QUALITY MANAGEMENT SYSTEM IN

CHANGE CONTROL AT INDUSTRY

LEVEL: AN OVERVIEW
ABSTRACT

Change is inevitable in a pharmaceutical manufacturing operation. Vendors change

processes, sources, and specifications for raw materials, equipment requires repair,
service, or replacement, manufacturing locations are changed, batch sizes are
increased or decreased and advancements in technology are made that dictate changes
to the operations. After issuing of Marketing Authorization and/or manufacturing,
many changes occurs across the Product lifecycle, i.e. Scaling up of pilot batch into
commercial batch and variation in manufacturing processes, excipients and
manufacturing sites. All these changes are considered as post approval changes or
variations. These variations need to be approved by the respective regulatory
authorities of a country. If not, it puts the marketing authorization holder and/or
license holder at risk. Proper management of changes is critical and proper change
management reduces the risk of suspension of licenses and the warning letter from the
regulatory authorities. The present review provides an industry perception on Change
Control system and importance of the Quality Management System.

Keywords: Marketing Authorization, Post Approval Changes, Marketing

Authorization Holder.

INTRODUCTION

Change is an inevitable phenomenon especially in the pharmaceutical industry where,

with an advent of technology and knowhow, machines and manufacturing processes
tend to change over a period of time in efforts to improve manufacturing and
operating efficiencies.

The question “How can we update or change the information in an approved

application?” is often asked. The answer varies (the batch sizes needs to change, there
are new methodologies and specifications developed, we want to manufacture and test
at a different site, etc.). These changes are called “post approval changes” (PACs)
because they effect applications that have already been approved [1].

Changes in the Pharmaceutical system are entirely different from the deviation.
Table 1: Comparison between change control and deviation

Change control Deviation

 Deviation is an aberration from the
given procedure which is done pre-
Change control is a strategic activity to bring planned or accidently. A deviation can
about changes in document/process/method. It be divided into critical & non critical.
can be for the smaller period of time or it can be Effects of critical deviations should be
long term usable. It must be informed to all the accessed through investigation CAPA
concerned departments for official approval of (Corrective action and preventive
Change Control. action system)

Deviation is defined as “Any non-compliance of an established GMP standard or of

approved requirements, specifications and standard operating procedures. Deviations
need to be documented, evaluated and when appropriate, investigated in order to
determine the originating causes to prevent recurrence” [2].

There are many different circumstances to use the term “deviation”. No well-
established definitions were found in the various regulatory documents in the USA or
the EU. The terms used by these authorities are not always the same (for example,
deviation, discrepancy, a typical situation, nonconformity). Therefore, it is
authoritative for a company to define internally, what is deviation? in order to avoid
ambiguity and possible mistakes concerning workflows and responsibilities [3].

Examples for potential deviations in different areas are listed in table 1 [3].

Table 2: Examples of potential deviations

Machines, plants, equipment,

Production process facilities, and media (includingQuality control
laboratory)
 Manufacturing Formula  Machine defects  Statistical reports of
 Processing Parameters (e.  System failures IPQC test results
g. Equipments, machines  Temperature, humidity, which results in
and instruments) number of particles or deviation (OOS)
 In process parameters pressure differences  Statistical results of
(IPQC limits and/or outside IPQC tests which
specification)  of limits results in out of trend
  Deviations in
 Standard operating
microbiological
procedures to conduct (OOT)
monitoring
IPQC tests  Results close to
 Calibration results
 Controls (e. g. Using specification limit
outside of limits
obsolete versions)  Using expired
 Failure to keep
 In-process specifications  Reference standards
calibration or
 Anomalies in the process
maintenance intervals

Sources of the changes in GMP

Change can come from many different directions, experience has proven that
change(s) within a critical compliance and quality system will have the largest impact.
The following are some area which is the sources for change: [4].

Potential changes during development and post commercialization [4].

