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Develop and Implement a

Cleaning Validation Master


Plan

Karem Y. Monge Seplveda


MS Physics, CQA
Senior Scientist Technical Services
Mylan LLC

03/15-16/16
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References
Pharmaceutical Inspection Convention (PIC/S): Recommendations on
Validation Master Plan, Installation and Operational Qualification, Non-Sterile
Process Validation, Cleaning Validation (PI 006-3, September 2007)
Health Sciences Authority Regulatory Guidance Preparation of Validation
Master Plan (January 2013)
White Paper: Reasons, Regulations, and Rules: A Guide to the Validation
Master Plan (VMP) Pharmaceutical Engineering 2001 - BW Saxton
PDA Technical Report No. TR 29 (Revised 2012) Points to Consider for
Cleaning Validation
PDA Technical Report No. TR 49 Points to Consider for Biotechnology
Cleaning Validation
FDA Guide to Inspections: Validation of Cleaning Processes (7/93)
EU GMP Guide: Annex 15 Qualification and Validation (February 2014)
World Health Organization (WHO) Technical Report Series, No. 937, 2006:
Annex 4 Supplementary Guidelines on Good Manufacturing Practices:
Validation
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IGH Quality Guidelines (QbD: ICH Q8, ICH Q9, and ICH Q10)
Overview1
Cleaning Validation is a required activity within the pharmaceutical,
biological, nutritional supplement, and medical device industries. From both
a regulatory and industry standpoint, cleaning validation is recognized as an
important activity to establish that product cross contamination is controlled
to ensure patient safety and product quality.
is the documented evidence that an approved cleaning procedure will provide
equipment that is suitable for processing of pharmaceutical products or active
pharmaceutical ingredients (APIs).2

It is an ongoing activity through the lifecycle of the facility.


It requires an investment of resources and time.

With appropriate cleaning development and risk assessments in place, a


streamlined cleaning program may be developed that is both science-based
and risk-based while ensuring patient safety and product quality.

1. Cleaning Validation for the 21st Century: Overview of New ISPE Cleaning Guide by A. Walsh from Pharmaceutical
Engineering Nov/Dec 2011, Vol. 31 No. 6
2. Health Sciences Authority: Regulatory Guidance; Cleaning Validation January 2013 3
Acts, Rules, and Regulations
The Code of Federal Regulations does not yield a single mention of a
Validation Master Plan in the actual regulation, it is mentioned in many
supplementary documents, such as:

Guidance for Industry and/or FDA Staff: Guidance on Quality System Regulation
Information for Various PreMarket Submissions (Draft Guidance-Not for
Implementation/August 3, 1999)
The QS regulation states, Each manufacturer shall establish quality system
procedures and instructions. An outline of the structure of the documentation used
in the quality system shall be established where appropriate. <21 CFR
820.20(e)>
A copy of the validation master plan or a description of which manufacturing
processes have been or will be validated. A validation master plan is a convenient
method of quality planning for process validations required in the manufacturing
of the device. <21 CFR 820.20(d)> Identify any processes that will be validated,
especially when the manufacturer has not performed a similar type of validation at
he particular manufacturing.

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Acts, Rules, and Regulations
Health Canada-Validation Documentation Requirements and Responsibilities for Drug
Fabricators, Packagers/Labelers, Testers, Distributors and Importers
At the site of fabricators, packagers/labelers and testers, inspectors will evaluate
the validation master plan, the qualification of systems and
equipment and the validation of cleaning and test methods,
as applicable.
Annex 15 to the EU Guide to Qualification and Validation
The key elements of the site qualification and validation programme should be
clearly defined and documented in a validation master plan (VMP) or equivalent
document.
Health Canada-Validation Guidelines for Pharmaceutical Dosage Forms (GUI-
0029)
A validation master plan is a document that summarizes the companys overall
philosophy, intentions, and approaches to be used for establishing performance
adequacy. The validation master plan should be agreed upon by management.

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Furthermore, a visit to the FDA site for Warning Letters and
Notice of Observations (483s) yields several mentions of a
Validation Master Plan. This is simple proof that this document
is an expectation of the FDAs auditors, often requested during
an inspection.
INTRODUCTION
We are moving from a period of collecting large amounts of data
and closing the exercise with a report (based on FDAs 1987
definition) TO collecting data throughout the lifecycle of the
process, method or system, evaluate if it is scientifically sound, and
determine if it supports the quality of such process, method or
system (based on FDAs 2011 definition).

It is the aim of the Validation Master Plan to help the Site


Management in understanding what entails the Validation Program
(Cleaning Validation Program), assign tasks and responsibilities, and
most importantly inform the Auditors how the Site is organized and
its approach to validation.

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General Information
VMP Definition
A written plan stating the overall philosophy,
intentions, and approach used by the Facility /
Functional Unit for planning, designing,
organizing, executing, and reporting validation /
qualification. The plan includes the current state
of validation.
It is used to establish performance adequacy,
define extent of testing expected, and outline test
procedure and protocols.

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General Information
Purpose
Provide a summary of the facilitys validation status
and strategy, including legacy plans, current
qualification and validation status and planned
validation and re-validation activities, with regard
to all products, processes, equipment, test methods,
cleaning, critical utilities, and computer-related
systems.
Legacy Plans project/activity gained from previous year
Present an overview of the operation,
organizational structure, and schedule.

