Nordic ISPE 20 Apr 2016 · Nordic ISPE 20 Apr 2016. ... –Final method: Acid detergent, Alkaline detergent, water, ... •Circuits and transfer panels –Multiple paths

1/

Presented by:

Beth KroegerTechnical Services ManagerSTERIS [email protected]

Nordic ISPE20 Apr 2016

2/Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation

Agenda

• Lab Studies for Cycle Development

• Residue Selection

• Equipment considerations and design issues


Why Cleaning process is

important

• Inspectional focus: – “Typical” Regulatory Observations

“There is not sufficient documentation to determine the effectiveness of your cleaning agent used”.

“You have not established an adequate rationale, including determining whether this product is the most difficult product to clean”.

“For example, your firm does not have data to demonstrate your cleaning processes for non-dedicated manufacturing equipment and utensils are adequate”.


Is this clean??


Cycle Development:

Where to start?

• Need to know and understand: – Process flow

– Equipment

– Process soils

– Components of cleaning


Cycle Development:

Where to start?

• Meet with your team or “Customer”– Discuss process residue details

• Aqueous, oil based, suspension, solids, powders, etc

– Equipment surface MOC

– Available cleaning methodology options

– Process temperature and process details

– Decontamination step?

– Dirty hold time

– Restrictions? • Schedules, waste, limitations


Parameters and attributes

of cleaning processes

• Critical Performance Parameters (CPPs)– Process times (includes Dirty-hold)

– Turbulence or flow

– Cleaning agent concentration

– Temperature

• Critical Quality Attributes– Visual Inspection

– Analytical residue limits (HPLC or TOC)

– Microbial (Bioburden/Endotoxin)

– Conductivity/pH


Cleaning parameters

(CPPs)

• Why parameters important?– Defining cleaning system

– Modeling lab study

– Selecting worst case


• Optimize cleaning parameters using

beaker/coupon study– Soiling is expensive large scale

– May not be feasible due to availability of

equipment

– Quantitative measurement of residue removal

easier at small scale

– Matrix approach: Run multiple conditions at the

same time.

Lab-Scale cleaning study


Why Perform a Lab-Scale Study

2 Cleaner B Ambient 1% v/v

3 Cleaner C Ambient 1% v/v

4 Cleaner A Ambient 5% v/v

5 Cleaner B Ambient 5% v/v

6 Cleaner C Ambient 5% v/v

7 Cleaner A 45°C 1% v/v

8 Cleaner B 45°C 1% v/v

9 Cleaner C 45°C 1% v/v








30 min

45 min

60 min

Run Cleaner Temperature Concentration

1 Cleaner A Ambient 1% v/v

15 min


Perform a Lab-Scale

cleaning study

• Parameters: TACT

• Criteria– Visually clean

– Water Break-free

– Gravimetric Assessment• Acceptance criteria: ± 0.0001 grams

– Scale accuracy ± 0.00005 grams

• Coupon blank weight, amount of residue spiked on

coupons.

• Amount of residue remaining after cleaning assessment


Perform a Lab-Scale cleaning

study

• Water break test method

– ASTM: A380: Standard

Practice for Cleaning,

Descaling and Passivation…

– Test for the presence of

hydrophobic contaminants on

a cleaned surface. • Contaminated area has lower

surface tension than water

causing water to bead up at that

location

• Only for items that can be dipped

• Test is rapid and non-destructive


Where to start:

Cleaning Agent Selection

Alkaline Cleaners

• Organic acids

• Tableting excipients

• Proteins/Fermentation

residues

• Oils/Waxes/Fats

• Grease

• Polysaccharides

Acidic Cleaners

• Particulates

• Alkaline Salts:

Bicarbonates,

carbonates

• Metal Oxides

• Hard water scale


• Multiple MOC and surface finish designations

can be evaluated.

• Prep residue in manner that is representative

of expected worse case conditions in

manufacturing– Amount of residue to apply

– Exposure to heat

– DHT

Coupon Preparation


• Use experimental design to vary parameters for

optimization– Start with agitated immersion: Calibrated digital

stirplate

– Vary detergent concentration and temperature• Check cleaning progress at specific time intervals.

Performing a Lab-Scale Cleaning

Study

Concentration Temperature °C Time

1% 60 15

1% 80 15

2% 60 15

2% 80 15

1% 60 30

1% 80 30

Temperature

Concentration


Performing a Lab-Scale

Cleaning Study

• Agitated immersion – Evaluates the “chemistry” of the

cleaning conditions under low

agitation conditions

– Used to evaluate impact of the

cleaning solution, concentration

and temperature on the rate of

cleaning.

– Outcome is the optimal

conditions for removing residue


Acceptance Criteria

Soiled Coupon Visual Failure Water Break Free Failure

18/Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation 18

Advantages of Lab-Scale Cleaning Study

Fails TOC/HPLC Passes Acceptance Criteria


Advantages of Lab-Scale

Cleaning Study

• Residue build-up over time



Cleaning Study

Same coupon, different angle.

Residue visible in first angle, not

in second.


Residue visible on both angles, 15 coating and cleaning cycles.



