Publications - 04.13.2020

Article: Quality Assurance in R&D for Biosimilars

In the past year, the pharmaceutical industry has seen substantial growth of biosimilars and an increase in the approvals of biologics. [1] With projected continuous growth there is a definitive need for biosimilar R&D spaces to implement necessary Quality Management Systems (“QMS”) when applying for approval with the FDA.  While biosimilars can rely on previously determined data for approval with the FDA, the approval process is no less rigorous.  Chemistry, Manufacturing, and Controls (“CMC”) issues are often cited in FDA complete response letters (“CRL”). [2] Therefore, how can sponsors proactively address and improve the approach to CMC to enable a more rapid and robust timeline to the Biologics License Application (“BLA”).

Per the FDA, a biosimilar manufacturer may partially rely on previous FDA determinations of a reference product by showing the proposed biosimilar product is highly similar and has no clinically meaningful differences. [3] Quality data of the reference product must be used for this determination, and, without a quality system for maintaining data, biosimilar manufacturers may find themselves generating full profiles of clinical and nonclinical data for the proposed biosimilar. By biosimilar manufacturers designing and implementing a QMS, the biosimilar industry can improve time to market.

While full traditional quality systems and 21 CFR Part 11 compliance and conformity to ICH Guidelines may restrict the flexibility that comes with R&D, there is a balance to be struck to ensure a structure is in place for tracking various systems while fitting the needs of R&D.  Use of a balanced QMS can reduce cost of development and curb regulatory barriers to innovation.  Development and implementation of a QMS for an R&D environment will protect data through archivable, retrievable, and auditable systems.  QMS also shows control over the equipment, process development, and changes to the process.  A strong QMS will provide control for documents, learning, equipment, and change management.  An integral part of a QMS may include a Document Management System, Learning Management System, Equipment Asset Management, and Change Management Process.

A Document Management System (“DMS”), will manage, track, and store documents, reviews, and approvals.  Documentation may contain, but is not limited to, policies, plans, protocols, procedures, specifications, and requirements.  For usage and application in laboratory operations, a DMS will operate for review and approval of standardized analytical procedures, experimentation records, and ad-hoc deviations within experimentation.  Implementation of a DMS allows for structure without reducing flexibility of operations and provides information for analysts to carry out consistent approaches.  An electronic DMS, such as ACE Document Management System,[4] can notify reviewers and approvers when a document is due, and can be configured to require quality assurance sign off.  A controlled DMS allows auditors to follow the course of work done and maintain data integrity principles for 21 CFR Part 11 compliance,[5] and follows ICH Guideline for Good Clinical Practice. [6] DMS can be implemented through use of forms and approved formats, audit trails, and traceable records (time, date, operator, equipment used).  Use of a DMS during R&D for biosimilars will greatly reduce time to market.

A Learning Management System (“LMS”) administers, tracks, and reports on-the-job education and training initiatives to appropriate individuals.  For laboratory applications, LMS can be used to capture routine work as written in Standard Operating Procedures (SOP).  An LMS such as Compliance Wire generate reports confirming personnel are trained on standardized procedures for equipment and processes.  They can also notify personnel when new training is due, and allow for monitoring of training compliance.  LMS creates a place for storage and managing of resumes, trainings (completed and uncompleted), qualifications, areas of expertise, and education.  Information is easily retrievable, captures training accomplishments for personnel, and allows for continuous process & professional development while maintaining 21 CFR Part 11 compliance.  A LMS is recommended as part of ICH Guidance for Industry Q10 Pharmaceutical Quality System. [7]

An Equipment Asset Management (“EAM”) system manages, tracks, and stores calibration and maintenance activities for equipment and instrumentation. This includes part replacement and spare parts, calibrations, and work orders. EAM for asset assignment and tracking for operations, financials, and quality is imperative for laboratory applications.  Electronic EAM systems like QAD [8] allow for monitoring of upcoming maintenance required on systems, and can contain organization for assets and spare parts. For R&D purposes, EAM can be implemented for managing analytical equipment calibration schedules, ensuring alignment with requirements, and allowing closer monitoring of performance.  Implementation of an EAM system demonstrates traceability and accuracy of equipment.  EAM establishes reliability for data produced by equipment while maintaining 21 CFR Part 11 compliance and ICH Q7 Good Manufacturing Practice. [9] EAM reduces time lost to out of tolerance equipment and not functioning analytical tools, allowing for more time spent on R&D.

A Change Management Process (“CMP”) formalizes the process to document, assess, approve, implement, and verify changes to process or equipment. For Deviation Reports Template in laboratory applications, CMP documents change, justifies change with an identified root cause, and assesses impact of change.  Some CMP processes can function though a DMS, such as ACE [10] which allows for full configuration of a uniquely defined CMP program.  CMP documents changes to the process with new equipment to analytical pipeline.  Changes outside of equipment are captured within CMP as well, such as changes to methods, SOPs, data collection, and reporting structure. Use of a CMP is recommended in the ICH Q10 Pharmaceutical Quality System. [11] An implemented CMP demonstrates control over procedural modifications, a routine for “non-routine” work. This will ensure no unnecessary changes are made, while providing justification to changes that are made.