Regulations Vendors
Customer requests/complaints Facility
Personnel Validation
Technology Research
Testing methodology Development

Table 3: Changes during product development & post commercialization

Particular Changes
Composition: Percentage of active and inactive ingredients per
Formulation
unit dose
Active Pharmaceutical Ingredient
Alternate manufacture
(API)
Altered impurity profile
Physical characteristic
New manufacturing process
New raw starting materials(s) excipients
 Official grade change
New raw starting materials(s) excipients
Official grade change
Raw material change
Equipment Bench scale
Pilot plant
Biobatch
Scale batches
Commercial size
Continuous improvement
Process optimization
Repairs and maintenance
Cleaning Procedures Manual to automated
Equipment configuration changes
Manufacturing Process Critical parameter changes
Operating range changes
Optimal condition changes
Scale-up
Technology transfer
Rework/reprocessing procedure
Analytical Method Development Qualified method
Validated method
Optimize and/or modernize method
Customize a compendial method
Stability Profile Container closure system(s)
Storage conditions
Expiry period
Facilities Controlled environment requirements
Preventative maintenance
Emergency repairs
Validated classified areas
Structural changes
Cross contamination prevention
General housekeeping and sanitation
Cleaning agents and pest control
Critical utilities
Critical utilities Clean steam
Potable and purified water systems
HVAC systems
Compressed air system
Dust collection system
Emergency repairs to critical utilities
Changes in PM maintenance schedule
Natural disasters Facility changes
Utility changes
Validated system changes
 Personnel turnover and loss
Critical components Containers
Closures
Labeling
Packaging materials
Inserts
Desiccants
Vials
Tubes
Changes to any critical parameters of these components must
be monitored

Change management system

A formal system by which qualified representatives of appropriate disciplines review

proposed or actual changes that might affect the validated status of facilities, systems,
equipment or processes. The intent is to determine the need for action that would
ensure and document that the system is maintained in a validated state. Paragraph is
the definition [6].

History of change management [7]

Change Management as a discipline initiated to emerge in the 1980s motivated by top

consulting organizations working with Fortune 50 organizations. Initial adopters, like
as GE, Ford, and AT&T, were very large companies that might derive important
savings through more competently applying new packages and were accustomed to
cutting edge thought management roles. This work resulted in early Change
Management models such as GE’s Change Acceleration Process (CAP) and John
Kotter’s Eight Step Process for Leading Change. At the moment, Change
Management offerings were typically accessible through consulting services, with a
limited number of books and textbooks available.

During the 1990s, industries undergoing important and fast change in areas such as
information technology and human resources began highlighting the benefits of
Change Management programs on a wider scale. The practices, consequences, and
prices of applying change without an organized method has helped staff and
companies embrace Change Management tools. Though use of Change Management
was still incomplete primarily to large corporations in the habit of regularly utilizing
specialized consulting firms, Change Management was getting more and more
perceptibility and reliability.

The 2000’s marked extensive acceptance of Change Management as a business

competency for leading change. This alteration improved the reliability of Change
Management in the commercial world and with project teams. The benchmarking data
on ‘use of a methodology’ shows a noticeable increase from 34% in 2003 to 72% in
2011. The value of Change Management was further validated through additional
research on the impact of Change Management on business success by Prosci, IBM
and McKinsey.

The market for Change Management tools and training grew fast through this period,
with as many as 320 accessing firms recognized as offering Change Management
facilities by 2011. Some were recognized with their own Change Management
procedures while others, that previously only offered consulting services, also
provided exercise and some level of product offerings as well.

Benefits of change management process [8]

 Change is a planned and managed process. The advantages of the change are
well understood before execution and serve as motivators and assessment of
progress
 The firm can respond quicker to client demands
 Helps an organization to line up current resources within the system
 Change control & management permits the firm to measure the total influence
of a change
 Variation scan be applied without undesirably effecting the regular process in
company
 Organizational effectiveness and efficiency is continued or even improved by
allowing the concerns of employees
 Timeline to implement the change will be reduced
 Shortcomings in the process can be reduced
 Employee’s will aware about the change associated with the company and
performance of employee will also increased
 Customer service and effective service will increase to clients and customer
 Change management offers a way to anticipate challenges and respond to the
prescribed changes efficiently
 Proper change management process lowers the risk associated with the process
and change
 investment on capital will be reduced and helps to contain costs associated with
change
 Increases revenue of the company
 Generates an chance for the growth of "best practices", leadership
development, and team development

Opinion on change management system by various authorities

As per EU GMP: “A formal system by which qualified representatives of appropriate
disciplines review proposed or actual changes that might affect the validated status of
facilities, systems, equipment or processes. The intent is to determine the need for
action that would ensure and document that the system is maintained in a validated
state” [6].

