EMAの査察での不適合
The manufacturer : FARMABIOS S.P.A.
Site address :
Via Pavia, 1, GROPELLO CAIROLI, 27027, Italy
2019-11-22
Name and signature of the authorised person of the Competent Authority of Italy
Confidential
Italian Medicines Agency
670996 001 AG22000038
670996 001 AG22000038
670996 001 AG22000038
From the knowledge gained during inspection of this manufacturer, the latest of which was conducted on 2019-09-20 , it is considered that it does not comply with the Good Manufacturing Practice requirements referred to in
The principles of GMP for active substances referred to in Article 47 of Directive 2001/83/EC
__________________________________________________________________________________________________________________________
(1) The statement of non-compliance referred to in paragraph 111(7) of Directive 2001/83/EC and 80(7) of Directive 2001/82/EC, as amended, shall also be required for imports coming from third countries into a Member State.
Part 2
1 NON-COMPLIANT MANUFACTURING OPERATIONS
1.4 Other products or manufacturing activity
1.4.3 Other: manufacture of active substances(en)
Manufacture of active substance. Names of substances subject to non-compliant :
[ 00000000006158 ] BECLOMETASONE DIPROPIONATE STERILE ( en ) [ 00000000007230 ] BUDESONIDE STERILE ( en ) [ 00000000005452 ] HYDROCORTISONE ACETATE STERILE ( en ) [ 00000000007232 ] LOTEPREDNOL ETABONATE STERILE ( en ) [ 00000000007231 ] METHYLPREDNISOLONE ACETATE STERILE ( en ) [ 00000000007413 ] PREDNISOLONE ACETATE STERILE ( en ) [ 00000000006159 ] TRIAMCINOLONE ACETONIDE STERILE ( en )- NON-COMPLIANT MANUFACTURING OPERATIONS – ACTIVE SUBSTANCES
Active Substance : BECLOMETASONE DIPROPIONATE STERILE
3.1 Manufacture of Active Substance by Chemical Synthesis
3.1.1 Manufacture of active substance intermediates
Special Requirements :
7 . Other : Hormones or substances with hormonal activity
3.1.2 Manufacture of crude active substance
3.1.3 Salt formation / Purification steps :
crystallisation
3.4
Manufacture of sterile Active Substance
3.4.1 Aseptically prepared
3.5 General Finishing Steps
3.5.1 Physical processing steps :
drying, micronisation
3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)
3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)
3.6
Quality Control Testing
3.6.1 Physical / Chemical testing
Active Substance : BUDESONIDE STERILE
3.1
Manufacture of Active Substance by Chemical Synthesis
3.1.1 Manufacture of active substance intermediates
Special Requirements :
7 . Other : Hormones or substances with hormonal activity
3.1.2 Manufacture of crude active substance
3.1.3 Salt formation / Purification steps : crystallisation
3.4 Manufacture of sterile Active Substance
3.4.1 Aseptically prepared
3.5 General Finishing Steps
3.5.1 Physical processing steps : drying, micronisation
3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)
3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)
3.6 Quality Control Testing
3.6.1 Physical / Chemical testing
Active Substance : HYDROCORTISONE ACETATE STERILE
3.1 Manufacture of Active Substance by Chemical Synthesis
3.1.1 Manufacture of active substance intermediates
Special Requirements :
7 . Other : Hormones or substances with hormonal activity
3.1.2 Manufacture of crude active substance
3.1.3 Salt formation / Purification steps :
crystallisation
3.4 Manufacture of sterile Active Substance
3.4.1 Aseptically prepared
3.5 General Finishing Steps
3.5.1 Physical processing steps : drying, micronisation
3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)
3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)
3.6 Quality Control Testing
3.6.1 Physical / Chemical testing
Active Substance : LOTEPREDNOL ETABONATE STERILE
3.1 Manufacture of Active Substance by Chemical Synthesis
3.1.1 Manufacture of active substance intermediates
Special Requirements :
7 . Other : Hormones or substances with hormonal activity
3.1.2 Manufacture of crude active substance
3.1.3 Salt formation / Purification steps : crystallisation
3.4
Manufacture of sterile Active Substance
3.4.1 Aseptically prepared
3.5 General Finishing Steps
3.5.1 Physical processing steps : drying, micronisation
3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)
3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)
3.6 Quality Control Testing
3.6.1 Physical / Chemical testing
Active Substance : METHYLPREDNISOLONE ACETATE STERILE
3.1 Manufacture of Active Substance by Chemical Synthesis
3.1.2 Manufacture of crude active substance
Special Requirements :
7 . Other : hormones or substances with hormonal activity
3.1.3 Salt formation / Purification steps : crystallisation
3.4 Manufacture of sterile Active Substance
3.4.1 Aseptically prepared
