Q. My company got a complaint from a patient that their prefilled syringe failed to inject. We make the drug product and purchase the syringe. How do we investigate a problem with the commercial syringe component that we used?

A. The drug manufacturer is responsible in the end for whatever the product does, even if it’s made up of components where the manufacturer doesn’t really have a lot of control over.

The question is, how well have you assessed the quality of the product? Have you assessed the supplier of this syringe? Because it’s all too easy to say, “Oh, something is off the shelf.”

But just because a product has been used by many doesn’t mean it’s suitable for everyone.

If the complaint is coming from the patient and the patient is self-administering the product, did they get instructions from the physician before they got the medication? Is this human error on the part of the patient?

Even if the patient did something wrong. The manufacturer needs to take this into account and should create either patient instruction or a device that is suitable for everyone. Because you can’t just say, “Well, we only sell to those who are capable and who do it right all the time.” That would be wrong.

The device, when you look at the regulations, needs to be fit for purpose, and fit for purpose means if you have a patient population that is from young to old, from very able to handicapped, then you need to provide for all of those.

And one way to do this, to prepare for this at least, is to perform usability tests If these usability tests weren’t done with a wide enough population of potential patients, perhaps you need to go back to these tests and see if they were good enough. Did they really understand, or were these already people who were used to do such testing?

We need to be very careful with testing because we can only test a certain limited number of people. And what we have here is real-world evidence if you want, and that points to where we have a gap here.

Complaint numbers can go up and down. It’s very unpredictable. The key thing is you don’t just need to have a procedure to address complaints, but you should revisit your procedure in intervals to look at not just what the regulators are saying, but also how the business environment has changed.

Look at your communication and supply chain and check your quality agreement for its robustness and to see who is responsible for these types of complaints. Because, if you don’t spell out who is responsible in your supply agreement, there may be finger pointing. This is a shortcoming with a lot of quality agreements; they may not be granular enough.

Articles

Drug manufacturers retain ultimate accountability for performance of combination products, even when key delivery components are sourced “off the shelf.” A failed prefilled syringe complaint requires a structured investigation spanning component supplier qualification, device suitability for the intended patient population, and potential use errors during self-administration. Human factors considerations are central: instructions and device design must accommodate broad user capabilities. Complaint handling should leverage real‑world signals, periodically reassess procedures against evolving regulatory and business contexts, and ensure robust quality agreements that clearly assign responsibilities across the supply chain.

Ask the Expert

Susan J. Schniepp, distinguished fellow at Nelson Labs, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss how companies can investigate patient complaints involving prefilled syringes and combination products.

Investigating Patient Complaints About Combination Products

The pharmaceutical industry continues to evolve at the intersection of digital transformation, regulatory rigor, and patient-centered innovation. Across development and manufacturing, companies are balancing the need for speed and efficiency with growing expectations around data integrity, product quality, and operational resilience. The articles in this issue reflect an industry increasingly defined by smarter systems, stronger analytics, and more adaptive manufacturing strategies.

“Hybrid Cloud Architecture in Pharmaceutical Development and Manufacturing,”

 highlights how digital infrastructure is becoming a strategic differentiator. As organizations manage growing volumes of development and manufacturing data, hybrid cloud models are enabling companies to accelerate workflows while maintaining the control and compliance required in highly regulated environments. The convergence of scalability, cybersecurity, and regulatory oversight is rapidly reshaping how life sciences organizations approach modernization.

At the manufacturing level, process understanding and statistical rigor remain essential. This issue’s peer-reviewed article examining T- and F-test evaluation for biased net fill weight calculations demonstrates the industry’s continued emphasis on scientifically justified, GMP-aligned approaches to in-process control. As manufacturing operations become increasingly data-driven, the ability to validate and defend analytical methodologies is more important than ever.

In development, biosimilars continue to present both opportunity and complexity. Our feature on biosimilar formulation explores the growing demand for patient-centric delivery approaches, including high-concentration and self-administered products. Developers must now navigate analytical comparability requirements, evolving regulatory expectations, and formulation challenges—all within compressed development timelines.

Quality and compliance also remain central themes throughout the industry. In 

“Risk-Based Lifecycle Management of Master Production and Control Records,”

 Dennis Cantellops examines how companies can strengthen data integrity and inspection readiness through structured governance of production records. As regulators place increasing focus on documentation practices and electronic systems, lifecycle management strategies are becoming critical to maintaining compliance and operational continuity.

 column addresses the complexities of investigating patient complaints involving prefilled syringes and combination products. As drug-device combinations become more common, manufacturers face heightened expectations for complaint handling, root-cause analysis, and patient safety oversight.

Together, these articles underscore a broader industry trend: success in modern pharma manufacturing depends not only on scientific advancement, but also on the ability to integrate digital capability, quality systems, and regulatory preparedness into every stage of the product lifecycle.

Mike Hennesy, Jr.
President and CEO
MJH Life Sciences

Pharma operations are increasingly shaped by digital transformation, heightened regulatory scrutiny, and patient-centered product design. Hybrid cloud architectures are emerging as strategic infrastructure for scaling development and manufacturing data while preserving compliance, cybersecurity, and control. Manufacturing science continues to demand statistically defensible, GMP-aligned methods, exemplified by rigorous evaluation of biased net fill weight calculations. Biosimilar formulation programs are intensifying around high-concentration, self-administered delivery amid tight timelines and comparability expectations. Strengthened governance of production records and robust investigation of combination-product complaints remain pivotal for data integrity and inspection readiness.