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General Information
Purpose of a Cleaning Validation Master Plan
Provide a summary of the facilitys Cleaning
Validation Program status, strategy, and
expectations including legacy plans, current
cleaning validation status, planned cleaning
validation and cleaning re-validation activities.
Legacy Plans project/activity gained from previous year

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General Information
Scope
A VMP documents the products and production
processes that impact the quality of the resulting
product.
Once it is approved, it should be reviewed by
means of supplements, which will focus on
changes to the approved revision and new
projects.
This review must be done at least annually.
A VMP should be considered a living document to
be referenced and updated throughout the project
and the life of the facility.
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General Information
Role1
Is to help an organization get its arms around a
project-specific validation effort by setting the
scope by which all subsequent documents shall be
bounded.
Serves as a validation roadmap, setting the
course, justifying the strategy, outlining the
preliminary test and acceptance criteria, and
documenting the necessary programs that ensure
a continuing state of validation.

1. Reasons, Regulations, and Rules: A guide to the Validation Master Plan (VMP) by Bryan W. Saxton in 12
May/June 2001 Pharmaceutical Engineering
General Information
A VMP:
Requires planning, a well defined approach, and preparation of the
different steps/stages in the process.
It should be structured taking into consideration SOPs, GMPs, and
regulations.
It is characterized by a multidisciplinary approach, time constraints,
and costs.

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VMP Documentation Design
General Format Requirements
Cover Page
Identify the Functional Unit which the VMP describes or in the case of a Project
specific master plan include the title summarizing the project.
Document should have a unique identification number, such as MP-XXXX/YY.
Approval Page
Include preparer, reviewers, and approvers signatures
Reviewers are representatives who review and agree with the VMP
requirements. In general, they are responsible of providing and supporting the
resources as indicated in the VMP, and assuring the extent of testing is in
conformance with cGMPs and facility standards.
Approvers are usually responsible in the approval of the documentation to be
used in validation and pre-approve test plans with acceptance criteria.
Projects of certain complexity / size may require additional approvers (Global
Management, Quality Unit, Engineering, Research and Development,
Regulatory Affairs) according to their responsibility in the execution of the
validation activities described in the VMP.

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VMP Documentation Design
General Format Requirements for
VMPs (Site VMPs)
Preamble Cleaning Validation
Introduction Product / Process Validation
Organizational Structure and Test Method Validation
Responsibilities Validation Maintenance
Facilities Description References
Manufacturing / Packaging Attachments
Operations History
Validation Documentation
Equipment Qualification
Utilities Qualification
Components Qualification

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VMP Documentation Design
General Format Requirements for CV
VMPs
Purpose Definition of Worst-case
Scope of the Cleaning Validation conditions associated with a
Program cleaning process (e.g. flow
Responsibilities rates or step durations)
List of Equipment and Products to Description of family approach
be validated and grouping of products,
equipment or system
Means of cleaning documentation
(e.g. SOPs and protocols) Approach to determine worst-
case product
Prerequisites to CV (e.g. equipment
and utility qualification) Use of dedicated or shared
equipment and single use
Use of various cleaning systems (disposable) equipment
(e.g. CIP, COP or manual cleaning)
Definition of circumstances in
Cleaning reagents which cleaning verification is
and mechanisms preferred or acceptable (e.g.
clinical stages)

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VMP Documentation Design
General Format Requirements for CV
VMPs Calculations and/or rationales
Strategies and definitions for and formulas for limits for
indirect product contact surfaces process residues, microbial
and non-product surfaces (e.g. contaminants and cleaning
lyophilizers) agents
Equipment hold study approaches Validation maintenance
(e.g. dirty hold time, clean hold time (including routine monitoring,
or storage hold) change control, and periodic
Microbial contamination (e.g. review)
bioburden and endotoxin) Attachments or Appendices
Sampling techniques (e.g. visual (e.g. tables or lists of items
inspection, rinse sampling or swan within the realm of the plan)
sampling) Requirement for reassessment
Training / qualification for sampling of cleaning validation master
techniques plan (i.e. review frequency)
Analytical Methods (e.g. validation Summary of current status and
and recovery requirements) upcoming plans
References
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VMP Documentation Design
Content
Preamble
Identify the version number of the VMP and the schedule for
validation activities and the dates covered.
Include the Legacy Plan section for qualification of equipment,
process, and system used for GMP related purposes, for which
there is no formal qualification documentation or when qualification
does not meet current standards.
Introduction
Summarize the VMP strategy. Establish the reasons for the
validation effort and key background information. Also, identify
applicable change control documents that authorize the validation.
Give the breadth and reach of the validation
effort.

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VMP Documentation Design
Content
Organizational Structure and Responsibilities
Include an Organizational Structure of the company, and identify the
departments responsible for all validation and validation support
activities. Usually the development of the VMP resides in Technical
Services, although input from other departments may be solicited and
integrated into the document.
Facilities Description
Describe, in general, the products manufactured, building design, and
areas classification.
Include the planning phase, purpose of the facility, the products to be
manufactured, and efficiency requirements.
If facility has various processes in different buildings, description of
the preventive measure to avoid contamination should be included.

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VMP Documentation Design
Content
Manufacturing / Packaging Operations
Describe briefly the manufacturing and packaging process,
components preparation, and process flow.
Validation Documentation
Include references to the SOPs that describe the protocol
generation and approval processes.
Include concerning validation documentation and reference
SOPs of the different validation/qualification programs.
Utilities Qualification
Describe briefly the utilities that require qualification and its
computerized control system, when applicable.

