Fundamental Cleaning Principles

(1)

Cleaning

Validation

Principles:

Developing,

Deploying and

Maintaining Your

Principles:

Maintaining Your

Cleaning Validation

Program

1 Cleaning Validation

Cleaning Validation Principles

• ISPE Welcome and Opening Remarks • Course Leader Introduction

• Housekeeping • Breaks • Lunch • Emergency Egress • ISPE Membership • Evaluations

• Rules of the Road

?

• Rules of the Road

• Overview of Notebooks

• Glossary / Acronyms • Index to Materials

(2)

Cleaning Validation Principles

Section Description

Cleaning Validation Principles

• Creation of scientifically sound rationales validation protocols

Learning Objectives

Creation of scientifically sound rationales, validation protocols and reports

• Identification and characterization of potential residues including product, processing aids, cleaning agents and adventitious agents

• Selection of appropriate analytical methodology for your selected residues

• Determination of suitable sampling techniques and the selectionDetermination of suitable sampling techniques and the selection of sampling locations that represent challenging locations for your cleaning process

• Calculation of residue limits that meet all necessary regulatory requirements

(3)

Cleaning Validation Principles

• Learning to manage the challenges of limits

Job-Focused Skills

Learning to manage the challenges of limits,

validation strategies and maintaining the validated

state in:

• Multi-product facilities

• Campaign-based production environments

• Differentiating the requirements for cleaning

lid ti

f

validation for:

• Manual

• Semi-automatic

• Automatic cleaning

Cleaning Validation Principles

• Determining scientific grouping or bracketing

Job-Focused Skills, cont.

• Determining scientific grouping or bracketing

approaches

• Comprehending common cleaning validation pitfalls

• Accomplishing analytical method validation and

recovery study requirements in cost-effective studies

• Evaluating your cleaning practices through internal

self-audits

audits

• Practicing what you have learned through hands-on

exercises

(4)

Class Introductions

• Name

• DepartmentDepartment

• Company

• Types of Products Your Company Produces • Status of Your Cleaning Validation Efforts

• What Topics / Questions You Came to Learn About

• This course is designed to address the concerns for all pharmaceutical dosage forms including the production of APIs pharmaceutical dosage forms, including the production of APIs • The principles are broadly applicable to IVD and consumer

products, as well

• If you have a question for your industry, please ASK!!

Module 1

Regulatory

R

i

t f

Requirements for

Cleaning Validation:

“Limit”ing the Risk

(5)

1997 – Quality System

Inspection Techniq e 2002 – 2004Ri k B d 1992/3 –

Mid-Atlantic Cleaning

1997 – HACCP Adopted for Food Industry

FDA Regulatory Timeline

(Relatively Speaking)

1978 – Last significant Update to Finished Pharmaceutical CGMPs 1986 – Process Validation Guidance 1996 – Quality System Regulation Issued for Devices Inspection Technique

(QSIT) for Devices Risk-Based Inspection Approach Identified & Rolled Out Atlantic Cleaning Validation Inspection Guide Finalized as National Document 2001 – Drug Inspection Program (6 Subsystems of Quality) Piloted -1992 – First E-Rec

Rule Draft – Not Finalized Until 1996 (P11) 1996 – 2001 SUPAC Drafted 1991 – 1993 Inspection Guides Issued • Aseptic Processing

• Bulk Pharmaceutical Chemical • Solid Dosage Form

• Semi-Solid Dosage Form • Biotechnology

• Laboratories (QC and Micro)

Quality) Piloted -Finalized in 2002 1998 – API Draft Guidance Issued 1996 (P11) 1996 – Proposed Revision to GMPs 9 Cleaning Validation

Significant Sources of Regulation on

Cleaning and Cleaning Validation

• Worldwide GMPs,

(Especially EU Annex 15 (¶ 36) (2006) & GMP Part II (formerly (Especially EU Annex 15 (¶ 36) (2006) & GMP Part II (formerly Appendix 18) (2005)

• US FDA, Guide to Inspections of Validation of

Cleaning Processes (1993)

• Pharmaceutical Inspection Convention (PIC),

Recommendations on…Cleaning Validation (2001)

• Canadian HPFB, Cleaning Validation Guidelines

,

g

(2001)

• WHO Supplementary Guidelines on GMP: Validation

(2005)

(6)

Worldwide cGMPs

Design and construction features and

Equipment design, size, and location 21 CFR 211.42 EU 3.1 – 3.25_{21 CFR 211.63 EU 3.34 – 3.44} Any building or equipment used in the manufacture, processing, packing, or holding of a drug product shall be of:

• Suitable size

• Suitable construction

• All surfaces can be readily contacted by cleaning process; accessed for inspection • Coved corners, free-draining, non-reactive,

non-additive, non-absorptive materials of construction

to facilitate cleaning, maintenance, and proper operations.

• Suitable location

construction

• Location appropriate to cleaning utilities / supplies; away from walls or other interfering surfaces

Worldwide cGMPs

(continued)

Sanitation

Equipment cleaning and maintenance 21 CFR 211.56_{21 CFR 211.67} EU 4.26_{EU 4.28} • Written procedures for cleaning and for use of cleaning and

sanitizing agents shall be followed and shall: • Assign responsibility for sanitation • Describe in sufficient detail:

• Schedules Prevent malfunctions or

contamination that would alter the • Methods

• Equipment

• Materials to be Used

contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

(7)

Worldwide cGMPs

(continued)

Equipment cleaning and maintenance 21 CFR 211.56 EU 4.26

21 CFR 211.67 EU 4.28

More specifics with regard to the procedures to be established:

• Responsibilities, Schedules, Methods, Equipment, Materials • Methods of Disassembling and Reassembling to ensure proper

cleaning and maintenance

• Removal or obliteration of previous batch identification

As before

• Removal or obliteration of previous batch identification • Protection of clean equipment from contamination prior to use • Inspection of equipment for cleanliness immediately before use • Records shall be kept of maintenance, cleaning, sanitizing, and

inspection

Record retention

Cleaning & Use Log

Worldwide cGMPs

(continued)

Equipment cleaning and use log _{21 CFR 211.182} _{EU 4.28 –}

4.29

A written record of major equipment cleaning, maintenance and use showing, for each batch processed:

• Date • Time • Product • Lot number

• Signature and date of person(s) performing • Signature and date of person(s) double-checking For dedicated equipment, the records of cleaning, maintenance, and use shall be part of the sequentially numbered batch record (if no separate log is kept).

