managing risk in cleaning validation

Copyright © 2012 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation.

MANAGING RISK IN CLEANING VALIDATION

Michael Gietl Technical Service Specialist

STERIS Corporation [email protected]


Agenda

•  Regulatory background •  Risk identification

–  Residues –  Sampling –  Analytical methods –  Microbial considerations –  Limits

•  Grouping •  Risk Management Tools


Cleaning Validation Master Plan

Equipment Characterization

Equipment Train Definition

Equipment Grouping

Cleaning SOP Definition

Cleaning Agent Use Matrix

Critical Process Parameters

Product Grouping

Product Characteristics

Sampling Method Selection

Hard to Clean Locations

Residue Selection

Methods Validation

Sampling Sites

Limits Definition

Recovery Studies Worst Case

Definition

Hold Time Definition

Hard to Clean Locations

Engineering Runs

Protocol Definition, Execution, and Summary Report


Why Clean?

•  Possible Reasons –  My boss said I have to do it –  The FDA/EMEA won’t approve my product without it –  I need job security –  It might be fun (?)

•  REAL Reasons –  Reduce possibility of product contamination –  Demonstrate cleaning process is consistent –  Demonstrate cleaning process removes residues and

environmental contaminants –  Provide equipment that can be safely reused


Cleaning Validation

•  “Documented evidence that an approved cleaning procedure will consistently reduce active pharmaceutical ingredients (API), process residues, cleaning agents and microbial residues from product contact equipment surfaces to acceptable levels for the processing of drug products”

–  Reference: FDA; Guide to Inspections Validation of Cleaning Processes, 1993


Regulatory Requirements

•  Worldwide GMPs –  EU Annex 15 (Paragraph 36) (2006) & GMP Part II

(formerly Appendix 18) (2005) –  US FDA, Guide to Inspections of Validation of

Cleaning Processes (1993) –  Pharmaceutical Inspection Convention (PIC/S),

Recommendations on…Cleaning Validation (2001) –  WHO Technical Report No. 937: WHO Supplementary

Guidelines on GMP (Annex 4): Validation (2006)


RISK IDENTIFICATION


Types of Soils

•  Potential Residues for consideration: –  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


Cleaning Chemistry

•  Cleaning depends on process control… Time Action Concentration / Chemistry Temperature •  Cleaning also depends on cleaning conditions…

–  Water Quality –  Individual Performing Cleaning (esp. in manual cleaning) –  Nature of Soil –  Surface being cleaned

•  Coupon/beaker studies


Understanding Your 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

•  In water?

–  Stability


Sampling

•  Sampling locations should be selected based on: –  Hard to clean locations or complex geometries (hot

spots) –  Locations that might disproportionately contribute

residue to the next product –  Materials of construction or surface finishes with an

affinity for the soil –  The role in the process that is likely to lead to build-up

or difficult to remove soils •  Number of locations?


Sampling Methods

Parameter Swab Rinse Placebo Physical Removal Good Poor Moderate

Technique Dependent Yes No No Hard to reach locations Poor Good Good Adaptable to irregular

surfaces Moderate Good Moderate

Controlled Area Yes No No Non-Invasive No Yes Yes

Adaptable to on-line monitoring

No Yes No

Can use solvents Yes Yes No


Identify and Define Sampling Methods •  Swabs – area to be used •  Rinse – define and qualify method •  Microbial – recovery? •  Blanks and controls – handling & methodology •  Sample locations

–  ID –  Justification –  Risk rationale


Analytical Methods

•  Analytical methods are preferred to be specific to the analyte

•  Non-specific methods may be used provided that all analyte identified is attributed to the worst case residue limit

•  Analytical methods and sampling methods must be demonstrated to be suitable through methods validation in conjunction with the sampling method / extraction system and through recovery studies


Microbiological Residues

•  Bioburden and endotoxin contaminants should be considered when required to be limited in the final product

