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Develop and Implement a Cleaning Validation Master

Plan

03/15-16/16

Karem Y. Monge SepúlvedaMS Physics, CQA

Senior Scientist Technical ServicesMylan LLC

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References

• Pharmaceutical Inspection Convention (PIC/S): Recommendations onValidation Master Plan, Installation and Operational Qualification, Non-SterileProcess Validation, Cleaning Validation (PI 006-3, September 2007)

• Health Sciences Authority – Regulatory Guidance – Preparation of ValidationMaster Plan (January 2013)

• White Paper: Reasons, Regulations, and Rules: A Guide to the ValidationMaster Plan (VMP) Pharmaceutical Engineering 2001 - BW Saxton

• PDA Technical Report No. TR 29 (Revised 2012) Points to Consider forCleaning Validation

• PDA Technical Report No. TR 49 Points to Consider for BiotechnologyCleaning 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

• IGH Quality Guidelines (QbD: ICH Q8, ICH Q9, and ICH Q10)

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Overview1

• Cleaning Validation is a required activity within the pharmaceutical,biological, nutritional supplement, and medical device industries. From botha regulatory and industry standpoint, cleaning validation is recognized as animportant activity to establish that product cross contamination is controlledto ensure patient safety and product quality.

– is the documented evidence that an approved cleaning procedure will provideequipment that is suitable for processing of pharmaceutical products or activepharmaceutical 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, astreamlined cleaning program may be developed that is both science-basedand 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

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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 company’s overall philosophy, intentions, and approaches to be used for establishing performance adequacy. The validation master plan should be agreed upon by management.”

• Furthermore, a visit to the FDA site for Warning Letters andNotice of Observations (483s) yields several mentions of aValidation Master Plan. This is simple proof that this documentis an expectation of the FDA’s auditors, often requested duringan inspection.

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INTRODUCTION

• We are moving from a period of collecting large amounts of dataand closing the exercise with a report (based on FDA’s 1987definition) TO collecting data throughout the lifecycle of theprocess, method or system, evaluate if it is scientifically sound, anddetermine if it supports the quality of such process, method orsystem (based on FDA’s 2011 definition).

• It is the aim of the Validation Master Plan to help the SiteManagement in understanding what entails the Validation Program(Cleaning Validation Program), assign tasks and responsibilities, andmost importantly inform the Auditors how the Site is organized andit’s 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 stateof validation.

–It is used to establish performance adequacy,define extent of testing expected, and outline testprocedure and protocols.

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General Information• Purpose

–Provide a summary of the facility’s validation statusand strategy, including legacy plans, currentqualification and validation status and plannedvalidation and re-validation activities, with regardto all products, processes, equipment, test methods,cleaning, critical utilities, and computer-relatedsystems.

• 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 facility’s CleaningValidation Program status, strategy, andexpectations including legacy plans, currentcleaning validation status, planned cleaningvalidation 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 productionprocesses that impact the quality of the resultingproduct.

–Once it is approved, it should be reviewed bymeans of supplements, which will focus onchanges to the approved revision and newprojects.

• This review must be done at least annually.

–A VMP should be considered a living document tobe referenced and updated throughout the projectand the life of the facility.

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General Information• Role1

–Is to help an organization get “its arms around” aproject-specific validation effort by setting thescope by which all subsequent documents shall bebounded.

–Serves as a validation roadmap, setting thecourse, justifying the strategy, outlining thepreliminary test and acceptance criteria, anddocumenting the necessary programs that ensurea continuing state of validation.

1. “Reasons, Regulations, and Rules: A guide to the Validation Master Plan (VMP) by Bryan W. Saxton in May/June 2001 Pharmaceutical Engineering

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General Information• A VMP:

– Requires planning, a well defined approach, and preparation of thedifferent steps/stages in the process.

– It should be structured taking into consideration SOPs, GMPs, andregulations.

– 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 Projectspecific 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 VMPrequirements. In general, they are responsible of providing and supporting theresources as indicated in the VMP, and assuring the extent of testing is inconformance with cGMPs and facility standards.

