multi-product facilities for high potency drugs june 26 ... · multi-product facilities for high...
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Multi-Product Facilities for High Potency Drugs
June 26, 2012
Sandra Schroeder & Andreas Flueckiger
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Multi-product facilities for potent compounds?
Background
Regulators have different views as to the level of controls
needed to manufacture certain highly potent compounds in
multi-product facilities.
Some regulatory agencies allow the production of highly potent
compounds by campaign, provided adequate segregation and
suitably validated cleaning procedures are present, others do
not. They require facility dedication.
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Health authorities’ view of cytotoxics, antibiotics,
high potency drugs and hormones
• ICH Q9 allows and asks for risk assessments.
• But: Risk assessments can be complex, sometimes poorly
presented and difficult for an inspector to assess.
Facility dedication is easier to verify than the quality of a risk
assessment.
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Rationales for dedication
Facility dedication traditionally for betalactams
Reason: «No safe level can be defined».
Additional products? [Certain] cytotoxics, anti-cancer drugs,
cytostatics, antibiotics, high potency drugs, hormones…
Two possible reasons: «No safe level can be defined»
(science) and/or
«Impossible to clean down to the required levels» (feasibility)
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Risk-assessment according to ICH Q9
for multi-product facilities
• Based on
a) scientific definition of a safe carry-over dose for each
compound (ADE*)
and
b) proof that ADEs can be consistently respected, i.e. every time
cleaning is performed.
• This is Roche’s approach
* ADE = Acceptable Daily Exposure
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Dedication requirement for ‘cytotoxics’:
a long discussion
• Potent sensitisers -> betalactams ->
No safe dose can be defined for an already sensitised person
«One molecule can kill a patient»
No safe cleaning standards can be defined. Obsolescent
paradigm!
• Are there other substance groups where no safe dose can be
defined?
Maybe ‘certain antibiotics’, ‘certain hormones’, ‘cytotoxics’?
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Dedication requirement for ‘cytotoxics’:
a long discussion
‘Cytotoxics’ = toxic to cells.
Everything is cytotoxic. Cytotoxicity is only a question of dose!
‘Cytotoxic’ = ‘mutagenic’ / ‘genotoxic’?
Non-threshold theory:
“The first molecule of a mutagen can induce a mutation/cancer”
“One molecule can kill a patient”
“No safe cleaning standards can be defined”
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A safe dose for genotoxic substances:
Regulatory approaches
If no data exist on a genotoxic substance, the maximum
acceptable daily lifetime exposure is 1.5 mcgr/d
This will lead to <1 additional cancer case in 100,000 persons.
It will at most increase the cancer risk of a person
from 25% to 25.001%
Based on the assumption of no absolutely safe level.
do
se
Mutations/cancer risk
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A safe dose for genotoxic compounds
Scientific view – the NOGEL (No Genotoxic Effect Level)
10
Bleomycin
Concentration µg/ml
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Does your potent compound facility look like this?
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Or does it look like this?
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WHO Draft Guideline to the Inspection of Hormone
Product Manufacturing Facilities; 2008
3.4 Hormone facilities should be separate, dedicated facilities and
should not form part of any other non-hormone facility….
Chapter 5 «Product protection»: 3 lines of text
On «Personnel … and environmental protection»: 2 pages of text
•6.2.2 A self-contained breathing apparatus (SCBA) or powered air
purifying respirator (PAPR) that is secured to the operator’s belt and
connects to the operator’s face mask. This system draws air from the
room in which the operator is working and the air supply is delivered to
the face mask by means of a battery-driven fan. The AR provides
superior protection to the PAPR apparatus.
•6.2.3 For zones with lower contamination levels a half mask HEPA
cartridge respirator of N95-type paper filter mask may be acceptable.
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And what is the «typical» facility
that the authorities inspect?
WHO depicts high potency facilities
•that probably correspond to the reality in many companies.
•that are out of compliance with occ health standards and ILO
guidelines.
•that do not correspond to modern state of the art production
standards.
•where there is massive leakage of product out of the equipment
--> facility impossible to clean and high cross-contamination risk
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Next question….
Could those who have state of the art facilities with
•high containment to the ng level
•excellent cleaning processes
be given the opportunity to demonstrate safe multi-purpose use
even for potent compounds?
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Another question….
5 groups of betalactams -> each needs a facility of its own
Many more than 5 groups of cytotoxics
Can they all be produced in the same facility??
From a patient risk point of view: probably NO.