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VMP Documentation Design
Content
Equipment Qualification
Include the approach to evaluate and perform the equipment validation,
which should include the computerized control system that controls
documents or acquire data for GMP related activities, when applicable.
Components Qualification
Describe the approach used to qualify the components, status and
approach.
Test Method Validation
Provide information/description regarding the current state of Method
Validation for each product and process.
In general, QC Laboratories generate their own VMP, thus it becomes a
subordinate VP of the Site VMP.
Validation Maintenance
This is the Monitoring and Control Program to ensure that a process once
validated continues to operate in a validated state.
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VMP Documentation Design
Content
Cleaning Validation
Describe the Cleaning Validation philosophy and include the approach, status, and
plan.
It should include equipment use profile, determination for both multi-product and
dedicated equipment, acceptance criteria, determination of worst-case, if using
rinse, swab, TOC samples, microbial testing, and visual inspection, analytical
method validation, chemical swabbing procedure, Clean Holding Time and Dirty
Holding Time definition, protocols, reports, data collection, and archiving.
It should include approach to protocols, technical reports, document review and
approval process, data collection and archiving, and support activities that are
performed as required in response to additions, modifications and changes to
equipment, processes, systems, and facilities
The validation approach section shall include a description of how risk analysis will
be applied in the site.

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VMP Documentation Design
Content
Product / Process Validation
Describe the product/process validation approach and philosophy: Process Design
(Stage 1), Process Qualification (Stage 2), and Continued Process Verification
(Stage 3)1.
It should be focused on providing prospective process validation to all products
manufactured in the facility.
Include the concept of product lifecycle.
Validation approach describes the philosophy and approach to validation including
protocols, technical reports, document review and approval process, data
collection and archiving, and support activities that are performed as required in
response to additions, modifications and changes to equipment, processes,
systems, and facilities.
The validation approach section shall include a description of how risk analysis will
be applied in the site.

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1. Guidance for Industry: Process Validation: General Concepts and Practices January 2011, CGMP, Revision 1
VMP Documentation Design
Content
References
Identify documents that were used in the generation of the
VMP, such as corporate guidelines, product monographs,
regulatory submissions documents, project scope documents,
functional requirements specifications, and validation
department SOPs.
Attachments
Identify and attach all applicable documents referenced
(value-added information) in the VMP.
History
Usually includes the revision history of the document in
sequential order.

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VMP Documentation Design
Content
Usually a section will have:
Approach, Status, Plan (Action Plan)
Action Plan
Include the Timelines and Milestone section of the VMP documents
and the sequence and hierarchy of operation of validation activities.
Specific action plans, responsibilities, and scheduled completion
dates need to be planned and approved for all
qualification/validation activities.
The department manager or person(s) responsible for assuring that
validation items are completed, as indicated, shall be identified and
listed on the Action Item plan. Charts, tables and lists, which are
subject to periodic updating, may be attached to the
VMP as appendices, when approved.

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Template: Site VMPs
VMP Documentation Design

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VMP Documentation Design

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VMP Documentation Design

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VMP Documentation Design

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VMP Documentation Design

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VMP Documentation Design

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Review Process and Approval
Process
Sign the VMP and route for review / approval.
All reviewers and approvers are responsible for the accuracy of the
VMP information.
Once all approval signatures are obtained, ensure all pre-requisite
conditions are met before releasing the VMP for execution.
Pre-requisite conditions may include:
Completion of construction, installation, startup, and
commissioning activities.
Generation of applicable draft SOPs and other relevant
documents, such as maintenance-calibration programs.
Documented training on operation of equipment/systems and
processes, as applicable.
Completion of predecessor protocols and approval of all
associated Technical Reports.

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Review and Deviation Management
(Supplements)
Supplements (Addendums) are used to review and/or
update information.
It should focus on changes to the approved revision and
new projects.
This review must be done at least annually.
Since VMP is a living document it should be updated
throughout the project and the life of the facility.

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VMP Closure Reporting and
Archiving
Sometimes a VMP is considered concluded with an approved Technical
Report.
The purpose is to summarize the results of the VMP listed activities,
completion of requirements, and compliance with the pre-approved
acceptance criteria.
Make sure to include the following information, as applicable:
Supplements that were generated.
Cross reference to and discussion of investigation reports.
Appropriate references to documentation that have been archived.
Corrective actions that were taken including Commitments and/or
CAPAs.
A summary statement of the validation status of the equipment,
process, product, and systems.
All the same level of approvers from the VMP shall approve the Technical
Report.

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VMP Documentation Design
Benefits ad Strategies
Kaizen / Lean / Continuous Improvement /Lean Manufacturing
What to include Value Added Activities
A Value Added Activity is one that either (1) directly adds value
to the final product or (2) directly satisfies the customer.
It generates a positive return of investment of resources and
cannot be eliminated without impairing the process.
The activity must be done right the first time.

What to exclude Non-Value Added Activities


A Non-Value Added Activity is one that do not help create
conformance to the customers needs (specifications).
It generates zero or negative return of investment and usually
can be eliminated / reduced / simplified without
impairing the process. 36
VMP Documentation Design
Benefits ad Strategies - Exercise
Value Added Non-Value Added
Preparing Engineering Drawings Reviewing (various cycles)
Archiving Validation Binder Reworking (may be the same
Approved Template sentence)
SOPs Copying Reports (that may be
Training in easy retrievable system)
Deviation System Obtaining Multiple Approvals
Transcribing Data

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VMP Documentation Design
Benefits ad Strategies - Examples

Have a robust protocol template


Clearly define the deviation management
Sort out how the review process of protocols /reports and data
will be performed
Signees and delegates should be dedicated to the project
Have robust SOPs
Know your pre-requisites and regulations
Clearly define what wants to be done (outcome)
Clearly define who is responsible for what task
Clearly inform the rationale behind why one system is not
validated while another is.

