change control luisa stoppa manufacture of sterile medicines – advanced workshop for sfda gmp...

Change Control

Luisa Stoppa

Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors

Nanjing, the People’s Republic of China – 16-20 November 2009

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Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectorsNanjing, the People’s Republic of China, 16-20 November 2009

Objectives of the presentationObjectives of the presentation

To answer to the following questions:

What is the purpose of change control?

What must be taken into consideration when introducing change control programs?

How can changes be graded?

What should be regulated in a “change control” operating instruction?

What is the function of the change control committee?

How shall the implementation of changes be recorded?

What has an inspector to inspect and to check?

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ProgrammeProgramme

To introduce the general elements on change control

To train you in the guidelines (WHO-GMP, PIC/S guidelines, EU-GMP)

To become confident with SOP, forms and records of Change Control System

To develop your inspection plan on change control

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Principles of change controlPrinciples of change control

Before a medicinal product can be released, we need:

the manufacture and quality control procedure should be documented in the form of instructions;

The materials to be used must be specified;

The basic conditions required for a reproducible quality, efficacy and safety must be defined (i.e. suitable rooms, qualified facilities, trained personnel, validated procedures, established specifications)

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Before the requirements can be implemented, the suitability of equipments/facilities and procedures must be proven with qualification / validation

This principle is not only valid the first time a medicinal product is manufactured or the first time a facility is used or a procedure comes into effect

The principle applies to the whole history of a medicinal product, a procedure or a facility and it is to be guaranteed

As each requirement is stated in a document, it is clear that each change control for the requirements must also always involve a documentation control

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Each change to previously approved requirements requires a review and authorization to keep the system in its original state of “proven suitability”

Formal change control guarantees that all changes are evaluated for their effect on product quality or validation status

Change control minimizes the risk that changes can have on the quality or process characteristics

Change control programs have become recognized as essential element of the pharmaceutical quality assurance system

The task of

change control

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In the WHO-GMP guideline glossary there is definition of the term “change control”

However, the GMP guideline basically contains only few notes about the handling of changes

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In the American Code of Federal Regulation CFR, the responsibility for the verification and authorization of changes is task of the quality control unit

In the EU regulations, the responsibility is assigned to Quality Unit

As the change control is considered an essential element of the pharmaceutical quality assurance system, it is logical the person responsible is quality assurance (QA representative, QA head)

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Change control is not department-specific, rather the task of the whole company

The change control monitors all types of changes which can influence the process or product quality and states the measures necessary for implementing the change or decides that a change should not be implemented

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records / forms and other relevant documents

standard operating procedure / instructions

QM statement

change requests and other relevant documents

operating instructionfor change control

changepolicy

Change control programsChange control programs

Change control program is a managerial task

We expect a quality structure of change control

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Many types of changes affect several areas at the same time:

GMP requirements Regulatory requirements

Process security (validation)

Product quality (specifications, approval)

Effectiveness / safety (approval)

Suitable rooms and equipment (qualification)

Suitable personnel (training, experience)

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A central processing of change procedures, coordinated by the quality assurance department, has several advantages:

– there is a common understanding of what a change represents;– the classification schemes used by the staff involved to rate

changes are congruent;– the risk connected with the change can be evaluated in a multi-

disciplinary manner;– there is uniform documentation and authorization procedure


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The type and scope of a change control program must comply with the requirements:

1. In the classical GMP-relevant areas the change control helps to maintain the validated and established status. Validated processes, qualified facilities, material specifications can be influenced by changes and medicinal products no longer comply with specifications


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2. Holder of marketing authorization must guarantee that necessary regulatory pre-requisites are met. Contract manufacturers that do not have their own authorization must guarantee that the contract giver is informed of internal changes that could have an influence on their application documentation (this requires that the contract giver is included in the change control program of the contract manufacturer)


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3. In areas where medicinal products are developed, processes are optimized or clinical research takes place, changes should also evaluated and documented so that the development of medicinal product or process must be consistently proved


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Many companies rate the changes requiring control

EU-GMP

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The example is one way to rate them:

Major changeMinor changeNot requiring control

Significance of change

Influences product quality or process reliability

Influences a unit requiring control

No relevance to GMP or authorization

Possible measures (selection)

Official license

New approval

revalidation

Amendment

Review

documentation

No relevance to GMP or authorization

examplesChange of manufacturer: other synthesis route of a starting material (other impurities)

Removal of processes to another site

Change in the product composition

Change to the process parameters

Replacement of apparatus part of the same design

Change of cleaning agent for floors

Change of laundry for work clothes (non-sterile or antibiotics area)

Change to working times

Installation of air conditioner in administrative area

Change in purchase procedure

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Other classifications are possible

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It is not decisive which and how many change-classes a company has rated, but how it is guaranteed that changes requiring control are recognized as such and implemented according to a defined procedure


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Not all changes require a revalidation


WHO-GMP

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In the PIC/S document PI 006 (chapter 6.7.4) there is a list of changes that may require a re-validation:


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Also in the WHO-GMP guidelines there is a list of changes that may require a re-validation


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WHO-GMP guidelines


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PIC/S document PI006


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The so called “trials” cause a problem in change control program.