(8)

European Requirements – EC Guide to GMP

Overall, wording and content nearly identical to various

US requirements

Pertinent Sections:

Section 3: Premises and Equipment

(3.34 – 3.44 equipment design for cleanability)

Section 5: Production

(5.19 cross-contamination; 5.21 – 5.24 Validat. & Change Ctrl)

Annex 2: Manufacture of Biologicals

(15, 17 – design to promote cleanability)

European Requirements – EC Guide to GMP

Overall, wording and content nearly identical to various

US requirements

Pertinent Sections:

Annex 15: Qualification and Validation

(36 – 42 – Cleaning Validation; 45 - Revalidation) – see next

GMP Part II: GMP for APIs

(5.2 – Equipment Maintenance and Cleaning; 6 2 Equipment Cleaning and Use Record; 6.2 – Equipment Cleaning and Use Record; 12.7 – Cleaning Validation) – aligns with ICH Q7A

(9)

Definition of Cleaning Validation

• Documented evidence to ensure that

cleaning procedures are removing

residues to predetermined levels of

acceptability, taking into consideration

batch size, dosing, toxicology, equipment

size, etc.

- World Health Organization

• Note that this definition immediately

employs “risk-based” language

Cleaning Validation –

Sections 36 – 42 of EU Annex 15 on Qualification

and Validation

• Cleaning validation should confirm effectiveness

g

of cleaning procedures; rationales should be

logical for:

• Limits for carry-over of drug product residue, cleaning

agents and microbial contamination

(10)

Cleaning Validation –

Sections 36 – 42 of EU Annex 15 on Qualification

and Validation

• Sufficiently sensitive validated analytical

methods should be employed

• Product contact surfaces only for validation;

although non-product contact parts should be

considered

• Intervals should be validated for:

• Time between use and cleaning

• Time between cleaning and reuse

Cleaning Validation –

Sections 36 – 42 of EU Annex 15 on

Qualification and Validation

• Worst-case approaches for similar materials /

processes may be employed

• Typically three consecutive trials should be

performed

• “Test Until Clean” is not an appropriate

substitute for validation

(11)

Cleaning Validation –

Sections 36 – 42 of EU Annex 15 on Qualification

and Validation

• Products which simulate the physiochemical

properties of the residues may be used where

those materials are either toxic or hazardous

Revalidation - Section 45 of EU Annex 15

• Facilities, systems, equipment and processes,

including cleaning, should be periodically

g

g,

p

y

evaluated to confirm that they remain valid; a

review with evidence may suffice if no significant

changes were made

Guide to Inspections of Validation of

Cleaning Processes (1993)

SOP Requirements

F

h

j

i

f

i

• For each major piece of equipment:

• Between batches of

same product

• Between batches of

different products

• For cleaning validation process, requiring:

• Cleaning validation protocols

S li d

Dedicate where equipment is difficult to clean or hazardous

• Sampling procedures • Analytical methods • Limits (“acceptable level”)

• Final Report

(12)

Guide to Inspections of Validation of

Cleaning Processes (1993) (continued)

Evaluation of Cleaning Process

• Examine objectivesof the validation process, written procedure and documentation

• Examinetrainingand level of experience of the cleaning operators • Examine allowed length of time

between the end of processing and each cleaning stepand its potential effect on the cleaning process

• Examine steps taken to prevent microbiological contamination At what point does a piece of equipment or system become clean? Does it have to be scrubbed by hand?

What is accomplished by hand scrubbing?

How variable are manual cleaning processes from batch to batch and product to product?

a e steps ta e to p e e t c ob o og ca co ta at o

IQ / OQ Elements to Consider

• Examine equipment design especially when using CIP

• Assure proper identification of process equipment to ensure correct implementation of cleaning procedures

Guide to Inspections of Validation of

Cleaning Processes (1993) (continued)

Scientific Design of Analysis

D t

i

th

ifi it

d

iti it

f th

• Determine the specificity and sensitivity of the

analytical method(s) used to detect residuals or

contaminants

• Testing of rinse solutions should include

testing for

residues

or contaminants rather than for water quality

(13)

Guide to Inspections of Validation of

Cleaning Processes (1993) (continued)

Scientific Design of Analysis

• Challenge analytical methods in combination

Challenge analytical methods in combination

with the sampling method(s) to

show recovery

• Sampling techniques include direct surface

sampling and sampling of rinse solutions

.

• “

Test until clean” systems should not be used. The

d f

t

ti

i di

t th t th

l

i

need for retesting may indicate that the cleaning

process is not validated.

Guide to Inspections of Validation of

Cleaning Processes (1993) (continued)

Scientific Limits Determination

• FDA does not intend to set limits

• Determine how the firm established their residue limits:

• Sensitivity of analytical methods is critical to establish valid limits • Logical, practical, achievable and verifiable

• Scientifically justifiable

• Three examples given:

10ppm, biological activity levels

1/1000 f

l th

ti d

d

l

ti

as 1/1000 of normal therapeutic dose and organoleptic

levels

• Cleaning Agents - “...no or very low detergent levels

remain after cleaning...”

