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De PIC'S normen en hun integratie in de Belgische wetgeving Ludo Willems UZ Leuven 29 januari 2011
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Inhoud • Een kleine toelichting bij … – Belgische Wetgeving en ‘1885’ – ‘PIC’s’ normen
• Betekenis voor Belgische ziekenhuisfarmacie
• Capita selecta uit ‘PIC’s’ normen 2
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www.ejustice.just.fgov.be/wet/wet.htm (gecoördineerde wetteksten)
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Koninklijk Besluit 1885 31 MEI 1885. - Koninklijk besluit houdende goedkeuring der nieuwe onderrichtingen voor de geneesheren, de apothekers en de drogisten Publicatie : 19-06-1885 Originele tekst alleen in het Frans gepubliceerd Article 1. Nul ne peut exercer dans le royaume la profession de docteur en médecine, chirurgie et accouchements, de pharmacien ou de droguiste, s'il n'a obtenu son grade conformément à la loi et s'il n'a pas fait viser son diplôme par la commission médicale de la province où il fixe sa résidence. (Loi du 12 mars 1818, et du 20 mai 1876. - Arrêtés royaux des 31 mai 1880 et 30 décembre 1884.) 4
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Van 1885 naar 201X FOG Volksgezondheid DG3 – 2003: Vraag aan Belgische Vereniging van Ziekenhuisapothekers om bemerkingen bij nieuwe versie 1885 te formuleren – Antwoord BVZA: beoefening van de farmacie in een voor het publiek toegankelijke apotheek is verschillend van deze in een ziekenhuis 5
Van 1885 naar 201X • Vanaf 2004: naar twee KB’s – ‘Koninklijk besluit voor de open apotheken’
Artikel de toepassing van dit besluit moet worden verstaan onder : – 1. KBVoor ziekenhuisapotheek 1° « Officina-apotheek », hierna « apotheek » genaamd : de lokalen die bestemd zijn voor de bereiding, het ontvangen, de bewaring en de aflevering van geneesmiddelen … indien de apotheek opengesteld is voor het publiek 2° « Apotheker van een voor het publiek opengestelde apotheek », hierna « apotheker » genaamd : 6
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Van 1885 naar 201X • Vanaf 2004: naar twee KB’s – ‘Koninklijk besluit voor de ziekenhuisapotheek’ • Koninklijk besluit houdende onderrichtingen voor ziekenhuisapothekers werkzaam in ziekenhuisapotheken en geneesmiddelendepots in verzorgingsinstellingen
• Publicatie?
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Koninklijk besluit … voor ziekenhuisapothekers … • Koninklijk besluit – Basis: KB voor open apotheken
• Bijlagen – Farmaceutische zorg – GMP voor ziekenhuisapotheken bij bereidingen • Vaste orale vormen • Vloeistoffen, zalven en crèmes • Steriele en aseptische bereidingen • Potentieel toxische stoffen • Radiofarmaca
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Waarom GMP in ziekenhuizen?
Kwaliteit
Kwaliteit
Kwaliteit
Risico
Risico
Risico
Bezorgdheid
Bezorgdheid
Bezorgdheid
Kwaliteitsgarantie en Patiëntveiligheid OVERAL voor ALLE patiënten ALTIJD
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Good Manufacturing Practices (GMP) • Kwaliteitsborgingssysteem voor de farmaceutische industrie, cosmetische industrie en voedingsindustrie • Controle op en documentatie van ALLE stappen in productieproces i.p.v. enkel eindproduct
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Principes GMP • • • •
Alle startproducten voldoen aan specificaties Alle procedures zijn vastgelegd Alle personeel is gekwalificeerd en getraind Alle ruimten en apparaten zijn specifiek ontworpen en worden gecontroleerd • Alle verantwoordelijkheden en taken zijn vastgelegd (incl. eindverantwoordelijkheid)
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PIC – PIC/S • • • • •
Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-operation Scheme 37 landen (binnen en buiten Europa) Samenwerking tussen Farmaceutische inspecties GMP adviezen aanvaard door EU
• www.picscheme.org/ 12