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Regulatory action
• 1996 FDA proposal - not only betalactams but also ‘other
agents’; ‘cytotoxic anti-cancer agents’ - withdrawn
• 2005 EMA concept paper – ‘cytotoxics’ are specifically
mentioned - pending
• 2008 WHO proposal – ‘certain hormones’ – withdrawn
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Relevant legislation in the LA region
Brazil (ANVISA)
Resolution RDC#17/2010 – Articles 5, 125 and 256
Colombia (INVIMA)
Resolution 3028 of 2008 – Articles 5, 14
Mexico (COFEPRIS)
GMP Regulation – NOM 059-SSA1 of 2006
All other LA countries
WHO GMP – Chapter 12.24 – Production Areas
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Meaning of important terms (typical US/EU interpretation based on OTR company review)
Segregated
Separated from other production trains by physical barriers, separate HVAC
systems, separate personnel access etc. Multiproduct use acceptable after
good cleaning.
Protects one product from another product that is made in the same building/on
the same site at the same time. Protects parallel processes.
Segregation without dedication is common practice.
Dedicated
Only one product can be made on the same equipment – multiproduct use is not
accepted.
Protects one product from the residues of a potential other product if this was
made on the same equipment. Protects serial processes.
Dedication without segregation is usually not meaningful.
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Meaning of important terms (Anvisa regulations wording)
Segregated
Art. 5. Para efeito desta resolução, são adotadas as
seguintes definições:
IX - área segregada: instalações que oferecem separação
completa e total de todos os aspectos de uma operação,
incluindo movimentação de pessoal e equipamentos, com
procedimentos, controles e monitoramento bem
estabelecidos. Pode incluir barreiras físicas bem como
sistemas de ar separados, mas não necessariamente
implica em prédios distintos
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Brazil (Resolução RDC N.º 17, 16 April 2010)
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Art. 125: Devem ser utilizadas instalações segregadas e dedicadas para a
produção de determinados medicamentos, tais como certas preparações
biológicas (ex. microorganismos vivos) e os materiais altamente
sensibilizantes (ex. penicilinas, cefalosporinas, carbapenêmicos e demais
derivados betalactâmicos)
Art. 125: A produção de certos produtos altamente ativos como alguns
antibioticos, certos hormônios, substâncias citotóxicas deve ser realizada
em áreas segregadas.
Art. 256:
I - produção em áreas exclusivas e fechadas (ex. as penicilinas, as
cefalosporinas, os carbapenêmicos, os demais derivados beta-lactâmicos,
os preparados biológicos com organismos vivos, determinados
hormônios, substâncias citotóxicas e outros materiais altamente
ativos)
II - produção em campanha….
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Mexico (Norma Oficial Mexicana
NOM-059-SSA1-2006)
•8.2.16 Las áreas de producción, muestreo, pesadas, envasado primario y todas aquellas donde se encuentren expuestos componentes, productos y sus servicios inherentes (particularmente los sistemas de aire) a penicilínicos, cefalosporínicos, citotóxicos, inmunodepresores, hormonales de origen biológico, hemoderivados, biológicos virales, biológicos bacterianos y otros considerados como de alto riesgo, deben ser completamente independientes y autocontenidas.
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Colombia (INVIMA) Artículo 14
•Artículo 14.- La fabricación de medicamentos en sus diferentes formas farmacéuticas, con base en principios activos clasificados como sustancias tóxicas*, que determine el INVIMA, debe efectuarse en áreas independientes y equipos dedicados exclusivamente para la fabricación de estos productos, por campañas entre ellos, siempre y cuando se demuestre ausencia de trazas de alguno de estos productos, antes de comenzar una nueva fabricación, lo cual deberá ser comprobable a través de registros de producción y disponiendo de la metodología de limpieza validada para garantizar la inexistencia de contaminación cruzada entre ellos.
•betalactámicos, sustancias endocrinas de tipo sexual (…), antineoplásicos, imunosupresores, radio fármacos, biológicos, ostros definido por el Ministerio de la
Protección Social (Artículo 5)
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Conclusion on LATAM regulations
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• Based on globally accepted standards: WHO, ICH etc
• Usual dedication requirements (betalactams, live
microorganisms) everywhere
• No formal dedication requirement for other products in
most countries
BUT
• «Special» or «segregated» or «exclusive» is often
interpreted as «dedicated»
• In Colombia, the authorities can define those «toxic»
products for which they want dedication
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Conclusion on EMA/FDA regulations
• Based on globally accepted standards: WHO, ICH etc • Risk assessments accepted to demonstrate justification for
multi-product use • High standards for critical risk assessments: multi-purpose
plant use in the manufacture of potent/cytotoxic products • But: EMA views are not harmonised
• Different inspectors from different countries – room for interpretation («certain» cytotoxic etc products, «exceptional circumstances»)
• Harmonisation efforts are ongoing (e.g. working group for guidance of setting ADEs)
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(second part )
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How to manage risks in a multi-product facility
To ensure that our manufacturing sites can safely be
operated as multiproduct facilities, we defined an approach
to assess and control risks which leverages ICH Q9 and the
ISPE baseline guide, Risk-Based Manufacture of
Pharmaceutical Products (‘Risk MaPP’) First Edition,
September 2010).
