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Risk Assessment of GMP Raw Materials

There is a GMP requirement within the Pharma/Biotech industry for the selection, qualification and approval of raw materials and their suppliers, both initially and periodically.

In addition to testing and acceptance programs, raw material and supplier management systems set the standards by which companies ensure that materials procured from appropriate supply chains meet the technical, regulatory, and supply needs for the designated use and function, referred to as ‘fit-for-use’ or ‘fit-for-function’. When identifying risks associated with raw materials, any potential for misalignment in the fit-for-function status should be assessed.

Raw material attributes to consider when assessing risk

Qualification of raw materials used within pharmaceutical product manufacturing, must consider three fundamental questions: 

  • What function is the raw material designated to perform?
  • What material attributes are essential to the designated function versus what might have unintended consequences?
  • Are there reliable supply chains available within the marketplace to assist in addressing the first two questions by providing materials of reasonable quality, both initially and in an ongoing capacity? 

Answering these questions gives a simple example of how to select procured raw materials for fit-for-function. 

However, for those tasked with executing raw material qualification in the pharmaceutical industry, it is only a surface scratch to the substance of the three fit-for-use qualification categories:

  • User requirements: the designated function of the chosen raw material; for example, at what phase of production the raw material is introduced to the process, whether the raw material will be delivered in the final drug product; the process needs for sterility assurance, compendia grade, or custom packaging, etc.
  • Material attributes: the unique characteristics of the raw material must be well understood; is it growth-promoting, pure, stable, well-characterized (i.e., compendia monograph), flammable, or hazardous in other ways? 
  • Supply chain: is the selected supplier capable of producing materials of reasonable quality? Are quantities available to fill the demand? Does the marketplace offer multiple sources of equivalent material that meet pharmacopeia needs with sufficient technical and regulatory support despite quantities purchased and expectations for high customer support?

User requirements risk attributes

1. Patient exposure 
  • Will the RM function as an excipient intentionally added for delivery?
  • Is the RM a known residual?
  • Is the RM removed upstream?

Impact to product quality
Always assuming the RM is in fact added to the 
process as intended:
  • will the RM individually and/or specifically result in OOS of a CQA, KPA, or other process attribute necessary for product acceptance?

Impact to process
Always assuming the RM is in fact added to the 
process as intended:
  • will the RM individually and/or specifically disrupt a CPP, KPP, or other process parameter deemed indicative or necessary for process control?

2. Microbial restrictions
  • Will the RM be added to the product/process upstream or downstream of the sterile envelope?
  • Will the RM undergo further processing to modify microbial content?

Regulatory/compendia requirements 
Does the function of the RM dictate:
  • novel excipient approval?
  • adherence to compendia grade?
  • reporting of detailed acceptance criteria in the dossier?
  • 100% ID testing?

Material acceptance requirements
Does the RM container design need to account for:
  • single-use or multi-use quantities?
  • sterility assurance?
  • 100% ID testing?
  • unique sampling or handling conditions necessary to meet functional requirements?

Material risk attributes

1. Microbial characteristics
  • Is the RM non-sterile, bioburden-reduced, or sterile? 
  • Is the RM growth-promoting, bacteriostatic, or bacteriocidal?
  • Does the RM require container closure integrity to maintain acceptable microbial characteristics?

Origin, composition, structural complexity
  • Is the RM derived from chemical, mineral, microbial, plant, or animal origin?
  • Is the RM pure or a composition?
  • Does the RM have a defined chemical formula, defined structure, or is undefined?
  • Is the origin/composition inherently at risk for adventitious agents or other naturally occurring impurities (e.g., metals, toxins)?

Material shelf life and stability
  • Is the RM stable?
  • Is there data to support stability?
  • Does the RM require adherence to specific handling controls to maintain acceptance criteria throughout shelf-life; temperature (e.g., controlled room temp, refrigerated, frozen), humidity, light exposure, oxygen/nitrogen overlay, etc.?

2. Manufacturing complexity and impurities
  • Is the RM produced by chemical-synthesis, biosynthesis, bioconversion, or refinement of natural substances?
  • Does the RM manufacturing process introduce, eliminate, concentrate potential impurities?
  • Is the manufacturing process robust or highly variable?

Analytical complexity/compendia status
  • Does the RM have an existing pharmacopeia compendia monograph for standardized identification and characterization?
  • Is the RM non-compendia?
  • Is the RM complex and proprietary requiring significant method development to effectively identify and characterize (e.g., high molecular weight contaminant; Poloxamar)?

Material handling requirements
  • Does the RM require unique, particular, or complicated shipping or storage conditions in order to maintain the qualified shelf life?

Supply chain risk attributes

Supplier quality system performance
  • Does the supplier adhere to certified or regulated quality system standards (e.g., ISO, IPEC, GMP, etc.)?
  • Has the supplier met the requirements of quality assessment?
  • Does the supplier effectively implement CAPAs?

Continuity of supply 
  • Is the supplier the only manufacturer of the material (e.g., sole-source)?
  • Do other suppliers offer the material?
  • Are alternate suppliers approved for dual sourcing?
  • Is the supplier constrained by sourcing?
  • Are lead times long?
  • Is shelf-life short?
  • Is safety stock maintained?

Supplier technical capability
  • Is the supplier considered an expert in their field?
  • Is the supplier familiar with the challenges of pharmaceutical or biopharmaceutical manufacturing standards?
  • Is the supplier the expert in the analytical characterization and method performance for the material?
  • Does the supplier assist in investigating deviations?
  • Is the supplier shelf life supported by data?

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