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‘PIC/S’ • Standaarden voor goede farmaceutische praktijk – GMP GUIDE (PART I: BASIC REQUIREMENTS FOR MEDICINAL PRODUCTS) – GMP GUIDE (PART II: BASIC REQUIREMENTS FOR ACTIVE PHARMACEUTICAL INGREDIENTS) – GMP GUIDE FOR BLOOD ESTABLISHMENTS – ISOLATORS USED FOR ASEPTIC PROCESSING AND STERILITY TESTING –… 13
‘PIC/S’ voor ziekenhuizen • PE 010-3 (okt 2008) GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL PRODUCTS IN HEALTHCARE ESTABLISHMENTS • www.picscheme.org/ All publications – miscellaneous – documents for inspectors
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‘PIC/S’ voor ziekenhuizen • Deel 1
Basis GMP guide for industry (PE 009)
– Definities – Kwaliteitsborgingssysteem – Vereisten met betrekking tot • • • • •
Personeel, gebouwen en uitrusting Documentatie Productie Kwaliteitscontrole Uitbesteding, klachtenbehandeling, terugroeping, zelfaudit
• Deel 2 – Bijlage 1: richtlijnen voor steriele bereidingen – Bijlage 2: richtlijnen voor bereiding van niet steriele vloeistoffen, zalven en crèmes. 15
‘PIC/S’ in realiteit • Architectuur – Aangepaste ruimten – Luchtzuivering en luchtverversing
• Apparaten – Weegschalen, verwarmingselementen, … – LAF kasten/ Isolatoren voor steriele bereidingen – …
• Procedures – – – –
Protocols Activiteiten strikt volgens protocols Documentatie bereiding Training
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Bereidingen in ziekenhuis en ‘PIC/S’ • Bereidingen ‘De novo’ – Capsules – Vloeistoffen – Injecteerbare vloeistoffen
• Eenheidsdosisverpakking • Ready to use injectables – – – –
Potentieel toxische stoffen Parenterale voeding Antibiotica …
• Radiofarmaca 17
Kostprijs ‘PIC/S’ • Architectuur – Capaciteit – Verbouwing<-> Nieuwbouw – Inbouwmodule steriele ruimte
• Apparaten – Weegschalen, …, software, … – LAF kasten: nieuw <-> aanwezig
• Procedures en uitvoering – Arbeidstijd (Werkvolume en werksnelheid ) – Gebruiksgoederen (bv kledij) 18
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Opportuniteiten? • Insourcing-Outsourcing – Samenwerking tussen ziekenhuizen – Voorzien in wetgeving (KB 19 okt 1978) – Capaciteit -> kostprijs bouw
• Vermijden van negatieve situaties, daarom GMP – – – – – – –
Toepassen zorgvuldigheidsprincipe België mee op internationaal niveau Houdbaarheid aseptische bereiding >24 uur (-> GMP) Vergoedbaarheid per mg mogelijk (bv cytostatica) Steeds conformiteit Waarborg voor patiëntveiligheid Farmaceutische inspectie = internationale aangelegenheid geen goedkeuring, geen activiteit 19
Ziekenhuisapothekers en PIC/S Belgische Vereniging van Ziekenhuisapothekers – belang van kwaliteit van activiteiten – belang van conformiteit van afgeleverd product – implementatie over bepaalde periode – indien nodig concentratie van activiteiten – bewust van kostprijs implementatie GMP 20
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Een evolutie: Het verleden Cytostatica 1970 Letter to the Editor van het tijdschrift Pediatrics To the Editor: ... As a hematology resident, I have to give 4-6 injections with antineoplastic drugs daily. These drugs are well known to be cytotoxic and I am distressed to find no published report on the hazards of handling such drugs. Is skin contact unable to bring about toxic effects? Editor's note: Dr. Ng is probably correct that there is insufficient evidence of reported case of contact dermatitis ... . However, nitrogen mustard is well known to cause a vesicant effect. With regard to systemic toxicity, this would be expected to be extremely small. I know of no reported occurrence of systemic toxicity due to trivial skin contamination. 21
Een evolutie: Nabije toekomst Cytostatica 2010 • Bereiding van potentieel toxische stoffen Robots: offertevraag en/of aankoop in Belgische ziekenhuizen
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Hoe zal het verder gaan voor de ziekenhuisfarmacie? • FAGG in samenwerking met BVZA – Verfijning Koninklijk besluit basistekst – Bijlagen Bereidingen • Werkgroep farmacopeecommissie • Elementen van andere teksten van PIC’s ? • Elementen van USP Chapter 797 ? – Pharmaceutical Compounding—Sterile Preparations
• Definitief KB – Datum publicatie? – Datum van in voegetreding?
