Regulatory aspect of pharmaceutical change control system

REGULATORY ASPECT OF
PHARMACEUTICAL CHANGE
CONTROL SYSTEM

PRESENTED BY
DEVESH SHARMA
M.PHARM (DRA)
devesh.m.pharmdra@gmail.com

CHANGE CONTROL

 A process that ensures that changes to materials,
methods, equipment and software are properly
documented, validated, approved and traceable.
 The process includes evaluation to determine
whether validation is required and the level of
validation required.

BENEFITS OF CHANGE CONTROL
SYSTEM
 Careful planning helps to ensure that the change
process is started and managed by the right people
at the right time
 Planned change management allows you to include
specific tasks and events that are appropriate for
each stage in the change process
 Change management ensures that customers,
suppliers and other stakeholders understand and
support the change
 Change control reduces disruptive aspects and
emphasizes positive opportunities in the change
process
 Change control allows easy tracking of changes
and compliance to FDA regulations.

Applying these steps, the system can be
designed for managing the configuration
and controlling the change, and then the
necessary procedures and forms can be
prepared. It is important that the system
design come first. Specifically:
 Identify the change to be made
 Accumulate and review the baseline
documentation, including drawings,
procedures, P&IDs, equipment data sheets
and MOC forms.

MANAGEMENT OF CHANGE AND
CONTINUOUS IMPROVEMENT
Changes to process, equipment, procedures, technology,
material and organization are necessary for continuous
improvement and a MOC system must also be
continuously improved. The process requires eight basic
steps:

 Identification
 Documentation review
 Change proposal
 Change classification
 Implementation plan
 Installation
 Verification
 Closure

PREPARE A CHANGE PROPOSAL

 used to document the changes in the specific
application area.
 It is assigned a change proposal number, identifies
approval authority, defines security, and establishes
issued date, effective date, and distribution.
 The baseline configuration and documentation are
verified.
 From this point on, the change proposal must be
controlled throughout the lifecycle.

CLASSIFY & APPROVE PROPOSED CHANGES
 The Change Control Board must review, evaluate,
and approve changes and then classify the change
as minor, moderate and major.

DEVELOP AN IMPLEMENTATION PLAN

 The implementation plan describes how the change
will be put in place.
 Baseline documentation is updated.

 Operators and maintenance personnel are trained
in the change.

INSTALL THE CHANGE
 This step speak for itself.

VERIFY INSTALLATION
 Verify that each step in the process is completed
and the documentation matches the “as-built”
configuration.
 Conduct a system audit.

CLOSE OUT THE CHANGE
 Everything is completed and the cycle is repeated
for the next proposed change.

 Managing change requires that the purpose
and justification of the change be
documented; change be reviewed for
impact on safety, health and environment;
cGMPs be reviewed for impact on GMP
values; additional risk is not introduced into
the process; authorization be documented;
process information be updated; operating
and maintenance procedures be revised;
personnel who are affected by the change
be trained; and configuration of the plant be
maintained.

FLOW CHART OF CHANGE MANAGEMENT SYSTEM

HANDLING AND CONTROLLING
CHANGES-
 Handling and controlling change, initiator call for a
meeting of change control team and puts the proposal
for change with the problems and consequences and
advantages.
 Team reviews-
Should the change be allowed?
Partly or Wholly?
Regulatory impact?
GMP & safety impact?
Need for requalification or revalidation?
Customer/ Agency to be informed?
Category of the change? Reporting category?
Documentation requires & documents affected?

 If the team has decided on above points, the CCIF
(change control initiation form) is processed by the
team members for a sign-off & each member
understands her/his responsibilities.
 the initiator coordinates the change process at all
levels.
 QA checks the adequacy of the process data,
impact and follow up closure and communicates to
the customers/clients and management.
 Regulatory prepares the reporting document for the
agency.

SOP ON CHANGE CONTROL
 The purpose of this SOP is to describe in detail the
change control process flow, starting with a request for a
change following necessary assessments and
approvals.
 This standard process ensures that all planned changes
related to any aspect of manufacture, testing and
distribution are reviewed, assessed and approved by
technical and quality competent site personnel, which
includes Quality Assurance.
 The main task is to evaluate potential impacts followed
by correlative consequences of the requested change
on product quality, current Good Manufacturing Practice
(cGMP), including qualification and validation and the
regulatory file/dossier before approval and
implementation of a change control request.

 This procedure applies to all new and existing
manufacturing/packaging processes, utilities, major
equipment, computerized systems, facilities, drug
products, drug substances, medical devices, raw
materials, components, testing requirements,
specifications and systems for marketed products
and clinical trials (clinical, preclinical and stability
with GMP implications). Documents and systems
that may be impacted by a given change in any of
these areas include, but are not limited to, all
master documents, Marketing Authorization
Applications (MAA‟s), New Drug Applications
(NDA‟s), validation, stability protocols and control
systems.