• Approvers are usually responsible in the approval of the documentation to beused in validation and pre-approve test plans with acceptance criteria.

• Projects of certain complexity / size may require additional approvers (GlobalManagement, Quality Unit, Engineering, Research and Development,Regulatory Affairs) according to their responsibility in the execution of thevalidation activities described in the VMP.

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VMP Documentation DesignGeneral Format Requirements for

VMPs (Site VMPs)• Preamble

• Introduction

• Organizational Structure and Responsibilities

• Facilities Description

• Manufacturing / Packaging Operations

• Validation Documentation

• Equipment Qualification

• Utilities Qualification

• Components Qualification

• Cleaning Validation

• Product / Process Validation

• Test Method Validation

• Validation Maintenance

• References

• Attachments

• History

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VMP Documentation DesignGeneral Format Requirements for CV

VMPs• Purpose

• Scope of the Cleaning Validation Program

• Responsibilities

• List of Equipment and Products to be validated

• Means of cleaning documentation (e.g. SOPs and protocols)

• Prerequisites to CV (e.g. equipment and utility qualification)

• Use of various cleaning systems (e.g. CIP, COP or manual cleaning)

• Cleaning reagents

and mechanisms

• Definition of “Worst-case conditions” associated with a cleaning process (e.g. flow rates or step durations)

• Description of family approach and grouping of products, equipment or system

• Approach to determine “worst-case product”

• Use of dedicated or shared equipment and single use (disposable) equipment

• Definition of circumstances in which cleaning verification is preferred or acceptable (e.g. clinical stages)

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VMP Documentation DesignGeneral Format Requirements for CV

VMPs• Strategies and definitions for

indirect product contact surfaces and non-product surfaces (e.g. lyophilizers)

• Equipment hold study approaches (e.g. dirty hold time, clean hold time or storage hold)

• Microbial contamination (e.g. bioburden and endotoxin)

• Sampling techniques (e.g. visual inspection, rinse sampling or swan sampling)

• Training / qualification for sampling techniques

• Analytical Methods (e.g. validation and recovery requirements)

• Calculations and/or rationales and formulas for limits for process residues, microbial contaminants and cleaning agents

• Validation maintenance (including routine monitoring, change control, and periodic review)

• Attachments or Appendices (e.g. tables or lists of items within the realm of the plan)

• Requirement for reassessment of cleaning validation master plan (i.e. review frequency)

• Summary of current status and upcoming plans

• References

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VMP Documentation DesignContent

• Preamble

– Identify the version number of the VMP and the schedule forvalidation activities and the dates covered.

– Include the Legacy Plan section for qualification of equipment,process, and system used for GMP related purposes, for whichthere is no formal qualification documentation or when qualificationdoes not meet current standards.

• Introduction

– Summarize the VMP strategy. Establish the reasons for thevalidation effort and key background information. Also, identifyapplicable change control documents that authorize the validation.

– Give the breadth and reach of the validation

effort.

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• Organizational Structure and Responsibilities

– Include an Organizational Structure of the company, and identify thedepartments responsible for all validation and validation supportactivities. Usually the development of the VMP resides in TechnicalServices, although input from other departments may be solicited andintegrated into the document.

• Facilities Description

– Describe, in general, the products manufactured, building design, andareas classification.

– Include the planning phase, purpose of the facility, the products to bemanufactured, 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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• 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 protocolgeneration and approval processes.

– Include concerning validation documentation and referenceSOPs of the different validation/qualification programs.

• Utilities Qualification

–Describe briefly the utilities that require qualification and itscomputerized control system, when applicable.

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VMP Documentation DesignContent• Equipment Qualification

– Include the approach to evaluate and perform the equipment validation,which should include the computerized control system that controlsdocuments or acquire data for GMP related activities, when applicable.

• Components Qualification

– Describe the approach used to qualify the components, status andapproach.

• Test Method Validation

– Provide information/description regarding the current state of MethodValidation for each product and process.

