Raw Material Compliance in Pharmaceuticals: Naming, Pharmacopeial Grade, and Safety Requirements

Introduction

Raw material compliance forms the foundation of pharmaceutical product quality, safety, and regulatory acceptance. While Part 1 of this blog explained the regulatory framework, GMP expectations, supplier qualification, and documentation requirements, the next step is understanding how raw materials directly influence product performance, safety controls, and regulatory compliance throughout the product lifecycle.

👉 Missed Part 1? Read it here :

Raw Material Compliance in Pharmaceuticals: FDA & GMP Requirements Explained – Part 1

In this second part, we examine the functional role of raw materials in pharmaceutical manufacturing, their identification and naming requirements, pharmacopeial grade compliance, and critical safety controls such as nitrosamine risk, elemental impurities, TSE/BSE, and viral safety. We also cover modern compliance expectations related to global regulations including REACH, CITES, the Nagoya Protocol, allergen declarations, and sterilization controls.

These controls are essential not only for meeting FDA, EMA, and global regulatory expectations, but also for maintaining consistent product quality, ensuring patient safety, and supporting successful regulatory submissions. Understanding these requirements helps manufacturers build robust raw material control strategies, reduce compliance risks, and maintain inspection readiness.

Functional Role of Raw Materials in Pharmaceuticals

Each raw material plays a critical role in ensuring the final drug is safe, effective, and manufacturable.

1. Ensuring Product Safety

    

   • Raw materials must be free from contamination (microbiological, heavy metals, nitrosamines, solvents).
   • Compliance with pharmacopeial standards ensures patient safety.
2. Supporting Drug Efficacy

    

   • API potency and purity determine clinical performance.
   • Excipients influence drug release, absorption, and bioavailability.
3. Enhancing Stability & Shelf Life

    

   • Antioxidants prevent API degradation.
   • Buffers maintain pH-stability.
   • Packaging materials protect against moisture, UV, and oxygen.
4. Improving Manufacturability

    

   • Lubricants, glidants, and binders help achieve consistent tablet quality.
   • Solvents enable purification and crystallization.
   • Gases and resins support sterile and biologics manufacturing processes.
5. Meeting Regulatory Requirements

    

   • Raw materials must comply with global standards (USP, EP, JP).
   • Supplier qualification, CoA verification, audits, and change control ensure consistent quality.
   • Documentation supports regulatory filings (DMFs, ANDAs, BLAs).

III. Identification and Naming Conventions for Raw Materials

Accurate identification and consistent naming of raw materials are fundamental GMP requirements. Regulatory authorities (US FDA, EMA, WHO) expect raw materials to be uniquely identifiable, unambiguous, and traceable across procurement, testing, release, and regulatory documentation.

1. CAS Number (Chemical Abstracts Service Number)

Role & Importance

• A CAS number is a unique numerical identifier assigned to a specific chemical substance.
• It eliminates ambiguity caused by synonyms, trade names, or regional naming differences.
• Widely used for chemical raw materials, solvents, reagents, and excipients.

Regulatory Use

• Included in raw material specifications
• Referenced in supplier documentation
• Used in regulatory dossiers to clearly identify chemical entities

Key Compliance Note

CAS numbers support global harmonization, but do not replace pharmacopeial or regulatory names.

2. INN (International Nonproprietary Name) – For Drug Substances

Role & Importance

• INN, assigned by WHO, is the globally recognized non-proprietary name for drug substances (APIs).
• Ensures uniform identification across countries and regulatory agencies.
• Mandatory for labeling, regulatory submissions, and pharmacovigilance.

Regulatory Use

Primary name used in drug substance specifications, drug product dossiers (CTD Modules 2 & 3), stability studies and labelling. It must be used consistently once assigned.