From the Chairman

Driving Resilience Through Digital Innovation

The World Health Organization (WHO) defines manufacturing instructions as a “Master Formula,” an approved master document that describes the complete manufacturing process for a specific product and batch size.

 Equivalent terminology is used globally across good manufacturing practice (GMP) frameworks, including guidance from the WHO, European Union (EU), Pharmaceutical Inspection Co-operation Scheme (PIC/S), and Health Canada.

 Although terminology varies across regions and regulatory organizations, these documents serve the same fundamental purpose: to ensure that manufacturing activities are performed in a consistent, controlled, and reproducible manner. For the purposes of this article, the term 

 (MPCR), as defined in 21 Code of Federal Regulations (CFR) 211.186, is used.

An MPCR is required for each product and batch size and forms the basis for the execution of batch production and control records (BPCRs). A 

, as defined in WHO GMP guidance, is a defined quantity of material produced in a single process or series of processes such that it is expected to be homogeneous.

 commonly refers to intermediates or bulk products and 

 to finished packaged products, the terms are often used interchangeably within GMP frameworks.

The MPCR is intended to ensure uniformity from batch to batch by providing complete, accurate, and approved manufacturing instructions. During batch execution, the MPCR is reproduced as a BPCR, which documents the actual manufacturing activities, materials, equipment, in-process controls, and critical process parameters associated with a specific batch. Under US current good manufacturing practice (CGMP) requirements, 21 CFR 211.186 establishes expectations for MPCR content, while 21 CFR 211.188 requires accurate and complete reproduction of the approved MPCR during batch execution.

Regulatory inspections frequently identify deficiencies in MPCRs and executed BPCRs, including incomplete documentation, omission of critical process parameters, lack of standardization, legibility issues, and inadequate second-person verification. Such deficiencies may compromise data integrity, delay batch release, and increase compliance risk. Inspection observations also indicate that these issues are often associated with inadequate document design, insufficient governance controls, and inconsistent application of electronic tools used to generate MPCR templates.

MPCRs may be implemented using paper-based, hybrid, or fully electronic formats. Paper-based systems remain widely used but are more susceptible to transcription errors, legibility challenges, and extended review timelines. Hybrid systems combine electronic templates with paper execution and are commonly used in industry; however, they may introduce additional complexity in document control and data management. Fully electronic MPCR and BPCR systems, when implemented in compliance with electronic records and signatures requirements under 21 CFRPart 11,

 can reduce documentation errors and enhance data integrity. However, such systems may require greater upfront investment, more extensive validation, and formalized change management processes, resulting in increased implementation complexity and resource requirements.

Spreadsheet-based applications are frequently used to support MPCR development across all documentation formats. When properly designed, validated, and governed, spreadsheet-based systems can provide structured data entry, automated calculation capabilities, improved standardization, and flexibility to accommodate manufacturing and regulatory changes. Compared with database-driven systems, spreadsheet-based tools may enable more efficient implementation of lower-risk changes and require fewer resources. Nevertheless, appropriate validation, access controls, and change management procedures remain essential to maintain GMP compliance.

The development and maintenance of MPCRs are closely linked to process validation and life cycle management. Changes to materials, equipment, processes, facilities, or procedures may require revision of MPCR templates to ensure continued assurance of product identity, strength, quality, purity, and potency. Effective MPCR design and governance support compliance with CGMP requirements, facilitate efficient review by quality units (QUs), and enable consistent execution of validated manufacturing processes.

This article presents a risk-based approach to the development, execution, and life cycle management of MPCRs, with emphasis on alignment with US CGMP requirements and internationally harmonized pharmaceutical quality system guidance, including International Council for Harmonisation (ICH) Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, ICH Q9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality System.

 Particular focus is placed on MPCR design, governance, and change management practices that support accurate execution of BPCRs, enhance data integrity, and reduce compliance risk throughout the product life cycle. The US Food and Drug Administration (FDA) guidance on data integrity further emphasizes the importance of reliable, complete, and traceable manufacturing documentation.

Regulatory Framework and Risk-Based Evaluation of MPCR and BPCR Systems

Inspectional observations, regulatory requirements, and industry practices related to the development and execution of MPCRs and BPCRs were evaluated to assess alignment with CGMP requirements. The evaluation focused on the completeness, accuracy, control, and reproducibility of MPCR templates, consistent with MPCR requirements described in 21 CFR 211.186 and master production instructions described in ICH Q7 Section 6.4. The evaluation also examined the accurate and complete execution of BPCRs in accordance with batch production and control record requirements described in 21 CFR 211.188 and batch production record expectations described in ICH Q7 Section 6.5.

 Additional evaluation criteria included documentation and record retention requirements under 21 CFR 211.180 and QU responsibilities for production record review, investigation of discrepancies, and approval or rejection of records under 21 CFR 211.22 and 211.192.

