Managing Risk

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

SelectionHard to Clean

Locations

Residue

Selection

Methods

Validation

Sampling Sites

Limits

Definition

Recovery

StudiesWorst 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 wont 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 onCleaning 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


Cleaning Chemistry

Laboratory experiments and engineering studies will help to establish the following criteria:

Time

Action

Clean in Place (CIP)

Washer (COP)

Manual

Chemistry / concentration

Temperature

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

000,1

1

BProduct of DoseDaily Maximum

AProduct 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 g

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)


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 increasingly difficult to clean

Be aware of potential changes in active/excipientphysicial 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



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



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


Risk Assessment Matrix

(Example)

Product Name Potency

Factor

Toxicity

Factor

Solubility

Factor

Cleanability

Factor

Risk

Priority

(PxTxSxC)

Acetaminophen 2 2 3 3 36

Fentanyl 5 3 4 3 180

Oxycodone HCl 4 3 2 2 48


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


Risk Control and Tools to

Manage Risk

(Partial List)

Failure Mode Effect and Analysis (FMEA)

Hazard Analysis and Critical Control Points (HACCP)

Hazard and Operability (HAZOP)

Cause & Effect Analysis (Fishbone Diagram)

Fault Tree Analysis

Quality Risk Classification and Filtering


Questions?

THANK YOU!

Managing Risk

Documents

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