Determining Acceptance Criteria · 2019. 4. 6. · Risk Based Approach Risk ranking for specific...

Cleaning Validation August 2015 1

CLEANING VALIDATIONSelecting Residue & Determining Acceptance Criteria

FITHRUL FARMASIINDUSTRI.COM

FARMASIINDUSTRI.COM


What Residue?

Potential residues for consideration include:– API (drug substance)– Excipients / Colorants / Dyes / Fragrances / Flavors– Preservatives– Degradants / Impurities– Starting materials / Processing Aids– Mother Liquors / Solvents– Lubricants– Bioburden– Mycoplasma / Prions / Viral Particles– Endotoxin– Particulate


FARMASIINDUSTRI.COM

Next

• Amount of soils on surface• Nature of soils on surfaces

– Freshly deposited– Dried on during process– Dried on during dirty hold time– Baked on during process– Compacted



Understanding Soils

• Which materials represent the greatest risk to the next process

• Is there justification to look for one residue as a “worst case” when compared to other selected residues?– Cleanability– Toxicity– Solubility, dalam air?– Stability



FARMASIINDUSTRI.COM

My Facility is Multi-Product Multi-line?

• The process is still works the same. – Analyse your facility and – Simplify if possible to promote understanding

• E.g. using Grouping or bracketing as appropriate)– Decide how much work needs to be done– Carry out the identified work

Cleaning Validation August 2015 Session 3 Slide 5


Soils CategorizationExample :Ø Group 1 Soils: contains target carryover such as; proteins,

nucleic acids, peptides or other active ingredients.Ø Group 2 Soils: non-specific soils that contain components

derived from in-process activities (e.g., inorganic salts, excipients, binders, etc.).

Ø Group 3 Soils: non-specific soils containing small molecule organic compounds and/or inorganic salts used in reagent solutions, inactivation solutions and buffers

The “Worst Case” soil should be selected from each product grouping based on the difficulty to clean and the risk that carryover would present to a subsequently manufactured product as appropriate.



Risk Based Approach


Parameter Risk Level0 1 2 3 4 5

Product difficulty to clean - lab study or subjective/experience

Very easy to clean - water

effective

Easy to clean and high mobile in

liquid state

Moderately easy to clean-

some viscosity issues

Moderately hard to clean - viscous or gelatinous

residue

Difficult to clean - oily

substance or exipient

Very difficult to clean such as detanured

protein, carbopol, titanium dioxide

Risk ranking non specific soilsThe “Worst Case” non-specific soils out of groups 2 and 3 areselected on sole criterion of “most difficult to clean”

Table for risk scoring :


Risk Based ApproachRisk ranking for specific soils

• The “Worst Case” soil out of Group 1 – the target active is ranked based upon difficulty to clean, solubility and toxicity of the target compound.

• The cleaning agent can be included in this group based upon rinsability and toxicity or it can be done separately

• The soil with the highest cumulative score based upon difficulty to clean and toxicity is selected as the “Worst Case” for cleaning validation

• If there is an equal cumulative score toxicity can be used as the tie-breaker to identify the “Worst Case”.



Risk Based Approach

Parameter Risk Level0 1 2 3 4 5

Product difficulty to clean - lab study or subjective/experience

Very easy to clean - water

effective

Easy to clean and high mobile

in liquid state

Moderately easy to clean-some viscosity

issues

Moderately hard to clean -viscous or gelatinous

residue

Difficult to clean - oily substance

or exipient

Very difficult to clean such as

detanured protein,

carbopol, titanium dioxide

Toxicity - LD50(oral rat) > 2500 mg/kg

>2500 mg/kg and <1250

mg/kg

>1250 mg/kg and <500 mg/kg

>500 mg/kg and <250 mg/kg

>250 mg/kg and <25 mg/kg > 25 mg/kg

Solubility -g/100 ml of water

Very soluble -100% in water

Freely soluble -99.9% in water

Soluble -99% in water

Slightly soluble - >10% but <90%

Very slightly soluble - <10% in water

Practically insoluble <0.01% in water


Risk Ranking Specific Soils


How Do We Choose?