FDA Laboratory Information Bulletins (LIBs) describing spreadsheet design, validation, and electronic record controls were also reviewed to evaluate spreadsheet governance and validation practices applicable to MPCR template development and life cycle management.

 These practices were evaluated within the regulatory framework established under 21 CFR Parts 210 and 211 for CGMP documentation requirements and 21 CFR Part 11 for electronic records and electronic signatures.

The assessment examined documentation control, data integrity safeguards, and the inclusion of critical manufacturing and control elements. These elements included document version control; identification of critical process parameters; yield calculations and theoretical yield ranges; environmental conditions, such as temperature and relative humidity, where applicable; storage conditions; documentation of deviations and investigations; second-person verification of critical process steps; and documentation of change history. Additional factors evaluated included record legibility, completeness, consistency of entries, and controls designed to prevent unauthorized modification, omission, or backdating of records, consistent with regulatory expectations for data integrity.

Documentation governance practices were also evaluated, including QU oversight of production record review and approval. The extent to which production records were reviewed for completeness, discrepancies, and compliance with established procedures was assessed in accordance with CGMP and pharmaceutical quality system requirements.

MPCR and BPCR systems were further evaluated across different implementation formats, including paper-based, hybrid (paper and electronic), and fully electronic systems. The assessment considered the ability of each format to support document control, traceability, data integrity, and life cycle change management. Spreadsheet-based tools and database-driven systems were evaluated as representative electronic documentation approaches, including considerations for validation, version control, access control, audit trail functionality, and implementation of electronic records and electronic signature controls under 21 CFR Part 11.

Spreadsheet Governance Policies and Template Standardization for MPCR Development

Inspectional observations identified variability and incomplete reproduction of MPCR templates during BPCR execution, consistent with deficiencies in documentation controls required under 21 CFR 211.186 and 211.188.

 The absence of defined software governance policies and standardized template controls contributed to documentation inconsistencies, transcription errors, and increased QU review burden.

Implementation of standardized spreadsheet governance policies improved MPCR template standardization, reproducibility, and documentation accuracy. Spreadsheet templates provided structured data entry, controlled formatting, and automated calculation capabilities, which reduced manual transcription errors and improved documentation consistency. Spreadsheet governance and validation practices were evaluated in accordance with established spreadsheet validation principles and documentation controls described in FDA LIBs.

Spreadsheet validation and governance controls included defined template structure, protection of calculation cells, standardized formatting, controlled formula implementation, data validation rules, conditional formatting, and documented version control and change management procedures. When implemented as electronic systems, additional controls such as audit trails, electronic signatures, and access restrictions were evaluated in accordance with 21 CFR Part 11 requirements for electronic records and electronic signatures.

These governance practices improved documentation reliability, enhanced data integrity, and supported life cycle management of MPCR templates consistent with CGMP requirements and pharmaceutical quality system expectations.

Risk-based principles consistent with ICH Q9 were applied to evaluate the impact of documentation design and system controls on data integrity, operational consistency, and compliance risk.

 Life cycle management considerations consistent with ICH Q10 were also evaluated, including the ability of MPCR systems to support controlled change management, process updates, version control, and continued maintenance of validated manufacturing processes throughout the product life cycle.

These evaluation criteria provided a structured regulatory and risk-based framework for assessing MPCR and BPCR documentation systems throughout the pharmaceutical manufacturing life cycle.

An example of a standardized spreadsheet-based MPCR template implementing these governance controls is provided in 

. This template illustrates structured data-entry fields, standardized formatting, controlled formula implementation, and defined documentation controls designed to support reproducibility, data integrity, and life cycle management consistent with CGMP requirements, 21 CFR Part 11, and the principles described in ICH Q7, Q9, and Q10.

Inspectional Findings and Documentation System Evaluation

Between 2012 and subsequent evaluation periods, approximately 80 inspections were evaluated across manufacturers of sterile and nonsterile drug products, biotechnology products, APIs, and finished drug products. These evaluations included assessment of MPCRs and executed BPCRs to determine their completeness, reproducibility, and alignment with current CGMP requirements.

The evaluation identified recurring deficiencies related to MPCR development, standardization, and BPCR execution. Common findings included inadequate document control, lack of standardized MPCR templates, and inconsistencies between approved MPCRs and executed BPCRs. In some cases, additional pages were added to or removed from batch records without appropriate authorization or control, compromising documentation integrity. Documentation deficiencies also included omission or incomplete identification of critical process parameters, missing or incorrectly calculated theoretical yield ranges, incomplete documentation of environmental conditions such as temperature and relative humidity, and absence of defined storage conditions. Additional issues included incomplete documentation of manufacturing deviations and investigations, lack of documented change history, and inconsistent implementation of second-person verification for critical process steps. These deficiencies are inconsistent with CGMP documentation requirements under 21 CFR 211.186 and 211.188.

 Common documentation deficiencies are summarized in 

Record legibility and completeness were frequent concerns in paper-based systems, particularly where handwritten entries, corrections, and cross-outs reduced clarity and traceability. These practices increased the risk of transcription errors and reduced the efficiency of production and QU review. Data integrity risks were also identified, including incomplete or inconsistent entries and insufficient controls to ensure appropriate documentation practices. In addition, QU review practices did not consistently ensure thorough review of production records for completeness, discrepancies, and compliance with established procedures, as required under 21 CFR 211.22 and 211.192.