In addition to systems for document, learning, equipment, and change management, an integral part of QMS is the quality asset management process.  A defined process for quality asset procurement ensures acquired equipment is reliable and the data generated is meaningful. Identification of GAMP Classification for laboratory systems is an important first step in asset procurement.  GAMP Class 2 and 3 are most common for laboratory applications.

GAMP Class 2 is defined for instrument and controllers with configurable and non-configurable firmware. [12] Required engineering actions and asset maintenance management for Class 2 includes assignment of asset identifier ID (make, model, cutsheets), and document configuration & versioning control.  Instrument is to be entered into EAM for preventative maintenance, calibration, and inventory spares while DMS captures engineering turnover packages (specifications, manuals, drawings, data sheets).  No validation actions are required for GAMP Class 2 as the instrument is compliant per the required engineering actions and asset maintenance management.

GAMP Class 3 is defined for commercial off-the-shelf (“COTS”) equipment and packages with existing code & setpoints. [13] Required engineering actions and asset maintenance management for Class 3 includes assignment of asset identifier (same as for Class 2), and documentation of COTS system installation and operations.  System is required to be entered in an EAM system for asset assignment, tag & label, calibrate as needed, establish PMs & inventory spares. Engineering turnover packages and parts lists are to be entered and maintained in DMS. Validation actions are required for GAMP Class 3 systems. For COTS systems, a series of commissioning and qualification documents are required deliverables.  System sustainability is required to validate system integration into infrastructures and systems for 21 CFR Part 11, user logins, historian, retrievable and accessible data storage.

Validation activities for GAMP 3 COTS systems follow the traditional V-model.  Prior to purchasing equipment, necessary specifications and requirements for the system are to be defined.  A COTS Commissioning Plan and Requirements (“CPR”) captures these requirements as well as the commissioning and qualification (“C&Q”) strategy.  Once the equipment that aligns with CPR requirements is procured and brought on site, a Receipt Verification (“RV”) is to be performed prior to installation. The RV verifies the system is received undamaged, confirms the inclusion of equipment shipping documents, verifies the make and model, and records the turnover packages (if applicable). After a successful RV, the system is ready to be installed and for commissioning testing to begin. Testing for verification of system requirements per the CPR and functionality is completed through a COTS Commissioning Verification or Qualification (“CCV” or “CCQ”). An Installation or Operational Qualification (“IQ” or “OQ”) may be executed if applicable for additional testing of CPR requirements.  When testing is complete, commissioning activities are summarized and testing traced per requirements in a COTS Commissioning Report (“CCR”).

Performance Qualification (“PQ”), if applicable, is performed to test the system consistently meets functional requirements in various scenarios including worst case scenarios and system capability limits and system failure. PQ activities, results, and findings are summarized in the Performance Qualification Summary Report (“PQSR”). Documents used for commissioning and qualification are reviewed, approved, and managed by appropriate parties within the DMS.

Commissioned systems will require routine maintenance that can be tracked and managed through EAM. Routine maintenance such as calibration, part replacements, or deep cleanings can all be tracked through the appropriate channels within the EAM.  For changes to equipment or processes outside of the scope of commissioning and maintenance procedures CMP is used.

Implementation of quality systems for documentation, learning, equipment, and change management benefits R&D spaces by providing systems for traceable, trackable data. Use of QMS and defined asset procurement process can greatly reduce the time for process development and application for biosimilar approval. Having QMS to show reliable lab systems and storage for archivable, retrievable, and auditable data allows for efficient process development within biosimilar R&D spaces.


[1] CPhI Pharma Insights (2018) Pharma’s Year of Accelerated Innovation & Convergence. CPhI Pharma Insights. Available via Accessed 18 Oct 2018.

[2] Wechsler J (2018) Biosimilars Raise Manufacturing and Regulatory Challenges. Pharmaceutical Technology 42 (7). Available via Accessed 17 Oct 2018.

[3] FDA (2017) Biosimilar Development, Review, and Approval. U.S. Food & Drug Administration. Available via Accessed 16 Oct 2018.

[4] ACE (2018) ACE Software.

[5] FDA (2003) 21 CFR Part 11, Electronic Records; Electronic Signatures. FDA. Available via

[6] ICH (1996) Guideline for Good Clinical Practice E6(R1). International Council for Harmonisation. Available via Accessed 18 Oct 2018.

[7] ICH (2009) ICH Pharmaceutical Quality System Q10. International Council for Harmonisation. Available via Accessed 18 Oct 2018.

[8] QAD (2016) QAD Enterprise Applications Solution Guide. QAD. Available via

[9] ICH (2000) ICH Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients Q7. International Council for Harmonisation. Available via Accessed 18 Oct 2018.

[10] See supra 6.

[11] ICH (2009) ICH Pharmaceutical Quality System Q10. International Council for Harmonisation. Available via Accessed 18 Oct 2018.

[12] McDowall R.D. (2009) Understanding and Interpreting the New GAMP 5 Software Categories. Spectroscopy Editors. Available via Accessed 18 Oct 2018.

[13] See supra 14.