• There has to be a risk assessment specific for your products– Identify which materials represent the greatest risk to

contamination of the next process• High potency / high toxicity / allergenic• Affect the ability to perform the next process correctly• Create a condition that is unacceptable to consumer (e.g.,

muddied fragrance, off-color, off-texture)• Hardest to clean / remove



How Do We Choose?

• If there is a justification to use one residue as a “representative” or “worst case” then – Establish limits for the chosen materials

based on some or all of the following criteria:• Pharmacologic / toxic properties• Percent carryover (< 10ppm)• Product specific issues (e.g., microbiological

contamination of aseptic products)



Factors which could be used for grouping / bracketing

Ø Same or worst-case high risk residues present at the same or higher concentration in the following product

Ø Similar manufacturing processesØ Equipment cleaned with same procedures / cleaning

agentsØ Equivalent or worst-case excipients / formulationsØ Most difficult to clean or equivalent difficulty in cleaning



Tips

• For Grouping – Make sure that you really test the “worst-case” or

“representative” family member• For bracketing,

– Make sure that you test the extremes of the family• Don’t forget to consider your cleaning agents!



Grouping Strategies

• Grouping– By product (soil)– By equipment train– Same cleaning process

• Reason for grouping– Simplify amount of validation work– Less analytical method validation and

recovery studies– Fewer validation runs



Residue limit selection• Lowest limit among group:

Product Active Limit (L3)A M 25 μg/cm2B N 15 μg/cm2C O 30 μg/cm2D P 10 μg/cm2

• If product A is worst case (most difficult to clean), then validate Product A at limit of 10 μg/cm2 of M.



Why Set Limits?

• It is the only way to manage the process• If we know how much of a product may end up

in the next product….• It gives us a control point to manage. • It also gives us a means to monitor the safety of

the process by building in appropriate safety factors into the calculations

• cGMP tells us we should



What’s In a Limit?Some Other Considerations

• We want to be conservative – we don’t want patients to be ingesting materials that they weren’t prescribed

• We need to recognize that some materials are more hazardous to patients than others based on their pharmacologic effects

• We need to recognize that there are aspects of our manufacturing process that change from lot to lot that need to be incorporated in our strategy …–Batch size–Equipment train

17Cleaning Validation August 2015


The Size TermEquipment Train Example

• Kontaminasi residu terkumulasi dari rangkaian mesin/peralatan ke dalamproduk berikutnya.

• Kalkulasi berdasar rangkaian peralatan termasuk saat mulai penangananmaterial sampai dengan mesin pengemasan.

• Limits are expressed as weight per unit area, therefore any unit area must live up to the established limit.



In Other Words . . .By dividing the allowable carryover by the equipment surface area, we are determining how much residue every square unit of surface area of the equipment is permitted to have.

When we interpret our results, we divide by the amount of surface area sampled in order to compare mass per unit surface area to mass per unit surface area.

This approach assumes uniform contamination, which we know is not always true, however we are conservative by picking those locations that we know are hard to clean and likely to have the highest concentration of residue.

In this approach every sample must pass the limit. It is inappropriate to average or factor the results.



Acceptance Criteria to consider• Visually clean• Cleaning capability of the method• Sample test time limit• Cleaning time limits:

– Time from Dirty to Clean– Time from Clean to Use

• Number of batches: – 3 consecutive batch often used, but is this enough?