The evaluation further examined the impact of documentation format on MPCR and BPCR management. Paper-based systems, commonly generated from word-processing templates and completed manually, were associated with increased risk of transcription errors, legibility challenges, and extended review timelines. Hybrid systems, which combine electronic templates with paper execution, provided some improvements in documentation management but introduced additional complexity in maintaining document control and traceability. Fully electronic systems, when implemented with appropriate validation, access controls, and audit trail functionality, supported improved documentation consistency, traceability, and data integrity in accordance with electronic records requirements under 21 CFR Part 11.

 MPCR implementation formats and their associated characteristics are summarized in 

An assessment of documentation technologies used across inspected facilities found that both word-processing and spreadsheet applications were commonly used to develop MPCR templates and execute BPCRs. Spreadsheet-based templates demonstrated improved standardization, structured data entry, and enhanced document control compared with word-processing templates, which were more frequently associated with formatting inconsistencies and manual entry variability. Spreadsheet systems were observed to support implementation across paper-based, hybrid, and fully electronic documentation environments. When used in paper-based and hybrid formats, spreadsheet templates improved template consistency, record legibility, and document maintenance.

When implemented as fully electronic systems, spreadsheet-based MPCR templates required additional controls to support compliance with electronic records and electronic signatures requirements under 21 CFR Part 11, including audit trail functionality, electronic signatures, access controls, and system validation.

 In some facilities, supplementary software tools were implemented to provide audit trail and electronic signature functionality for spreadsheet-based MPCR and BPCR templates operating within electronic documentation environments. A comparison of documentation technologies, including word-processing, spreadsheet-based, and database-driven systems, is provided in 

Implementation of structured spreadsheet governance controls—including standardized template design, controlled formatting, validation, protected formula implementation, and defined change control procedures—supported improved MPCR template reproducibility, enhanced documentation accuracy, and strengthened data integrity controls. These governance practices aligned with CGMP documentation requirements

 and electronic records requirements under 21 CFR Part 11.

 Spreadsheet governance controls supporting MPCR template standardization and regulatory compliance are summarized in 

A representative example of a standardized MPCR spreadsheet template implementing these controls is provided in 

MPCR development and management challenges varied by product type. Drug substance manufacturing, particularly for multistep synthesis processes, presented increased documentation complexity due to repeated processing steps, extended production timelines, and the need for precise control of critical process parameters. Biological product manufacturing similarly presented documentation challenges due to the complexity and number of process steps and associated control requirements. These factors increase the importance of structured documentation systems and standardized MPCR templates to support consistent execution and documentation reliability.

Across all evaluated systems, implementation of structured governance practices, standardized MPCR templates, and validated electronic documentation controls was associated with improved reproducibility of batch records, enhanced data integrity, and increased efficiency of production and QU review processes. Systems incorporating structured data entry, controlled template management, and appropriate validation and security controls demonstrated improved consistency between MPCR templates and executed BPCRs, supporting more reliable documentation and improved alignment with regulatory expectations.

The author acknowledges Tyson Mew, president of Ofni Systems Inc, for technical consultation regarding spreadsheet-based electronic documentation systems and implementation considerations related to electronic records, audit trails, and data integrity controls. His technical perspective contributed to the practical context discussed in this article. The author also acknowledges his former colleagues at the FDA for their dedication to advancing pharmaceutical quality, regulatory compliance, and data integrity practices.

The author declares no conflicts of interest.

The views expressed in this article are those of the author and do not represent the official position of the US Food and Drug Administration.

Guide to Master Formulae. Guidance Document. 

WHO/FWC/IVB/QSS/VQR; 2011. Accessed April 7, 2026. https://studylib.net/doc/18121346/guide-to-master-formulae---world-health-organization

WHO. Good manufacturing practices for pharmaceutical products: main principles

 WHO Technical Report Series No. 908, Annex 4, 2003. Geneva, Switzerland. Accessed April 7, 2026. https://gmpua.com/World/WHO/Annex4/trs908-4.pdf

EudraLex; The Rules Governing Medicinal Products in the European Union, Volume 4

: EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Chapter 4: Documentation. Brussels, Belgium: European Commission. Current version. Accessed April 7, 2026. https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

Guide to Good Manufacturing Practice for Medicinal Products (PE 009-17), Part I and Part II.

 Effective August 25, 2023. Geneva, Switzerland. Accessed April 7, 2026. https://picscheme.org/docview/660

Good Manufacturing Practices Guide for Drug Products 

(GUI-0001). July 1, 2020. Accessed April 7, 2026. https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/good-manufacturing-practices/guidance-documents/gmp-guidelines-0001/document.html

, Title 21, Part 210: current good manufacturing practice in manufacturing, processing, packing, or holding of drugs; general; and Part 211: current good manufacturing practice for finished pharmaceuticals. Updated April 30, 2026. Accessed April 7, 2026. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-210
https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211

 Title 21, Part 11: Electronic Records; Electronic Signatures. Updated April 30, 2026. Accessed April 7, 2026. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-11

International Council for Harmonisation. Q7. 