•  Important considerations –  Environmental conditions

•  Guidance for limits taken from: –  Product Specifications –  Historical data


Residue Limits

•  FDA Guide to Inspection of Cleaning Validation (7/1993) –  Rationales should be logical, practical, achievable,

and verifiable –  Sensitivity of analytical methods is critical to

establishing valid limits –  Three examples given:

•  10 ppm •  1/1000 of normal therapeutic dose •  Organoleptic levels (e.g. visually clean)


Residue Limits

•  Fourmen and Mullen approach for active: –  Most stringent of dose calculation and 10 ppm (in next

product) AND –  Visually clean

•  PIC/S Approach: –  Most stringent of…

•  Dose calculation in next product •  10 ppm in next product •  Visually clean


Residue Limits

•  Possible uses of “limit” –  Daily amount allowed (ADI or ADE) –  Concentration in next product –  Absolute amount in manufacturing vessel/train (MAC

or MACO – maximum allowable carryover) –  Amount per surface area –  Amount per swab –  Concentration in swab extract solution –  Concentration in rinse solution


Residue Limits •  Need to determine how much product we just

cleaned will be administered to each patient taking the next product –  How much will that represent in the next batch? –  How much will that represent on the surface? –  Need the residual amount to be “safe”, add safety

factor –  Need to recognize variability in manufacturing

process that may change from lot to lot and incorporate into the strategy


The Three Types of Limits

•  Limits associated with the nature of the substance being cleaned (pharmacological properties)

•  Limits associated with the percentage of contamination (10 ppm, for example)

•  Limits associated with the process by which the material is manufactured, cleaned, or analyzed (e.g. visibly clean)


Calculating Residue Limits

•  Limit in subsequent product (L1)

•  Safety factor (in this case) is 1,000

000,11

BProduct of DoseDaily MaximumAProduct in Active of DoseDaily MinimumL1 ×=


Minimum Daily Dose of Active in Product A •  How much of the product we just cleaned

(Product A) –  May be expressed as one of the following:

•  Toxicity or LD50 (with appropriate safety factor) •  Therapeutic Dosage •  Allergenic Level •  Minimum pharmacological effect level •  NOEL (No Observable Effect Level)

–  Most Conservative Approach


Maximum Daily Dose of Product B •  Amount that will be administered to each patient

taking the next product (Product B) –  The amount of the next product that may be

administered –  Always most conservative to over-estimate this term


Safety Factor Term

•  We want the amount of residual soil to be “safe”, therefore may add a safety factor –  Safety factor is any convenient number, usually a

factor of 10 (e.g. 100, 1000, 10000) –  Safety factor is optional in some cases (not optional

when using terms such as LD50) –  The greater the safety factor, the larger the reduction

in the limit


Safety Factor Term (Continued) •  One option is to apply safety factors uniformly

within a plant –  Topical Products: 10 to 100* –  Oral Dosage Products: 100 to 1000* –  Parenteral/Opthalmic Products: 1,000 to 10,000 –  Research/Investigational Products: 10,000 to 100,000 *Note: Significant rationale must be given if safety factor

is less than the industry-standard 1,000

(Hall, W.A. 1997. Cleaning for bulk pharmaceuticals chemicals. In Validation of bulk pharmaceutical chemicals)



•  Limit per Surface Area (L2)

•  In this case, 1,000 is a conversion factor to account for ppm and to convert kg to µg

area surfaceequipment shared,000)product)(1 subsequent of size (L1)(BatchL2 =


Batch Term

•  How much of the soil will be present in the next batch? –  May be expressed as batch size (L or kg) or in the

number of doses (1,000,000 tablets for example) –  Most conservative to work with smallest possible

batch size (worst case)