UhOh! Don’t use words such as “absence, no or none” when creating your procedures or rationales!!

(14)

Guide to Inspections of Validation of

Cleaning Processes (1993) (continued)

Other Important Statements:

• Microbiological aspectsMicrobiological aspectsof equipment cleaning should beof equipment cleaning should be considered; there should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation; equipment should be driedbefore storage

• “When variable residue levels are detected following cleaning, one must establish the effectiveness of the process and operator performance.”

• “Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. … Any indirect test method must have been shown to correlatewith the condition of the equipment.”

Guide to Inspections of Validation of

Cleaning Processes (1993) (continued)

Other Important Statements:

• “There are two general types of sampling that have been • There are two general types of sampling that have been

found acceptable. The most desirable is the direct method of samplingthe surface of the equipment. Another method is the use of rinse solutions.”

• “Rinse and/or swabsamples should be used in conjunction with the placebomethod” (when it is justified for use) • “The firm should challenge the analytical method in

bi ti ith th li th d( ) d t h th t combination with the sampling method(s) used to show that contaminants can be recoveredfrom the equipment surface and at what level, i.e. 50% recovery, 90%, etc.”

Does not mean that these values presented here are “acceptance criteria” for recovery.

(15)

Guide to Inspections of Validation of

Cleaning Processes (1993) (continued)

Other Important Statements:

• “In establishing residual limits, it may not be adequateto focus only on the principal reactantsince other chemical variations may be more difficult to remove…. the issue of by-products needs to be considered if equipment is not

dedicated.”

• “When cleaning is between batches of the same product(or different lots of the same intermediate in a bulk process) the fi d l t it i f " i ibl l "f th

firm need only meet a criteria of, "visibly clean"for the equipment. Such between batch cleaning processes do not require validation.”

Not scientifically justifiable!! Does not consider by-products, cleaning agent, micro, the area in which the equipment is cleaned / stored, etc.

PIC/S, Canadian and WHO

Guidance on Limits

Limits shall be logical, practical, achievable, verifiable; for

example, the most stringent of the following first three

criteria:

• No more than 0.1% (1/1000th) of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product

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

• No visible residue on the equipment after cleaning procedures are performed *

*Based on spiking studies that show the visible levelBased on spiking studies that show the visible level

• Also, for certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods (or may require dedication)

(16)

US - May 1996 Proposed Revision to cGMPs

Being Revised as Part of Risk-Based GMPs

¶ 211.220 Process validation

• (a) The manufacturer shall

validate all drug product

• (a) The manufacturer shall

validate all drug product

manufacturing processes

including, but not limited to,

computerized systems that monitor and/or control the

manufacturing process.

• The manufacturing process includes all manufacturing

steps in the creation of the finished product

including

,

but not limited to the following procedures:

Cleaning

but not limited to, the following procedures:

Cleaning

,

weighing, measuring, mixing, blending, compressing,

filling, packaging, and labeling.

Cleaning is not only considered a step in

the manufacturing process, but it is the FIRST step in getting ready for the next process.

US - May 1996 Proposed Revision to cGMPs

Being Revised as Part of Risk-Based GMPs

¶ 211.220 Process validation (continued)

• (b) Validation protocols that identify the product and product

ifi ti d if th d d t it i

specifications and specify the procedures and acceptance criteria for the tests to be conducted and the data to be collected during process validation shall be developed and approved.

• The protocol shall specify a sufficient number of replicate process runs to demonstrate reproducibilityof the process and provide an accurate measure of variability among successive runs

Number of runs to be justified. Rule of three typically applies.

Th b th i i !!

• Validation documentation shall include evidence of the suitability of materials and the performance and reliability of equipment and systems. The manufacturer shall document execution of the protocol and test results.

Three may be the minimum!!

(17)

US - May 1996 Proposed Revision to cGMPs

Being Revised as Part of Risk-Based GMPs

• (c) The manufacturer shall design or select equipment and ( ) g q p processes to ensure that product specifications are consistently achieved.

• The manufacturer's determination of equipment suitability shall include testing to verify that the equipment is capable of operating satisfactorily within the operating limits required by the process. • Parts of the process that may cause variabilityor otherwise affect

product quality shall be tested.

p q y

Considerations for worst-cases in cleaning validation include:

• Maximum hold times • Maximum residue loads • Minimum process parameters

during validation

US - May 1996 Proposed Revision to cGMPs

Being Revised as Part of Risk-Based GMPs

• (d) There shall be a quality assurance system in place which ( ) q y y p requires q revalidation whenever there are changesin packaging, component

characteristics, formulation, equipment, or processes, including reprocessing, that could affect product effectiveness or product characteristics, and whenever changes are observed in product characteristics.

Change control considerations include:

• Cleaning agents

• Cleaning process parameters • Cleaning procedures • Cleaning procedures • Training procedures • Formulation • Equipment

• Environments / storage locations for clean

equipment

• Introduction of a new product (as it might

affect the limit for an existing product – see limits section)

(18)

Module 2:

Fundamentals of

Cleaning Validation:

Emphasis on Fun!

