AUFTAUEN von DEM VERDÜNNEN Die Mehrdosendurchstechflasche wird Nicht mehr      als      gefroren gelagert und muss vor der Verdünnung aufgetaut werden. Die 2 Stunden bei           gefrorenen Durchstechflaschen sollten Raum-               zum Auftauen in eine Umgebung von 2 °C bis 8 °C gebracht werden. Das temperatur             Auftauen einer 195- (bis zu 30 °C)          Durchstechflaschen-Packung kann _ 3 Stunden dauern. Alternativ können gefrorene Durchstechflaschen zur sofortigen Verwendung auch 30 Minuten lang bei Temperaturen bis zu 30 °C aufgetaut werden. Lassen Sie die aufgetaute Durchstechflasche Raumtemperatur annehmen und drehen Sie diese vor der Verdünnung l0-mal vorsichtig um. Nicht schütteln. Vor dem Verdünnen kann     die aufgetaute Dispersion weiße bis grauweiße, undurchsichtige, amorphe Partikel enthalten. VERDÜNNUNG Der aufgetaute Impfstoff muss  in seiner ursprünglichen Durchstechflasche mit 1,8 ml Natriumchlorid-lnjektionslösung 9 mg/ml (0,9 %) unter Verwendung einer 2l-Gauge- oder schmaleren Nadel unter aseptischen Techniken verdünnt werden. 1,8 ml der Natriumchlorid- Injektionslösung 9 mg/ml (0,9 °/o) 33

i)    QÜ4 5 Gleichen Sie den Druck in der Durchstechflasche aus, bevor Sie die Nadel aus der Durchstechflasche entfernen, indem Sie 1,8 ml Luft in die leere Spritze des Verdünnungsmittels ziehen. Ziehen Sie den Kolben bis 1,8 ml hoch, um Luft von der Durchstechflasche zu entfernen Drehen Sie die verdünnte Dispersion lO-mal vorsichtig um. Nicht schütteln. Der verdünnte Impfstoff sollte als grauweiße Dispersion ohne sichtbare Partikel vorliegen. Entsorgen Sie den verdünnten Impfstoff, wenn Partikel oder Verfärbungen vorhanden sind. Vorsichtig X I0 ~ 34

\‚ Die verdünnten Durchstechflaschen sollten mit dem neuen Datum und Uhrzeit der Entsorgung gekennzeichnet werden. Die verdünnte Dispersion nicht einfrieren oder schütteln. Lassen Sie eine gekühlte, verdünnte Dispersion vor der  Verwendung Raumtemperatur annehmen. Notieren Sie das neue Datum und die Uhrzeit der Entsorgung. Innerhalb von 6 Stunden nach Verdünnung verwenden ~ ZUBEREITUNG VON EINZELNEN 0,3 ml DOSEN VON COMIRNATY Nach    der Verdünnung  enthält die ‘i 0,3 ml verdünnter                         Durchstechflasche 2,25 ml, aus der "         Impfstoff                            6 Dosen zu 0,3 ml entnommen werden können. Reinigen Sie den Stopfen der Durchstechflasche unter aseptischen Bedingungen mit einem antiseptischen Einmaltupfer. Entnehmen Sie 0,3 ml Comirnaty. Es sollten Spritzen und/oder Nadeln mit geringem Totvolumen verwendet werden, um 6 Dosen aus einer Durchstechflasche zu entnehmen. Die Kombination aus Spritze und Nadel mit geringem Totvolumen sollte ein Totvolumen von nicht mehr als 35 Mikrolitern haben. Wenn    Standardspritzen und —nadeln verwendet werden, reicht das Volumen möglicherweise nicht aus, um eine sechste Dosis aus einer einzelnen Durchstechflasche zu entnehmen. Jede Dosis muss 0,3 ml des lmpfstoffs enthalten. Wenn die in der Durchstechflasche verbleibende lmpfstoffmenge nicht für eine volle Dosis von 0,3 ml ausreicht, entsorgen Sie die Durchstechflasche mit dem überschüssigen Volumen. Entsorgen Sie nicht verwendeten Impfstoff innerhalb von 6 Stunden nach der Verdünnuß Entsorgung Nicht verwendetes Arzneimittel oder Abfallmaterial ist entsprechend den nationalen Anforderungen zu beseitigen.

