11_Cleaning Validation the Toxicological Approach_Lorcan Allen

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Contamination Control in

Multi Product Facilities • Cleaning Validation ‐ The Toxicological Approach

Dr Lorcan Allen

Pre-clinical assessor

Irish Medicines Board

Member of Safety Working Party at EMA

14th October 2010



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Objectives

1) Current and Future Role of Toxicology in Cleaning

Validation2) Derivation of Toxicological Reference Values

3) Application of relevant data and issues forharmonisation

4) Going Forward

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1. Current and Future Role of Toxicology inCleaning Validation

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Principles of Pharmacology and Toxicology

“Poison is in everything, and no thing is

without poison. The dosage makes it either

a poison or a remedy” Paracelsus 1493-

1541

No Effect TherapeuticEffect

Toxic Effect



Schematic of Cleaning Validation Process:

Determine the most appropriate cleaning procedure for the equipment:

1. Generate acceptance criteria data for the contaminant.

2. The cleaning method will be determined by the process, the equipment, the

cleaning agents and the cleaning techniques available.

3. All aspects of the cleaning procedure should be clearly defined in SOP’s be theymanual / CIP or COP

Develop and validate the sampling and chosen analytical methods for the

compound(s) being cleaned.1. Swab

2. 2. Rinse

(determine % recovery, limit of detection, limit of quantitation, accuracy of method,

reproducibility, stability over time … etc.

Evaluate equipment surfaces and determine

1. Worst case locations to sample (swab sampling)

2. Volume and type of rinse solvennt to be employed (rinse sampling)3. Equipment surface area (necessary to calculate carryover into subsequent batches)

APIC: Cleaning Validation in Active Pharamceutical Ingredient manufacturing plants



Current Situation:

Prevention of cross-contamination in production5.18 Contamination of a starting material or of a product by another material or

product must be avoided. This risk of accidental cross-contamination arises from the

uncontrolled release of dust, gases, vapours, sprays or organisms from materials andproducts in process, from residues on equipment, and from operators’ clothing. The

significance of this risk varies with the type of contaminant and of product being

contaminated. Amongst the most hazardous contaminants are highly sensitising

materials, biological preparations containing living organisms, certain hormones,

cytotoxics, and other highly active materials. Products in which contamination is likelyto be most significant are those administered by injection, those given in large doses

and/or over a long time. (EU-GMP; Medicinal Products of human and vetinary use; Ch 5)

Current role of toxicologist/ safety assessor:For API’s which are considered not to be covered under these criteria “the philosophy

has been to reduce the levels of residual product in each piece of equipment, such that

no greater than 1/1000th if the normal therapeutic dose will be present per typical dose

of the next product to be run in the equipment.”



Revision of Chapters 3 and 5 of the GMP Guide:

"Dedicated facilities"

No Change

“GMP/GDP Inspectors Working Group has agreed that the use of

dedicated facilities should normally be required when beta-lactam

antibiotics are produced. In addition dedicated facilities should be used when live pathogenic organisms are handled .” (EMA/INS/GMP/809387/2009)

Going Forward?“for other products, manufacturers introducing a product into

shared facilities should carry out an assessment of all relevant product and

process characteristics to evaluate whether it is suitable for production in

shared facilities. This assessment should include input from a toxicologist.

Where the product has known sensitizing potential, or is highly potent or

toxic, the Supervisory Authority should be consulted to discuss the

manufacturer’s risk management measures.” (EMA/INS/GMP/809387/2009)



ISPE Risk-MaPP “ Pharmacological and toxicological descriptions (dose-

response, no-observed-adverse-effect level (NOAEL) and ADI) should be

used to assess compounds instead of hazard labels. Terms such as potent,

cytotoxic, cytostatic, and other product class definitions tend to induce anemotional response that might imply that these compounds are always

difficult to handle and require the highest level of control” ISPE baseline

guide Risk-MaPP

Future role of toxicologist in Cleaning Validation

Lowest marketed dose X Batch Size

1,000 Maximum

Daily Dose

Maximum

allowable carryover

=

Batch Size

Maximum

Daily Dose

Safe threshold value=ADI X

Improved

ScientificApproach



2 - Toxicological reference values



“Pharmacological and toxicological descriptions (dose-

response, no-observed-adverse-effect level (NOAEL) andADI) should be used to assess compounds instead of hazardlabels. Terms such as potent, cytotoxic, cytostatic, and other

product class definitions tend to induce an emotionalresponse that might imply that these compounds are alwaysdifficult to handle and require the highest level of control”

ISPE baseline guide Risk-MaPP

Scientific Approach



Concerns are related to :

– Highly sensitizing materials (e.g. penicillins)

– Biological preparations (e.g. from live micro-organisms)

– Non-medicinal products, including pesticides, herbicides

– Some antibiotics

– Some hormones

– Some cytotoxics

– Some genotoxicants

– Some highly active drugs

– Sensitizers ?

