Change Control in Pharmaceuticals

Change Control Program or Change Management System

Change Control Program is the most important pillar of the Quality Management System (QMS). The system is followed by various industries such as pharmaceuticals, biopharmaceuticals, biotechnology, Active Pharmaceutical Ingredient manufacturers, and organizations following QMS as per ISO 9001. Process steps for change management remain similar irrespective of industry and organizations. However, it requires customization depending on the individual organization’s needs, types of business model, and regulatory requirements. The change control program is also called a Change Management System.

The examples covered in this article are of pharmaceutical industry.

1. Reference guidelines for Change Control Program or Change Management System

Change control program is an essential element of pharmaceutical quality systems and referred in various guidance and regulatory documents. Following are few references of guidance and regulations.

EudraLex:

 Change-control-EudraLex-1

EudraLex:

 Change-control-EudraLex-2

Code of Federal Regulations (CFR): 21 CFR, 211.100 and 21 CFR, 211.160

 Change-control-CFR-Part-F
 Change-control-CFR-Part-I

PI 006-3 Recommendation on Validation Master Plan

 Change-control-PI-006

PI 002-3 Quality System Requirements For Pharmaceutical Inspectorates

 Change-control-PI-002-3

Quality assurance of pharmaceuticals, Volume 2, 2nd updated edition Good manufacturing practices and inspection, WHO”

 Change-control-WHO

2. Types of changes

Changes in pharmaceutical industry can be broadly classified as product specific changes and general changes. These two groups can be further expanded as follows with examples of changes:

  1. Product specific changes:
    1. Change in batch manufacturing record and batch packaging record:
      • Batch size change
      • Change in formula
      • Change, addition or removal of equipment
      • Change in manufacturing process
      • Tightening or relaxation in manufacturing in-process parameters
      • Change in document template
      • Inclusion of additional instruction/ simplification or editorial changes without changing actual process
      • Artwork change
      • Change in pack profile or configuration
      • Change in holding time of in-process materials
      • Change in batch size
    2. Change in specification and method of analysis:
      • Revision of specification limits
      • Change in analytical procedure
      • Pharmacopoeial changes
      • Tightening or relaxation in manufacturing specification
      • Addition or deletion of test
      • Change in document template
      • Inclusion of additional instruction/ simplification or editorial changes without changing actual method of analysis and specification limit
    3. Other product specific changes
      • New-product introduction
      • Change in vendor of product specific starting materials
      • Change in starting material manufacturing process
      • Change in customer of product
      • Change in storage condition based on destination market
      • Change in master formula records
      • Addition or deletion of stability study condition
      • Extension or reduction of product shelf life
  2. General changes:
      • Change on Standard Operating Procedure (SOP)
      • Facility change
      • Equipment change
      • Modification of equipment
      • Upgrade equipment or system software
      • Permanent change in working shift timing
      • Change in layouts and drawings
      • Modification of facility
      • Heating Ventilation and Air Conditioning (HVAC) system modification
      • Revision of documents, such as, Site Master File, Validation Master Plan, Quality Manual, Protocols, or any other GMP documents

3. Rating or classification of changes

Change controls required to be further classified based on nature and criticality of impact on system, facility, equipment/ instrument, material, product, procedure or process. Depending on the criticality, changes can be classified as Major Changes or Minor Changes.

    1. Major change:

Major changes are those changes that have a direct impact or potential impact on the product quality, safety, strength, identity, efficacy, and purity of a product, validation status of the process, equipment, utility, facility or GMP compliance, procedures, systems or regulatory filings.

    1. Minor Change:

Minor changes are those changes that do not have a direct impact or potential to have a direct impact on the product quality, identity, safety, strength, purity, and efficacy of a product or validation status of the process, equipment, utility, facility or GMP compliance/ procedures, and systems or regulatory filings.

Table: 1 – Classification of change control
Major changes Minor changes Changes do not require change control
  • Modification of manufacturing facility
  • Introduction of new product
  • Change in batch size
  • Change in manufacturing equipment
  • Change in specification of product or product component
  • Change in HVAC design
  • Modification of equipment or change in critical component of equipment e.g. change in motor or Rapid Mixture Granulator, modification of RABS in the aseptic area
  • Change in document template
  • Periodic review of Standard Operating Procedure or any other documents
  • Adding additional instruction in the batch record or analytical method without changing core process
  • Modification of lifting device
  • Change of laundry for work in non-sterile and non-potent drug manufacturing facility
  • Facility modification outside manufacturing area, e.g. modification of office area furniture, pipeline modification in garden, modification of road surrounding the building
  • Replacement of change part of equipment (like to like)
  • Replacement of HVAC motor with similar capacity
  • Installation of air conditioning system in staff room

4. Category of changes

A change may be permanent or temporary.

    1. Permanent changes:

Permanent changes mean the changes that remain in effect till the next required revision or modifications.

    1. Temporary change controls:

A change that is implemented for a specific predetermined period. Temporary change controls are also called planned deviation by some of the organizations.