Cleaning Study


Both coupons wet


Both coupons dry


Agenda





Residue Selection

• Potential Residues for consideration:– API (Drug substance)

– Excipients / Colorants / Dyes / Fragrances /

Flavors

– Preservatives

– Degradants / Impurities

– Starting materials / Processing aids

– Mother liquors / Solvents

– Lubricants / antifoams - silicates

– Bioburden

– Mycoplasma / Prions / Viral particles

– Endotoxin


How do we choose?

• Which materials represent the greatest risk to

the next process?– High potency; high toxicity; allergenic

– Creates condition that is unacceptable to

consumer (e.g. off-color, abnormal fragrance,

particulates)

– Hardest to clean / remove.

• Is there justification to look for one residue as

a “worst case” when compared to other

selected residues?– Cleanability

– Toxicity

– Solubility


Residue Properties as Basis

for Cleaning

• Example: Antibiotic suspension containing API

– Original cleaning method: Water, PW, dry• No documented cleaning validation for many years

• API and unknown peaks on original cleaning validation

attempts

• API insoluble

– Second method: Alkaline detergent, water, PW, dry• Unknown peaks again

• API insoluble

– Final method: Acid detergent, Alkaline detergent,

water, PW, dry• No residues or unknown peaks detected

• Unknown peaks determined to be flavors

• API dissolves


pH solubility profile, pH 1 – 12

Note of caution…..


Determination of most

difficult to clean

• Basis for cleaning program: – Water Solubility – USP Tables

• Is it adequate: NO

– Understand the effect of pH and solubility in

cleaning agent

– Determine solubility at range pH 1-12

– Understand solubility at pH of cleaning detergent


Agenda





Equipment Surface and Design

• What the regs say: – § 211.63: Appropriate design, easy to

clean

– § 211.65: Surfaces not reactive, additive

or absorptive • No defects

• Smooth surface

– § 211.67: cleaned to prevent

malfunctions or contaminations• No corrosion

• Standards and guidelines– ASME BPE (Bioprocessing Equipment)

• Discusses equipment design


Equipment Surface & Design

• Coverage

– Shadow areas

– Riboflavin Testing

• Riboflavin Procedure:

• Coat with riboflavin (0.2 g/L)

• Observe with UV light while wet

• Dry and then short rinse cycle with water

• Observe with UV light while wet

• If poor coverage, make changes and repeat until 100% coverage


Spray Devices

• Spray balls may provide adequate coverage

but not uniform impingement at all locations– Use agitated immersion, cascading flow and

impingement

– Static spray balls rely high volume, low flow

cascading cleaning action


Spray Devices

• Operating parameters– Pressure: 3 – 8 bar dynamic

– Flowrate: ASME® BPE standard targets: • Static spray device flow:

– 31 Liter per minute/meter of circumference

(lpm/m) (2.5 gpm/ft of circumference)

– Results in turbulent sheeting action for tanks with

180°up spray ball

• Lower flow rate may be used when static or dynamic

spray devices are used with 360° spray pattern

• Rotary spray device flow:

– 26 lpm/meter of circumference (2.1 gpm/ft)


Spray Devices

Calculated CIP flowrate (gpm) = π*d*desired flowrate per ft of circumference

lpm lpm


Spray Device Selection

• Spray Device Selection– Static balls vs. dynamic devices

• Impingement , time, drainability, reliability, maintenance, cost

– Throw length: • Pressure, flow rate, effective diameter

– Potential for clogging

– Potential for re-deposition


Equipment Surface and Design

• Circuits and transfer panels– Multiple paths

• Rotate for short periods multiple

times?

• Each path once for longer duration?

• Consider lab study results and how

impacted

– Consider what is transferred

and added if using induction

ports• Separate coupon study for raw

materials vs. blend?


CIP Pipe Design Criteria

• Piping sloped to drain points with proper

support to maintain alignment

• Number and length of dead legs minimized

• Dead legs oriented to be easily cleanable

• Welded joints for permanent pipes

• Sanitary joints for semi-permanent

connections

• Flush self positioning gaskets


Equipment Surface & Design

• Go to the manufacturing area and look at the

equipment, not just the P&ID…..– Look for possible problems areas BEFORE you

start.• Corners, crevices, deadlegs, valves, seals,

• Sample locations

– Consider where can contamination occur?

– Where can problems be fixed by re-engineering?

– What portions of the process can be cleaned in

place?

– Do sections need to be removed for cleaning?

COP or use of jumpers/manifolds? Cleaning and Cleaning Validation, Volume 1, by Paul Pluta; Chapter 8, “Cleaning Engineering and Equipment Design” by George Verghese and Paul Lopolito; PDA, Davis healthcare International Publishing, LLC ©2010

38/

Presented by:

Beth KroegerTechnical Services ManagerSTERIS [email protected]

Nordic ISPE20 Apr 2016

Thank you for your attention

Documents

Nordic ISPE 20 Apr 2016 · Nordic ISPE 20 Apr 2016. ... –Final method: Acid detergent, Alkaline detergent, water, ... •Circuits and transfer panels –Multiple paths