First, Some Definitions

Cleaning Validation

• Documented evidence that provides a high degree of

assurance that a cleaning process can reproducibly produce

a clean piece of equipment in accordance with the

designated specifications

• Generally cleaning validation applies the “rule of

three” for the number of validation trials to be

three for the number of validation trials to be

completed

(19)

First, Some Definitions

Verification

• documented evidence that provides a high degree

of assurance that a single cleaning event can

produce a clean piece of equipment in accordance

with the designated specifications, suitable for the

next use

• Generally verification is used for development batches

Generally verification is used for development batches

where three may not be made or for infrequently

manufactured products; when three runs have been

completed they may be summarized as a validation if

all conditions used in the three studies were the same

First, Some Definitions

• Certification– depending on the firm, certification often has the same meaning as verification; some companies

diff ti t tifi ti t d th t ill

differentiate certification as an expected process that will occur after each production event as a change over process, for example

• Monitoring– a routine evaluation of cleaning to determine whether the original cleaning validation conditions are still being achieved; may involve fewer samples or less invasive sampling techniquesp g q

• Engineering Trials– experimental cleaning trials that help to evaluate whether a cleaning process for a new / revised product or process will be effective; still requires validated test methods and sampling procedures

(20)

Fundamentals of Cleaning

Cleaning depends upon process control… T ime A ction C oncentration / Chemistry T emperature

Cleaning also depends upon the conditions of cleaning

conditions of cleaning… W ater

I ndividual Performing Cleaning N ature of Soil

S urface Being Cleaned

T.A.C.T. W.I.N.S. Example

(21)

Influences on Cleaning

Equipment Type – Major, Minor, Dedicated, Non-Dedicated R l i th P U t Product Type Manufacturing Process

Surface

Soil

Chemistry

Role in the Process – Upstream, Downstream Materials of Construction Surface Finish Geometry / Complexity Manufacturing Process Hold Times Campaign Length

Soil

Chemistry

Water Quality Time

Action / Type of Cleaning – Manual (Individual), CIP, COP Concentration Temperature 41 Cleaning Validation

Equipment Categories

Major Equipment

-i t iti l t th

Attributes of Each Category • Generally large and

equipment critical to the manufacturing process (usually has a unique identification number)

Minor Equipment

-apparatus and utensils (such

• Generally large and significant contributor to overall contamination • May be dedicated

• Generally small but may be used for highly concentrated as scoops, hoses, beakers)

which perform a support function

g y materials

(22)

Equipment Categories

Major Equipment

-i t iti l t th

Consequences of Each Category S f

equipment critical to the manufacturing process (usually has a unique identification number)

Minor Equipment

-apparatus and utensils (such

• Significant contamination contributor; position / role in process will be highly critical • Generally easy to track for

cleaning status

• Generally not a significant contributor but we can’t leave as scoops, hoses, beakers)

which perform a support function

contributor, but we can t leave them out of our program • Difficulties arise in tracking of

small parts through the cleaning process

Equipment Categories

Dedicated Equipment

q p

- Attributes of Each Category

equipment which is used for the manufacture of one product only

Non-Dedicated Equipment

-i t l d f

• Lower risk of cross-contamination

• Multi-use nature presents equipment commonly used for

several products or processes

p significant cross-contamination concerns

(23)

Equipment Categories

Dedicated Equipment

-Consequences of Each Category

equipment which is used for the manufacture of one product only

Non-Dedicated Equipment

-equipment commonly used for

• Potentially higher risk of degradant and impurity build-up, especially if campaigned

• Validation will be required

f h d t (

equipment commonly used for several products or processes

Remember the precautions stated earlier for the Guide to Inspection of Cleaning Validation Processes with regard to the pitfalls in not validating the cleaning of dedicated equipment.

for each product (or representative from a grouping / bracketing) • May also be at risk for

degradants and impurities if campaigning is observed 45 Cleaning Validation

Types of Cleaning

Manual Cleaning- scrub brushes and high pressure hoses used by

t t d t

• Adaptable to varying soil loads Attributes of Each Type

an operator to remove product

residue • Highly dependent upon training

Automated Cleaning(e.g., CIP – (Clean-In-Place) - cleaning performed by a control system or microprocessor which

automatically controls functions of wash, rinse and dry

Semi-Automated Cleaning(e g

• Reproducible if equipment is qualified for use

• Will not recognize variability in the incoming soil condition

Semi-Automated Cleaning(e.g., COP – Clean-Out-of-Place) -cleaning performed in a parts washer or sink; often requires manual intervention or

disassembly; may be automated

• Often combines strengths and weakness of the above

• May depend upon accurate load placement / disassembly for proper cleaning

(24)

Types of Cleaning

Manual Cleaning- scrub brushes and high pressure hoses used by an operator to remove product

• Lack of inherent reproducibility may require extensive monitoring over

Consequences of Each Type

an operator to remove product residue

require extensive monitoring over time

• Detailed procedures a must! Automated Cleaning(e.g., CIP –

(Clean-In-Place)- cleaning performed by a control system or microprocessor which

automatically controls functions of wash, rinse and dry

• Need to ensure that cleaning validation considers the worst-case soil loads or that production can adequately identify outliers for study in the future

Semi Automated Cleaning(e g

Semi-Automated Cleaning(e.g., COP – Clean-Out-of-Place) -cleaning performed in a parts washer or sink; often requires manual intervention or

disassembly; may be automated

• Detailed procedures and load maps are typically required • May require monitoring as

with manual above

Position / Role in Process

Upstream i t l i th Ma ha e nreacted starting

Attributes of Each Position

Upstream – equipment early in the manufacturing process, for example primary reactors, initial culture, initial blending

• May have unreacted starting materials present on equipment • In-process materials may still be

“crude” in that they have not yet undergone purification

Downstream– equipment used later in the manufacturing or finishing process including such process steps as final

• Residues are less likely to be homogeneously distributed throughout the batch as often process steps as final

crystallization, purification or viral reduction, filling equipment or tableting equipment

throughout the batch as often there is limited mixing after the upstream processes

• Product is often purified

(25)

