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7/30/2019 11_Cleaning Validation the Toxicological Approach_Lorcan Allen
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Dat e 1 3 Oct o ber
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Sl ide 1
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
7/30/2019 11_Cleaning Validation the Toxicological Approach_Lorcan Allen
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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
Dat e 1 4 Oct o ber
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1. Current and Future Role of Toxicology inCleaning Validation
Dat e 1 4 Oct o ber
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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
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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
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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.”
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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)
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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
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2 - Toxicological reference values
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“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
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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?
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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
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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
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• 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
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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
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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
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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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Sl id e 18
•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?
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3. Application of relevant data
Issues for harmonisation
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Sl id e 20
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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Sl id e 22
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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Sl id e 24
Thank you for your attention