Example:

• INN: Paracetamol
• CAS No.: 103-90-2

3. National Nonproprietary Names

(USAN / BAN / JAN)

Role & Importance

National naming systems may exist prior to or alongside INN assignment :

• USAN – United States Adopted Name
• BAN – British Approved Name
• JAN – Japanese Accepted Name

These names are often harmonized with INN, but historical or regional differences may exist.

Regulatory Use

Acceptable in country-specific regulatory documents and it must be cross-referenced to INN in Specifications, CoAs, Regulatory dossiers.

Compliance Expectation

Where different names exist, a clear equivalence statement must be maintained.

4. Pharmacopeial Names (USP, Ph. Eur., BP, IP, JP)

Role & Importance

Pharmacopeial names are legally recognized names used in official compendia.

• Define quality standards and test methods
• Mandatory when a monograph exists
• Apply to APIs, excipients, and some packaging materials

Regulatory Use

• Used as the official name in specifications
• Referenced in CoAs, Batch records, Quality agreements

Example : Paracetamol USP / Ph. Eur.

5. Best Practices for Compliance

• Maintain a controlled raw material master list
• Define an approved primary name and allowed synonyms
• Use INN / pharmacopeial names as primary identifiers
• Ensure alignment between Purchase orders, Specifications, CoAs, Regulatory filings
• Apply strict change control for any name updates

IV. Pharmacopeial Grade & Naming Compliance for Raw Materials

Pharmacopeial grade and naming compliance for raw materials is a core GMP and regulatory requirement in pharmaceutical manufacturing. Regulatory authorities (US FDA, EMA, WHO) expect raw materials to be correctly named, appropriately graded, and demonstrably compliant with recognized pharmacopeial standards wherever such standards exist.

1. A pharmacopeial grade raw material is one that complies with the requirements of an official pharmacopeial monograph, such as:

• USP–NF (United States Pharmacopeia–National Formulary)
• Ph. Eur. (European Pharmacopoeia)
• BP (British Pharmacopoeia)
• IP (Indian Pharmacopoeia)
• JP (Japanese Pharmacopoeia)

Compliance includes:

• Correct identity
• Defined purity and impurity limits
• Approved test methods
• Required labeling and storage conditions

2. Importance of Pharmacopeial Grade Compliance

• Ensures minimum quality standards recognized by regulators
• Reduces variability in raw material quality
• Simplifies regulatory review and inspection
• Provides a legally enforceable quality benchmark

Regulators expect pharmacopeial-grade materials by default, unless a justified alternative is approved.

3. Naming Compliance Requirements

1. Use of Official Pharmacopeial Name

    

   When a pharmacopeial monograph exists:

   • The official monograph title must be used as the primary material name
   • This name must appear consistently in Specifications, Certificates of Analysis (CoAs), Batch records, Regulatory dossiers

   Example:

   ✔ Microcrystalline Cellulose Ph. Eur.

   ✖ MCC powder / cellulose filler

2. Inclusion of Grade & Compendial Reference

   The name must clearly state the pharmacopeia, the grade (if multiple grades exist)

   Examples: Magnesium Stearate USP–NF, Magnesium Stearate Ph. Eur.

3. Alignment with INN (for APIs)

   For drug substances:

   • Use the INN as the primary name
   • Add pharmacopeial designation where applicable

   Example: Paracetamol (INN), Paracetamol USP

4. Handling Multiple Pharmacopeias

When multiple pharmacopeias apply:

• Specifications may reference more than one pharmacopeia
• Differences must be assessed and harmonized
• The most stringent requirement is typically applied

5. Non-Pharmacopeial Raw Materials

If no monograph exists:

• Use an in-house specification
• Clearly state “Non-pharmacopeial”
• Justify quality attributes based on intended use and risk
• Ensure traceability and control equivalent to pharmacopeial materials

6. Certificates of Analysis (CoAs)

Regulatory expectations for CoAs:

• Material name exactly matching the approved specification
• Clear pharmacopeial reference
• Statement of compliance (e.g., “Complies with USP–NF”)
• Batch number, test results, and authorized signature

7. Regulatory & Inspection Expectations

US FDA, EMA, and WHO expect:

• Consistent naming across all GMP and regulatory documents
• No use of ambiguous or trade names
• Justification for use of non-pharmacopeial grades
• Controlled change management for monograph revisions

V. Key Safety Controls in Raw Material Compliance

Raw materials are a primary source of quality and patient safety risk. Regulatory authorities require specific controls to address biological, chemical, and toxicological hazards that may originate from raw materials or be introduced during their manufacture.