Position / Role in Process

Upstream– equipment early in the

f t i f l • Additional residues may need to be

Consequences of Each Position

manufacturing process, for example primary reactors, initial culture, initial blending

considered for cleaning validation

Downstream– equipment used later in the manufacturing or finishing process including such process steps as final

crystallization, purification or viral reduction, filling equipment or

• Sampling sites will have to be selected highly critically to ensure that non-homogeneous distribution of residues does not adversely affect portions of batch

• Limits may need to be more reduction, filling equipment or

tableting equipment

Limits may need to be more conservative to accommodate the critical nature of many sampling sites • Be careful that purification processes

don’t concentrate contaminants

Precautions with

Purification Processes

• Purification processes are generally intended to

remove process-related impurities only

• Don’t falsely assume that residues from prior

cleaning operations will be successfully removed

by purification without validation

(26)

Precautions with

Purification Processes

• Remember that cleaning validation affects the

next product to be produced – don’t assume that

next product to be produced don t assume that

the residues from a prior process will be

compatible with the next product or purification

process

If part of your rationale intends to use the

purification process as part of your basis for residue

or limits selection, remember that FDA stated in

Human CGMP Notes that impurities are intended to

come from the starting materials or the

manufacturing process itself and not from elements

left over from the cleaning process

Module 3: Cleaning

Validation Master

Pl

It i Al

Plans: It is Always

Good to Have a

Plan

(27)

Transformation of Data – Knowledge Management

Source: The Certified Quality Manager Handbook, 2nd_{Ed., ASQ}

Wisdom

Wisdom is derived from the collective database of knowledge, built from experience and values, by being able to see the connectivity among seemingly disparate knowledge sets enabling deductive solutions

Knowledge

Wisdom

Information

Information has meaning, but the meaning is based on the interpretation of the user of the information.

Knowledge is built through the correlation and integration of information with policies, procedures and regulations.

knowledge sets enabling deductive solutions.

Data

Data is meaningless unless something is done with it.

Transformation of Data –

For Cleaning Validation

Wisdom

You will achieve wisdom when you understand whether or not your policies, procedures and master plans adequately support the complexity of your plant! Often in-depth analysis such as risk and impact assessments

Knowledge

Wisdom

Information

Relate the various forms of data to understand the equipment, cleaning process and product residue interactions.

Establish policies, procedures and master plans that integrate the information collected about your plant.

in depth analysis such as risk and impact assessments are necessary to become truly enlightened!

Data

Collect information about your equipment, products and processes.

(28)

So What Data Need to Be Collected?

Data Required Required For …

Formulation Attributes • Analytical method selection

(i.e., dosage, toxicity, concentration, excipients, degradants, impurities)

y

• Sampling method selection • Limits determination

• Worst-case determination (if grouping / bracketing) • Segregation requirements (if hazardous)

Equipment Characteristics

(i.e., materials of construction, geometry,

• Materials of Construction for Recovery Studies • Surface Area for Limits Determination • Hard to clean sampling locations or “hot spots”

• Sampling locations where non-homogeneous contamination is

surface area, cleaning procedure, cleaning agent, disassembly requirements)

likely or “critical sites”

• Worst-case determination (if grouping / bracketing)

• Segregation requirements (if highly difficult to clean effectively)

So What Data Need to Be Collected?

Data Required Required For …

Process Attributes

(i.e., batch size, upstream / downstream, extreme temperatures / holds, etc.)

• Residue selection • Limits determination • Sampling location selection

• Worst-case determination (if grouping / bracketing) • Segregation requirements (if hazardous)

Standard Operating Procedures

• Process parameters for validation • Witnessing requirements • Sampling locations

• Grouping / Bracketing (if applicable) • Grouping / Bracketing (if applicable)

So what activities convert

these Data into Information? . . .

(29)

Cleaning SOP Defintion

Engineering Operations Validation and Technical Operations

Equipment Characterization Critical Process Parameters Product Grouping / Bracketing Product Attributes Equipment Train Definition

Cleaning Validation Master Plan or Policy and SOPs for Cleaning Validation

Quality Control Cleaning Agent Usage Matrix Equipment Grouping / Bracketing Hard to Clean Locations Residue Selection Sampling Sites And MOC Methods Validation Recovery Studies

Hold Time Definition

W t C Limits Definition Sampling Method Selection Campaign Definition Protocol Definition Worst-Case Definitions Engineering Runs / Cycle Development

Protocol Execution and Summary Report Preparation

Now We Have Data and Information, Where

Does the Knowledge Come From?…

• Knowledge is the integration

of Information with policies

Wisdom

of Information with policies,

procedures and regulations

• We must first start by

creating our policies or

master plan for cleaning as

well as the SOPs that will

Knowledge

Information

well as the SOPs that will

govern our Cleaning

Validation Program

Data

(30)

**What is a Master Plan*?**

Our Needs for an Effective

Program:

Roles of the Master Plan:

• Single source for information • Consistent understanding by

all team members

• Assessment of what needs to be done and by whom

• Effective control of strategies to ensure that they are

• High Level Philosophy

• Framework for consistent risk-based decision-making • Inventory of actions and

projects, resource planning, scheduling

• Location to consolidate our to ensure that they are

consistent

• Less time spent by regulators in our facility

Location to consolidate our scientific rationales

• Single source for regulatory review

* Frequently Master Plans are called Project Plans, Validation Plans or Policies, depending on the site’s document hierarchy

What are Typical

Master Plan Sections?

