Pharmaceutical manufacturing operates under some of the most stringent quality and safety regulations of any industry. Even trace-level impurities can compromise drug efficacy, stability, or patient safety. As a result, regulators worldwide require analytical results that are not only accurate but fully traceable, validated, and defensible.
This is where Certified Reference Materials (CRMs) play a critical role. CRMs are the benchmark for method validation, calibration verification, and ongoing quality control in pharmaceutical impurity testing. At Graham B Jackson(GBJ), we provide Inorganic Ventures certified reference material in Australia, supporting laboratories that demand regulatory confidence and analytical precision.
Why Certified Reference Materials Are Essential in Pharmaceutical Testing
Increasingly Strict Regulatory Limits
Global guidelines such as ICH Q3A–Q3D, USP <232>/<233>, and USP <1086> define strict limits for elemental impurities, residual solvents, and degradation products. For elemental impurities like arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg), permitted daily exposure limits are often in the single-digit microgram range.
At these ultra-trace levels, calibration accuracy cannot rely on in-house standards or unverified reagents. Only ISO 17034-accredited certified reference material, with full uncertainty budgets and NIST-traceable documentation, can reliably demonstrate method suitability and compliance during audits.
Matching CRM Matrices to Complex Pharmaceutical Samples
Pharmaceutical matrices are rarely simple. Active pharmaceutical ingredients (APIs), excipients, coatings, and preservatives all influence analytical performance. Selecting the correct CRM matrix is essential to minimise matrix effects and ensure accurate recovery.
Common CRM matrix requirements include:
- Acidified solutions (HNO₃ or HCl) for ICP-MS or ICP-OES elemental impurity testing
- Aqueous matrices for raw material analysis
- High-organic or solvent-based matrices for finished dosage forms
Inorganic Ventures offers matrix-matched single-element and multi-element standards, allowing laboratories to closely replicate real sample conditions and improve data reliability.
Key Criteria for Selecting Pharmaceutical CRMs
1. Matrix Compatibility
CRMs should mirror the digestion and analytical environment of the sample. For USP <232> and ICH Q3D testing, acidified elemental standards are critical to maintain stability and recovery.
2. Appropriate Concentration Range
Mid-level stock concentrations (typically 100–1,000 µg/mL) allow flexible dilutions while reducing waste and minimising handling errors during trace-level analysis.
3. Certification and Documentation
A compliant CRM Certificate of Analysis must include:
- Expanded uncertainty (k=2)
- Traceability to national metrology institutes (e.g., NIST)
- Gravimetric preparation methodology
- Homogeneity and stability studies
- Verified purity of starting materials
Inorganic Ventures documentation meets all major regulatory expectations.
4. Stability and Shelf Life
Certain impurities require stabilisers to prevent degradation. For example:
- Mercury CRMs require gold chloride to prevent volatilisation
- Some metals require specific acid concentrations to maintain oxidation state
Failure to account for stability can lead to inaccurate results and compliance risk.
Single-Element vs Multi-Element CRMs: Choosing the Right Approach
| Application | Recommended CRM Type | Key Benefit |
| Primary calibration | Single-element | Maximum flexibility, minimal interaction risk |
| Routine QC checks | Multi-element | Time-efficient, consistent matrix |
| Method validation | Matrix-matched blends | Realistic recovery assessment |
While multi-element CRMs improve efficiency, reactive elements may require isolation to maintain long-term stability.
Class 1 Elemental Impurities: Special Considerations
Elements such as Cd, Pb, As, and Hg must be monitored in all pharmaceutical products. These impurities often require detection at sub-µg/mL levels after digestion.
Best-practice CRM considerations include:
- Gold-stabilized mercury standards
- Fully oxidised arsenic (As⁵⁺) for a consistent ICP response
- Documented uncertainty at working concentration levels
Using properly designed CRMs reduces method variability and audit exposure.
A Practical CRM Validation Workflow
- Instrument Setup & Tuning – Verify ICP-MS or ICP-OES performance
- Blank Analysis – Establish baseline contamination
- Calibration Curve – Minimum five points around reporting limits
- Initial Calibration Verification (ICV) – Independent CRM lot, target 95–105% recovery
- Continuing Calibration Verification (CCV) – Every 10–20 samples
- Matrix Spike Recovery – Assess real-world matrix effects
- Control Charting – Detect analytical drift early
Inorganic Ventures offers CRMs specifically designed to support these validation steps.
Frequently Asked Questions
Can elemental and organic impurities be combined in one CRM?
Generally not recommended due to differing stability requirements.
How often should multi-component standards be replaced?
Typically, within 6–12 months after opening, depending on usage and storage.
Is a separate CRM lot required for ICV?
Yes. Regulatory bodies, including the FDA, EMA, and WHO, require independent verification.
Inorganic Ventures Australia: Trusted CRM Solutions from Graham B Jackson(GBJ)
As a trusted supplier of Inorganic Ventures certified reference material in Australia, Graham B Jackson(GBJ) supports pharmaceutical laboratories with standards built for compliance, consistency, and confidence. From gold-stabilized mercury standards to custom multi-element impurity blends, every CRM is designed to meet modern regulatory expectations.
When accuracy matters at the microgram level, certified reference materials from Inorganic Ventures make the difference.
For Further Enquiry Contact: sales@gbjpl.com.au