Trials are preliminary, temporary changes which can permanently established or revoked after a trial period

With trials, there is a risk that these intended temporary changes gradually become permanent changes without a formal change control procedure being carried out

How long a trial is retained and whether it is withdrawn after a trial phase or be introduce permanently, should be included in the same procedure “change control” as all other changes


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“Deviations” should not be treated as changes, not even when deviations become changes after a failure has been clarified

Deviation is an unplanned and undesirable deviation from a requirement; it occurs spontaneously

Deviations should be dealt with according a procedure about “handling deviations”

All variations implemented in emergency (no planned, no controlled, no permanent) are included in deviations


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Changes )planned changes(

Deviations )unplanned changes(

Submission of request -description of change

-rationaleEvaluation

-effect on validation status -definition of revalidation measures

ApprovalImplementation of changeClosing

Notification -description of deviation

Evaluation -effect on product quality

-definition of corrective actions -effect on validation status

-definition of revalidation measures

Implementation of deviationClosing


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An important function as part of the change control program is fulfilled by the “change control committee CCC” (also known as change control team or change control board)

This committee consists of the head of Quality assurance, the heads of manufacturing, quality control, regulatory affairs, IT department, engineering, sales

The task of the committee is to evaluate the changes, establish and coordinate measures to put in place and authorize the changes


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PIC/S guideline

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A problem is the issue of which changes the change control team should dealt with

It is obvious that this team cannot deal with all changes in the company

As matter of fact, only changes requiring control should be processed by this team


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Firstly, these are changes relevant for the regulatory status

Secondly, they are changes which could have an influences on the attributes of a GMP-relevant system, facility, equipment, material/product, procedure/process

The team should also deal with all changes whose grade or implementation is unclear or questionable


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How the team members communicate with each other?

Not all changes require a meeting

In cases which are easy to make a decision about, it can be useful traditional paper-based circulation procedures, e-mail agreement or access to Intranet-based forms


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When a change control program has been introduced, the effectiveness of the system can be reviewed using data which is easy to determine

Total number of changes request /year

Number of completed change requests / year

Change type / department involved

Duration of procedure: from application to closing

Number of deviations/year

Number of internal or external complaints /year

Number of OOS /year


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EU-GMP

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Change control requires a written procedure to establish at least the following steps:

What type of changes does change control take into account?What are the requirements for urgent changes?For which areas does this operating procedure apply?Who can suggest changes?How are changes requested (forms, method of communication)?How are changes graded and who is responsible for the rating?How are the measures for carrying out the change established?Who is responsible for the implementation and monitoring of all measures?Who is included in the change control team?What are the duties of the change control team?How is the change documented (format, content, storage)?Who is responsible to authorize changes?

DocumentationDocumentation

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All quality-relevant changes should be documented

All actions to be taken, including the need for and extent of qualification or validation, should be described

The records can be archived in paper form or electronically

When storing documents, raw data and other relevant documents for change should be kept accessible


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Changes requiring control are generally documented in the form of a “change request” in which the applicant for the change proposes the type of change, suggests the timeframes and measures for carrying out the change

The change control team authorizes or not the change

The documentation for the change procedure should show that the change was evaluated (risk analysis)


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WHO-GMP

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Change control procedure (example 1)


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Change control procedure (example 2, 1/2)


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Change control procedure (example 2, 2/2)


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Change control procedure includes flow chart of the change control process and the change request form (or change form)

Change request form records a request for change so that each change is documented before it is approved

The change request form includes the description of the change, the benefits, costs, urgency of the change, change impact


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Change control procedure: flow chart (example 1)


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Change control procedure: flow chart (example 2)Change Request

Submission

Evaluation ofChange Impact

Validation Change Request

More information

required

Change Activities

Change Closed

Approval

Activities Completion

Change Activities

Approval

Activities Completion

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CCB = change control board

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Change control procedure: flow chart for change master documents (example 1)

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Change request form (example 1, 1/2)


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Change request form (example 3)


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Change database: electronic copy

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Change control logbook

Change control logbook (year:________)

Nb. Request date

Requester / department

ItemDescriptionApproval date

Actions and time limit

Closing date

Page:__ of____

QA Manager signature _________ Date_______

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Examples of changesExamples of changes

Changes to the cleaning procedure- use of a new cleaning agent

- change in concentration / volumes of cleaning agent

- change in volumes of rinsing water

- change of cleaning process parameters

Changes to the production equipment- changes to the CIP equipment

- changes to / replacement of equipment parts (difficult to give detailed examples as these changes are too diverse)

- change of process parameters

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Examples of changesExamples of changes

Changes to the product

- changes to composition (reformulation with different excipients)

- changes to the manufacturing process (i.e. transfer of a product)

Changes to HVAC system / unidirectional flow

Changes in lay-out (i.e. implementation of a pass-box)

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Inspection planInspection plan

To ask for the Change Control standard operating procedure

To check that all relevant steps for change control implementation are detailed

To choose some applications (from the list in the logbook)

To verify the applications and all requested documents (change request form, investigation, request and closing date)

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ConclusionConclusion

The old adage says: the only thing constant is change!

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Reference documentsReference documents

WHO GMP guidelines – Technical Report series n. 937

EU GMP guidelines, Part I annex 15

ICH Q7A or EU GMP Part II chapter 13

PIC/S Recommendations PI 006-3

62 |Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

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change control luisa stoppa manufacture of sterile medicines – advanced workshop for sfda gmp...

Documents

principles of change

change control programs

purpose of change control

change control committee

task of change control

quality control procedure

documentation control

sfda gmp inspectors