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

. November 10, 2000. Accessed February 23, 2026. https://database.ich.org/sites/default/files/Q7%20Guideline.pdf

International Council for Harmonisation Q9(R1) 

January 18, 2023. Accessed February 23, 2026. https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2023_0126_0.pdf

International Council for Harmonisation. Q1. 

June 4, 2008. Accessed February 23, 2026. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf

Data Integrity and Compliance with Drug cGMP: Questions and Answers: Guidance for Industry.

 December 2018. Accessed April 7, 2026. https://www.fda.gov/media/119267/download

Cantellops D, Bonnin E, Reid, A. Spreadsheet design and validation for the multi-user application for the chemistry laboratory, Part I. 

No. 4317. FDA. 2003. Accessed April 7, 2026. https://www.spreadsheetvalidation.com/pdf/LIB_Design_Multi-User2A.pdf

Cantellops D. Spreadsheet design, verification and validation, use and storage of single-user workbook files in the US FDA laboratories, Part II. 

 No. 4349. FDA; 2005. Accessed April 7, 2026. https://www.spreadsheetvalidation.com/pdf/LIB_Part_II_Single-User.pdf

Cantellops D, Kage E, Manzano MJ, et al. Evaluation of ExcelSafe to implement part 11 rules in FDA analyst workbook files. 

No. 4524. FDA. 2012. Accessed April 7, 2026. https://www.ofnisystems.com/LIB-4524-FDA-431-and-ExcelSafe.pdf

Dennis Cantellops is an independent GMP and data integrity consultant and a former consumer safety officer for the US Food and Drug Administration.

Master production and control records (MPCRs) underpin reproducible manufacturing by defining approved instructions for each product and batch size and driving batch production and control records (BPCRs). Review of ~80 inspections found recurring gaps—missing critical parameters, yield calculations, environmental/storage conditions, deviation documentation, and second-person verification—often tied to weak document design and governance. Paper and hybrid records raise legibility and transcription risks; fully electronic systems improve traceability when validated to 21 CFR Part 11. Standardized, validated spreadsheet templates with controlled formulas and change control strengthen data integrity and QU review efficiency.

Quality

This article evaluates a structured, risk-based framework for the development, execution, and life cycle governance of master production and control records and batch production and control records systems aligned with current good manufacturing practice requirements and internationally harmonized pharmaceutical quality system guidance.

Risk-Based Life Cycle Management of Master Production and Control Records to Strengthen Data Integrity and GMP Inspection Readiness Part 1: Regulatory Framework, Inspectional Findings, and Documentation System Evaluation 

Despite the inherent variability of recombinant proteins and antibodies, biosimilars must be comparable to their corresponding branded counterparts with respect to safety, efficacy, and pharmacokinetic and stability profiles.

 Trends in the sector include an increasing focus on patient centricity—such as citrate-free buffer systems—and a move to high-concentration formulations that allow subcutaneous (SC) administration. Together, these pose growing challenges for biosimilar formulators seeking to demonstrate comparability through analytical and functional characterization, particularly amid complex intellectual property issues.

What Are the Main Biosimilar Formulation Development Challenges?

Biosimilar formulation development requires navigating scientific, regulatory, and legal challenges, according to Sung Keun Chang, drug product team leader for Samsung Bioepis. One of the main challenges he highlights is the thicket of patents for reference products that are designed to extend patent protection.

Such patents not only include the core molecule, but also excipients or a class of excipients in the drug formulation, manufacturing processes, and delivery devices, Chang notes. “Due to such protection, buffers, stabilizers, or surfactants that are included in biosimilar formulations need to be re-optimized or replaced with alternatives. In extreme cases, excipients such as buffers cannot be utilized at all if there is patent protection for the class of excipients,” he says.

The industry shift toward high-concentration protein formulations (HCPF), primarily designed to enhance patient convenience through SC delivery, is making biosimilar formulation optimization even more difficult. Maintaining the stability of high-concentration formulations and managing their higher viscosities during manufacturing and administration can be challenging.

“A key issue is the constraints placed on formulators of SC formulations by proprietary-based excipient systems, which create bottlenecks to demonstrated comparability with reference products,” observes Venkat Reddy Sunkara, global head of Regulatory CMC at ICON.

Recent regulatory trends toward waiving comparative efficacy studies (CES) in biosimilar development offer additional opportunities to develop biosimilars. However, with analytical comparability replacing clinical proof of efficacy because biologic products are process-defined, not composition-defined, it is even more essential to define uncertainties analytically in a manner that is aligned with regulatory requirements, according to Kimberly Salgado, head of ICON’s Center for Biosimilar Drug Development. Chang agrees that the new regulatory flexibility poses challenges for biosimilar formulators in meeting the rigorous, comprehensive requirements for analytical characterization. Demonstrating the comparability of post–translational modifications can be particularly challenging.

What Are the Implications for Biosimilar Commercialization?

Surmounting these scientific, regulatory, and legal hurdles is a prerequisite for approval and commercialization of a biosimilar product. “In many cases, formulation-related patents can evolve into a family of patents that minimize the possible design space for biosimilar formulations during the life cycle of the product. As a result, biosimilar companies need to navigate around a moving and evolving target when developing biosimilar formulations,” Chang comments.

