Pharmaceutical Raw Materials: Definition, Specification Development, And Their Impact On API Quality

Introduction and Outcome

Pharmaceutical raw materials are key determinants of the quality, safety, and efficacy of an Active Pharmaceutical Ingredient (API). Poor control of raw materials can cause impurity-related issues, regulatory observations, and inconsistent API quality.

In this article, you will learn:

• What pharmaceutical raw materials are?
• How do raw materials affect API quality?
• Impurity control strategy for pharmaceutical raw materials
• How to decide raw material specifications?
• Which test parameters should be included?
• A practical case study on Salicylic Acid

After reading this article, you will be able to confidently answer common regulatory and technical questions related to raw material control in API manufacturing.

What Is a Pharmaceutical Raw Material?

Pharmaceutical raw materials are chemicals used during the manufacturing of APIs or their intermediates. These materials may be present at the starting, intermediate, or final stages of the API manufacturing process.

Pharmaceutical raw materials include:

• Starting materials (SM)
• Key starting materials (KSM)
• Intermediates
• Solvents
• Reagents
• Catalysts and metals
• Filter aids and charcoal

Related: Pharmaceutical Analysis

How Do Pharmaceutical Raw Materials Affect the Quality of an API?

Raw materials can significantly influence API purity, stability, safety, and regulatory compliance. The following components present in raw materials may impact API quality:

Potential Quality-Affecting Components

• Reagents, chemicals, solvents
• Catalysts and metals
• Filter aids and charcoal
• Degradants
• Mutagenic impurities
• Nitrosamines
• Polymorphic forms
• Foreign particles
• Extractables and leachables
• Microbiological attributes
• Packaging material interactions

During API manufacturing, many chemicals—apart from key starting materials—are used. These substances can carry over into the API and must therefore be controlled at:

• Raw material stage
• Intermediate stage
• API stage

Information Required to Control Impurities

To establish a robust impurity control strategy, the following information must be obtained from the raw material manufacturer:

• Route of Synthesis (ROS)
• Possible and actual impurities (process-related and potential)
• Solvents, reagents, catalysts, and metals used
• Impurity trend data
• Existing impurity control strategy

This information enables a risk-based evaluation of raw materials.

Impurity Control Strategy for Raw Materials

While reviewing or designing raw material specifications, the following factors must be considered:

• API quality requirements
• Regulatory requirements (ICH, GMP, DMF expectations)
• Pharmacopoeial requirements (USP, EP, IP, BP, JP)

If the raw material manufacturer adequately controls impurities as per API and regulatory requirements, their specification may be accepted. Otherwise, in-house specifications must be designed to control impurities using appropriate analytical techniques—preferably chromatographic methods.

Who Decides Pharmaceutical Raw Material Specifications?

During the development phase, the responsibility lies primarily with:

• Synthetic (Process) Scientists
• Analytical Scientists

Once draft specifications are prepared, inputs from QC, QA, and Regulatory Affairs (RA) are incorporated before final approval.

Test Parameters to Be Included in Raw Material Specifications

Both universal tests and API-specific tests should be considered.

Universal Test Parameters

• Description
• Identification (minimum two tests)
• Loss on Drying (LOD) or Water Content
• Residue on Ignition / Sulphated Ash
• Assay

Additional Critical Tests (as applicable)

• Related substances/impurity profile
• Residual solvents / organic volatile impurities
• Chiral impurities and specific optical rotation
• Metals / heavy metals
• Counter ions
• Microbiological attributes

How to Decide Specifications for Pharmaceutical Raw Materials?

The following systematic approach should be followed:

1. Develop appropriate analytical methods (preferably chromatographic)
2. Generate trend data using multiple batches from each vendor
3. Include at least two identification tests:
   • One chromatographic
   • One spectroscopic
4. Study the purification behaviour of:
   • Impurities
   • Solvents
   • Metals
5. Evaluate the impact of each parameter on API quality
6. Review all data and finalize specifications

Typical Example of Raw Material Specification

• Description
• Solubility (if required)
• Identification
  • Chromatographic / Chemical
  • Spectroscopic
• LOD or Water Content
• Related Substances
  • Known impurities
  • Any unspecified impurity
  • Total impurities
• Residual Solvents
• Assay
• Any other test as per the process requirement

Case Study: How to Decide Specifications for Salicylic Acid

Manufacturing Process Overview

Salicylic Acid is typically manufactured from Methyl Salicylate through a two-step process:

Step 1:
Methyl Salicylate → Sodium Salicylate

• Reagent: Sodium hydroxide
• By-product: Methanol

Step 2:
Sodium Salicylate → Salicylic Acid

• Reagent: Sulphuric acid

Discussion on Specification Parameters

Description:
White powder (based on trend data and process needs)

Solubility:
Optional; decided based on process requirement

Identification:

• IR spectroscopy
• HPLC
  (Mandatory: at least two identification tests)

Loss on Drying:
NMT 0.5% (limit based on trend data)

Related Substances

• 4-Hydroxybenzoic acid: NMT 0.10%
  (related to Methyl Salicylate)
• 4-Hydroxyisophthalic acid: NMT 0.05%
  (process-related impurity)
• Phenol: NMT 0.02%
• Any unspecified impurity: NMT 0.05%
• Total impurities: NMT 0.20%

Residual Solvents

• Acetic acid:
  • 500 ppm at raw material/intermediate stage
  • 5000 ppm at API stage

Assay

• 99.5% – 101.0% (on dried basis)
  (Limits may vary based on process requirements)

Other Tests

• Heavy metals
• Limit tests
• Melting point
  (Included based on process and regulatory needs)

Conclusion

Pharmaceutical raw materials play a vital role in determining API quality. A scientific, risk-based, and data-driven approach to raw material specification design ensures:

• Improved API quality
• Controlled impurity profiles
• Regulatory compliance
• Fewer deficiency letters (DLs)

Careful attention at the raw material stage helps avoid surprises during regulatory inspections and strengthens overall product quality.

Related: Active Pharmaceutical Ingredients (APIs) Vs Raw Materials

Abbreviations

• LOD – Loss on Drying
• SM – Starting Material
• KSM – Key Starting Material
• DL – Deficiency Letter

Further reading:

• What are Pharmaceutical Raw Materials? Biopharmaceutical