5. Change management process flow

Diagram: 1 – Typical change management process flow

Flow chart of Change Control tech publish

6. Impact and risk assessment

Any change in the system or process, there is an impact. The impact could be favorable, which is expected as an outcome of the change proposal. However, there could be an impact on upstream and downstream processes or related systems because of the change. The effect could be for the initiator department, other cross-functional departments, other locations, regulatory filings, validation status of product, site approval status. The impact needs to be assessed before the change proposal is approved. There is a crucial role of initiator, cross-functional team, regulatory affairs department, and Quality Assurance department. If the change requires a mitigation plan, it shall be documented as a part of the change control assessment and actionable while implementing the change.

The impact can be assessed under the following headings but not limited to each change. These are few examples; however, it could be different depending on organizational structure, regulatory markets, and other quality system elements.

Table: 2 – Parameters to be considered for impact and risk assessment for change control evaluation
Sr. no Impact of change to be evaluated for Sub sections
1 Facility approvals
  • Site approval status
  • Approvals for additions of facility or expansions
  • Layout approvals
  • Any other legal approvals
2 Buildings and facilities
  • Facility concept design
  • Building design approval
  • Validation master plan for the facility
  • Direct impacting utility requirements and design
  • Layout design for material movements, AHU distribution, pressure zoning, classification layouts, HVAC ducting layouts
  • Service area design
  • Environment/ classification requirement
  • Rodent and pest control design
  • Drainage layouts
  • Facility blue print
  • Facility qualification
3 Equipment/ instrument
  • Identification of equipment/ instrument
  • Requirement of vendor support for list of activities
  • User Requirement Specification (URS)
  • Design Qualification (DQ)
  • Factory Acceptance Test (FAT)
  • Site Acceptance Test (SAT)
  • Installation Qualification (IQ)
  • Operation Qualification (OQ)
  • Performance Qualification (PQ)
  • Preventive maintenance program and schedule
  • Calibration of instrument and schedule
  • Equipment list
  • List of spare parts
  • Supporting utility requirement
  • Annual Maintenance Contract
  • Re-qualification/ re-validation program
  • Passivation of equipment
  • Data backup
  • User rights
  • Discontinuation of equipment
  • Data archival
  • Process validation
  • Cleaning validation
4 Components and drug product containers and closures
  • Vendor approval
  • Supplier approval
  • Specification
  • Method of analysis
  • Legal requirement of storage
  • Facility for material receipt, handling and storage
  • Toxicological assessment
  • Safety assessment
  • Technology transfer
  • New artwork
  • Process validation
  • Packing validation
  • Material code generation
  • Working standard
  • Reference standard
  • New instrument for analysis
  • Contract testing laboratory requirement
5 Production and process controls
  • Master formula record
  • Batch manufacturing record
  • Process validation
  • Cleaning validation
  • Manufacturing area and facility
  • Utility requirements
  • Gowning requirements
  • Dedicated facility
  • Dedicated equipment
  • Sampling tools
  • Regulatory submission
  • Stability studies
  • Hold time studies
  • Annual product quality review
  • Continuous process verification
6 Packaging and labeling control
  • Batch packing record
  • Artwork approvals
  • Packing validation
  • Track and trace
  • Temper evident
  • Equipment and facility
  • Product price tag
  • Serial number generation requirement
  • Label approval
  • Change part validation
  • Packing configuration trails
7 Holding and distribution
  • Storage facility
  • Data logger placement requirement
  • Transportation requirement
  • Transport validation
8 Laboratory controls
  • Specification
  • Method of analysis
  • Method validation
  • Method transfer
  • Method verification
  • Contract laboratory
  • Stability studies
  • Worksheets
  • Working standard
  • Reference standards
  • Primary standards
  • Instrument requirement
  • Instrument capability
9 Records and reports
  • Standard operating procedure
  • Master lists
  • Batch manufacturing record
  • Batch packing record
  • Site master file
  • Validation master plan
  • Training
  • Documents to be made obsolete
  • Bill of material
  • Formats
  • Logbooks
  • Protocols
10 Electronic system
  • Use requirement specification
  • High level risk assessment/ preliminary risk assessment
  • Validation plan
  • Vendor assessment
  • Design specification
  • Functional specification
  • Risk assessment
  • Installation qualification
  • Operation and performance qualification
  • Traceability matrix
  • Validation summary report
  • Application of system policies and restrictions at OS level
  • Antivirus requirement
  • Allocation of user rights
  • Backup policies
11 Aseptic processing
  • Media fill
  • Environmental monitoring
  • Media fill matrix
  • Media fill protocol
  • Media fill batch record
  • Visual inspection qualification

7. Trending of change controls

Trending of changes in the facility is very important to monitor and control the changes. Changes which were rejected, canceled, major changes, open changes etc. are required to be closely monitored and trended. During regulatory inspections, primary focus are major changes, facility related changes, rejected changes etc.
Following is an example template which can be used for trend analysis.

Table 3 Change Control Trending tech publish

8. Post implementation review of change controls

Changes such as major changes, new procedures, upgraded procedures, procedure implemented in response to deviation or complaint CAPAs and compliance require post-implementation review that after implementation of the changes, it is giving intended outcome. Measurement criteria can be qualitative, qualitative, or a mix of both. For example, a reduction in the number of complaints after implementation of new process, that could have implemented as an outcome of a complaint investigation. Reduction in the number of human errors and reduction in documentation errors can also be considered a measure of post-implementation review.

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