U (f? ÜÜ47 7 https:/lwww.ema.europa.eulenIdocuments/assessment-reportlcomirnaty-epar-public-assessment- report_en.pdf Seite 23 abgerufen am 06.04.2021 EUROPEAN MEDICINES AGENCY S C   I  E  NCL            MEDICINES                     HEALTH 19 February 2021 EMA/707383/2020 Corr.1*‘                                            _ Committee for Medicinal Products            for   Human Use (CHMP) Assessment report Comirnaty Commoh name: COVID—19 mRNA vaccine                                                 (nucleoside-modified) Procedure No. EMEA/H/C/005735/0000 Note Assessment report as adopted by the CHMP with                          all  information of a commercially confidential nature deleted. E 1   * Correct/‘on dated 19 February 2021        to c/arify    ERA Statement Official  address Dnamenict) Scarlattilaan 6 o 1083 HS Anwsterdam o The Netherlarwds Address for visits and deliveries Rafer" m \--n.=.'\-v.errn:.europe3.e\J/hov=: trwfsrxd-us; Send us a question (30 ro x-vxvvqxernxa.c2uropxn‚cun/rcxntaat Telephone +31 (0)88 781 6000             An agentv oFthe Eurouean Unten {c}  European Mechcines Agency, 2021. Reproduction        i3 authoriserfl prcxvided the source «s acknowledged.

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r‘: \/  {   {f    11 8 7 https://www.ema.europa.eulenldocuments/assessment-report/comirnaty-epar-pubIic-assessment- report_en.pdf Seite 23 abgerufen        am 06.04.2021 Chloride    and disodium phosphate dihydrate (buffer components), sucrose (cryoprotectant) and water ' for injections. All excipients except the functional Iipids      ALC—O315 and ALC—01S9 and the structural Iipid DSPC comm with Ph. Eur. The functional Iipid excipients ALC—O315 and ALC—01S9, are classified as novel excipients. Both structural lipids DSPC and cholesterol are used in several already approved finished products. A justification was provided for why DSPC is not considered to be a novel excipient. DSPC is used as part of the LNP for the EU approved finished product Onpattro which is administered intravenously in a much higher dose than the intramuscular dose for this product. Additionally; DOPC, a structurally related Iipid, is present in finished products approved in the EU for intramuscular administration. It was therefore concluded that the Ievel of information provided for DSPC, is in line with the requirements for a known excipient are sufficient and approprlately justified. The   vial,  stopper and seal components are compliant with the appropriate Ph. Eur. monographs for primary containers and closures. Formulation deve/ogment The section on formulation development describes and             justifies the chosen formulation and 1s sufficiently   comprehensive. The formulation development studies of the RNA containing llpid nanoparticles have been thoroughly described. The. LNPs consists of four Hpids, each has a functional or structural purpose. The formed             _ RNA—containing LNPs are solid particles. Furthermore, the accumulated batch—data to date show consistent manufacture of Iipid nanoparticles both with respect to size and polydispersity. Lipid-related impurities      have been identified in the fimshed product and have been characterized. An investigation has been initiated and is ongoing to assess and review potential root causes. The outcome of the investigation shall be provided (S02). ' Visual particulate matter has occasionally       been observed in finlshed product batches. Characterization data have been presented and the control strategy has been discussed. The data demonstrates that the particles are comprised of components of the finished product formulation. A 100% visual inspection is performed during rhanufacturing and the automatic inspection system is updated to improve the inspection. Routine release or routine stability data indicate that the propensity of particles to form following storage is low. If particles are observed In the diluted vaccine the vial should be discarded. Nove/ excigientg Two   novel excipients are included      in the finished product, the cationic   Iipid ALC—O315 and the PEGyIated    Iipid ALC-0159. Limited information regarding the novel excipients are provided. ALC—O315      (cationic l/‘gidz The ALC—O315 novel excipient        is a cationlc  Iipid containing a tertiary amine and two ester moieties, ((4- hydroxybutyI)azanediyI)bis(hexane-6,1-diyl)bis(2-hexyldecanoate). Figure 1    ALC—O315 structure Assessment report EMA/707383/2020                                                                                          Page 23/140