1. TSE / BSE and Animal-Derived Materials

Controls for Transmissible Spongiform Encephalopathy (TSE) and Bovine Spongiform Encephalopathy (BSE) ensure that animal-derived raw materials do not pose a risk of prion transmission.

Key Compliance Expectations

• Identification of all animal-derived materials (e.g., gelatin, lactose, magnesium stearate)
• Traceability to species, tissue, and country of origin
• Supplier TSE/BSE declarations
• Compliance with EMA/410/01, WHO TSE guidelines
• Preference for vegetable or synthetic alternatives

Regulatory Significance

Mandatory for EU, US submissions and globally expected as part of risk management.

2. Biological / Viral Safety (Especially for Biologics)

Ensures that raw materials do not introduce viruses, mycoplasma, or adventitious agents, particularly critical for biological products.

Key Compliance Expectations

• Raw material risk classification (human, animal, microbial origin)
• Viral safety evaluation per ICH Q5A
• Supplier qualification and viral clearance validation
• Testing or certification for absence of adventitious agents
• Use of virus-inactivated or recombinant materials where possible

Regulatory Significance

Viral safety is a critical quality attribute (CQA) for biologics and vaccines.

3. Residual Solvents and Process Impurities

Residual solvents and process-related impurities can be toxic and may accumulate if not controlled at the raw material stage.

Key Compliance Expectations

• Compliance with ICH Q3C (Residual Solvents)
• Defined solvent limits in raw material specifications
• Supplier disclosure of manufacturing process and solvents used
• Periodic testing or risk-based justification

Regulatory Significance

Regulators expect impurity control to begin at the raw material source, not only in the finished product.

4. Nitrosamines Risk & Compliance

Nitrosamine impurities have become a major regulatory focus due to carcinogenic risk. Suppliers of raw materials especially amines, solvents, catalysts, and starting materials must assess and control nitrosamine formation. Required documentation includes:

• A formal nitrosamine risk assessment identifying any amine/nitrosating agent presence.
• Analytical results confirming absence or control of nitrosamine impurities.
• Information on potential nitrosating conditions in synthesis routes.
• Change control commitments to prevent unannounced process changes.
• Manufacturers use this data to build robust nitrosamine control strategies per EMA/FDA guidance.

5. Heavy Metals / Elemental Impurities

ICH Q3D requires control of elemental impurities in pharmaceuticals to protect patient health. Raw material suppliers must:

• Provide elemental impurity data for Class 1 (highly toxic), Class 2A/2B, and Class 3 metals.
• Use validated methods such as ICP-MS for analysis.
• Declare compliance to expected limits or provide risk-assessment-based justifications.

Ensure consistency of impurity profiles across batches.

This data is critical for manufacturers to complete product-level ICH Q3D risk.

Raw material compliance requires control of known adulterants and biological risks that can compromise quality, safety, and regulatory acceptability. Melamine contamination and GMO status are specifically assessed due to past safety incidents and evolving regulatory and market expectations.

6. Melamine Compliance

Melamine control is a critical element of raw material compliance because melamine is a toxic industrial chemical that has been used fraudulently to adulterate materials to falsely inflate nitrogen or protein content. In pharmaceuticals, any melamine contamination represents a direct patient safety risk, particularly for renal toxicity and a significant regulatory non-compliance.

