The Challenges and Solutions of Raw Material Requirements in the Manufacture of Biologic Products

Raw materials are basic to the final product. Raw materials used in the making of a biologic product can impact drug interaction, quality, and patient safety. As the goal of the biologic drug is to treat a patient, raw material quality can influence the efficacy of the drug. The other qualities of a biologic drug including its shelf life can be affected if the raw materials used are impure or of low quality. If animal-derived products are used in the development of a product, there is the inherent risk of adventitious agent contamination. Poor quality raw materials can result failed lots and in costly delays.


Raw material requirements in a cGMP environment should not be overlooked when developing new products.

Some of the causes of ingredient contamination include:

  • Globalization and greater drug complexity
    • Deception by suppliers for economic gain
  • Slow adoption of modern standards
    • Chemical industry
    • Developing economies
  • Access to a diverse and expansive network of suppliers increased the potential of weak links
  • Lack of detailed knowledge to manage risk

Raw material regulations

21 CFR 610.15: Constituent materials: 'Ingredients, preservatives, diluents, adjuvants. All ingredients used in a licensed product, and any diluent provided as an aid in the administration of the product, shall meet generally accepted standards of purity and quality. Any preservative used shall be sufficiently nontoxic so that the amount present in the recommended dose of the product will not be toxic to the recipient, and in the combination used it shall not denature the specific substances in the product to result in a decrease below the minimum acceptable potency within the dating period when stored at the recommended temperature.'

21 CFR 211.80: Components are required to be controlled by quality control unit to ensure appropriate management, testing and monitoring of components...components should be tested for identity and for conformity, purity, strength and quality.

21 CFR 211.110: In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process.

Detecting and preventing the issues associated with raw materials

Management support

Management support is vital to prevent bad infiltrations of the supply chain. The management can demonstrate their support by

  • Promoting knowledge about suppliers, how the raw materials are derived as well as provide resources to identify and manage risk in the raw material supply chain.
  • Fostering the use of modern technology
  • Reducing too much reliance on CoA

Integration of process controls

The many issues associated with raw materials can be identified or prevented by integrating process control procedures during the development of the manufacturing processes, including the managing of the supply chain for raw materials. Control of raw materials alleviates the risk of contamination derived from sources such as microbes and chemicals.


The consistency between different lots must be checked through testing of cytokines, growth factors, serum sources, and other additives. Whether the testing involves simple assessments such as pH, osmolality, or physical appearance or a complex analysis such as immunoblot, or potency tests, testing is a critical part of the process.

Addressing raw material variability

Challenge: The complexity of the raw material used in the manufacture of a biologic drug product ranges from mammalian cell lines that produce a biologic and media and media components to gels and filters that are used in the purification process. What makes the process even more overwhelming is the fact that the manufacturing of biologic happens at different sites globally. Each of the suppliers and the number of raw materials require contingencies for back up. And then, there is also the possibility of quality difference from one lot to another.

The solution:

  • The solution is to test each component that is used in the production of the biologic drug and monitor products of each phase during production and release testing for a variety of attributes. Such a testing, monitoring, and release testing will inform the production team to take steps to resolve any identified issues.

Challenge: Although high quality and reputable vendors usually have tight controls over production and low variability lot-to-lot, problems do occur. The use of different suppliers, the discontinuation and disruption of the supply chain, the substitution of low-quality raw materials to the raw materials list present new challenges.

The solution:

  • The solution is to test the raw materials and have a solid baseline of information to fix the gap between the old and new raw material vendors. Perform comparison studies using reliable consistent methods for trend analysis.

A common solution to both of the above-mentioned challenges is to understand the raw material attributes of their raw materials, which of those affect the variability and control the variability.

Ensuring Quality and Purity of raw materials with analytical best practices

  • Use qualified or validated methods and rigorous quality control reviews in testing for the potency of raw materials
  • Some established labs use in-house created SOPs to assess raw material attributes
  • For more complex assessments, having highly trained personnel and instrumentation
  • In addition to the supplier certification of analysis, test and verify raw materials in cGMP laboratories with associated control and procedures
  • Apply the same principles of technologies used to test critical quality attributes to the final products for raw materials
  • Ensure real-time inventory tracking and access to raw material testing data

Raw material guidance

ICH in context with the manufacture of API:

No raw material should be released or used before the satisfactory completion of evaluation by the quality units...

Specifications should be established and documented for raw materials... Acceptance criteria should be established and documented for in-process controls.

The API impurity profile should be order to detect changes to the API resulting from modifications in raw materials...

Attend the Semnar Raw Material Requirements (Health Canada/USP/EP) in a cGMP Environment - Issues and Solutions' to explore raw materials and their requirements - issues and solutions. It will also explore how water impacts the final product since water is the single largest raw material that is used within most processes. Another objective is to assure that your organization is maintaining itself within a cGMP compliance framework to include ICH Q7, Q9, and Q11. Case studies to include Warning Letters will be discussed to illustrate regulatory raw material issues.