Company Name Page
Department SOP No.+ Version No.
Change Control Supersedes: SOP No.
Attachments:
Effective date: DD/MM/YYYY

1. Regulatory Basis, Reference Documents
 CFR 314.70 “Supplements and other changes to an
approved application”
 Commission Regulation EC 541/95 “Variation to
the terms of a marketing authorization
 ISO 9004 08.8 Design Change Control

11.6 Process Change Control

 PIC – PH 1/96
 ICH Q7A chapter 13 „Change Control‟

2. PURPOSE

 The purpose of this SOP is to describe in detail the
change control process flow, starting with a request
for a change following necessary assessments and
approvals.
 This standard process ensures that all planned
changes related to any aspect of manufacture,
testing and distribution are reviewed, assessed and
approved by technical and quality competent site
personnel, which includes Quality Assurance.

 The main task is to evaluate potential impacts
followed by correlative consequences of the
requested change on product quality, current Good
Manufacturing Practice (cGMP), including
qualification and validation and the regulatory
file/dossier before approval and implementation of a
change control

3. SCOPE
 This procedure applies to all new and existing
manufacturing/packaging processes, utilities, major
equipment, computerized systems, facilities, drug
products, drug substances, medical devices, raw
materials, components, testing requirements,
specifications and systems for marketed products
and clinical trials (clinical, preclinical and stability
with GMP implications).

 Documents and systems that may be impacted by a
given change in any of these areas include, but are
not limited to, all master documents, Marketing
Authorization Applications (MAA‟s), New Drug
Applications (NDA‟s), validation, stability protocols
and control systems.

4. RESPONSIBILITIES AND ACCOUNTABILITIES
4.1 Applicant/Change requester
 As a matter of principle every individual who had
been trained on the change control SOP should use
the change control form attached to this SOP to
request a change

CATEGORY OF CHANGES
 Impact assessment of changes is extremely
important to the agency & changes are outlines as
Major, Moderate & Minor.
 A compliance of regulatory group within the
company determines the filing impact and submits it
to FDA,-

A Prior- Approval Supplement (PAS) for major
changes,
A CBE -30 or CBE-0 for moderate changes or
Annual report for Minor changes.

MAJOR CHANGES-
 Is likely to have a detectable impact on the critical
attributes of the product, significantly.
 Could shift the process in a discernible manner ( Such
as: quality, yield, stability, impurity profile, crystal form,
particle size, bulk density)
 Warrants definite additional/ major testing & suitable
revalidation studies to justify changes.
 Reviewed by QA at the facility level & approved by
corporate groups.
 Requires prior FDA approval.
Eg. Change in equipment type ( Dryer, configuration,
Blender type, crystallizer type, tablet compression
machine, coating equipment)
Revision of standard test procedure for assay
(potentiometric to HPLC) for related substance ( TLC to
HPLC), for residual solvents (GC to Head space)

Change work flow task from initiation to closure from traceable
authenticity

MODERATE CHANGES-
 Is usually for improvements to process, materials,
product or procedure
 Therefore, no reason to wait for approval
 Does not require prior approval by regulatory /FDA
before implementation
 The agency will want to review it
 Can go in annual report to FDA
 Can be evaluated by QA, at the facility & then approved
by corporate groups.
 These are called “ change being effected”
 Categories are CBE-30 & CBE-0
Eg. Improvement in yield
Improvement in critical quality

MINOR CHANGES

 Is unlikely to have a detectable impact on the
critical attributes of the products.
 Does not shift the process in any discernible
manner
 Can be implemented with minimal testing and
revalidation
 Can be reviewed and approved by QA at the facility
level
 Is reported in annual reports to FDA and does not
require FDA approval
Eg. Like for like equipment replacement
Noncritical process parameter

Regulatory aspect of pharmaceutical change control system

When developing a change control procedure
following points must be considered
 Developing a robust change control system

 Educate users of the change control system, and

 Enforce change control system policies and
procedures

ENSURING TRAINING & PROCEDURES IN A
MANAGEMENT OF CHANGE PROGRAM
 Training in change is required for all changes in process
and operation; technology; facilities and equipment; and
procedures.
 It may be as simple as reading and initialing simple
changes in a procedure if it does not affect skills or
knowledge. In other cases, it could require developing
new lesson plans to teach the new skills and knowledge,
or developing and delivering structured on-the-job
training.
 Reinforcement training, an FDA requirement, is targeted
for performers to maintain their skills and knowledge.
Training in change should be critical and may cover
much of the reinforcement training.

LEVEL OF APPROVAL-
 The change control proposals are formal
documents and must be initiated by the affected
group. For eg production unit is the effected group
for changes to equipment and facility expansion. in
this eg, production unit will initiate the change
proposal
 This proposal could reviewed and discussed by
other responsible persons from departments, such
as R & D ,QA ,Regulatory and affected client.
 However, the final approval is granted by Quality
Unit.