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VMP Documentation Design
Benefits ad Strategies - Examples

Deliverables and Milestones due date must be as real as possible


Clearly delineate a decision tree in terms of validation
Define who is part of the committee to close out all
Investigations and Change Controls, give training to impacted
areas, make effective all new SOPs
Define which activities can be performed at the same time
Have all materials on hand and involve the laboratories who will
give support so that they know the timelines
Clearly indicate the selection criteria governing what
equipment/utility will undergo qualification / process validation.
Clearly inform when to re-validate, when to re-qualify

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Cleaning Validation
Master Plan
CV VMP Criteria
Cleaning Validation Master Plan
written plan stating the overall philosophy, methodology, and approach
used by the Site for planning, designing, executing, and reporting
Cleaning Validation Program
should reflect the key elements of cleaning validation
should be concise and clear
should be considered a living document to be referenced and updated
throughout the life of the facility

The Cleaning Validation Master Plan becomes your Cleaning


Validation Program.

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CV VMP Criteria
Why clean?
Prevent or reduce possibility of product contamination / cross-contamination
Provide a clean system / equipment that is suitable for its intended use
Demonstrate that residues from product and/or detergent can be removed
Establish a consistent cleaning process
What is the objective / goal of cleaning?
Have an acceptable cleaning process that prevents possible contamination / cross-
contamination and removes product, detergent, and microbial residues.
In doing so, product integrity is protected, equipment can be reused, and there is
compliance with regulatory agencies.
Why create and maintain a Cleaning Validation Program?
To create consistency and control of the cleaning process.
Provide documented evidence that cleaning procedures will provide clean
equipment that is suitable for its intended use which will ensure patient safety and
product quality.

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Cleaning Validation Program

Residue Evaluation
Equipment (product-cleaning
Characterization Worst-Case agent-micro)
Definition

Critical Process Methods Validation


Equipment Train
Parameters (T, t,
Definition
rinse, soak, etc.)

Equipment Hard-To-Clean Recovery Studies


Grouping Locations
Definition

Sampling Method
Product Selection
Characteristics Sampling Sites

Limits Definition

Clean and Dirty


Product Grouping Hold Time
Cleaning Agent
Definition
Selection

CV Protocols and
CV Master Plan CV Assessments CV SOP CV Runs
Reports

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CV VMP Criteria
What is needed to establish the CV Program?
The basis is having a plan (VMP) that describes the overall validation
approach.
Define:
types of cleaning that are used in the facility/site
equipment and its characteristics
product attributes
any operational issues
Define the cleaning methods; once defined
important aspects of the process like control and reproducibility come
to light
how to best challenge the process, collect samples, and monitor the
cleaning effectiveness during routine cleaning process can be
delineated.

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CV VMP Criteria
What is needed to establish the CV Program? Contd
The rationale for any grouping philosophies utilized and the validation program
to be implemented should be identified.
The rationale for selecting limits of carry over of product residues, cleaning
agents, and microbial contamination should be logically based on the materials
involved.
The limits should be achievable and verifiable.
Validated analytical methods having sensitivity to detect residues or contaminants
should be used.
The detection limit for each analytical method should be sufficiently sensitive to
detect the established acceptable level of residue or contaminant.
Consideration should be given to contact and non-contact parts.
Cleaning intervals and cleaning methods should be determined.

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CV VMP Criteria
Types of Cleaning
Automated Cleaning vs Manual Cleaning
Automated Cleaning provides reproducible results
Process Control is built-in and process monitoring is commonly integrated
with the control of the system.
Cycle must be validated so that it provides reproducible results for the
operating conditions.

Manual Cleaning is known as the universal practice


It is a necessity because of the numerous equipment, equipment parts,
and configurations.
Its control is achieved by operator training, clear/defined cleaning
procedures, and visual inspection.
Attention is given to hard-to-clean and/or hard-to-reach equipment parts.
Success is obtained by consistently performing written procedures
instructions.

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CV VMP Criteria
Types of Cleaning
Clean-In-Place vs Clean-Out-of-Place
Clean-In-Place
The cleaning is performed in the equipments permanent location.
It is recipe driven.

Clean-Out-Of-Place
The cleaning of smaller pieces of equipment is performed in a designated
cleaning/wash area.
It is required to validate the transport of the part to/and from the wash
room, identification, assurance of potential cross-contamination during the
transfer, and storage.
This is equal to a Manual Cleaning where it is operator, SOP, and visual
inspection dependent.

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CV VMP Criteria
Equipment Characteristics
It is important that the role the equipment plays in the equipment train is
known.
Thus, an equipment is usually defined as dedicated, non-dedicated,
product contact, and non-product contact.
Also, the material of construction and measurements must be known.

Dedicated Equipment is the one used multiple times to manufacture the


same product.
Usually a dedicated equipment has a detergent requirement only.

Non-Dedicated Equipment, usually used for a range of product


formulations, must be cleaned to prevent cross-contamination between
products.