• Werkelijkheid in ziekenhuizen – Erkenning voor de verschillende modules – Nog alle bereidingen in alle ziekenhuisapotheken? 23
GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL PRODUCTS IN HEALTHCARE ESTABLISHMENTS GENERAL PART
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General Principles • In order to protect public health, medicinal products should be of high quality, safe and effective • They should be prepared in such a way that they are fit for their intended purpose and that their quality consistently complies with the defined requirements • To achieve this objective reliably, there should be a comprehensively designed and correctly implemented quality assurance system, incorporating the principles of Good Preparation Practices as described in this Guide • The quality assurance system should be documented and its effectiveness should be monitored 25
Personnel and Equipment • It should be guaranteed that no risk of contamination exists, either for personnel or products • Dedicated rooms should be provided for hazardous products, e.g. cytostatics, penicillins, biologicals, radiopharmaceuticals, blood products
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Documentation • Good documentation on paper or in electronic form constitutes an essential part of the quality assurance system • In order to establish product specific specifications, instructions and procedures, a pharmaceutical assessment of therapeutic rationale, safety data, toxicity, biopharmaceutical aspects, stability and product design should be carried out, before preparation takes place 27
Production • Production should be performed by trained personnel • The risk potential for health damage in case of failures (e.g. quality defects) varies with different types of products and should therefore be assessed and documented by an appropriately competent person • The date of the first opening should be indicated for starting materials with a short inuse expiry date 28
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Production • Before any processing operation is started, it is important to ensure (and document) that the work area and the equipment are clean and free from any … products not required for the current operation … • Packaging material may only be used if suitable for the particular purpose … sufficient protection against external influences and possible contamination • Labels should comply with national legislation 29
Returned products • Dispensed products that have been returned … , should be destroyed unless there is no doubt their quality is satisfactory. • They may exceptionally be considered for reprocessing or recovery only after they have been critically assessed under the responsibility of the Responsible Person in accordance with a written procedure. • Any action taken should be appropriately recorded 30
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Release • The Responsible Person is ultimately responsible for the quality of the medicinal products prepared and released • The actual release can be delegated to another appropriately competent person (i.e. Releasing Officer)
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Outsourcing Depending on the local situation and on national legislation, the work contracted out by a healthcare establishment may include activities, which are directly involved with preparation, such as processing, packaging or quality control, but also services, which are not directly involved with preparation, … Services: - maintenance of the air handling system, … - handling of waste, … - environmental monitoring services, … 32
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GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL PRODUCTS IN HEALTHCARE ESTABLISHMENTS GUIDELINES ON THE STANDARDS REQUIRED FOR THE STERILE PREPARATION OF MEDICINAL PRODUCTS
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Introduction • The sterile preparation of medicinal products includes: – The preparation of terminally sterilized products – The aseptic preparation of products
• Sterile preparations are considered to be high risk category products • For individual product types examples of their more specific risk factors are: – Cytotoxics and radiopharmaceuticals (High level of hazard) – Total parenteral nutrition solutions (Complexity) – Epidurals and cardioplegia solutions (Microbial contamination) 34
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Personnel (definitions) Responsible Person (Qualified Person) … who is ultimately responsible for all aspects of the preparation of medicinal products including the release of these items. This person must have sufficient scientific and technical education and experience to perform this duty.
Releasing Officer … who releases the prepared medicinal products. This person may be the Responsible Person.
Production Supervisor … responsible for supervision should be in the department where the production takes place. He/she should be aware of what is going on …
Staff (pharmacists and pharm. technicians) … competent personnel to carry out all the tasks. Individual responsibilities should be documented and clearly understood …. All personnel should be aware of the principles of Good Preparation Practice … Personnel should receive initial and continuing training, … 35
Personnel • Before undertaking sterile work, all staff should be appropriately trained and have their competence assessed • Special requirements for aseptic preparation activities: Supervisory personnel within the aseptic preparation department should have an understanding of clean area and clean air device technology together with a thorough knowledge of all the particular design features in their department e.g. ventilation systems, position and grade of HEPA filters, type of work station, isolator design etc
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Equipment • Special requirements for aseptic preparation activities: – After washing, components should be handled in at least a grade D environment. Handling of sterile starting materials and components, …, should be done in a grade A environment. – Handling and filling of aseptically prepared products (open and closed) should be performed … in a laminar flow cabinet (LFC) or a positive pressure pharmaceutical isolator (= grade A) – The room should have a positive pressure … 37
Hazardous drugs • Preparation under negative pressure, protecting operator and environment from contamination, should only be used for the preparation of hazardous pharmaceuticals (e.g. cytotoxic drugs, radiopharmaceuticals, … • Laminar Flow Cabinets (LFCs) are not suitable for the preparation of hazardous drugs. Biohazard safety cabinets (BSCs) should be used instead, with a vertical downward air flow …
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Equipment • Special requirements for aseptic preparation activities: – … the background environment for LFCs and BSCs should meet grade B requirements, with grade D required for pharmaceutical isolators – Any justification for background environments of a lesser grade should be based on a documented risk assessment which should be performed with great care. – Possible factors which could be considered in such a risk assessment include: • Time between preparation and use • Use of a closed system • … 39