1. Introduction Objective and Scope 2. Description and Background 3. References

4. Responsibilities 5. Validation Approach

• Strategy and organization

• Inventory of qualification activities to be accomplished

6. Acceptance Criteria (as appropriate) 7 Procedures & Format (as appropriate) 7. Procedures & Format (as appropriate)

8. Risk / Hazard / Failure Analysis (or may be in separate document) 9. Planning & Scheduling (as appropriate, high level, typically) 10. Appendices

(31)

Master Plan Contents

• Introduction Objective and Scope - Goals of the

Master Plan and brief content insight as well as

boundaries of the Validation Project and of the

j

Master Plan

Typical scope boundary elements:

• Production areas included: marketed production,

clinical trial materials, R&D, laboratories, contract

manufacturer / packagers

• Types of Residues / Analysis included: chemical,

microbiological

Master Plan Contents

• Description and Background - overview and

orientation to the facility, process, technology or

project; may include product overviews as

project; may include product overviews, as

appropriate

Typical elements:

• Program progress to date or significant iterations

• Dosage forms primary manufacturing processes

• Dosage forms, primary manufacturing processes,

significant attributes of products (e.g., toxic, potent),

production characteristics (e.g., batch, campaign)

(32)

Master Plan Contents

References - pertinent internal and external documents Examples include:

• Scientific rationales, SOPs, risk analyses, literature supporting key rationales or strategies

Avoid excessive generic references (e.g., GMPs)

Responsibilities – high level overview of key project participants – sufficient detail here may supercede the need to continue to reiterate responsibilities in protocols

Department Responsibilities QC Methods Validation QC Methods Validation Recovery Studies Analysis of Samples Engineering Surface Area Calculations

Materials of Construction ID Validation Protocol and Report Preparation Operations Cleaning in accordance with SOPs

Collecting samples

Master Plan Contents

(continued)

Validation Approach – highlight the key elements of the

validation program

• Scientific rationales (see next slide) – the basis for the selection of the validation testing and trade-offs

• Basis for the selection of validation priorities (e.g., New product introductions, worst-case products, multi-purpose equipment, etc.) • Project management overview of the responsibilities for the

oversight of the cleaning validation program

• Inventory of validations to be accomplished or already li h d i f h l

accomplished in support of the plan

Cleaning Validation is as much about what you

choose not to do

as it is about what you

choose to

do.

Ensure your scientific rationales defend both!

(33)

• Product grouping / bracketing rationale • Equipment grouping / bracketing rationale • Residue selection criteria

Scientific Rationales Will be Needed for …

• Limit selection and calculation rationale

• Analytical approach (specific / direct vs. non-specific/ indirect / screening)

• Sampling method selection • Sampling site selection criteria

• Others? (e.g., disassembly philosophy, campaign or minor clean strategies, etc.)

Document these well as these will serve as the guideposts for future personnel or auditors navigating your cleaning validation program.

Master Plan Contents

(continued)

Acceptance Criteria

For cleaning validation, the acceptance criteria section

typically refers to the way in which the acceptance criteria

will be calculated; if more than one criterion applies, the

acceptance criteria section will need to define how the

terms will be applied

Visually Clean and Visually Clean and

1/1000th_{of a Therapeutic Dose or}

(34)

Master Plan Contents

(continued)

Procedures & Format

Refers to Reference section for the procedures and formats

to be followed; in some cases samples of specific

documentation samples or outlines of document headings

may be included

Scope – Products and Procedures Equipment Boundaries / Train Definition Pre-Requisites (e.g., methods validation,

recovery studies, IQ, OQ of equipment, training, etc.) Validation Study Design

Sampling Plan Acceptance Criteria

Master Plan Contents

(continued)

• Risk / Hazard / Failure / Criticality / Impact Analysis – may

be provided here or in a separate document to substantiate

scientific rationales priorities trade-offs overall approach

scientific rationales, priorities, trade offs, overall approach,

CTQs or critical parameters

• Planning & Scheduling – include or reference a project

schedule for major milestones; if referenced, ensure that it

exists; if included, remember the audience and keep it high

level

• Appendices – sample flow diagrams for key processes,

specimen documentation formats, supporting

documentation for the approach, data tables of key product

attributes, tables including product-specific limits, etc.

(35)

• Master Plans may also capture compliance and

regulatory requirements beyond validation in order

g

y

q

y

to ensure that the project correctly integrates

these activities with the completion of validation

• This is especially valid if the program is

undergoing any significant changes in strategy or

if

ti

h

b

id

tifi d

if corrective actions have been identified

• For example:

• SOP development

• Training package preparation and training of operators /

technicians

• Development of test methods or in-process controls

• Vendor audits / surveillance / visits

• Factory / Site Acceptance Tests (FAT / SAT) /

y

(

)

Commissioning and/or Qualification Activities for new

CIP or COP systems

(36)

Master Plan Maintenance

• Maintain a Revision History

• Circulate approved copies of the Validation

Circulate approved copies of the Validation

Project Plan to all involved departments

• Keep the Master Plan up to date with regard to

changes in priorities and schedule

• Place the Master Plan on a periodic review cycle

to ensure that there is frequent challenge to

scientific rationales and current approaches to

validation

Summary Reports for Master Plans

• In some cases, where a plan is developed for a

specific project such as a new product

i t d

ti

t t th

l

introduction, a summary report to the plan can

provide project closure

• In other cases, an annual summary can provide

updates on critical activities / accomplishments

f

i

hil

idi

hi hli ht

f

l

from prior year while providing highlights of goals

for next year

(37)

Summary Reports for Master Plans

• Summary report to a Master Plan can provide:

• Closure to validation activities for regulators or

change control purposes

• Mechanism to describe and defend deviations

from the original plan

• Location to tie together disparate validation

protocols and reports and their conclusions in a

high level overview

Standard Operating Procedures

for Cleaning Validation

• Develop an infrastructure of procedures that define the

validation program responsibilities and activities.