3.5 General Finishing Steps
3.5.1 Physical processing steps :
drying, micronisation
3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)
3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)
3.6 Quality Control Testing
3.6.1 Physical / Chemical testing
3.6.4 Biological Testing
Active Substance : PREDNISOLONE ACETATE STERILE
3.1 Manufacture of Active Substance by Chemical Synthesis
3.1.1 Manufacture of active substance intermediates
Special Requirements :
7 . Other : Hormones or substances with hormonal activity
3.1.2 Manufacture of crude active substance
3.1.3 Salt formation / Purification steps :
crystallisation
3.4 Manufacture of sterile Active Substance
3.4.1 Aseptically prepared
3.5 General Finishing Steps
3.5.1 Physical processing steps :
drying, micronisation
3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)
3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)
3.6 Quality Control Testing
3.6.1 Physical / Chemical testing
Active Substance : TRIAMCINOLONE ACETONIDE STERILE
3.1 Manufacture of Active Substance by Chemical Synthesis
3.1.1 Manufacture of active substance intermediates
Special Requirements :
7 . Other : Hormones or substances with hormonal activity
3.1.2 Manufacture of crude active substance
3.1.3 Salt formation / Purification steps :
crystallisation
3.4 Manufacture of sterile Active Substance
3.4.1 Aseptically prepared
3.5 General Finishing Steps
3.5.1 Physical processing steps :
drying, micronisation
3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)
3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)
3.6 Quality Control Testing
3.6.1 Physical / Chemical testing
3.6.2 Microbiological testing excluding sterility testing
3.6.4 Biological Testing
Part 3
Nature of non-compliance : 30 deficiencies were found, 10 classified as “Major” in the following areas:
– Premises/equipment (4)
– Production (2)
– Quality control (3)
– Personnel (1)
Six out of ten major deficiencies are mainly referring to the aseptic production and quality control which constitutes a critical risk for public health due to the lack of sterility assurance of the drug substances.
10の重大な観察事項の6の重大な観察事項は、主に無菌の製造と品質管理に関してである。これは原薬の無菌性の保証ができなく、健康への重大なリスクである。
Action taken/proposed by the NCA :
Recall of batches already released
If there are alternative API manufacturing suppliers and there is no risk of shortage, recall of medicinal product manufactured using APIs aseptically manufactured by Farmabios should be evaluated by involved NCAs following assessment conducted in conjunction with the concerned MAHs.
代替のAPI製造者が存在し、欠品のリスクがない場合、Farmabiosが製造した無菌APIを用いた医薬品の回収は、関連するMAHとともに実施された評価に従って、関係するNCAによって判断されること
Prohibition of supply
Prohibition to use APIs aseptically manufactured by Farmabios is recommended. Lack of alternative service providers and risk of shortage should be assessed case by case.
Suspension or voiding of CEP (action to be taken by EDQM)
Farmabiosが製造した無菌APIの使用を禁止することを推奨する。代替の供給者がないことと、欠品のリスクは、ケースバイケースで評価すること。製造所の証明の停止または失効（EDQMがとるアクション）
Suspension of CEP (RO-CEP2017-286-Rev 00). for the active substance Prednisolone acetate micronised sterile should be considered
Others
The Company holds authorization for manufacturing sterile APIs and registration for non sterile APIs. Proposed actions: 1. Authorisation for production of aseptically manufactured sterile APIs to be suspended. Authorisation for APIs sterilized by gamma irradiation to be maintained as the statement of non compliance does not impact the gamma irradiation that is performed by a contract manufacturer. 2. Registration for production of non-sterile APIs to be maintained as the statement of non compliance does not impact the not sterile APIs manufactured at the site. The GMP certificate for non sterile APIs and for sterile APIs sterilized by gamma irradiation will be issued after favourable conclusion of the CAPA evaluation.
当社は、無菌APIの製造許可と非無菌APIの登録を保持しています。 提案されたアクション：1.無菌的に製造された無菌APIの製造中止の許可。 非準拠の声明が契約製造業者によって実行されるガンマ線照射に影響を及ぼさないため、ガンマ線照射によって滅菌されたAPIの承認は維持されます。 2.非準拠の声明はサイトで製造された非滅菌APIに影響を与えないため、非滅菌APIの生産登録は維持されます。 非滅菌APIおよびガンマ線照射により滅菌された滅菌APIのGMP証明書は、CAPA評価の有利な結論の後に発行されます。
無菌APIの製造許可は取り消し
ガンマ線照射の殺菌工程と非無菌原薬製造工程は、今回の査察の結果の影響は受けない。このnon-compliance letterへのCAPA案が認められたのち、ガンマ線照射の殺菌工程と非無菌原薬製造工程には再発行される。
追加コメント；
このnon-complianceの判定は、動物薬も含まれる。
が
Additional comments :
BECLOMETASONE DIPROPIONATE STERILE is sterilized by filtration under aseptic condition or alternatively by gamma irradiation.
Other sterile APIs manufactured with final sterilization by gamma irradiation is MEDROXYPROGESTERONE ACETATE STERILE. The statement of non-compliance also impact on the active substances of veterinary use: PREDNISOLONE ACETATE STERILE and PREDNISOLONE STERILE