Use of a closed system Closed Procedure (Glossery) (general definition ‘PIC/S’) • A procedure whereby a sterile pharmaceutical product is prepared by transferring sterile ingredients or solutions to a pre-sterilised sealed container, either directly or using a sterile transfer device, without exposing the solution to the external environment
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Clothing • Grade C – Hair, arms and, where relevant, beard and moustache should be covered – A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be worn. – They should shed virtually no fibres or particulate matter. 41
Clothing • Grade A/B – Headgear should totally enclose hair and, where relevant, beard and moustache; it should be tucked into the neck of the suit; a face-mask should be worn to prevent the shedding of droplets – Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn – The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body 42
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Clothing • Outdoor clothing should not be brought into changing rooms leading to grade B and C areas • For every worker in a grade A/B area, clean sterile (sterilised or adequately sanitised) protective garments should be provided at each working session. • Gloves should be regularly disinfected during operations. 43
Cleaning • Clean areas should be regularly cleaned according to a documented and approved procedure • Cleaning and disinfecting agents should be free from viable micro organisms and those used in Grade A and B areas should be sterile and spore free. • For sterile alcohol sprays and other materials brought into clean areas an in use expiry date should be defined 44
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Documentation • Completed processing records should be retained for a sufficient period to satisfy legislative requirements • In any case, records should be retained at least one year after the expiry date of the relevant finished product • Procedures and preparation instructions (including prescriptions) should be retained for at least five years after their use
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Aseptic Processing Key elements of the process • Maintaining the integrity of the aseptic processing area, and care of the workstation and its environment • Handling and preparation of starting materials, especially any disinfection processes • Entry of materials into the processing area • Standard aseptic processing techniques, including not-touching critical surfaces, correct positioning of materials within the laminar air flow, and use of specific pieces of equipment and regular sanitization 46 of gloves
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Aseptic Processing Key elements of the process • Segregation and flow of materials to ensure no accidental cross contamination or mix up of prescriptions or products • Removal of product and waste materials from the processing area. • All aseptic processing should be carried out by competent staff who are authorized to perform their work by the Responsible Person. • The number of people present in the room should be kept to a minimum 47
Aseptic Processing Key elements of the process • Only sterile materials should be taken into grade A or B areas e.g. settle plates, swabs, and cleaning materials. – Product solutions that are non sterile should be filtered through a sterile filter of nominal pore size of 0.22 micron (or less) before being taken into Grade A or B areas – When this is not possible, adequate decontamination measures should be taken
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Aseptic Processing • Process validation of aseptic procedures should be performed by using broth or a similar nutrient media to simulate the aseptic procedure (media fills) and should be performed initially as well as subsequently on a regular basis, … • The transfer of materials into the Grade A workstation is usually done by disinfection or sanitisation rather than sterilisation
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Quality control • If starting materials are themselves licensed medicinal products then it is not usually necessary to test these before use • If a product is prepared for a single patient, it is assumed that no end product testing will be required • The Responsible Person should ensure that the testing laboratory has a comprehensive knowledge of microbiology and that quality assurance systems are regularly reviewed. Off-site testing facilities should be regularly audited. 50
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Monitoring • The extent to which monitoring is performed should be defined and based upon a risk assessment • Potential circumstances which may justify a reduced monitoring frequency (i.e. less often than recommended in this section) include: – – – –
Use of closed systems during preparation Immediate use of prepared products Terminal sterilisation of products Decrease of workload (less operational activities to be observed) 51
Classification ‘at rest’ Recommended frequencies for classification tests • Laminar flow cabinets (LFCs) / Biohazard Safety Cabinets (BSCs) Particle counts
Yearly
Room air changes per hour
Yearly
Air velocities on workstations
Yearly
HEPA filter integrity checks
Yearly 52
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Classification ‘at rest’ Recommended frequencies for classification tests • Isolators Isolator alarm functional tests
Yearly
Isolator leak test
Yearly
HEPA filter integrity checks
Yearly
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Environmental monitoring ‘in operation' Recommended frequencies of physical monitoring • Laminar flow cabinets (LFCs) / Biohazard Safety Cabinets (BSCs) Pressure differentials between rooms
Before beginning of work, usually daily
Pressure differentials across HEPA filters (workstation)
Before beginning of work, usually daily
Particle counts
Quarterly in the operational state 54
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Environmental monitoring ‘in operation' Recommended frequencies of physical monitoring • Isolators Pressure differentials across HEPA filters
Before beginning of work, usually daily
Isolator glove integrity
Visual checks every session
Isolator pressure hold test (with gloves attached)
Weekly
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Environmental monitoring ‘in operation' Recommended frequencies of microbiological monitoring Direct working environment (Grade A)
Background environment
Settle plates
Every working session
Weekly
Glove finger dabs
At the end of each working session
At the end of each working session
Surface samples (swabs or contact plates)
Weekly
Monthly
Active air samples
Quarterly
Quarterly 56
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Toekomstige ziekenhuisfarmacie
Investeringen Samenwerking Documentatie Apparatuur en omgeving Activiteiten Opleiding
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