• Allowed contaminant limit (chemical)– General limit– Maximum daily dose– Toxicity based carry over

• Allowed contaminant limit (microbiological)• Special limits (e.g. pyrogens, prions etc)



PIC/S• A visual check for cleanliness is an important part of the

acceptance criteria for cleaning validation. • It is not generally acceptable for this criterion alone to be used. • Repeated cleaning and retesting until acceptable residue results

are obtained is not considered an acceptable approach. • Limits for the carryover of product residues should be based on a

toxicological evaluation. • The justification for the selected limits should be documented in a

risk assessment which includes all the supporting references. • Limits should be established for the removal of any cleaning

agents used.• Acceptance criteria should consider the potential cumulative

effect of multiple items of equipment in the process equipment train



Number of Batches for cleaning validation – isn’t it 3?

• Historically 3 consecutive batches has been considered sufficient – but….

• With the publishing of recent FDA guidance on Process Validation (January 2011), the general approach to validation has been questioned by regulators and in future the number of batches required will have to be justified in the overall validation lifecycle i.e.– Step 1 Cleaning Process Design (Design phase)– Step 2 Cleaning Process Qualification– Step 3 Continued Cleaning Process Verification



Cleaning Time limits

• Don’t forget to identify in your cleaning validation study certain time based limits such as– Campaign length (maximum number of batches

before cleaning is necessary)– Dirty Hold Time : Time from dirty to cleaning

(especially if the residues “harden” over time making cleaning more difficult)

– Clean Hold Time : Time between cleaning and use (especially if there could be an extended time period before the equipment is used again)



Setting Limits

• To calculate limits we consider the following elements– The pharmacology of the current product (toxicity,

dose, allergencicity etc)– The batch size of the next product (expressed in

relevant units – eg kg, doses)– A measure of the shared equipment (usually surface

area)– The dosage regime of the next product– The safety factor we wish to use



Quantitating the Pharmacology

The potential for harm for any product may be expressed as any of the following:• Therapeutic Dosage• Toxicity (e.g. LD50)• No Observable Effect Level (NOEL)• Lowest Observable Effect Level (LOEL)• Allergenic levels



Dosage Regime for Next product

• What is the maximum amount of the next product that might be administered in a day

• May include attributes such as:– The size of the dose (mg) and generally reflects the

total dose weight (including excipients)– The number of doses or– Term of the administration (to incorporate aspects of

cumulative effect)



Safety Factors

• The use of a Safety Factor may compensate for the number of non-conservative assumptions made in the calculation of the of the limit

• In a single facility, several different safety factors may be appropriate depending on such things as– Therapeutic category– Relative toxicity– Route of administration / dosage form– Potential use and misuse of product



Safety Factors

• Examples of common usage– Topical products = 10 - 100– Oral dosage products = 100 - 1000– Parenteral / ophthalmic products = 1000 -

10,000– Investigational products = 10,000 - 100,000



Types of Limits for Chemical Residue

Cleaning Validation August 2015

• Visually clean• Therapeutical dosage :

Ø No more than 0.1% of normal therapeutic dose of any product will appear in the maximum daily dose of the following product

• 10 ppm CriteriaØ No more than 10 ppm of any product will appear in the

next product• For certain allergenic ingredients, penicillins,

cephalosporins, potent steroids and cytotoxics, the limit should be < LOD by best Analytical Methods ---àdedicated plants.

29


Visually Clean• There is no avoiding

that equipment must be visually clean before any further testing can be performed

• Can be very sensitive but needs verification

– Use between same product batches of same formulation

– Illuminate surface– Spiking studies– Can detect 4ug/cm2


1FDA : Guide to Inspections Validation of Cleaning Process


Visually Clean

• Baseline cleanliness conditions should be documented, especially for legacy equipment

• Visual threshold can be quantified and should be, if used as a primary indicator – be careful of inspection technique equivalency if conducting quantification

• May be appropriate for dedicated equipment or noncritical limits (non-toxic or non-product contact surfaces)

• Remember that this approach is not safety related unless specifically compared to a safety based limit.