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CV VMP Criteria
Equipment Characteristics Contd

Product Contact surfaces


are those that come into contact with the product during normal course of
operations including utensils.

Product Exposure surfaces (non-product contact)


are those which contact with product may be incidental during normal
course of operations.
Residue of product of these surfaces does not represent a risk of
carryover to the next manufactured product.
Since contact is incidental, a visually clean requirement is usually needed.

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CV VMP Criteria
Material of Construction (MOC)
The attributes of the surface to be cleaned will define the residue to
surface interactions, identify possible contaminants, and point to areas
which may not be readily cleaned or accurately sampled. 1
This areas are hard-to-reach and hard-to-clean parts that must
become worst-cases in terms of sampling.
Equipment should not be reactive, additive or absorptive with the process
materials which contact them.2
Use of porous products, such as filters, filter bags, fluid bed dryer bags,
membrane filters, should be avoided.
The practice is to dedicate them per product.
If using detergent to clean, for example fluid bed dryer bags, a sample
for detergent residue is performed.
The interactions with surfaces that are likely to display these properties
(e.g. seals, gaskets, valves) should be assessed.
1. PDA TR29 Draft 2. cGMPs (211.65)
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CV VMP Criteria
Product Attributes
Product formulation, including interaction at intermediate steps of manufacture,
is key in establishing appropriate cleaning procedures, acceptance criteria,
analytical methods, and sampling techniques.
Chemical and physical attributes of the product should be taken into account
when establishing the limit criteria, cleaning process, and analytical method for a
specific product.
solubility concentration physical property of the active ingredient and
excipient possible degradation effect of the cleaning agent
Limits of high risk drugs should be more stringent with a more robust cleaning
process than those with a lower pharmacological activity.
It may be chosen to dedicate the equipment to manufacture this type of
product.
If non-dedicated equipment is chosen, then risk management and robust
cleaning validation is needed.
Sometimes a facility may choose to use a deactivation or degradation step
such that residues from the active ingredient do not have the property that
make it highly hazardous.
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CV VMP Criteria
Formulation Attributes
Formulation attributes are categorized between solids, liquids, soluble, and
insoluble.
Have a great influence on the ability to clean a product.

Liquid formulations have a greater ability to reach certain parts of an


equipment inhibiting its removal.

Solid formulations may have unique abilities to form aggregates of product.


Thus, restricting the cleaning agents ability to remove product residues.

In terms of solubility, the more soluble the product the easier to remove.
However, there are products that exhibit both behaviors and requires a
combination of detergent and physical process.

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CV VMP Criteria
Product Grouping How to Do it?
The purpose of grouping is to find a common denominator whereby
similar products may be grouped. Thus making cleaning validation more
simple and manageable.

Grouping, in general, should be as follows:

Divide products first by dosage form and then by formulation.


Potency, toxicity, and solubility should be considered.
Then, further subdivide the group by types of equipment used during
manufacture, cleaning method and cleaning agent.

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CV VMP Criteria
Product Grouping How to Do it? Contd
Once the grouping by product is established, then a worst-case can be
determined. One per group is chosen. Here is where toxicity and
solubility comes into the equation.

It is important to note that in some cases you may have a group or


product that has a combination of dosage, toxicity and/or solubility.
Thus, you may have 2 worst-cases: one due to toxicity and one due to
solubility.

The most important aspect of the grouping is to have a documented


scientific rationale to justify the grouping and selection of the
representative worst-cases.

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CV VMP Criteria
Example of Grouping by Product
START
Group 1 Group 2 Group 3

10 Tableted 6 Ointment
Products Products 4 Liquid Products

6 wet 4 dry, direct 6 wet


2
granulation compression granulation
suspensions
process method process

Sub- Sub- Sub- Sub-


Group Group Group Group
1a 1b 3a 3b

Group 1 Group 2 Group 3 Group 4 Group 5


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1. PDA Technical Report No. 29, Points to Consider for Cleaning Validation.
CV VMP Criteria
Equipment Grouping How to Do it?
Define the grouping by equipment form and function.
Equipment with similar design and function are grouped together.
If there is equipment with similar design and function but differs in
scale, it may be grouped together.
IF the same cleaning procedures are to be implemented, largest and
smallest scale equipment may be validated within a group.
Note: Always include major process equipment in the cleaning
validation program effort.
Minor equipment may be validated separately.
Usually a procedure for miscellaneous parts is created to validate and
subsequently clean the smaller equipment. However, complexity,
geometry, and size are critical factors in the design of the cleaning
process.

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Cleaning Equipment and Sample
Development
There are 3 types of cleaning processes: manual, semi-automated, and
automated.

Which is best?
It depends on the facility, resources, product solubility, chemical reaction
and physical action of the residue removal.

Variables to consider are: equipment surface characteristics, equipment


geometry and composition, cleaning agent, temperature, and time exposure.

Note: No matter the type of cleaning, disassembly of the equipment may be


necessary to have an effective and reproducible cleaning.

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This is the direct cleaning of equipment by a trained operator using a variety of
hand tools (brushes, lint free cloth) and cleaning agents.
Parameters monitoring are the responsibility of the operator.
Critical parameters are: cleaning agent, temperature of wash and rinse solutions,
duration of wash and rinse cycles, and detergent concentration.
These critical parameters are part of the instructions within a SOP, where
the operator documents the values obtained.