Melamine control in raw materials is a preventive safety measure aimed at eliminating adulteration risk and protecting patient health, even when melamine is not a specified pharmacopeial requirement.

High-Risk Raw Materials

• Excipients of biological or protein origin
• Lactose, starch, gelatin
• Amino acids and protein hydrolysates
• Materials sourced from regions with historical adulteration risk

Key Compliance Expectations

• Supplier declaration confirming absence of melamine
• Risk assessment based on material type, origin, and supply chain
• Testing where risk is identified (e.g., HPLC / LC-MS)
• Inclusion in specifications or periodic monitoring
• Supplier change control and traceability

Supplier change control and traceability

Regulators expect melamine risk to be proactively assessed and controlled as part of raw material adulteration prevention. This aligns with ICH Q9 (Quality Risk Management) and GMP requirements for prevention of contamination and adulteration.

7. GMO / Non-GMO Status

GMO control is an important element of raw material compliance because it ensures regulatory transparency, traceability of biological origin, and alignment with market and labeling requirements, particularly for materials derived from plants, microorganisms, or fermentation processes.

Materials Commonly Assessed

• Starch, cellulose, sugars
• Fermentation-derived excipients
• Enzymes and culture media components
• Biological raw materials

Key Compliance Expectations

• Supplier declaration of GMO or non-GMO status
• Traceability to source organism and production method
• Compliance with EU GMO Regulations (EC 1829/2003, 1830/2003), WHO guidance (where applicable)
• Impact assessment on Product labelling, Market authorization, Patient acceptability

Regulatory Significance

GMO status must be documented and consistent with regulatory filings and labeling claims.

Raw material compliance is a foundational component of pharmaceutical quality systems. It ensures that all substances used in drug manufacturing such as active ingredients, excipients, intermediates, reagents, solvents, process aids, and packaging-contact materials meet regulatory, safety, environmental, and ethical requirements. Manufacturers rely on comprehensive supplier documentation, risk assessments, and analytical verification to confirm that each material is safe, compliant, and suitable for its intended use.

Below are some of the modern compliance elements for raw materials.

1. CITES Compliance

The Convention on International Trade in Endangered Species (CITES) controls the trade of endangered plants and animals. Raw materials derived from biological sources such as botanicals, animal extracts, marine components, or traditional medicines must comply with CITES requirements. Suppliers must:

• Confirm that materials do not originate from species listed under CITES Appendices I–III.
• Provide legally required CITES permits if the species is regulated.
• Maintain traceability of biological sourcing.

Compliance prevents legal violations, supply-chain disruptions, and ethical concerns related to biodiversity loss.

2. REACH Compliance

REACH (Registration, Evaluation, Authorisation, and Restriction of Chemicals) is an EU regulation governing the safe use of chemicals. Pharmaceutical manufacturers require REACH statements for raw materials to ensure:

• The substance itself or any intentionally released component is properly registered.
• Raw materials do not contain restricted or banned substances.
• The presence of SVHCs (Substances of Very High Concern) is declared if present above 0.1% w/w.
• Safety Data Sheets (SDS) meet REACH requirements.

REACH compliance ensures environmentally responsible sourcing and reduces chemical hazards throughout the supply chain.

3. Nagoya Protocol Compliance

The Nagoya Protocol governs access to genetic resources and equitable benefit-sharing arising from their utilization. For raw materials of biological or genetic origin:

• Suppliers must confirm lawful sourcing from the country of origin.
• Prior informed consent (PIC) and mutually agreed terms (MAT) must be documented when required.
• Benefit-sharing obligations must be respected.

Non-compliance can cause legal liability and regulatory rejection. Pharmaceutical companies must ensure supplier declarations for all materials sourced from genetic or biological resources.