EU GMP also provides notes regarding handling of the Changes: “Significant

amendments to the manufacturing process, including any change in equipment or
materials, which may affect product quality and/or the reproducibility of the process,
should be validated” [9].

21 CFR 211.100 and 21 CFR 211.160 is also provides two brief notes on “Change
Control”

211.100 Written Procedures; deviations: “There shall be written procedures for

production and process control designed to assure that the drug products have the
identity, strength, quality, and purity they purport or are represented to possess. Such
procedures shall include all requirements in this subpart. These written procedures,
including any changes, shall be drafted, reviewed, and approved by the appropriate
organizational units and reviewed and approved by the quality control unit” [10].

211.160 General Requirements: “The establishment of any specifications, standards,

sampling plans, test procedures, or other laboratory control mechanisms required by
this subpart, including any change in such specifications, standards, sampling plans,
test procedures, or other laboratory control mechanisms, shall be drafted by the
appropriate organizational unit and reviewed and approved by the quality control unit.

The requirements in this subpart shall be followed and shall be documented at the
time of performance. Any deviation from the written specifications, standards,
sampling plans, test procedures, or other laboratory control mechanisms shall be
recorded and justified” [11].

As per the Pharmaceutical Inspection Convection and Pharmaceutical Inspection Co-

operation Scheme (PIC/S)

Change Management: Written procedures should be in place to describe the actions to

be taken if a change is proposed to a starting material, product component, process
equipment, process environment (or site), method of production or testing or any other
change that may affect product quality or reproducibility of the process. Change
control procedures should ensure that sufficient supporting data are generated to
demonstrate that the revised process will result in a product of the desired quality,
consistent with the approved specifications [12].
Change Control: “Change control is an important element in any Quality Assurance
system. Written procedures should be in place to describe the actions to be taken if a
change is proposed to a product component, process equipment, process environment
(or site), method of production or testing or any other change that may affect product
quality or support system operation” [13].

Responsibilities

Process Owner/Principle Investigator [14]

 Responsible for technical changes and to follow the valid change control
procedure
 Decides about the impact of the technical change on product quality
(major/minor impact). The participation of the QU in this decision should be
clearly established according to the company in this matter.
 It is recommended that the process owner prepares a list of changes with no
impact expected on product quality (Standard changes).

Quality Unit [14]

 The involvement of the quality unit is required if the change is thought to have,
or potentially have, impact on the product quality.
 The quality unit is responsible for the implementation and maintenance of the
change control system.
 The quality unit has to approve the standard change list.

Process owner/Principle Investigator and quality unit [15]

Every technical change with major impact should be assessed at least by the process
owner and/or principal investigator and the quality unit.

They should decide about the measures to be taken to document the change
appropriately.

Functional Group Responsibilities [1].

Table 4: Functional group responsibilities

Conformance to Regulatory
Initiation regulation Review Impact and
of ChangeProofreading(cGMP) andand Worldwide Validation
Control applicability toApproval Filling
other system Strategy
Quality     
-
Assurance
 
Quality Control - - - -
 
Manufacturing - - - -
Process  
- - - -
Engineering
Technical  
- - - -
Services
Regulatory  
- - -
Affairs
Owner of
System or  
- - - -
procedure being
changed

Elements of an Integrated, Comprehensive, and Far-reaching change

management system [4]