Manual Cleaning
The critical factor is the ability to provide reproducibility of
the cleaning process.
Control is accomplished by training, having a well defined
SOP, and visual inspection.
The benefit is that the operator is conscious of what he is
performing and is able to adjust to and report changing
conditions.
This requires more sophisticated equipment to assist the operator.
There is some automation involved.
Usually the operator disassembles certain parts of the equipment prior to an
automated CIP or COP and some of those parts are cleaned manually.
OR the operator uses a spray device (e.g. spray balls) to clean the surface of the
equipment.

Semi-Automated
Cleaning
The critical factor is the still the ability to provide reproducibility
of the cleaning process for those steps that are manual.
Control is accomplished by training, having a well defined SOP,
and visual inspection for the manual steps and validation of the
cycle recipe for the semi-automatic portion of the cleaning.
The benefit is that the operator is conscious of what he is
performing and is able to adjust to and report changing
conditions.
Typically does not involve personnel intervention.
Usually the system is programmable for various cleaning cycles.
Critical parameters are: volume of cleaning agent, volume of rinse water, flow
rates, temperature of wash and rinse solutions, duration of wash and rinse
cycles, pressure of solution, operating ranges, and detergent concentration.
There may be some disassembly required to clean delicate parts separately.

Automated
Cleaning
Validation of the control system is very critical since it
regulates the cycles, addition of cleaning agents,
temperature, and time, among others.
Control is already accomplished by validation of the cycle
recipe.
The benefit is having consistent cleanings due to an
automated process.
Cleaning Equipment and Sample
Development
What is considered a residue and How to remove it?
The first thing to do is identify the substance to be cleaned.

Residues may be the active drug, excipients, processing aids, cleaning


agents, bioburden, endotoxin, and degradants.

Residues have physical and chemical properties which affect the way they
are removed.
Thus, type of cleaning and cleaning agents must be chosen carefully
depending on the physical and chemical properties of the residues to
be removed so that the cleaning process is successful.

61
Cleaning Equipment and Sample
Development
What is considered a residue and How to remove it? Contd
What aids in the removal of residues?
A cleaning agent is widely used for physical removal.
Water may be a simple/adequate way of removing highly soluble
material, unless the material has a combination of soluble and
insoluble properties where both a cleaning agent and cleaning process
must be chosen to do so.
Acids and base rinses are effective in removing certain proteins.
When using a cleaning agent one must be certain to demonstrate that
it also can be successfully removed.
For microbial contaminants, microbial limits must be established based
on route of administration and the nature of the product itself OR it
must be ensured the absence of objectionable organisms based on the
nature of the product AND/OR the amount of endotoxins on product
contact surfaces must be limited.

62
Cleaning Equipment and Sample
Development
What is the approach of Cleaning Frequency?
The frequency and rigor is usually determined by the nature of the
change-over process.

Usually, it depends if it is a single product or multiple product facility.


Between batches of different products
Cleaning takes place to prevent product cross-contamination when
changing from one product to another.

Between batches of the same product (campaign length)


Cleaning frequency within batches of the same product is
determined by validation.
By means of validation, number of lots of the same product that
may be consecutively manufactured before a rigorous cleaning is
established.
63
Cleaning Equipment and Sample
Development
What should be the considerations for New Products?
If a new product or significantly different raw material is introduced to the
facility, it must be tested to ensure that the cleaning process will remain
the same.
Generally, the cleaning effectiveness of an existing system for the new
product can be tested by performing laboratory studies using coupons of
relevant material.
A DOE can be made to test both the effectiveness of the proposed
cleaning process and the relative difficulty of cleaning the new product.
If the new product is easier to clean than the most difficult already being
cleaned, introduction of the new material using existing cleaning
procedures can be made with confidence.
Risk Assessments can be generated to justify the number of confirmatory
runs needed, if necessary.
If the material is more difficult to clean, modifications to current cleaning
procedures may be required and is expected to be validated.

64
Cleaning Equipment and Sample
Development
What should be the considerations for New Products? Contd
Introduction of new product into and already validated grouping requires
an assessment using the same science and risk-based evaluation process
of the validated grouping.
When testing the new product in the laboratory, it is recommended to
include the worst-case of the already validated grouping as a control.

If new product is easier-to-clean, then just the laboratory exercise and


confirmatory run is sufficient.
If new product is more difficult-to-clean, then full validation is required as
new product is the new worst-case.

65
Sampling Technique and Limits
Determination
The purpose of sampling is to evaluate the cleaning method in order to
determine cleaning procedure effectiveness.
The choice of sampling depends on the nature of the product residue,
cleaning agent, residue limit, desired analytical method, and manufacturing
equipment.
The agency expects a diagram that shows where (location) a sample is to be
taken.
Location must include the worst, most difficult to clean locations.

No matter the sampling technique chosen, recovery studies with the


sample/analytical method combination must be performed.
The objective is reproducibility in terms of recovery.