ÜÜÜ        F‘? 9 7 https:l/www.ema.europa.eu/enldocuments/assessment-report/comirnaty-epar-pubIic-assessment- report_en.pdf Seite 23 abgerufen am 06.04.2021 DSPC    is a non-compendial excipient    sufficiently controlled by an in-house specification. The other excipients (sucrose, sodium       Chloride, potassium chloride, disodium   phosphate dihydrate, potassium dihydrogen phosphate and water for injection) are controlled according to respective Ph. Eur.  monograph. The processing aids ethanol and citrate buffer are controlled according        to Ph. Eur. standards and for HEPES and EDTA, reference is made to the active substance. Product specification The release and stability testing specifications for BNT162b2 finished product include tests for Appearance (Visual), Appearance (visible Partlculates), Subvisible Particles (Ph. Eur.), pH (Ph. Eur.), Osmolality (Osmometry), LNP Size (Dynamic Light Scattering), LNP Polydispersity (Dynamic.Light Scattering)‚ RNA Encapsulation (Fluorescence assay), RNA content (Fluorescence assay), ALC-O315 content (HPLC—CAD)‚ ALC-0159 content (HPLC-CAD), DSPC content (HPLC—CAD)‚ Cholesterol content (HPLC-CAD), extractable volume (Ph. Eur.), Lipid identitles (HPLC-CAD), Identity of encoded RNA sequence (RT-PCR), Potency/ in Vitro Expression (CeII-based flow cytometry)‚ RNA Integrity (CapiIIary Gel Electrophoresis), Bacterial Endotoxin (Ph. Eur.), Sterility (Ph. Eur.) and Container Closure Integrity (Dye incursion). For aII quality attributes tested on stability except for RNA integrity‚ the acceptance criteria for release and stability testing throughout shelf Iife are the same. The specifications document for finished product in section 3.2.P.5.1 of the dossier includes        a comprehensive panel of relevant tests along with corresponding acceptance criteria. With the exception of osmolaIity‚ volume of injections in containers‚ HPLC-CAD (Iipid identities) and RT-PCR (Identity of encoded RNA sequence), which are performed only at FP release, all other analytical procedures are conducted at release and stability studies for finished product. It is stated by the applicant that the acceptance criteria used for stability during shelf-Iife will be the same as the acceptance criteria used for Iot release. Several questions     in relation to the acceptance criteria in the FP specifications  were  raised during the procedure (i.e. the LNP size, polydispersity,      RNA  encapsulation, in-vitro expression and   RNA  integrity). The acceptance criteria were tightened. For potency,     RNA  integrity‚ RNA  encapsulation, Iipid content and polydispersity index, the acceptance criteria will be re-assessed during Q2 2021 in order to ensure a consistent product quality by providing additional information to enhance the control strategy. This is found acceptable subject to a specific obligation.    (S02) The   vial  contains an overfill in order to ensure that the full required volume (5 doses) can be delivered following dilution and administration in line with the product information. The finished product specification includes a test to confirm the extractable volume from the vial provides S doses. During the procedure the applicant proposed to update the product information and instructions for use to indicate that up to 6 doses can be delivered from the vial. This proposed        change  to the product information     was not considered acceptable as no supporting data were provided        to demonstrate that 6 doses can be consistently extracted. In order to support such a change in the product information, a Variation should be submitted to update the specification Iimits for extractable volume, supported by appropriate pharmaceutical development data to support the claim of 6 doses (REC21). A  risk evaluation   regarding the risk of N-nitrosamines impurities was provided concluding that there        is no risk of the presence of nitrosamines in the finished product taking into account the active Assessment report EMA/707383/202O V Page 29/140

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