In addition, for biosimilars being designed for improved patient convenience (eg, SC delivery), it is necessary to demonstrate not only therapeutic equivalency, but improved performance attributes, such as lower local irritation and better tolerability, according to Salgado.

How Can Biosimilar Developers Demonstrate Analytical Comparability?

The first step, says Salgado, is to identify tiered, risk-based critical quality attributes (CQAs) likely to impact clinical safety and efficacy, and link them to the product’s mechanism of action (MoA) and clinical relevance.

Equally important is the need to account for the inherent lot-to-lot variability of reference products and regional sourcing differences using high-resolution sensitive techniques that can detect subtle differences, according to Sunkara.

Demonstrating analytical similarity is therefore often achieved by analyzing a large number of batches of the reference product over an extended period to determine the acceptable variability range for the biosimilar product, Chang observes. “Using an insufficient sample size may result in a similarity range that is too narrow to be met,” he adds.

Finally, both Sunkara and Chang emphasize the importance of using complementary, orthogonal analytical methods based on different scientific principles to ensure that target CQAs are robustly met.

Overcoming Challenges in High-Concentration Formulations

High-concentration formulations can pose multiple challenges, Chang observes, including an increased propensity for aggregation and particle formation due to dense protein concentrations, as well as difficulties in manufacturing and drug delivery because of higher viscosities.

In addition, Sunkara notes that most of these formulations use proprietary excipient systems for which establishing analytical comparability can be difficult.

Some of these challenges can be overcome by optimizing pH, ionic strength, or excipients during formulation development, according to Chang. Indeed, using innovative excipients may be necessary to achieve stable formulations that can be administered using “patient-friendly” delivery mechanisms.

“For example, altering the pH away from the isoelectric point can reduce electrostatic-driven interaction,” Chang comments. “Certain amino acids can also effectively mask the hydrophobic patches on protein surfaces, thereby preventing protein-to-protein interaction. In addition, viscosity can be further controlled by minimizing or avoiding the use of certain stabilizers that increase viscosity, or by adding excipients that disrupt self-association,” he says.

Biosimilar formulations must also meet product shelf-life expectations and support device functionality, and properties such as syringeability, injector performance, and patient usability must also be considered, says Salgado. The latter issues can be managed by fine-tuning formulations for pH and osmolality and using advanced filtration techniques to reduce particle seeding. Container closure systems must also be optimized to ensure minimal silicone oil use.

Underlying all these solutions to overcoming challenges in the formulation of high-concentration biosimilars, Sunkara contends, is the use of advanced characterization techniques to offset any risks.

Are There Best Practices for Overcoming Regulatory Hurdles for More Patient-Friendly Biosimilars?

Biosimilars benefit patients and health care systems through affordability, expanded patient access, and innovation. One of their key benefits, emphasized by Chang, is to enhance the usability of the reference product by adding innovative features. He highlights the removal of citrate from biosimilar formulations, as it is now known to be a potential cause of injection site pain (ISP) during subcutaneous delivery. Biosimilar developers also often provide a wider choice of drug delivery devices than available for the reference product, such as autoinjectors or other advanced drug delivery devices, in addition to existing vials and prefilled syringes.

During formulation development, Sunkara emphasizes following International Council for Harmonisation’s (ICH) Q5E principles for comparability strategies and using orthogonal analytical and functional assays that are relevant to the MoA to mitigate potential risks.

 Equally important, he notes, is conducting device and drug product formulation development in parallel and employing human factors/usability studies to demonstrate dose accuracy, implementing controls for extractables and leachables, and assuring container closure integrity.

Developers of more patient-friendly biosimilar formulations may also need to establish a robust bridging strategy to demonstrate that the improvements do not affect the product’s quality, safety, or efficacy, according to Chang. “As part of the bridging strategy, it is important to build a robust data package along with a comprehensive risk assessment to justify such changes,” he adds. He also highly recommends engaging with regulators early in the development stage to determine whether proposed analytical and clinical bridging strategies will be sufficient for justification.

Overcoming Challenges Created by Shrinking Timelines

Biosimilar developers are under intense pressure to shorten development timelines while still meeting ever‑higher regulatory and scientific expectations. “To meet these objectives,” contends Salgado, “it is necessary to adopt a combination of scientific, regulatory, operational, and strategic solutions to compress timelines without compromising approvability or commercial viability.”

Salgade highlighted the following examples:

Early and iterative regulatory engagement to avoid rework triggered by post–submission questions;

Reference product procurement strategies;

Platform-based approaches to process and analytical method development that are backed by accumulated knowledge;

Parallelization of chemistry, manufacturing, and controls (CMC), and nonclinical and clinical activities;

Leveraging advanced analytics to de-risk clinical programs;

Ensuring access to ready-to-use manufacturing capacities/capabilities.

Formulation development can also be accelerated using high-throughput screening technologies that enable parallel testing of a wide range of buffers, stabilizers, and surfactants in a short timeframe, adds Chang. He also points to the use of automated equipment for sample preparation and analytical testing as a means for further shortening development timelines.