• Possible topics to include (in a single or in several SOPs):

• Equipment Characterization (New and Existing)

• Standard Operating Procedure Development for Cleaning • Developing and Maintaining Limits Calculations

• Cleaning Validation Methods Validation and Recovery Studies • Engineering Studies / Cycle Development g g y p

• Developing Cleaning Validation Protocols and Reports • Collecting and Testing Cleaning Validation Samples

• These topics will form the outline of the remaining sections

of the presentation

(38)

Module 4: Equipment

Characterization: Do

t L

“Sit ” f

not Lose “Site” of

What you Are

Cleaning!

Equipment Characterization

• We’ve already examined that the surface

f

is a critical to the success of the cleaning

• So let’s examine what we can do about it:

• Equipment Design / Construction

• Equipment Characterization

• Sampling Site Selection

• Documentation of Equipment Characterization

(39)

Equipment Design and Construction

Production equipment and facilities should be designed to be cleanable and maintainable in accordance with CGMPs – other critical attributes may apply depending on the nature of your production process

• Coved corners • Welded seams

• Sealed joints or crevices, when necessary

(with temperature / chemical resistant caulk or sealant) • Sanitary clamp type connections

• Minimize dead leg opportunities

(not only length of T but also orientation of lines) Positive slope

• Positive slope

(typically minimum for long runs of 1/8th _{in/ft or 10.4mm/m)}

• Free-draining

• Non-additive, non-reactive, non-absorptive materials of construction • Smooth, polished finishes (ex: 20 – 25 µin or 0.5 – 0.625 µm Ra on

316L SS)

Existing Equipment Design Survey

• Survey the equipment (see example of potential tool on the next

slide)

• Identify weaknesses in the design • Identify weaknesses in the design

• Identify risks associated with the weaknesses • Mitigate as possible

When ranking, it may also be helpful to rank each section of the equipment by the Product Contact ? Yes No Non-Critical or Incidental Contact Critical Site

(i.e., location likely to be non-homogeneously equ p e t by t e nature of its product contact: Contact non homogeneously

distributed in next batch or location which is likely to be in contact with highly concentrated active)

Low Risk High Risk

(40)

Example of Design

Survey Risk Assessment

Characteristic High Rating Low Rating

Equip. Section Surveyed

Possible Mitigations / Actions for High Ratings

Positive Slope / Free Draining

Non-free draining

Free draining Reengineering Forced flow and forced drying Non-additive / Non-reactive / Non-absorptive MOC MOC not appropriate for easy cleaning MOC appropriate Reengineering

Special considerations for cleaning action / chemistry Enhanced inspection / testing to confirm testing to confirm cleanliness Smooth, polished finishes Finish was not designed to be smooth or finish has significant damage Finish is smooth, polished and in tact Refinishing surfaces Enhanced cleaning action / chemistry Enhanced inspection / testing to confirm cleanliness 79

Example of Design

Survey Risk Assessment

Characteristic High Rating Low Rating

Equip. Section Surveyed

Possible Mitigations / Actions for High Ratings

Coved Corners

Not coved and critical product contact

Coved or non-critical surface

Tool selection for cleaning

Special instructions during cleaning Joints Not sealed or

sealant inapprop-riate to rigors of cleaning Sealed with the correct material or not critical to product / Replace sealant Use different chemistry or tool for that location More frequent PM and replacement p cleaning contact replacement Dead leg survey

Dead legs are present or orientations that would hold up product and fluids

No dead legs or poor orientations

Reengineering

Disassembly for cleaning or disassembly after CIP for inspection and additional off-line cleaning

(41)

Equipment Design

Risk Assessment Results

Product Risk  Equipment Design High Low Equipment Design Risk High Reengineering to mitigate is your best course of action

Reengineering is still best, but procedural improvements may suffice

Low Equipment is not q p No worries! likely to be a problem,

but take care in your cleaning program design

Equipment Characterization

Gather Develop

Goals of Equipment Characterization are to: Gather

• Equipment design data: • MOC / finish / geometry • Difficult to clean locations • Cleaning SOP #s and

Cleaning Agent types

E i t f d t

Develop

• MOC list for recovery studies • Sampling site identification • Sampling method determination • Cleaning procedure and

cleaning agent correlation to equipment for grouping / bracketing

• Equipment surface area data • Equipment train data

bracketing

• Equivalency rationales for grouping / bracketing • Limit determination

(42)

Equipment Characterization

Field Assessments

•

Set Priorities for Equipment –

(new, dedicated major, downstream,

non-dedicated minor, upstream, etc.)

•

Identify potential equivalent equipment

Equipment Characterization

Field Assessments

•

Initiate the Assessment:

• Identify product contact materials of construction for

processing equipment and their locations

• Use drawings, vendor certifications, field inspections • Identify the approximate percentage of surface area that

each MOC comprises (may be approximate)

• Calculate or contact vendor for the product contact surface

area calculations for the total piece of equipment

• List the cleaning SOPs and cleaning agents in use for the

equipment

• Interview operations personnel for hard to clean locations

(43)

Equipment Characterization Field

Assessments

(cont’d)

Repeat the review for any potential equivalent members R i f i l h ld i l d

Grouping or Bracketing

Review for equivalency should include: • Make / Model / Geometry / Features • Scale / Size / Capacity

• Materials of Construction / Surface Finish

• Installation and Operational Qualification Equivalence • Same Position / Role in the Process

Equivalency will also be determined based on: • Cleaned with same procedure

• Cleaned with identical cleaning agent

• Overlap in products produced on those pieces Grouping / bracketing equipment will then drive:

Number / organization of cleaning validation trials

Equipment Characterization Field

Assessments

(cont’d)