Swab, rinse, and visual inspection are mentioned as acceptable sampling


techniques in most regulatory documents.
66
Sampling Technique and Limits
Determination
Sampling Techniques
Swabs
The most widely used sampling technique.
Usually a swab is saturated with a solvent (e.g. water, alcohol,
methanol) aiding the solubilization and physical removal of residues.
PROS CONS
physically removes sample invasive technique that may
can be adapted to almost introduce fibers
any surface results may be technique
is cost effective and widely dependent
available swab material may inhibit
applies to active, cleaning recovery
agent, and microbial large, complex, hard-to-reach
residues areas may be difficult to evaluate
(e.g. pipes, valves, crevices,
mesh)
(may require more swabs) 67
Sampling Technique and Limits
Determination
Sampling Techniques
Rinse
This type of sampling is usually done at the end of the cleaning
process.
It should consider location, timing, and volume.
PROS CONS
easy to sample may lower test sensitivity
non-intrusive inability to detect location of
Less technique dependent residues
allows sampling of large rinse volume is critical to ensure
areas accurate interpretation of results
allows sampling of singular sampling methodology definition is
surfaces (e.g. porous) critical since method and location
applies to actives, cleaning may influence results
agents, excipients control of areas sampled may be
difficult, thus sample represents
complete equipment
68
Sampling Technique and Limits
Determination
Sampling Techniques
Coupon
The concept is to obtain a piece (2x2, 4x4, 5x5) of the MOC of the
equipment that is to be cleaned, attach it to the equipment, soil it with
product, and clean it per procedures. Once cleaned, it must be
submitted to the laboratory for recovery studies.
OR simply the laboratory performs a soiling process and the does the
recovery study.
PROS CONS
allows for direct surface invasive
sampling if used as part of the exercise, it
non-technique dependent may interfere with the cleaning
useful in development studies process
reduces variability in recovery subject to equipment geometry at
The most used technique to moment of attachment
evaluate multiple MOCs in
a Recovery Study.
69
Sampling Technique and Limits
Determination
Sampling Techniques
Visual Inspection
Well accepted practice; cleaning process should remove visible
residues from the equipment surfaces OR there is a until visually
clean instruction.
Regulatory expectation is that the equipment be visually clean by
viewing with the unaided eye.
PROS CONS
economical subjective
fast may require disassembly
complies with cGMPs cannot indicate whether a
history of satisfactory residue is at an acceptable level
results lighting, angle, distance affect
in conjunction with other the result
techniques (swab-rinse),
may aid in the cleaning
process
70
Sampling Technique and Limits
Determination
Sampling Techniques
Microbial Sampling (Test Methods)
The FDA states that Control of the bioburden through adequate cleaning and
storage of equipment is important to ensure that subsequent sterilization or
sanitization procedures achieve the necessary assurance of sterility.
Science- and risk-based rationales for excluding microbiological testing in
protocols may include manufacturing considerations, such as all solvent
processing for small molecule API manufacture, use of a final alcohol rinse for
oral dose drug products, use of subsequent sterilization cycles, and/or
demonstration of adequate microbial control in sufficiently similar cleaning
processes.
Bioburden Endotoxin
Testing performed through rinse water Typically performed for cleaning
sampling, swab sampling, and contact plate validation runs if the next product has
sampling. an endotoxin specification.
The rationale for rinse water sampling is that Are typically compendial methods.
it provides an overall picture of equipment Exclusions are science- and risk-based.
cleanliness. However, the full range of the
acceptance criteria is not able to be utilized.
Swab sampling is a direct measuring on
surfaces. 71
Sampling Technique and Limits
Determination
Limits Determination
A good Cleaning Validation Program depends in the determination
of cleaning limits and acceptance criteria.
Limits and acceptance criteria should be:
Practical limit chosen should be appropriate for the actual
cleaning situation to be validated
Verifiable by means of detection with a qualified analytical
procedure
Achievable by the analytical methodology available for the
specific product
Scientifically Sound rationale for the limit chosen,
appropriately documented in a logical, comprehensive and
readily understood way

72
Sampling Technique and Limits
Determination
Limits Determination Contd
What are the considerations for developing limits?
Since residues may transfer to the next manufactured product,
information must be readily available about potential residues as well
as the next product to be manufactured. Also, understand the cleaning
process.

Subsequently manufactured product: formulation product


specifications dosing route of administration batch size,
shared equipment
Cleaned product: formulation dosing toxicity route of
administration
Cleaning Process: cleaning agent cleaning method cleaning
parameters

73
Sampling Technique and Limits
Determination
Limits Determination Contd
What is the basis for quantitative limits?
Limits are usually based in:
Pharmacological potency of the drug active: formulation product
specifications dosing route of administration batch size, shared
equipment
Toxicity of the residue: formulation dosing toxicity route of
administration
Analytical Limit of Detection: cleaning agent, cleaning method,
cleaning parameters

MAC =
Where:
MAC = maximum allowable carryover If next product is not known, then the
TD = single therapeutic dose smallest batch size of any product
BS = batch size of the next product to be manufactured previously in the equipment
manufactured in the same equipment can be used.
SF = safety factor
LDD = largest daily dose of the next product
to be manufactured in the same equipment 74
Sampling Technique and Limits
Determination
Limits Determination Contd
Limit based on Toxicity of residue
The therapeutic dose is the basis of limits calculations for situations where the
material is an active ingredient and the therapeutic dosage level is known.
Sometimes there are materials where no quantitative therapeutic dosage level
is known BUT the effect of toxicity is known. Thus, the calculations are based
on the toxicity of the material.
NOEL = LD50 empirical factor
Where: ADI = NOEL AAW SF
NOEL = no observable effect level
LD50 = lethal dose for 50% of animal population study
Empirical factor = derived from animal model developed by Layton et.al.
ADI = acceptable daily intake
AAW = average adult weight
SF = safety factor
This equation can be applied to a pharmaceutical cleaning validation study as follows:
ADI B
Where: MAC =
R
MAC = maximum allowable carryover
B = smallest batch size of any subsequent product
R = largest daily dose of any product made in the same equipment 75
Sampling Technique and Limits
Determination
Limits Determination Contd
Safety Factor
We want the amount of residue to be safe, therefore a safety factor is added
to the equation
It is optional in some cases BUT not when using LD50.
The greater the Safety Factor, the larger the reduction in the limit.
1/1000 is the industry standard.