Example Calculations

Setting limits: “10ppm”• Historical• In some poisons regulations• Pharmacopoeias limit test• Assumes residue to be harmful as heavy metal• Could be used for materials for which there is no

available toxicological data• Not for pharmacologically potent material

mgkg


Limit 10 ppm (mg) = 10 x BS (kg)


Example CalculationsLimit 0,1% :• Pharmaceuticals often considered to be nonactive at 0.1 of their normal

dosage• A safety factor• The CV program must be robust, i.e. acceptable for some time in ever

tightening standardD (mg/day) x BS (kg) x 106

I (mg/day) x FS

where– D is lowest therapeutic dose of the product to be cleaned– BS is the batch size of the following product– I is the maximum daily dose of the following product– Fs is the safety factor (in this case 1000)


Limit 0.1% (mg) =


Example Calculations

Toxicological Limit :• Therapeutic dose is not available

ADE (mg/day) x BS (kg) x 106

I (mg/day)where

– ADE is the Acceptable Daily Exposure of the product to be cleaned. ADE can be calculated from the NOEL, which in turn can be calculated from LD50 data.

– BS is the batch size of the following product– I is the maximum daily dose of the following product

NAOEL x BW

UFc x MF x PK


Limit Tox (mg) =Limit Tox (mg) =

ADE (mg) =


Limit to use

• Limit = MACo = Maximum Allowable Carry Over• After the calculations, it is usual to identify the

smallest result as the control point to use. It is then easier to convert to a surface area based calculation or sample based calculation depending on the study design.



Example Calculations ISPE Risk-MaPP• To convert to area :

TA x RFSSA

Where – STV is the safe threshold value– Limit (e.g. TOX if this is the lowest) previously calculated– TA is the sample test area– RF is the recovery factor– SSA is the equipment Shared Surface Area with the next product

• Similar calculations can be carried our for rinse samples.RA x RF V X SSA

Where :– RA is the rinsed area (cm2)– V is rinse volume (L)


STV (mg/L) =

STV (mg/swab) = limit x


New Regulation• PDA Technical Report no 29 (Revised 2012)• PDA Technical Report 49



EU Guide Annex 15, 30 Maret 2015

PIC/S Guide Annex 15, 1 April 2015


New Regulation

Implemented 1 Oktober 2015.


• Limits for the carryover of product residues should be based on a toxicological evaluation*

• Justification for the limits should be documented in a risk assessment and include all supporting references.

• Limits should be established for the removal of any cleaning agents used.

• Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.


New RegulationFITHRUL FARMASIINDUSTRI.COM

EMA Guide – November 2014• Guideline on setting health based

exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities

• Based on ICH Q3C (R4) Guideline for Residual solvents

• A Permitted Daily Exposure (PDE) represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime



PDE

• Weight adjustment = 50kg• Adjustment factors (e.g. safety-, uncertainty-, assessment- or modifying

factors)• F1: Extrapolation between species (value between 2 and 12)• F2: Variability between individuals• F3: Repeat-dose toxicity studies of short duration, i.e., less than 4-weeks• F4: Applied in cases of severe toxicity (value between 1 and 10)• F5: Applied if the no effect level was not established. When only LOAEL is

available apply a factor depending on severity of the toxicity (value up to 10)



PDE• The PDE represents a substance-specific dose that is

unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.

• PDE determination involves :(i) hazard identification by reviewing all relevant data,(ii) identification of “critical effects”, (iii) determination of the no-observed-adverse-effect level

(NOAEL) of the findings that are considered to be critical effects, and

(iv) use of several adjustment factors to account for various uncertainties



Where to obtain PDE Value• From an assessment by an occupational toxicologist

and generation of a PDE evaluation report• Not common and some not yet established• Currently only a few PDE can be found in public

literature• So :

– Ask the cleaning agent company (some now have data)– Ask your supplier (e.g. for raw materials)– Ask your customers (e.g. in contract manufacturing)– In drug development, NOAEL of a new drug is assessed in

laboratory animals prior to initiation of clinical trials to establish a safe clinical starting dose in human trials



Next Calculation



Bagaimana dengankita ?