Assign levels of approval within departments for
changes
 Categorized as major, the review and approval
must be dealt with by senior experts from
stakeholder department and Quality Unit.
 In contrast ,for the change categorized as Minor,
the review and approvals can be delegated to
trained personnel who are not necessarily from
senior management.
Once a manual process has been implemented,
one of the stakeholder groups such as Regulatory
needs to conduct an internal audit once a year.
When all of the pieces, are in place, change control
process /program will provide the ability to submit,
evaluate, approve, communicate, correctly
implement and document all change that impact
SQIPP.

REGULATOR PROSPECTIVE OF CHANGE
CONTROL
Considering the regulatory prospective of change control
procedures, it is important to note that there are many
guideline which describe the control of changes in
manufacturing few references includes
 21 CFR Part 211: Sec. 211.100
There shall be written procedure for production and
process control designed to ensure that the drug product
have the identity, strength, quality and purity. They
purport or are represents to process.
These written procedure, including any changes, shall we
drafted, reviewed, and appointed by the appropriate
organizational units & reviewed & approved by the quality
control unit.

 21 CFR Part 211.194 (Laboratory Records)
Complete record shall be maintained of any modification of an
established method employed in testing. Such records shall
include the reason for the modification & data to be verify that
the modification produced results that are at least as accurate
& reliable for the material being tested as established method.
 ICH Q7A

A formal change control system should be established to
evaluate all changes that could affect the production & control
of the intermediate or API. Written procedures should provide
for the identification, documentation, appropriate review, &
approval of changes in raw materials, specifications, analytical
methods, facilities, support systems, equipment, processing
steps, labeling & packaging materials & computer software.

 USFDA Guidance for Industry: Change to an
approved NDA or ANDA ( April 2004- Revison-1)
 This guidance provides recommendations to holders of
new drug applications (NDAs) & ANDAs who intend to
make post approval changes in accordance with section
506A of federal Food, Drug & Cosmetic Act ( the act) &
$314.70 (21 CFR 314.70)
The guidance covers recommended reporting categories
for post approval changes for drugs other than specific
biotechnology & specified synthetic biological products.

CONCLUSION-
 Change is inevitable, and because continuous
improvement is impossible without change, progress is
built on change.
 The key to making successful change in the
pharmaceutical world is to manage it, both from internal
and external perspectives.
 Changes can happen at any time during a product‟s
lifecycle. The impact of the change needs to be balanced
against the cost of making the change (safety, time and
money).
 Impact of change may require amendments to registered
details. Changes must be formally documented and
approved via a change control process. It needs to
evaluate risk assessments throughout change control
process.

REFERENCE-
1. Change Control in the FDA-regulated Industry,
http://www.metricstream.com/insights/chg_ctrl_FDA.htm
2. "Guidance for Industry: Quality Systems Approach to
Pharmaceutical CGMP Regulations"(PDF). U.S. Food and
Drug Administration. September 2006.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceR
egulatoryInformation/Guidances/UCM070337.pdf.
3. Infusion. "Challenges of Change Control in a Regulated
Industry". http://www.infinityqs.com/asset-
library/articles/ChangeControlChallenges.pdf.
4. ICH. "Q7: Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients".
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/
Guidelines/Quality/Q7/Step4/Q7_Guideline.pdf.
5. “Change management methods and implementation best
practices”
http://www.itsm.info/ITSM%20Change%20Management%20
Best%20Practices.pdf

6. “Standard operating procedure SOP-Pharma”
http://www.gmp-online-
consultancy.com/standard_operation_procedure.htm
7. “Change of Control”http://www.gmp-online-
consultancy.com/e/info_preview/Change_Control_V2_P3.p
df
8. “Pharmaceutical change control”
http://www.pigmp.com/pdf/pharmaceutical-change-
control.pdf
9. U.S. Food and Drug Administration, 21 CFR Part 314.70,
Supplements and other changes to an Approved
Application, Revised as of April 1, 2000.
10. U.S. Food and Drug Administration, 21 CFR Part 211,
Current Good Manufacturing Practice for Finished
Pharmaceuticals.
11. U.S. Food and Drug Administration, Compliance Program
Guidance Manual 7346.832, Preapproval
Inspections/Investigations.
12. U.S. Food and Drug Administration Modernization Act of
1997, Public Law 105-115, 105th Congress.

13. U.S. Food and Drug Administration, Center for Drugs and
Biologics and Center for Devices and Radiological Health,
Guideline on General Principles of Process Validation.
14. Parenteral Drug Association, Current Practices in the
Validation of Aseptic Processing, 2001, Technical Report No.
36.
15. “ICH Q10 Pharmaceutical Quality System”
http://www.ich.org/fileadmin/Public_Web_Site/
GMP_Inspector_perspective.pdf
16. “GOOD LABORATORY PRACTICE (GLP)”
http://apps.who.int/tdr/... /good-laboratory-practice-
handbook/pdf/glp-handbook.pdf
17. Change Control – Perspective from a Pharmaceutical
Company,
http://www.ipacrs.com/PDFs/SQC%2028%20May/Riddell.pdf
18. “Management of change”
http://www.pharmamanufacturing.com/articles/2008/057.html?
page=2

Regulatory aspect of pharmaceutical change control system

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