All of these efforts must be pursued while maintaining adherence to regulatory expectations. Salgado notes that biosimilar developers should focus on the totality of evidence of similarity derived from their analytical data, followed by a more abbreviated clinical trial to confirm this similarity if needed. She adds that using final formulations in pharmacokinetic similarity studies can reduce risk and ensure a stronger demonstration of comparability, which is important because if similarity can be demonstrated through a strong CMC and nonclinical package, CES can potentially be avoided.

Impact of FDA’s Proposed Changes for Demonstrating Biosimilarity

The FDA in October 2025 introduced several proposed changes to its requirements for establishing the comparability of biosimilars to reference products.

 The draft guidance eliminates the need for comparative human clinical studies if biosimilar developers can provide sufficient analytical testing data to demonstrate similarity.

 In a separate initiative, the agency has elected to stop recommending that “switching studies” be conducted to show interchangeability between different biosimilars.

These regulatory updates from the FDA, as well as streamlined pharmacokinetic requirements and the expanded acceptance of non-US-licensed comparator products, are expected to significantly reduce biosimilar development costs by up to 25% while shortening timelines, according to a Celltrion official. “In this evolving environment, biosimilar developers are increasingly focused on enhancing efficiency across the entire development process while maintaining robust analytical comparability and regulatory compliance,” the spokesperson remarks. “These changes are meaningful and are expected to accelerate pipeline expansion, including into small and mid-sized markets that were previously less accessible due to high development costs.”

Are There Any Emerging Challenges to Biosimilar Formulation Development?

With innovator companies increasingly launching line extensions (eg, high‑concentration, citrate‑free, device‑enabled, longer shelf life, room‑temperature stable), biosimilar developers often still chase original reference products. However, observes Salgado, “Future commercial relevance and clinical acceptance will depend on matching (or at least not falling behind) the latest reference product attributes.” Successful biosimilar developers will need to find a way to eliminate these gaps.

Using novel excipients is one way to do so, but there is currently no separate regulatory pathway for approving such excipients. Consequently, novel excipients are considered high-risk and often are avoided in biosimilar formulations (especially in SC products), particularly where switching/substitution is expected, according to Sunkara. He also notes that regulatory expectations are increasing for particle analysis, with data now typically required not only on particle counts but also on particle morphology, composition, and immunological relevance.

Newer technical challenges with increasing relevance for biosimilar developers highlighted by Sunkara include the inability of current screening tools to fully predict nonlinear behaviors such as self‑association, shear sensitivity, and viscosity jumps, of high-concentration formulations; the increasing role of autoinjectors and other advanced delivery systems in dictating formulation limits, including maximum viscosities, injection forces, and dwell times; and the rising ability to detect minor formulation‑related differences previously invisible to older, less-sensitive analytical methods.

What Will Matter Most for Future Biosimilar Formulation Development?

Given the current trend in biologics development to more patient-friendly, convenient products, biosimilar developers will need to balance innovative formulation approaches with regulatory compliance, quality assurance, and cost management to ensure commercial success.

 Selecting optimal formulations will require input from cross-functional teams of experts, incorporation of patient-centric formulation innovations, comprehensive characterization and establishment of comparability, and the use of quality-by-design approaches, process analytical technologies, and artificial intelligence tools. This strategy will ensure cost-effective development, product performance (quality, safety, efficacy), regulatory compliance, and avoidance of patent-based legal restrictions.

In this vein, companies such as Celltrion are strengthening competitiveness through integrated capabilities spanning development, manufacturing, and direct sales, while driving formulation innovation that reflects the needs in clinical practice, according to the Celltrion spokesperson. “The launch of differentiated formulations—such as liquid intravenous and SC options—demonstrates how biosimilar developers can improve patient convenience and operational efficiency in real-world settings,” the Celltrion official concludes.

Bas TG. Innovative formulation strategies for biosimilars: trends focused on buffer-free systems, safety, regulatory alignment, and intellectual property challenges. 

Leukocare Editorial Team. Biosimilar formulation development: navigating the delicate balance. Accessed May 6, 2026. 

https://www.leukocare.com/blog/biosimilar-formulation-development

ICH. Q5E Comparability of biotechnological/biological products subject to changes in their manufacturing process,

tep 4 version. November 18, 2004. Accessed May 6, 2026. 

https://database.ich.org/sites/default/files/Q5E_Guideline.pdf

FDA. FDA moves to accelerate biosimilar development and lower drug costs. October 29, 2025. Accessed May 6, 2026. 

https://www.fda.gov/news-events/press-announcements/fda-moves-accelerate-biosimilar-development-and-lower-drug-costs

FDA. Scientific considerations in demonstrating biosimilarity to a reference product: updated recommendations for assessing the need for comparative efficacy studies. Draft guidance for industry. October 29, 2025. Accessed May 6, 2026. 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product-updated-recommendations

Development

High-concentration formulations and patient centricity are challenges to the formulation of biosimilars, which already face patent protection barriers.

Overcoming Formulation Challenges for Biosimilars

Submitted: January 8, 2026
Accepted: March 4, 2026

Net fill weight in capsule in-process control (IPC) is often calculated by subtracting a fixed average shell weight from gross weight. Because individual shell weights vary, this computation introduces bias and artificial variance. This work justifies using 

 tests to evaluate whether the computed (biased) net fill weight remains acceptable for IPC decision-making during capsule filling operations.

