Multi-Product Facilities for High Potency Drugs

June 26, 2012

Sandra Schroeder & Andreas Flueckiger

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

A safe dose for genotoxic compounds

Scientific view – the NOGEL (No Genotoxic Effect Level)

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Bleomycin

Concentration µg/ml

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)

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)

(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

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

Multiproduct Risk Categories

• There are 4 main risk categories:

– Product Mix-ups

– Retention/Residue

– Mechanical Transfer

– Airborne Transfer

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

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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