Limits for Cleaning Agents

• Cleaning agents constituents generally do not have data regarding therapeutic effect

• To determine safety for cleaning agents, it is often best to follow the approach based on toxicology (e.g. LD50)– LD50 are specific to an animal model (e.g., rat, guinea pig, etc.)

and to the route of administration (e.g., oral, topical, etc.)• The data is can be used to calculate either an

Acceptable Daily Exposure or (ADE) or a No Observed Effect Level (NOEL)

• The ADE can be used in the equations as previously described



Microbiological Considerations

• Bioburden and endotoxin are typically included in the cleaning validation program if these contaminants are required to be limited in the final product based on product specifications

• Bioburden includes bacteria, yeast and moulds that are present in water systems and the environment and can be contributed by raw materials, equipment and personnel

• Endotoxin is a lipopolysaccharide present in the cell membranes of the gram negative microorganisms; it is released when the organisms die and can cause a fever in patients when introduced to the blood stream



What lead to Microbiological Contamination?

• Bioburden is heavily dependent upon environmental conditions– Is equipment dry, covered and closed when not in

use?– Is the environment a clean manufacturing area that

limits viable and nonviable particulate levels, temperature and relative humidity to levels appropriate for the product (non-sterile vs terminal sterilisation vs aseptic) both for manufacturing and clean equipment storage?

– Do environmental conditions change based on season of the year?



What Is Used To Derive Microbiological Limits?

• Guidance for limits should be taken from:– Product specification requirements for limiting specific

categories or total levels of contamination– Historical monitoring results – (especially useful once

a trend has been established and when the product permitted levels are significantly higher than experiential levels)

Note: Not all products will require endotoxin limits



Microbiological criteria :§ Internal specifications§ Official specifications: e.g. USP <1111>, “Microbial

Examination of nonsterile Products: Acceptance criteria forPharmaceutical Preparations and Substances for PharmaceuticalUse”

48

Adminstrationroute

Total aerobic count (cfu/g or cfu/mL)

Total combined yeasts/molds count (cfu/g or cfu/mL)

Nonaqueous oral 103 102

Aqueous oral 102 10

Most topicals 102 10



Microbiological criteria :§ Environmental specifications: EU GMP, Annex – 1, “Recommended limits for microbiological monitoring of clean areas during operation”

49

Grade Contact plates (diam. 55 mm), cfu/plateA < 1B 5C 25D 50

i.e. recommended limit for microbial contamination in grade Darea is : 50/{π × (5.5/2)2}= 2.10 cfu/cm2



Example calculations for Micro

• Case history: What should be the acceptance criteria for a blender used to process a wet granulation tablet?– Approach: limit CFU/25 cm2 determined from internal surface

area of the blender, quantity of granulation processed and Microbial Limit for the product (oral solid dosage form)

• Example: The blender has internal surface area 46,000 cm2 – granulation capacity of 220 kg– Surface bioburden of 100 cfu/ 25cm2 potential to transfer <1

cfu/g to the granulation. (Note Microbial Limit for an oral solid dosage form NMT 1000 cfu/g)



Sources of contamination

Type of Contaminant

Common Causes (not exhaustive, just typical)

Bacillus species

• HVAC• Environment• Sanitizer efficacy

Gram positive bacteria

• Personnel• Gowning• Aseptic techniques

Gram negative bacteria

• Water• Environment

Mould • HVAC• Environment

Yeast • Personnel• Gowning• Aseptic Technique

It is useful to identify colonies in order to trend typical fauna and to identify potential causes for contamination



Determining Acceptance Criteria · 2019. 4. 6. · Risk Based Approach Risk ranking for specific...

Documents

Transcript of Determining Acceptance Criteria · 2019. 4. 6. · Risk Based Approach Risk ranking for specific...