Surface Area Term

•  How much of the soil may remain on the surface? –  Size of the equipment –  May represent full shared or maximum surface area

of an equipment train –  Conservative approach is to over-estimate surface

area of shared equipment



•  Limit in the analyzed sample

•  Recovery factor from swab recovery studies may be employed here, or apply to analytical result

solvent desorptionamount area) surface ed(L2)(swabbL3=


Limits for Cleaning Agents

•  No therapeutic index for cleaning agents •  Commonly, only information available is LD50

•  LD50 specific to animal model (e.g. rat) and route of administration (e.g. oral, IV)

•  First calculate either Acceptable Daily Intake (ADI) or No Observed Effect Level (NOEL):

ADI = LD50 (mg/kg)× body weight x 1/Safety Factor

NOEL = LD50 (mg/kg)×(5.6×10-4) x 60 kg1

1 Doursman and Stara, J. Regulatory Toxicology and Pharmacology, 3, 224-238, 1983


Other Considerations

•  Route of administration –  Topical, oral, parenteral, etc.

•  Type of patient likely to receive product –  Adult vs. Child

•  Position / role of equipment in process –  Conservative strategies moves one toward a purer

product as the product is processed to a finished dosage (e.g. UF/DF skids, fillers)


Visually Clean

•  Visually clean can be sole acceptance criteria provided: –  All critical surfaces (especially those most difficult to

clean) can be visually examined –  The lowest level of surface residue of the target

residue which is consistently judged dirty has been established and documented

–  The surface acceptance criterion (in µg/cm2) of the target residue has been calculated, and is above the level of surface residue at which a surface is judged visually dirty (visual limit)


Visually Clean

•  Generally not enough to compare calculated limit to level typically referenced (~4 µg/cm2) –  Level should be determined experimentally

•  Requires consideration of: –  Distance of observer from surface –  Level of lighting –  Angle of lighting


Things to Avoid in Setting Limits •  Limits based on analytical assay

–  LOQ (maybe?) –  LOD (never!)

•  Limits based on compendial water specs •  Limit unrelated to target residue •  Limits selected arbitrarily •  No documentation of rationale or risk ranking for

how selected


Clean Hold Time (CHT) and Dirty Hold Time (DHT) •  Clean Hold Time

–  Following cleaning, how long equipment remains “clean” before reuse.

–  Not concerned with process residue; focus is on controlled storage (bioburden proliferation)

•  Dirty Hold Time –  How long “dirty” equipment can remain dirty prior to

cleaning –  Generally, longer DHT à increasingly difficult to clean –  Be aware of potential changes in active/excipient

physicial or chemical properties


RISK ASSESSMENT


Product Grouping (Matrixing)

•  Develop overall approach to cleaning validation for current products and provide framework for future development of cleaning program –  Potency: potency of products based on normal daily

dose of products •  Example: Normal Daily Dose Potency Factor

< 5mg 5 5 – 199 mg 4

200 – 400 mg 3 400 – 600 mg 2 600 – 800 mg 1


Product Grouping (2)

•  Toxicity: Generally reflects rank of groups in terms of potency. –  Example:

Product Grouping Toxicity Factor Prescription Products 3

OTC Products 2 Dietary supplements 1


Product Grouping (3) •  Solubility: Solubility of active in water/solvent/

cleaning agent being used to clean equipment •  Example:

Solubility (From USP) Solubility Factor Very Soluble 1

Freely Soluble 2 Soluble 3

Sparingly Soluble 4 Slightly Soluble 5

V. Slightly Soluble 6 Practically Insoluble 7


Product Grouping (4)

•  Cleanability: Represents situation where product may be difficult to clean or high risk to clean because of issues due to the nature of product (other than potency, toxicity, and solubility)

•  Examples: Coated tablets, extended release products, etc.