– In general, QC Laboratories generate their own VMP, thus it becomes asubordinate 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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• 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 anddedicated equipment, acceptance criteria, determination of worst-case, if usingrinse, swab, TOC samples, microbial testing, and visual inspection, analyticalmethod validation, chemical swabbing procedure, Clean Holding Time and DirtyHolding Time definition, protocols, reports, data collection, and archiving.

– It should include approach to protocols, technical reports, document review andapproval process, data collection and archiving, and support activities that areperformed as required in response to additions, modifications and changes toequipment, processes, systems, and facilities

– The validation approach section shall include a description of how risk analysis willbe applied in the site.

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• 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 productsmanufactured in the facility.

– Include the concept of “product lifecycle”.

– Validation approach describes the philosophy and approach to validation includingprotocols, technical reports, document review and approval process, datacollection and archiving, and support activities that are performed as required inresponse to additions, modifications and changes to equipment, processes,systems, and facilities.

– The validation approach section shall include a description of how risk analysis willbe applied in the site.

1. Guidance for Industry: Process Validation: General Concepts and Practices January 2011, CGMP, Revision 1

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• References

– Identify documents that were used in the generation of theVMP, such as corporate guidelines, product monographs,regulatory submissions documents, project scope documents,functional requirements specifications, and validationdepartment SOPs.

• Attachments

– Identify and attach all applicable documents referenced(value-added information) in the VMP.

• History

–Usually includes the revision history of the document insequential order.

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VMP Documentation DesignContent• Usually a section will have:

– Approach, Status, Plan (Action Plan)

• Action Plan

– Include the Timelines and Milestone section of the VMP documentsand the sequence and hierarchy of operation of validation activities.

– Specific action plans, responsibilities, and scheduled completiondates need to be planned and approved for allqualification/validation activities.

– The department manager or person(s) responsible for assuring thatvalidation items are completed, as indicated, shall be identified andlisted on the Action Item plan. Charts, tables and lists, which aresubject to periodic updating, may be attached to the

VMP as appendices, when approved.

Template: Site VMPs

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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 theVMP information.

– Once all approval signatures are obtained, ensure all pre-requisiteconditions are met before releasing the VMP for execution.Pre-requisite conditions may include:

• Completion of construction, installation, startup, andcommissioning activities.

• Generation of applicable draft SOPs and other relevantdocuments, such as maintenance-calibration programs.

• Documented training on operation of equipment/systems andprocesses, as applicable.

• Completion of predecessor protocols and approval of allassociated 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 TechnicalReport.

• The purpose is to summarize the results of the VMP listed activities,completion of requirements, and compliance with the pre-approvedacceptance 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 DesignBenefits ad StrategiesKaizen / 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 customer’s needs (specifications).

– It generates zero or negative return of investment and usually can be eliminated / reduced / simplified without

impairing the process.

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VMP Documentation DesignBenefits ad Strategies - Exercise

• Preparing Engineering Drawings

• Archiving Validation Binder

• Approved Template

• SOPs

• Training

• Deviation System

• Reviewing (various cycles)

• Reworking (may be the same

sentence)

• Copying Reports (that may be

in easy retrievable system)

• Obtaining Multiple Approvals

• Transcribing Data

Value Added Non-Value Added

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VMP Documentation DesignBenefits ad Strategies - Examples

• Have a robust protocol template

• Clearly define the deviation management

• Sort out how the review process of protocols /reports and datawill 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 notvalidated while another is.

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VMP Documentation DesignBenefits 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 allInvestigations and Change Controls, give training to impactedareas, 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 willgive support so that they know the timelines

• Clearly indicate the selection criteria governing whatequipment/utility will undergo qualification / process validation.

• Clearly inform when to re-validate, when to re-qualify

Cleaning Validation Master Plan

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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 iscompliance 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 cleanequipment that is suitable for its intended use which will ensure patient safety andproduct quality.

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Cleaning Validation Program

CV Master Plan CV Assessments CV SOPCV Protocols and

ReportsCV Runs

Limits Definition

Worst-Case Definition

Hard-To-Clean Locations Definition

Clean and Dirty Hold Time Definition

Cleaning Agent Selection

Sampling Method Selection

Critical Process Parameters (T, t, rinse, soak, etc.)

