Specifications for Pharmaceutical Raw Materials: How to Design

Table of Contents

• Introduction and Outcome
• What is the Pharmaceutical raw material?
• How does Pharmaceutical raw material affect the quality of an API?
• Informations needed to control the impurities in Pharmaceutical raw materials
• Impurities Control Strategy of Pharmaceutical Raw Material
• How to Decide the Specifications for Pharmaceutical Raw Materials?
• Conclusion

Introduction and Outcome

The quality of an Active Pharmaceutical Ingredient (API) depends on various factors and one of them is quality of Pharmaceutical raw material. In this post, I will explain Pharmaceutical raw materials, raw materials and quality of an API, raw material impurity control strategy, and procedure of deciding specifications of raw material. After reading this post you will able to answer several questions:

• What is the Pharmaceutical raw material?
• How do pharmaceutical raw materials affect the quality of an Active Pharmaceutical ingredient?
• What is the procedure to control impurities in pharmaceutical raw materials?
• What test parameters should be included in the specifications of any pharmaceutical raw material material?
• What should be the strategy for determining the specifications of any pharmaceutical raw material material?

What is the Pharmaceutical raw material?

Pharmaceutical raw materials are the chemicals that are used in the manufacturing of APIs or their stages. It may be solid chemicals, solvents, reagents and catalysts used in the process.

How does Pharmaceutical raw material affect the quality of an API?

The following components present in raw material can affect the quality of an API:

• Reagents, chemicals, solvents, catalysts/metals, filter aids, charcoal
• Degradants
• Mutagenic impurities
• Nitrosamines
• Polymorphic forms
• Foreign particles
• Extractable and Leachable
• Microbiological attributes
• Packaging material

In the manufacture of an API; Apart from key raw materials (starting materials) many other chemicals like reagents, chemicals, solvents, catalysts/metals are used. These chemicals can reach the final product (API) stage and affect the quality of the API. Hence, these chemicals is to be controlled either at the raw material stage or at the intermediate stage or at the API stage.

Informations needed to control the impurities in Pharmaceutical raw materials

The following informations must be taken from a respective raw material manufacturer for review:

• ROS (Route of synthesis)
• Possible impurities and actual impurities (process as well as potential)
• Solvents, reagents, chemicals, solvents, catalysts/metals
• Impurities trend data
• Impurities control strategy

Impurities Control Strategy of Pharmaceutical Raw Material?

Following factors must be considered while reviewing the raw material specification:

• API requirement
• Regulatory requirement
• Pharmacopoeial requirement

If the manufacturer of Raw materials is controlling the above impurities as per the guidelines and API requirements then it is okay otherwise the in-house specification should be designed in such a way that all these impurities should be controlled preferably by chromatographic method at any stage of the process. Pharmacopeia should also be considered while designing the universal test specification like description, solubility, and melting point. Now the question is, who will design the specifications?

During the development phase, the Synthetic scientists and Analytical scientists should finalize the
specification and later, the opinion of QC, QA and RA can be taken. How is the specification finalized and what are the parameters to be considered in the specification?

Universal test (test which are applicable for all drug substances irrespective of material) and all other tests that may affect the quality of the drug substance should be considered while designing the specification:

• Description
• Identification (at least two identification tests)
• LOD (loss on drying) or water (based on process)
• Residue on ignition/Sulphated ash
• Chiral impurities and Specific optical rotation (if applicable)
• Related substances/Impurity profile
• Residual solvents/Organic volatile impurities: Should be controlled as API requirements and guidelines
• Assay

Note: Other tests like Solubility, Melting point, Limit tests, Counter ions, Heavy metals/metals etc. can be included

How to Decide the Specifications for Pharmaceutical Raw Materials?

The following criteria should be followed while finalising the specification:

• Appropriate methods (preferably chromatographic method) such as impurity profile, residual solvents and assay should be developed for each test.
• Trend data should be prepared (using individual lots of each vendor). Trend data for other tests like Description LOD or water etc. should be generated (for all purchasing materials of each vendor).
• At least two identification tests should be kept. Out of two identification tests, one should be the chromatographic method and the second should be the spectroscopic method
• Purification of  impurities/solvents/metals should be studied
• The impact of other tests on the quality of API should be studied
• All data should be reviewed and specifications should be finalised

Typical example of Purchasing material specification:

• Description
• Solubility:
• Identification
• Chromatographic technique/Chemical technique
• Spectroscopic technique
• LOD or Water content
• Related substances
• Known impurity
• Any unspecified unknown impurity
• Total impurities
• Residual solvents:
• Assay
• Any other tests (as per requirement)

Case studies: How to decide the specifications of Salicylic acid?

Generally, Salicylic acid is prepared from Methyl Salicylate. It is two step process:

Step-1: Methyl Salicylate to Sodium Salicylate: In this step, Methyl salicylate is converted into Sodium Salicylate in the presence of Sodium hydroxide. Methanol is also formed as a byproduct.

Step-2: Sodium Salicylate to Salicylic acid: In this step, Sodium Salicylate Salicylic acid is converted into Salicylic acid in the presence of Sulphuric acid

Discussion on test specification parameters:

Description: White powder(It must be part of the specification and should be decided based on trend data and process requirements)

Solubility: May or may not be kept. Decisions will be taken based on process requirements.

Identification: By IR and By HPLC (It must be part of the specification. At least two identification tests should be kept. Out of two one should be the Spectroscopic technique and the second
should be the Chromatographic or Chemical technique)

LOD: NMT 0.5% (LOD or water must be part of the specification. Limit should be decided based on trend data and process requirements)

Related substances:

• 4-hydroxybenzoic acid: NMT 0.10% (Reported) or any other limit-based process requirement. It is used in the preparation of  Methyl Salicylate
• 4-hydroxy isophthalic acid:  NMT 0.05% (Reported)  or any other limit-based process requirement. It
  is formed in the process
• Phenol: NMT 0.02% (reported)   or any other limit-based process requirement. This impurity is related to  Methylsalycylates
• Any unspecified unknown impurity NMT 0.05% (reported) any other limit-based process requirement
• Total impurities: NMT 0.02% (reported) any other limit-based process requirement

Residual solvents: Acetic acid should be controlled at 500 ppm at purchasing material at any other intermediate stage or at 5000 ppm at the API stage.

Assay: 99.5 to 101% (on a dried basis) or any other limit can be kept based on process requirements.

Other tests: Heavy metals, limit tests, melting point etc. should be kept based on process requirements

Conclusion

Since Pharmaceutical raw-material plays a vital role in deciding the quality of API therefore best effort should be made while deciding the specification. This will not only enhance the quality of the API but also avoid surprises and unnecessary deficiency letters (DLs).

Abbreviations:

• LOD: Loss on drying
• SM: Starting material
• KSM: Key starting material
• DL: Deficiency letter

References:

• USP
• IP
• Cordoba-Rodriguez R. Raw Materials in the Manufacture of Biotechnology Products: Regulatory Considerations. PDA J. Pharm. Sci. Technol. 64(5) 2010: 445–450.