Product Grouping Cleanability Factor Description Example

1 Easiest to clean Very soluble tablets; product does not stick to

surfaces

2 Average cleaning time/effort

Uncoated tablets, capsules

3 More difficult to clean Coated tablets

4 Very difficult to clean Insoluble actives in ointments/creams

5 Most difficult to clean Dyes that stain equipment, strong odors


Example (Dietary Supplements)

Oral Dosage Form Solubility (ac5ve) Potency -‐ RDA

(mg) Toxicity

Oral LD50 (mg/kg)

Cleanability in Alkaline Detergent

Total RPN (S×P×T×C)

Calcium 7 Prac5cally insoluble 1 800-‐1200 1 6450 2 14

Chromium 4 Not specified 5 0.050-‐0.2

00 2 100-‐400 2 80

Iron 3 Soluble 4 10-‐15 2 319 4 96

Magnesium 5 Slightly soluble 3 270-‐400 1 TD Lo 4722 2 30

Potassium 3 soluble 3 Not

specified 1 7200 2 18

Selenium 7 Insoluble 5 0.200 3 4.8 -‐7.0 2 210

Zinc 3 Soluble 4 10-‐15 1 5000 2 24


Equipment Grouping •  Similar equipment design

–  Materials of construction –  Equivalent geometries/design risks –  Equivalent “hot spots” and critical sites (sampling

sites) •  Similar manufacturing process

–  Role/position in process –  Campaign length/dirty hold time

•  Identical cleaning process –  Cleaning agent –  TACT –  Frequency of cleaning


EXAMPLE: DETERMINING WORST-CASE LOCATIONS IN FERMENTOR


2 Spray balls 1 baffle

Instrument ports (pH, DO, etc)


1.  Coverage testing (riboflavin testing)

2.  Instrument/sample port(s)

3.  Air-liquid interface 4.  Representative

surface


References & Additional Reading •  Fourman, G.L. and Mullen, M.V., “Determining Cleaning Validation Limits for

Pharmaceutical Manufacturing Operations,” Pharmaceutical Technology 17(4), 54-60 (1993).

•  FDA, 1993, Guide to inspections of validation of cleaning processes. Rockville, MD, USA: Food and Drug Administration, Office of Regulatory Affairs.

•  Forsyth, R., O’Neill, J.C. and Hartman J.L. (2007) Materials of construction based on recovery data for cleaning validation. Pharmaceutical Technology, Oct., pp. 103–116.

•  LeBlanc, D.A. (2000) Validated Cleaning Technologies for Pharmaceutical Manufacturing. USA: Interpharm Press.

•  Verghese, G. and Lopolito, P. (2007) Process Analytical Technology and Cleaning. Contamination Control, Fall 2007, pp. 22–26.

•  LeBlanc, Destin A. et al., Cleaning Technology for Pharmaceutical Manufacturing Pharmaceutical Technology 17:7, 84-92 (1993).

•  Points to Consider for Cleaning Validation. PDA Technical Report No. 29. PDA. Bethesda, MD.March 30, 1998.

•  Forsyth, RJ. et al., Correlation of Visible-Residue Limits with Swab Results for leaning Validation. Pharmaceutical Technology 30 (11), 90-100 (2006).


References & Additional Reading (2) •  LeBlanc, Destin A., Issues in Setting Limits for Actives in Bulk Biotech Manufacture.

Journal of Validation Technology 15 (1), 71-76 (2009). •  Pluta, P (editor). Cleaning and Cleaning Validation Volume I. PDA Books (2009).

ISBN 1933722371. •  Troy, F., Hold Time Studies: A Lost Parameter for Cleaning Validation. Journal of

Validation Technology 13 (3) 206-209 (2007). •  Rathore, N. et al., Bench-Scale Characterization of Cleaning Process Design Space

for Biopharmaceuticals. BioPharm International 22 (3), 32-44 (2009). •  Kendrick, K. et al., Analysis of Degradation Properties of Biopharmaceutical Active

Ingredients as Caused by Various Process Cleaning Agents and Temperature. Journal of Validation Technology 15 (3), 69-77 (2009).

•  *Note: This is not a complete listing, just a guidance to literature the speaker has found to be interesting/beneficial.


Questions?

THANK YOU!

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