Define anAcceptable

Daily

IntakeI?

Application of the Toxicological Approach?



Acceptable Daily Intake (ADI) : Daily dose of a substance below which no

adverse effects are anticipated in the human. Used when there is a

threshold in the dose response curve: Derived based on animal or human

data.

ADI

Safety factors

animal

NOAEL

human, heterogeneous population

Dose level

Occurrence of toxic effect

in the population

Defining and Acceptable Daily Intake



Example: PDE calculation (ICH Q3C)

PDE = NOAEL x weight adjustement / F1 x F2 x F3 x F4 x F5

z F1: Interspecies extrapolation, takes into account surface area. From 1 to 12.

z F2: Interindividual variability. Equal to 10.

z F3: Relevance of the duration of the animal study. From 1 to 10.

z F4: Severity of the effect. From 1 to 10.

z

F5: Quality of the data. From 1 to 10.z Additional modifying factor for additional uncertainties (e.g. enzyme

immaturity in children). Equal to 10.

Thus, minimal safety factor could be 10, maximal could be 120,000 or 1,200,000

Î The choice of the safety factors depends on the professional judgment of thetoxicologist: there is a need for consensus

Format of Toxicological Tool to Define an ADI



• Hormones :

¾ Safety threshold could be derived from pharmacological data

• Cytotoxic compounds: with a threshold-related mechanism of toxicity:

¾ Safety threshold could be derived from NOAELs

• Genotoxic Compounds: no threshold related mechanism

¾ Application of the Threshold of Toxicological Concern (TTC) as outlined

in the Guideline on the Limits of Genotoxic Impurities(EMEA/CHMP/QWP/251344/2006)

Deriving Safe Levels for Different Classes



Avoidable versus Unavoidable:

Availability of data and benefit risk

Zero risk is not scientifically achievable. As stated in the Report to the FDA

commissioner from the Task Force on Risk Management, May 1999

« although medicinal products are required to be safe, safety does not

mean zero risk. A safe product is one that has reasonable risks, given the

magnitude of the benefits expected and the alternative available. » As

such, quantified risk must be balanced against unmet medical needs »

Reference by: ISPE baseline guide Risk-MaPP draft Sept 2007

Impurity vs Contaminant



Genotoxicity – Based on the analysis of data from 343 carcinogens

– TTC of 0,15 µg/day in food (excess cancer risk of <1 in 1,000,000

over a lifetime)

– 1,5 µg/day for drugs because of an awaited benefit (excess cancer

risk of <1 in 100,000 over a lifetime) – Exceptions: aflatoxin-like-, Nnitroso-,and azoxy-compounds

Threshold of Toxicological Concern

Impurities, solvents, degradants: Reduced but Unavoidable

Contaminant API:

•Potentially avoidable (Dedicated facility),

•No related benefit



Compound C / Allergenic

Compound A /

embryo-fœtal development

Case by case evaluation

Compound B / genotoxicity

Threshold of toxicological

concern

TTC (all compounds) / genotoxicity

TTC (all compounds) / allergy

TTC (all compounds) /

embryo-fœtal development

No accepted regulatory value today

Threshold of Toxicological Concern



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•Sensitizer

1. Are there have non sensitizing dose levels ? Non

elicitating dose level ?

2. How many compounds are raising concerns about theirsensitizing potential ? Could be categorize taken into

account the severity, the magnitude of exposure ?

Sensitizers: Safe Level?



3. Application of relevant data

Issues for harmonisation



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Derivation of the ADI:

Animal Data:•Derived during drug development

•Published literature

•Toxicological Databases

Human Data:•Clinical Trials

•Published literature studies•Registries



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Issues regarding submitted data: Disharmony

Animal Data•Not all endpoints covered during development

¾(long-term, juvenile, developmental, alternative route)

•NOAEL not identified or disagreement•LOAEL identified: Application of Safety factors??

•Quality of the studies/ GLP?

•All appropriate data submitted? Search criteria/ databases utilised

Human Data:•Small well controlled populations: Real population effect?

•Reporting of adverse events•Some toxicological endpoints are not addressed

¾Reproductive toxicology (1st gen 2nd generation effects)

¾Carcinogenicity endpoints?

UNABLE TO DEFINE AN ADI



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4. Going Forward



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Going Forward:

Toxicological Approach:¾Scientific approach: Toxicological reference values: potential to be

used on case by case basis,

¾A general basis using class thresholds of toxicological concerns?Implementation of this use would generate toxicological

discussions/debates.

¾Case by case: transparent decisions all member states

Issues to be addressed:¾Consistent harmonised approach

¾Inspectors and toxicologists: Agency resources

¾Reassessment? Company or inspector involvement

¾For allergenic substances, no MED (minimal eliciting dose) are

available today

¾Following a contamination, neither the indication nor the population

are likely the same. There is no benefit awaited from a contaminant.



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Thank you for your attention

11_Cleaning Validation the Toxicological Approach_Lorcan Allen

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