A simulation-based approach was applied to generate empirical acceptance limits for 

 (variance ratio) statistics by modeling fill-weight and shell-weight distributions. These limits replace conventional critical values and reflect practical process variability. The method enables determination of equivalence between idealized and computed net fill weights in terms of mean and variance and provides a good manufacturing practice–aligned statistical justification for continued IPC use of computed net weight measurements.

In capsule filling operations, in-process control (IPC) of net fill weight is a critical element for ensuring dosage accuracy and maintaining compliance with good manufacturing practice (GMP) requirements. In routine manufacturing, net fill weight is commonly computed by subtracting a fixed average empty-capsule shell weight from the measured gross capsule weight. Although operationally convenient, this approach assumes uniform shell weight and does not account for inherent shell-to-shell variability.

In practice, individual capsule shells exhibit measurable weight variation. When a fixed shell-weight average is applied to all capsules, this variability introduces bias and artificial dispersion into IPC net fill-weight data. As illustrated in 

, shell-weight variability alone can widen the observed net fill-weight distribution and reduce calculated process capability indices (CpK), even when the true fill-weight process remains unchanged. This effect complicates interpretation of IPC trends and may lead to conservative or misleading conclusions regarding process control.

From a statistical perspective, the impact of shell-weight variability raises a fundamental question: Can the computed (biased) net fill weight still be considered equivalent to the idealized net fill weight for IPC purposes? In pharmaceutical process validation (PV) and continued process verification (CPV), equivalence is often assessed in terms of central tendency (mean) and dispersion (variance) rather than point-by-point agreement. Classical statistical tools for this purpose are the 

 test, which evaluates equality of means, and the 

 test, which evaluates equality of variances. These tests have been widely applied in pharmaceutical validation contexts to justify interchangeability of analytical or process-related data sets, provided that appropriate acceptance criteria are established.

However, direct application of theoretical critical values for 

 tests may not adequately reflect realistic manufacturing variability, sampling uncertainty, or combined decision risk when both tests are applied simultaneously. Prior work by the author has demonstrated that simulation-based approaches can be used to derive empirical acceptance limits for 

 statistics that better represent practical process behavior and joint confidence requirements in PV and CPV applications.

Accordingly, this study focuses on justifying the use of 

test–based equivalence evaluation for biased net fill-weight data used in IPC during capsule filling operations. A simulation-based framework is employed to establish empirical acceptance limits for both statistics, enabling equivalence decisions to be made on the basis of realistic process and measurement variability rather than solely theoretical assumptions.

The objective of this article is to provide such a statistically defensible and GMP-aligned justification for continued IPC reliance on computed net fill weight when equivalence in mean and variance can be demonstrated. In practice, samples evaluated need to be collected separately during PV and/or CPV activities but not taken from routine IPC trending data. For each sample set (eg, n = 30 during PV or n = 10-20 during CPV), gross capsule weight was measured and the net fill weight was computed by subtracting a fixed average empty capsule shell weight. The computed net fill weights were then compared with reference net fill weights obtained from direct weighing of the capsule contents for the same units.

Effect of capsule shell-weight variability on observed net fill-weight distributions.

 Figure 1 summarizes the effect of empty capsule shell-weight variability on the observed distribution of net fill weights under identical mean fill conditions. In all cases, the mean net fill weight is centered at 100% of target, indicating that shell-weight variability does not introduce a systematic shift in central tendency. However, the presence of shell-weight variability results in a clear widening of the observed net fill-weight distribution.

Figure 1a presents Monte Carlo–simulated normal distributions for idealized and computed net fill weights. When shell-weight variability is absent (idealized condition), the simulated net fill-weight distribution exhibits an SD of 2.38% of target. Introduction of shell-weight variability through computation using a fixed average shell weight increases the SD to 2.56% of target. This variance inflation occurs despite identical mean fill weight and identical underlying fill-weight process assumptions.

illustrates the same variance inflation effect using idealized normal distributions. In this conceptual comparison, the only difference between distributions is the magnitude of the SD, which increases from 2.38% to 2.56% of target when shell-weight variability is incorporated. This idealized illustration confirms that the observed widening of the distribution arises solely from shell-weight variability and not from changes in the fill-weight process itself. This variance inflation is accompanied by a reduction in calculated process capability, with CpK decreasing from 1.05 under idealized conditions to 0.98 under computed conditions.

Computed capsule net fill weight derived by subtracting a fixed average shell weight from gross weight can distort IPC datasets because shell-to-shell weight variability propagates into the calculation. This inflates observed variance without shifting the mean, depressing CpK and potentially triggering unnecessary investigations. A Monte Carlo framework (up to 2.4 million iterations) supports using paired T- and F-tests to assess equivalence of computed versus reference net weights, but with empirically derived, joint-confidence–adjusted acceptance limits. The approach provides a GMP-aligned justification for continued IPC use during PV/CPV.

This article provides a statistically defensible and GMP-aligned justification for continued IPC reliance on computed net fill weight when equivalence in mean and variance can be demonstrated. 

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Justification of t and F Test Evaluation for Biased Net Fill Weight as Part of In-Process Control Data During the Capsule Filling Operation

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