Typical Approach Applicable to: Approach


Topical Products 1/10th to 1/100th of normal daily dose
Oral Products 1/100th to 1/1000th of normal daily
dose
Parenteral, Ophthalmic Products 1/1000th to 1/10,000th of normal
daily dose
Research, Investigational Products 1/10,000th to 1/10,000th of normal
daily dose

76
Sampling Technique and Limits
Determination
Limits Determination Contd
The meaning of None Detected
This is a very common term in the laboratory.
None Detected does not equal zero
That is, it does not mean that there was no residue present.
It means that the level of residue was below the detection capability of the
analytical technique or instrument, often referred to as the sensitivity of
the method.
Thus, the sensitivity parameter is very important and must be validated.
It is expressed as the limit of detection OR the limit of quantitation

77
Ongoing of Verification of Cleaning
Maintenance of Validated State
Standard Operating Procedure
An SOP should consider the following:
Maximum allowable hold time for a piece of equipment,
after use but before cleaning,
after cleaning but before use, sanitization, or sterilization
steps for disassembly
critical sites or hard-to-clean areas with instructions
Cleaning process parameters
Explicit description of the methods, equipment, and materials used for
cleaning
Diagrams, photos with locations for sampling and locations for hard-to-
clean areas
Visual inspection
Separate SOP for sampling technique
Where / how clean equipment will be placed, tagged
to prevent cross-contamination
78
Ongoing of Verification of Cleaning
Maintenance of Validated State
Documentation
A Protocol should consider the following:
purpose, validation design, strategy, scope, responsibilities, applicable
product(s) and equipment, cleaning procedure and associated
documentation, acceptance criteria, training, and requirement for a final
report.
Key elements should be:
residue limits, sampling procedures, and analytical methods
Number of Runs
Traditional approach: 3 consecutive runs
Consecutive means that no cleaning events of the same process are
skipped without an appropriate rationale.
Lifecyle approach: provide a rationale, based on an understanding of the
cleaning process, documentation from the design and development phase,
and data from sufficiently similar cleaning processes, for a specific number
of validation runs required.
This might result in fewer than 3 run. 79
Ongoing of Verification of Cleaning
Maintenance of Validated State
Documentation
Worst-case Process Conditions
Traditional Approach: include the worst-case process conditions in the 3
runs, where the rationale is given or referenced from the VMP.
Worst-case conditions may be: maximum dirty hold time, maximum
batches or elapsed time in a campaign, shortest allowed time for
manual cleaning steps, lowest allowed temperature for manual
cleaning processes, and worst-case circuit for CIP skid selection.
New approach: address specific worst-case process conditions in each run
or in the design and developing phase.
Disposition of Products and Equipment
Generally, the cleaning process only affects the next product manufactured in
the cleaned equipment. Therefore, following protocol execution the cleaned
product may be released following company procedures for product release.
The release is independent of the data obtained immediately following the
cleaning process. The data from that cleaning process is
used for the release of the cleaned product.
80
Ongoing of Verification of Cleaning
Maintenance of Validated State
Operator Training (and re-training)
This is a critical step for the program.
Operators should be trained in the evolving draft SOPs until they become
effective.
They need to understand the instructions and demonstrate the correct
procedure of cleaning
They need to understand Why we clean
Should be under a qualification / re-qualification basis
Samplers must also be trained and qualified / re-qualified for sampling
techniques of the day-to-day activities.
Training may be improved by:
Clearly written and detailed SOPs
Use of checklists to document each critical step and parameter and the
parts of the equipment cleaned
Periodic monitoring of the cleaning process to ensure continued
compliance
Feedback of operators to modify cleaning procedures 81
Ongoing of Verification of Cleaning

Maintenance of Validated State


The main tools to ensure the validated state are critical parameter controls, risk-
based periodic monitoring, data trending, training / re-training (specially for
manual cleaning).
Critical Parameter Control
Once the critical parameters used to control the cleaning process are defined
and theres an understanding of the process and its variability, strategies to
maintain the process control should be put in place.
An examples is defining ranges to those critical (scrub-temperature-time)
cleaning process steps so that they can be monitored and maintained during
the day-to-day activities. This assures that they do not vary outside the
defined range.
Trending
Trending of performance data (continuous data like final rinse discrete date
like yes/no if alarm activated) is important for identifying potential cleaning
issues before they result in ineffective cleaning processes.
Performance data not in compliance must trigger investigations.

82
Ongoing of Verification of Cleaning

Maintenance of Validated State Contd


Cumulative Changes Evaluation
The importance is to review the cumulative impact of the changes on the
cleaning process.
Consider two scenarios: (1) many minor changes, each deemed to have no
impact on the validated state, but as a whole could have an adverse impact in
the process OR (2) one major change that makes you re-evaluate the cleaning
validation program.
The key is to provide documented evidence that the cleaning meets the pre-
approved requirements.
Annual Product Reviews
Annual review of cleaning process and cleaning validation data is used to
identify areas for improvement by analyzing trends, investigations, and
cumulative changes; and determine the need for changes to parameters,
specifications, procedures or other control documents related to the cleaning.

83
THANKS

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