Implementation of Primary Reference Standard and Working Reference Standard Procedures in a Biopharmaceutical Company

A case study from BioPharma Consulting Group

Background

Biopharmaceutical Company A, a mid-sized company specializing in monoclonal antibody therapeutics, was scaling up its commercial manufacturing operations. As part of its Quality Management System (QMS), the company needed to formalize its Reference Standard program to comply with regulatory expectations (ICH Q6B, USP <11>, USP <1235>, and EU GMP Annex 11).

Prior to this initiative, the company relied on ad-hoc qualification of analytical standards, which created risks of inconsistency in product release, method validation, and stability testing.

Problem Statement

The lack of a robust, documented process for establishing Primary Reference Standards (PRS) and Working Reference Standards (WRS) posed the following risks:

1. Non-compliance with FDA, EMA, and WHO guidance.
2. Potential variability in assay results (potency, purity, concentration and identity testing).
3. Limited traceability of analytical standards across labs and product lines.
4. Inadequate control of stability and requalification timelines.

Management mandated the development and implementation of a formal PRS and WRS lifecycle procedure.

Objectives

1. Establish governance around creation, qualification, approval, and maintenance of PRS.
2. Define procedures for qualification, storage, distribution, and requalification of WRS.
3. Ensure alignment with global regulatory expectations.
4. Reduce variability and ensure reproducibility of analytical testing.

Approach

Phase 1 – Gap Assessment

1. Reviewed regulatory requirements (ICH Q6B, USP <11>, USP <1235>, WHO TRS 1011 Annex 3, EudraLex Vol 4).
2. Benchmarked practices from industry peers and pharmacopoeias.
3. Identified gaps: no formal PRS and WRS definitions, lack of expiry/requalification procedures, poor chain-of-custody documentation.

Phase 2 – Policy, Protocol & SOP Development

1. Drafted Reference Standard Management Policy describing roles, responsibilities, and lifecycle management.
2. Developed SOPs and Protocols for:

1. Establishing and qualifying PRS.
2. Preparing and qualifying WRS against the PRS.
3. Labeling, storage, distribution, and usage tracking.
4. Requalification and retirement.

Phase 3 – Implementation

Primary Reference Standard (PRS):

1. 1. Prepared from a GMP-compliant drug substance batch.
   2. Fully characterized (identity, purity, potency, stability, impurities profile).
   3. Approved by Quality Control (QC), Analytical Development (AD), and Quality Assurance (QA).

Working Reference Standard (WRS):

1. 1. Derived from PRS under controlled conditions.
   2. Qualified through side-by-side analytical comparison with PRS.
   3. Stability monitored under controlled storage (-80°C, -20°C and 2–8°C).

• • • Established a digital Reference Standard Inventory System to track usage, storage location, expiry/requalification, and chain of custody.
    • Expanded system to include Secondary Standards for raw materials.
    • Integrated reference standard stability trending into company’s LIMS.
    • Explored collaboration with pharmacopeial organizations for long-term alignment.

Phase 4 – Training & Rollout

1. Conducted cross-functional training for QC, Analytical Development, and Manufacturing Science and Technology (MSAT).
2. Rolled out controlled document systems with e-signatures for traceability.

Outcomes

1. Regulatory Compliance: Aligned with FDA, EMA, and WHO expectations.
2. Improved Consistency: Reduced assay variability by 25% (measured through control charts).
3. Data Integrity: Full traceability of standard usage across sites and methods.
4. Audit Readiness: Successfully defended approach during FDA PAI and EMA inspection.
5. Business Impact: Reduced delays in batch release due to standard qualification issues.

Lessons Learned

1. Early cross-functional involvement (QC, QA, Regulatory Affairs) was critical.
2. Establishing clear requalification intervals based on real-time stability data improved control.
3. Digital tracking systems reduced risk of mislabeling or expired standard usage.
4. Maintaining a small, centralized committee to approve PRS/WRS minimized delays.