Identify sampling locations and sampling techniques

Sampling locations should be selected based on:

p

g

• Hard to clean locations or complex geometries – hot spots • Locations that might disproportionately contribute residue to

the next process (e.g., filling needles, discharge valves, punch and dies, chromatography skid fraction collection valves and piping, etc.) – critical sites

• Materials of construction or surface finishes with an affinity for the residue

• Role in process that is likely to lead to build up or difficult to • Role in process that is likely to lead to build-up or difficult to

clean residue

Number of sampling locations should be based on the:

• Number of locations that fit the descriptions above • Overall size of the equipment

(44)

Documenting Sampling Site Selection

Rationales Through Risk Assessment

S li C iti l Affi it t MOC

Role in Process Likely t L d t Sampling Location Critical

Site Hot Spot

Affinity to MOC or surface finish

to Lead to

Residue Ranking

Risk assessment technique aids in ensuring that sampling sites are effectively rationalized and eliminates some of the subjectivity

• Rankings can be scaled as H, M, L or given a number scaleRankings can be scaled as H, M, L or given a number scale

Methods for identifying sampling locations include:

• Interviewing operators for difficult to clean locations

• Witnessing cleaning procedures to identify weaknesses in cleaning • Conducting screening studies such as Riboflavin testing

Sampling Methods - Survey

Sampling Method 

Swab Rinse

(see Baby) Placebo Coupon

Direct Surface Analysis Physical Removal Good Poor * Moderate* Good * N/A

* May get a different rating depending upon technique

Baby in the Bathwater

Module 4 – Equipment Characterization Slide 88

Technique

Dependent Yes No No No No * Hard to Reach

Locations Poor Good Good Poor Poor Adaptable to

Irregular Surfaces Somewhat Yes Somewhat No No * Controlled Area

Sampling Yes No * No Yes Yes Non-Invasive No Can Be Yes Yes * No Adaptable to On-Line

Monitoring No Yes No * No No Can Use Solvents Yes Yes No Yes N/A

Highly Dependent On…: Site Selection Training Recovery Solubility of Residue Contact Time Homogeneity of Rinse Solution Recovery Ability of Placebo to Remove Residue (e.g., solubility) Homogeneity of Residue in Placebo for Detection Recovery Ability to Defend that Soiling and Cleaning of Coupon is Equivalent to the Production Equipment Recovery Surface Character-ization Qualification of Method Limit of Detection

(45)

Example of Equipment Characterization

Documentation

1. Equipment Name

2. Equivalent Equipment IDs 3. Equipment Description & Role

i th P

5. Sampling Site Selection Rationale and Sampling Method

in the Process

• Key Design Features • Key Performance

Attributes (esp. those that affect cleaning)

• Critical Sites or Hot Spots • Rationales for Equivalency

(as required) 4. Materials of Construction 6. Digital Photographs of Sampling Sites • Highlighted sampling area • Text description of sampling location 7. Calculation of Sampling Site

Surface Area

8 Calculation of Equipment • Material

• Location

• % of Total Surface Area

8. Calculation of Equipment Surface Area

Appendix – Sampling Data Sheet*

* To be discussed in Limits section

Establish an Equipment Use Matrix

Equipment Name

Cleaning SOP Cleaning Agent Product A Product B

Tank 11 (600 L) SOP 1234 CleanAll 345 X (600 L) Tank 12 (500 L) SOP 1234 CleanAll 345 X X Transfer Line 101 (2”) SOP 6789 SonicCare 657 X X Pump 602 (diaphragm) SOP 4567 CleanAll 345 X X

• Matrix helps to establish which products share equipment in order to determineMatrix helps to establish which products share equipment in order to determine the maximum shared equipment train between products (esp. if you use equipment surface area instead of X’s)

• Can assist in seeing logical relationships for equipment groupings / bracketing

• Records similarities and differences between pieces based on cleaning SOPs and cleaning agents

Fundamental Cleaning Principles

Cleaning

Validation

Principles:

Developing,

Deploying and

Maintaining Your

Principles:

Maintaining Your

Cleaning Validation

Program

Cleaning Validation Principles

?

Cleaning Validation Principles

Table of Contents

Cleaning Validation Principles

Learning Objectives

Cleaning Validation Principles

• Learning to manage the challenges of limits

Job-Focused Skills

Learning to manage the challenges of limits,

validation strategies and maintaining the validated

state in:

• Multi-product facilities

• Campaign-based production environments

• Differentiating the requirements for cleaning

lid ti

f

validation for:

• Manual

• Semi-automatic

• Automatic cleaning

Cleaning Validation Principles

• Determining scientific grouping or bracketing

Job-Focused Skills, cont.

• Determining scientific grouping or bracketing

approaches

• Comprehending common cleaning validation pitfalls

• Accomplishing analytical method validation and

recovery study requirements in cost-effective studies

• Evaluating your cleaning practices through internal

self-audits

audits

• Practicing what you have learned through hands-on

exercises

Class Introductions

Module 1

Regulatory

R

i

t f

Requirements for

Cleaning Validation:

“Limit”ing the Risk

FDA Regulatory Timeline

(Relatively Speaking)

Significant Sources of Regulation on

Cleaning and Cleaning Validation

• Worldwide GMPs,

• US FDA, Guide to Inspections of Validation of

Cleaning Processes (1993)

• Pharmaceutical Inspection Convention (PIC),

Recommendations on…Cleaning Validation (2001)

• Canadian HPFB, Cleaning Validation Guidelines

,

g

(2001)

• WHO Supplementary Guidelines on GMP: Validation

(2005)

Worldwide cGMPs

Worldwide cGMPs

(continued)

Worldwide cGMPs

(continued)

Worldwide cGMPs

(continued)

European Requirements – EC Guide to GMP

Overall, wording and content nearly identical to various

US requirements

Pertinent Sections: