such as cross-linking agents, solvents, anaesthetics and preservatives, with specification of their concentration; (g) the recommendation for the user to consider any previous procedures, accidents, conditions, medications or other simultaneous treatments of the consumer that may affect the procedure (for example skin diseases, traumas and auto-immune diseases); (h) the recommendation for the user of a post-administration monitoring time in order to identify any potential undesirable side-effects; (i) a requirement for the user to provide the consumer with a copy of the annex provided for in Section 6.2 before the consumer is treated with the device. 6.2. The instructions for use shall contain an annex, written in a language commonly understood by lay persons and in the form that is easy to be handed over to all the consumers. The annex shall contain: (a) information listed in Section 12.1, points (a) to (e), of Annex I; (b) all residual risks and potential undesirable side-effects listed in a clear way and described in a language commonly understood by lay persons. This includes a clear declaration on the presence of any substances referred to in Section 10.4.1 of Annex I to Regulation (EU) 2017/745, heavy metals or other contaminants; (c) information on when and how to report undesirable side-effects to the manufacturer; (d) information on when to contact healthcare professional; (e) any contra-indications to the procedure; (f) the statement “The users received appropriate training on the conditions to safely use the device.”, where relevant. In addition, a specific part of the annex shall be designed to record information on the location, the number and the volume of the injections, for each consumer. The manufacturer shall recommend the healthcare professional to fill in this specific part.