1. Empowers an organization’s personnel by inviting anyone to propose a change:

Everyone in your organization holds unique knowledge and perspective. Make
it easy for anyone to suggest a change by having a simple form and an SOP on
how to use it.
2. Affords a way to communicate both vertically and horizontally around issues of
change: with many changes occurring simultaneously, it is very important to
have a system that will keep track of them and keep people current as to the
status of each pending change.
3. Provides a viable mechanism for continuous improvement to forward quality:
Change can be a big contributing factor toward continuous improvement. A
good system gives you a systematic, documented way to evaluate and
incorporate product and process improvements.
4. Allows for full assessment of a particular change prior to implementation:
What appears to be a good change for one area may in fact have a negative
impact on another area. A good system allows for everyone to give input
regarding the impact of change.
5. Provides a systematic and formalized approach to review proposed changes: A
system helps ensure that change justification is documented and the right
people are evaluating and approving each change, and identifies other systems
impacted.
6. Allows for a coordinated implementation. With the potential for many areas to
be impacted by a change, all these activities and documents must have a
synchronized implementation.
 7. Provides a documented trail and various levels of accountability. ‘‘Not
documented, not done.’’ This old rule is still applicable when it comes to
change management.

Pharmaceutical quality system (PQS) [16]

Management system to direct and control a pharmaceutical company with regard to

quality; the elements described below might be, required in part under regional GMP
regulations. These four elements are:

 Process performance and product quality monitoring system

 Corrective action and preventive action (CAPA) system
 Change management system
 Management review of process performance and product quality

Change management system [16]

Innovation, continual improvement, the outputs of process performance and product

quality monitoring and CAPA drive change. In order to evaluate, approve and
implement these changes properly, a company should have an effective change
management system.

There is generally a difference in formality of change management processes prior to

the initial regulatory submission and after submission, where changes to the
regulatory filing might be required under regional requirements.

The change management system ensures continual improvement is undertaken in a

timely and effective manner. It should provide a high degree of assurance there are no
unintended consequences of the change.

The change management system should include the following, as appropriate for
the stage of the lifecycle:

a. Quality risk management should be utilized to evaluate proposed changes. The

level of effort and formality of the evaluation should be commensurate with the
level of risk;
b. Proposed changes should be evaluated relative to the marketing authorization,
including design space, where established, and/or current product and process
understanding. There should be an assessment to determine whether a change
to the regulatory filing is required under regional requirements.
 c. Working within the design space is not considered a change (from a regulatory
filing perspective). However, from a pharmaceutical quality system standpoint,
all changes should be evaluated by a company’s change management system;
d. Proposed changes should be evaluated by expert teams contributing the
appropriate expertise and knowledge from relevant areas (e. g., Pharmaceutical
Development, Manufacturing, Quality, Regulatory Affairs and Medical), to
ensure the change is technically justified. Prospective evaluation criteria for a
proposed change should be set;
e. After implementation, an evaluation of the change should be undertaken to
confirm the change objectives were achieved and that there was no deleterious
impact on product quality.

Application of Change Management System throughout the Product Lifecycle:

Table 5: Application of change management system

Pharmaceutical Commercial Product

Technology transfer
development manufacturing discontinuation
Change is an inherent
The change A formal change
part of the development
management system management system
process and should be Any changes after
should provide should be in place for
documented; the product
management and commercial
formality of the change discontinuation
documentation of manufacturing. Oversight
management process should go through an
adjustments made to by the quality unit should
should be consistent with appropriate change
the process during provide assurance of
the stage of management system.
technology transfer appropriate science and
pharmaceutical
activities. risk based assessments.
development.
0.6.7 0.6.8 Procedure of change control

Process of change control [13]

“Commitment of the company to control change to premises, supporting utilities,

materials, equipment and processes used in the manufacture of medicinal products is
essential to ensure a continued validation status of the systems concerned. This
commitment should be stated in the relevant company documentation. For example,
the Quality Manual, Quality Policy Documents or the Validation Master Plan; as part
of its Quality Management System the company should have a defined and formalized
Change Control Procedure.”
Flowchart 1: Process of change management system [1]

Procedure for change control process at Company and/or Sponsor Level

Following procedure is applies for both GMP [14]