Sampling Sites

Residue Evaluation (product-cleaning

agent-micro)

Methods Validation

Recovery Studies

Product Characteristics

Product Grouping

Equipment Characterization

Equipment Train Definition

Equipment Grouping

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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 validationapproach.

– 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 cometo light

• how to best challenge the process, collect samples, and monitor thecleaning effectiveness during routine cleaning process can bedelineated.

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CV VMP Criteria

• What is needed to establish the CV Program? Cont’d

– 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 integratedwith the control of the system.

– Cycle must be validated so that it provides reproducible results for theoperating 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 cleaningprocedures, and visual inspection.

– Attention is given to hard-to-clean and/or hard-to-reach equipment parts.

– Success is obtained by consistently performing written proceduresinstructions.

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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 equipment’s 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 Cont’d

• 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, andinsoluble.

• Have a great influence on the ability to clean a product.

– Liquid formulations have a greater ability to reach certain parts of anequipment 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 acombination 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 wherebysimilar products may be “grouped”. Thus making cleaning validation moresimple 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 duringmanufacture, cleaning method and cleaning agent.

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CV VMP Criteria

• Product Grouping – How to Do it? Cont’d

– Once the grouping by product is established, then a worst-case can bedetermined. One per group is chosen. Here is where toxicity andsolubility comes into the equation.

• It is important to note that in some cases you may have a group orproduct that has a combination of dosage, toxicity and/or solubility.Thus, you may have 2 worst-cases: one due to toxicity and one due tosolubility.

– The most important aspect of the grouping is to have a documentedscientific rationale to justify the grouping and selection of therepresentative worst-cases.

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CV VMP Criteria• Example of Grouping by Product

6 Ointment

Products

10 Tableted

Products 4 Liquid Products

6 wet

granulation

process

4 dry, direct

compression

method

6 wet

granulation

process

2

suspensions

Group 1 Group 2

Sub-

Group

1a

Sub-

Group

1b

Group 3

Sub-

Group

3a

Sub-

Group

3b

START

Group 1 Group 2 Group 5Group 3 Group 4

1. PDA Technical Report No. 29, Points to Consider for Cleaning Validation.

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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 inscale, it may be grouped together.

– IF the same cleaning procedures are to be implemented, largest andsmallest scale equipment may be validated within a group.

• Note: Always include major process equipment in the cleaningvalidation program effort.

– Minor equipment may be validated separately.

– Usually a procedure for miscellaneous parts is created to validate andsubsequently clean the smaller equipment. However, complexity,geometry, and size are critical factors in the design of the cleaningprocess.

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Cleaning Equipment and Sample Development

• There are 3 types of cleaning processes: manual, semi-automated, andautomated.

• Which is best?

– It depends on the facility, resources, product solubility, chemical reactionand physical action of the residue removal.

• Variables to consider are: equipment surface characteristics, equipmentgeometry and composition, cleaning agent, temperature, and time exposure.

• Note: No matter the type of cleaning, disassembly of the equipment may benecessary to have an effective and reproducible cleaning.

Manual Cleaning

• This is the direct cleaning of equipment by a trained operator using a variety ofhand 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.

• The critical factor is the ability to provide reproducibility ofthe cleaning process.

• Control is accomplished by training, having a well definedSOP, and visual inspection.

• The benefit is that the operator is conscious of what he isperforming and is able to adjust to and report changingconditions.

Semi-Automated Cleaning

• 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.

• The critical factor is the still the ability to provide reproducibilityof 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 thecycle recipe for the semi-automatic portion of the cleaning.

• The benefit is that the operator is conscious of what he isperforming and is able to adjust to and report changingconditions.

Automated Cleaning

• 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 rinsecycles, pressure of solution, operating ranges, and detergent concentration.

• There may be some disassembly required to clean delicate parts separately.

• Validation of the control system is very critical since itregulates the cycles, addition of cleaning agents,temperature, and time, among others.

• Control is already accomplished by validation of the cyclerecipe.