4. Allergen Statement

Allergens pose a significant risk for patient safety, especially in oral and parenteral formulations. Manufacturers require allergen declarations to assess contamination risks. Suppliers must confirm:

• Presence or absence of major allergens (e.g., gluten, lactose, soy, nuts, sesame, shellfish, eggs).
• Potential for cross-contamination during manufacturing.
• Measures taken to prevent allergen carryover.

Allergen statements support labeling compliance, GMP risk assessments, and patient safety analyses.

5. INCI Database / INCI Naming

The International Nomenclature of Cosmetic Ingredients (INCI) standardizes naming for ingredients used in topical, dermal, or cosmetic-pharmaceutical hybrid products. For materials used in such formulations:

• INCI names ensure global harmonized labeling.
• Suppliers must confirm correct INCI nomenclature.
• Regulatory submissions (e.g., for OTCs, dermaceuticals, or cosmetic drug products) rely on INCI consistency.

This compliance ensures clarity, transparency, and regulatory acceptance in cosmetic and pharmaceutical markets.

6. Presence of TiO₂ (Titanium Dioxide)

Titanium dioxide is widely used as a pigment and opacifier in tablets and capsules. Regulatory scrutiny, especially in the EU, has increased due to potential genotoxicity concerns when used as a food additive. While its use in pharmaceuticals remains permitted, suppliers must:

• Declare the presence or absence of TiO₂.
• Provide detailed specifications such as particle size distribution, grade (pharmaceutical, food, or industrial), and coating status.
• Demonstrate compliance with pharmacopeial monographs (e.g., Ph. Eur., USP).
• Provide safety data supporting the intended use to aid manufacturers’ risk assessments.

This transparency enables manufacturers to anticipate regulatory changes and prepare scientific justifications for its continued use.

7. Ethylene Oxide Statement (EO/EtO)

Ethylene oxide is sometimes used to sterilize raw materials, especially heat-sensitive ones. EO sterilization may leave harmful residues such as ethylene oxide, ethylene chlorohydrin, and ethylene glycol. To ensure patient safety, suppliers must:

• Declare whether EO is used during sterilization or processing.
• Provide validated analytical data confirming residual levels meet pharmacopeial limits.
• Demonstrate adherence to standards such as ISO 11135 for EO sterilization.
• Provide periodic requalification data and change-notification commitments.

Manufacturers integrate this information into their impurity control strategies and toxicological assessments.

Conclusion

Raw material compliance is a critical foundation of pharmaceutical quality, safety, and regulatory integrity. Each material whether an API, excipient, solvent, intermediate, biological substrate, packaging component, or process aid plays a specific and essential role in ensuring that the final drug product performs as intended. Regulatory authorities worldwide expect manufacturers to maintain stringent control over all raw materials through comprehensive specifications, supplier qualification, documentation review, and ongoing risk assessments.

Modern compliance requirements extend beyond traditional quality tests and now include environmental, ethical, and safety considerations such as REACH, CITES, the Nagoya Protocol, allergen declarations, nitrosamine control, elemental impurities, Ethylene oxide and TiO₂ scrutiny. These evolving expectations underscore the need for robust supplier communication, well-designed qualification programs, and transparent documentation practices.

Ultimately, effective raw material compliance not only safeguards patient health but also strengthens supply chain reliability, supports successful regulatory submissions, and ensures the consistent production of high-quality medicines. By integrating scientific, regulatory, and sustainability-focused practices, pharmaceutical manufacturers can achieve a resilient and compliant raw material management system that meets global standards.

To build a complete understanding of raw material compliance, including supplier qualification, GMP expectations, and regulatory documentation requirements, refer to Part 1 of this series:

👉 Read Part 1 :

To build a complete understanding of raw material compliance, including supplier qualification, GMP expectations, and regulatory documentation requirements, refer to Part 1 of this series:

Raw Material Compliance in Pharmaceuticals: FDA & GMP Requirements Explained – Part 1

Celegence provides comprehensive DMF authoring and filing services tailored to meet global regulatory requirements. Contact us at info@celegence.com.