 The procedure should always begin with a request for a change. This request
should be formalized in some way, for example as a form, and be signed.
 The request triggers the question of the impact of the change on the product
quality/safety of the population. It can be necessary to define several levels of
impact on product quality but there should be at least two categories; major and
minor impact. The treatment of these two options should be clearly different.
 There should be clear rules for the decision, whether the impact of the change
on the product quality and/or on study is major or minor: who decides and why
the decision is taken.
 For the management of changes, an early decision is required of who should be
involved. The decision should be taken by the process owner, who normally
has the best knowledge of the impact of changes on the product or study (or at
least can estimate it with a high degree of certainty). The principle of double
checking should be implemented at this point of the procedure. A signature by
the technical department is first required. Depending on the company’s or
sponsor’s procedure, the quality unit can be involved as an approver to check
periodically by self-inspection audits.
 If the owner has decided that the change is minor and there is no likely to
impact on the quality of the product, it can be implemented. The change should
be adequately documented.
 The implementation of the changes with minor impact can be achieved in a
very rapid and efficient manner using checklists of standard changes. The list
of these changes should have been approved by the quality unit.
 If the decision has been taken that the change can or will have an impact on the
quality of the product and/or safety of the population, the quality unit has to be
involved. An adequate rationale and an appropriate action plan should
accompany such request. This builds the basis for the approval by the quality
unit.
 After the Quality Unit approval, the change can be implemented. If other
aspects are affected by the change, for example safety aspects, additional
release activities can be needed. Where such activities have been defines, these
should be fulfilled before the refuse of the equipment. Release of the equipment
itself can be one of these activities.
 The start of a change control system for technical equipment should be
established after the completion of qualification. This will ensure that the
qualified status is maintained.
 Change control before completing qualification need not possess the same
degree of formality as it can be easier regulated and can proceed without the
formal and immediate involvement of the quality unit. The required activities in
this case are adequate documentation of the changes and a periodical adaption
of the documentation.
  The change requests for emergency changes can be formalized after the
replacement. Emergency cases should be defined by each company in an
appropriate way.

Documentation

“All changes should be formally requested, documented and accepted by

representatives of production, QC/QA, R&D, Engineering and Regulatory Affairs as
appropriate. The likely impact (risk assessment) of the change on the product should
be evaluated and the need for, and the extent of Re-validation discussed. The change
control system should ensure that all notified or requested changes are satisfactorily
investigated, documented and authorized”[13].

“All changes that may affect product quality or reproducibility of the process should
be formally requested, documented and accepted. The likely impact of the change of
facilities, systems and equipment on the product should be evaluated, including risk
analysis. The need for, and the extent of, re-qualification and re-validation should be
determined.”

Change control requires a written procedure (change control program) to

regulate at least the following points: [5]

 What types of changes does change control take into account; for which areas
does this operating instruction apply?
 Who can suggest/initiate changes?
 How changes are requested (forms, methods of communication)?
 How changes are graded, who is responsible for the grading?
 How are the measures necessary for carrying out the change determined; who
compiles the directions required?
 Who is responsible for the execution and monitoring of all necessary measures?
 How is the change controls committee assembled; what are the duties of the
committee?
 How the change is documented (format, content, storage)?
 Who is responsible for authorizing changes?
 What are the special regulations for urgent changes?

Change requests

Changes requiring control are generally documented in the form of a change request,
in which the applicant for the change proposes the type of grade/evaluation of the
change, specifies the time frames and measures for carrying out the change, and
requests that and the change is authorized or declined by the change control
committee. The documentation for the change procedure should prove that the change
was evaluated (risk analysis) and the subsequently defined measures were
implemented as predetermined [5].

Post approval change management protocol

A post-approval change management protocol describes specific changes that a

company would like to implement during the lifecycle of the product and how these
would be prepared and verified. It is a step-wise approach in the assessment of
changes, which allows an early evaluation of the strategy for the change and a later
separate evaluation of the data produced based on the agreed strategy. Such a stepwise
approach is expected to lead to faster and more predictable implementation of changes
post-approval, since the MAH will have obtained agreement from the Regulatory
Authorities about the proposed strategy and tests to verify the effect of the change on
product quality [15].

Content of the change management protocol [15]

In general, in order to support the proEEWAposed change, the company should

submit all relevant information that can demonstrate that it has acquired adequate
knowledge to prepare and manage the impact of the change.