• The benefit is having consistent cleanings due to anautomated process.

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• 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, cleaningagents, bioburden, endotoxin, and degradants.

– Residues have physical and chemical properties which affect the way theyare removed.

• Thus, type of cleaning and cleaning agents must be chosen carefullydepending on the physical and chemical properties of the residues tobe removed so that the cleaning process is successful.

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• What is considered a residue and How to remove it? Cont’d

– 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 solublematerial, unless the material has a combination of soluble andinsoluble properties where both a cleaning agent and cleaning processmust 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 thatit also can be successfully removed.

• For microbial contaminants, microbial limits must be established basedon route of administration and the nature of the product itself OR itmust be ensured the absence of objectionable organisms based on thenature of the product AND/OR the amount of endotoxins on productcontact surfaces must be limited.

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• What is the approach of Cleaning Frequency?

– The frequency and rigor is usually determined by the nature of thechange-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 whenchanging from one product to another.

• Between batches of the same product (campaign length)

– Cleaning frequency within batches of the same product isdetermined by validation.

– By means of validation, number of lots of the same product thatmay be consecutively manufactured before a rigorous cleaning isestablished.

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• What should be the considerations for New Products?

– If a new product or significantly different raw material is introduced to thefacility, it must be tested to ensure that the cleaning process will remainthe same.

• Generally, the cleaning effectiveness of an existing system for the newproduct can be tested by performing laboratory studies using coupons ofrelevant material.

• A DOE can be made to test both the effectiveness of the proposedcleaning process and the relative difficulty of cleaning the new product.

– If the new product is easier to clean than the most difficult already beingcleaned, introduction of the new material using existing cleaningprocedures can be made with confidence.

• Risk Assessments can be generated to justify the number of confirmatoryruns needed, if necessary.

– If the material is more difficult to clean, modifications to current cleaningprocedures may be required and is expected to be validated.

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• What should be the considerations for New Products? Cont’d

– Introduction of new product into and already validated grouping requiresan assessment using the same science and risk-based evaluation processof the validated grouping.

• When testing the new product in the laboratory, it is recommended toinclude the worst-case of the already validated grouping as a control.

– If new product is easier-to-clean, then just the laboratory exercise andconfirmatory run is sufficient.

– If new product is more difficult-to-clean, then full validation is required asnew product is the new worst-case.

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Sampling Technique and Limits Determination

• The purpose of sampling is to evaluate the cleaning method in order todetermine cleaning procedure effectiveness.

• The choice of sampling depends on the nature of the product residue,cleaning agent, residue limit, desired analytical method, and manufacturingequipment.

• The agency expects a diagram that shows where (location) a sample is to betaken.

– Location must include the worst, most difficult to clean locations.

• No matter the sampling technique chosen, recovery studies with thesample/analytical method combination must be performed.

– The objective is reproducibility in terms of recovery.

• Swab, rinse, and visual inspection are mentioned as acceptable samplingtechniques in most regulatory documents.

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• 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• physically removes sample• can be adapted to almost

any surface• is cost effective and widely

available• applies to active, cleaning

agent, and microbial residues

CONS• invasive technique that may

introduce fibers• results may be technique

dependent• swab material may inhibit

recovery • large, complex, hard-to-reach

areas may be difficult to evaluate (e.g. pipes, valves, crevices, mesh) • (may require more swabs)

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– Rinse

• This type of sampling is usually done at the end of the cleaningprocess.

• It should consider location, timing, and volume.

PROS• easy to sample• non-intrusive• Less technique dependent• allows sampling of large

areas• allows sampling of singular

surfaces (e.g. porous)• applies to actives, cleaning

agents, excipients

CONS• may lower test sensitivity• inability to detect location of

residues• rinse volume is critical to ensure

accurate interpretation of results• sampling methodology definition is

critical since method and location may influence results

• control of areas sampled may be difficult, thus sample represents complete equipment

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– Coupon

• The concept is to obtain a piece (2x2, 4x4, 5x5) of the MOC of theequipment that is to be cleaned, attach it to the equipment, soil it withproduct, and clean it per procedures. Once cleaned, it must besubmitted to the laboratory for recovery studies.