Our approach:
1. define a scientifically sound, acceptable level of carry-
over of one product into another product.
2.describe and assess the measures necessary to ensure
that this acceptable level of carry-over is not exceeded.
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How to manage risks in a multi-product facility
Focus on process steps/sources that may give rise to cross
contamination, e.g. from a product
•produced earlier on the same equipment and/or
•produced in the same facility at the same time (on different
equipment) and/or
•introduced by other transport mechanisms (’touch-points’)
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Control strategy to prevent cross-
contamination
• Adequate design of process equipment and parts
• Air handling, ensuring appropriate air quality
• Training and gowning of personnel to prevent cross-
contamination of the product
• Design of utilities to avoid cross-contamination
• Design of facilities, ensuring adequate separation between
products
• Easy-to-clean design of production areas
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Process Improvements
• Continual improvement demands a systematic
approach to risk management.
• Control strategies shall be holistic and shall cover the
life cycle of the facility.
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Setting health-based cross-contamination and CV
limits
Acceptable Daily Exposure (ADE) values are a central
element of risk assessment.
ADEs adapted to the worker target population have been
used for decades for the purpose of setting occupational
exposure limits.
Roche ADE definition:
A dose that is unlikely to cause an adverse health event or
undesirable physiological effects if an individual is exposed
at or below this dose for the maximum expected duration of
use of the drug carrying the contaminant. If this duration
cannot be estimated reliably, lifetime use is assumed.
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ADE value safety profile
Exposure Toxicity
Overdose
Efficacy (therapeutic dose)
No-effect level
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Different Safety Profiles (Idealized Examples)
Chemical Biopharmaceutical “Classical” Drug
Exposure
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ADE Derivation from Fragmented Information
Clinical Data
Safety Profile
in Animals
Safety Profile in Humans
Data
Extrapolation
Data
Extrapolation
Data
Extrapolation
Non-Clinical
Data
Phase I
Phase II
Phase III
ADE
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Scope of Multi-product Risk Assessment
In Scope
– Manufacturing and packaging facilities
– Risks associated with product cross-contamination
– Risks associated with multi-process events (mix-ups,
wrong materials, etc)
– Dispensing operations through final packaging
(including open processing)
Out of Scope - Betalactams
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Multi-product Risk Assessment Approach
Generic Risk Assessment
(serves as 80-90%
template for all sites)
Includes all risks (failure modes) typical
to a multiproduct facility
Includes all baseline controls
Included Participation from multi-site
SMEs
Includes Severity Scoring
Site-specific Risk
Assessments
(for each site)
Add site-specific risks to the generic
risk assessment
Complete scores for occurrence and
detection based on site-specific
controls
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Multiproduct Risk Categories
• There are 4 main risk categories:
– Product Mix-ups
– Retention/Residue
– Mechanical Transfer
– Airborne Transfer
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Touch Point Analysis
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What is FMEA?
– recognizes and evaluates potential failure and its
effects
– prioritizes potential failures, from the vital few to
numerous trivial failures
– identifies actions to reduce/eliminate the chance
of failure
– documents analysis findings
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FMEA considerations
– FMEA is an early warning preventive technique
– It is subject to bias, thus needs a cross-functional team
– There are different types: Process, Equipment, System,
Design
– FMEAs must be based on robust data (self generated or
from published literature) – not only experts “feelings”
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Steps in FMEA
A Failure Mode and Effects Analysis is executed in different steps:
- Risk Identification
- Risk Analysis
- Risk Evaluation
- Risk Control
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Key Definitions
• Multiproduct Facility – Facility capable of producing 2 or more products
either concurrently or on a campaign basis
• Product cross contamination – level of product carry-over that exceed
established cleanliness limits
• Dedicated Equipment – Equipment that is allocated to (or used for) the
exclusive production of a particular API or drug product and must not
be used for production of another
• Segregated Area- Premises, including airing systems, equipment,
personnel and material displacement, that provide demonstrated level
of containment and controls to maintain safe levels of risks of
contamination /cross-contamination during drug products
manufacturing.
Source: Roche internal definition
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Summary
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Summary
• Sites use a risk assessment ‘master template’ developed in-
house to performing risk assessments on their particular
products and facilities.
• As ADE values are one of the key elements to the multi-product
facility concept, a documentation and archiving system for ADE
values has been developed.
• A Guidance document has been written to ensure harmonized
ADE value calculation across the network.
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We Innovate Healthcare
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