The content of the protocol could include the following, depending on the nature of
the change [15].

 Justification that there is a recognized future need for the specific change
within a reasonable timeframe and that adequate knowledge has been acquired
to define criteria to appropriately evaluate and manage the change for the
specific product concerned; A detailed description of the proposed change. The
differences with what is already approved should be clearly highlighted
(preferably in a tabular format). Depending upon the nature of the change, it
should be demonstrated, preferably with data from development or pilot scale
studies, that the proposed approach is feasible. If only lab-scale data are
provided the potential scale up effect should be discussed;
 Risk assessment of the impact of the change on product quality. This should
include identification of the potential risks and detailed strategy of how these
risks will be mitigated or managed;
 Discussion on the appropriateness of the approved control strategy to identify
and manage these risks and, if required, description of the additional controls
that might be needed to be put in place. This should take into consideration the
extent of the change and therefore the potential impact on the quality of the
active substance and/or finished product, as appropriate;
  Description of the studies to be performed, and the test methods and acceptance
criteria that will be used to fully assess the effect of the proposed change on
product quality1. The applicant should justify the appropriateness of the
methods proposed to assess the impact of the proposed change. Data from
development or pilot scale studies can provide assurance about the relevance
and adequacy of the proposed tests;
 For biologics, the approach to be used to demonstrate the comparability of the
pre-and post-change product;
 A plan for stability studies should be included, if appropriate;
 Commitment to update the approved protocol, if this becomes invalid, due to
significant changes to the proposed test methods/acceptance criteria or a
significant body of new knowledge or new regulatory requirements;
 In case that the protocol describes several changes, a justification showing that
how the changes are related, and that a simultaneous review under a single
protocol is meaningful;
 For chemical medicinal products, a proposal of how the implementation of the
change will be reported to the relevant competent authorities using the existing
variation procedures;
 For biological medicinal products, in accordance with the Variations
Classification Guideline.

Change control process at regulatory submission level

The report must contain information about the formulation, including justification for
any and all Changes made in the methods during the development process.
Additionally, the report will include information about the following [4].

 Justification for all ingredients used

 Justification for all analytical methods selected
 Justification for all of the final manufacturing and analytical processes stated in
the application (IND, ANDA or NDA)
 Types of equipment used
 Manufacturing process (description of evolution of the process)
 Scale-up to production
 In-process results
 Final dosage form test results
 Critical parameters of bulk drug substance
 Acceptance criteria for critical steps
 Conclusions with key variables identified
 Stability
 Description of pivotal batches
The entire purpose of this change control report is to point the authority toward a
document that delineates the science and technology that went into making the
product and that includes all preliminary studies right up to the regulatory submission
stage.

CONCLUSION

In the current study, it is affirmed that in the pharmaceutical industry, change control
does not mean the elimination of any change; it means the systematic control of
changes to ensure the changes made do not have any adverse impact on the safety,
quality, purity, or potency of the pharmaceutical product. Changes made in a
pharmaceutical manufacturing plant that has any potential to impact the safety,
quality, purity, efficacy, or potency of a pharmaceutical preparation must be made in a
way that assures these characteristics are not adversely impacted. Because of the
highly globalized level of the modern pharmaceutical industry, implementing the
change in the system and/or operation is not as simple as it would seem. With the
advances in science and technology that we have witnessed over the decades, it is
opinioned that a balance must be struck in order to properly utilize all of the tools
available to improve living conditions and address health problems across the globe.

It is obvious that management of post approval changes is a multidimensional task

and calls for many different actions and strategies which need to be aligned with
national laws and international treaties and practices. Post Approval Changes in GMP
level are seriously influenced by the market needs, market response and so on. In
other words, trade and commerce considerations are important in the management of
post approval changes.

Different forms of changes demand different treatment, handling, planning, and

strategies and engagement of persons with different domain knowledge such as life
science, engineering, medicines, pharmaceutical regulatory professional and
marketing. Each industry should evolve its own change control policies, management
style, strategies, etc. Depending on its area of specialty.