• OR simply the laboratory performs a soiling process and the does therecovery study.

PROS• allows for direct surface

sampling• non-technique dependent• useful in development studies• reduces variability in recovery• The most used technique to

evaluate multiple MOCs in a Recovery Study.

CONS• invasive• if used as part of the exercise, it

may interfere with the cleaning process

• subject to equipment geometry at moment of attachment

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– 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• economical• fast• complies with cGMPs• history of satisfactory

results• in conjunction with other

techniques (swab-rinse), may aid in the cleaning process

CONS• subjective• may require disassembly• cannot indicate whether a

residue is at an acceptable level• lighting, angle, distance affect

the result

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– Microbial Sampling (Test Methods)

• The FDA states that “Control of the bioburden through adequate cleaning andstorage of equipment is important to ensure that subsequent sterilization orsanitization procedures achieve the necessary assurance of sterility.”

• Science- and risk-based rationales for excluding microbiological testing inprotocols may include manufacturing considerations, such as all solventprocessing for small molecule API manufacture, use of a final alcohol rinse fororal dose drug products, use of subsequent sterilization cycles, and/ordemonstration of adequate microbial control in sufficiently similar cleaningprocesses.

Endotoxin• Typically performed for cleaning

validation runs if the next product hasan endotoxin specification.

• Are typically compendial methods.• Exclusions are science- and risk-based.

Bioburden• Testing performed through rinse water

sampling, swab sampling, and contact platesampling.

• The rationale for rinse water sampling is thatit provides an overall picture of equipmentcleanliness. However, the full range of theacceptance criteria is not able to be utilized.

• Swab sampling is a direct measuring onsurfaces.

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• 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

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• Limits Determination Cont’d

– 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

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– 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 = 𝑇𝐷 × 𝐵𝑆 × 𝑆𝐹

𝐿𝐷𝐷

Where:MAC = maximum allowable carryoverTD = single therapeutic doseBS = batch size of the next product to be manufactured in the same equipmentSF = safety factorLDD = largest daily dose of the next product to be manufactured in the same equipment

If next product is not known, then the smallest batch size of any product manufactured previously in the equipment can be used.

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– 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

ADI = NOEL × AAW × SF Where:NOEL = no observable effect levelLD50 = lethal dose for 50% of animal population studyEmpirical factor = derived from animal model developed by Layton et.al.ADI = acceptable daily intakeAAW = average adult weightSF = safety factorThis equation can be applied to a pharmaceutical cleaning validation study as follows:

MAC = ADI × B

R Where:

MAC = maximum allowable carryoverB = smallest batch size of any subsequent productR = largest daily dose of any product made in the same equipment

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– 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

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– 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

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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 forcleaning

– 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

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– Documentation

• A Protocol should consider the following:

– purpose, validation design, strategy, scope, responsibilities, applicableproduct(s) and equipment, cleaning procedure and associateddocumentation, acceptance criteria, training, and requirement for a finalreport.

– 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 areskipped without an appropriate rationale.

– Lifecyle approach: provide a rationale, based on an understanding of thecleaning process, documentation from the design and development phase,and data from sufficiently similar cleaning processes, for a specific numberof validation runs required.

» This might result in fewer than 3 run.

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– Documentation

• Worst-case Process Conditions

– Traditional Approach: include the worst-case process conditions in the 3runs, where the rationale is given or referenced from the VMP.

» Worst-case conditions may be: maximum dirty hold time, maximumbatches or elapsed time in a campaign, shortest allowed time formanual cleaning steps, lowest allowed temperature for manualcleaning processes, and worst-case circuit for CIP skid selection.

– New approach: address specific worst-case process conditions in each runor in the design and developing phase.

• Disposition of Products and Equipment

– Generally, the cleaning process only affects the next product manufactured inthe 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 thecleaning process. The data from that cleaning process is

used for the release of the cleaned product.

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– 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

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– 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 there’s 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.

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• Maintenance of Validated State Cont’d

– 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.

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