Excipient Risk Assessment: Approach, Templates

According to the EU GMP guidance—“Guidance for Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use (2015/C 95/02)”—MAH Holders and Manufacturers of drug products are required to ensure that the excipients are suitable for use in medicinal products. This shall be based on a formalised risk assessment with respect to safety, quality and function of each excipient in a drug product and ascertaining the appropriate good manufacturing practice (GMP) for the excipient.

Pharmaceutical excipients can be source of various quality and safety risks and drug product failures with serious concerns for patient safety, regulatory actions. For example:

• Contamination of cough syrups with Diethylene glycol (DEG) / Ethylene Glycol (EG) from excipients like Propylene glycol due to use of cheap substituents and industrial solvent grade material, which led to death of several children
• Increasing incidence of recalls of drug products due to NDSRI (Nitrosamine Drug Substance Related impurities). Most NDSRI can be linked to nitrosating factors or impurities from excipients
• Recall of several lots of Testosterone Gel for Benzene contamination due to one of the excipient used in the formulation, Carbomer 940

The EU GMP guidance provide a broad framework for performing the excipient risk assessment,  identifying GMP elements applicable and implementing control measures. However, the guidance does not provide detailed instructions on how to perform and document this assessment. A systematic evaluation of excipient related risks and the implementation of appropriate mitigation measures enhance product safety, quality, and stakeholder confidence—not only in Europe but also in other regulated or semi-regulated markets

Qvents provides a set of comprehensive templates for excipient risk assessment that break down the requirements into distinct areas for evaluation.

Key Steps in the Excipient Risk Assessment Process

As per the EU guidance:

• MA Holder should ensure excipients are suitable to use in pharmaceutical products
• This should be done by ascertaining what the appropriate GMP is by a risk assessment
• Risk assessment should look at:
  • Source of excipient
  • Function of the excipient
  • Previous instances of quality and performance defects of excipients
• Then MA holder should ensure the ascertained GMP is applied, reviewed in an ongoing manner.

Practically the MA holder will perform:

• A risk assessment of each excipient across a range of parameters looking at
  • the source of the excipient and
  • function of the excipient in a drug product. Since a drug product manufacturing site may be using the same excipient in different drug products and even the function of the excipient could be different in different products, the functional risk assessment should be performed covering all the drug products in which it is used.
  • its historical quality issues if any, across a list of parameters.
• For each parameter identify the level of risk as Low, Medium, High. When an excipient is used in multiple products, the final risk score for each functional attribute should be the highest score observed across all those products.
• Further compile a list of GMP elements that will be applicable to the excipient and excipient manufacturer based on the risks level. The list will have two sections
  1. Fundamental GMP elements applicable for all excipient suppliers and manufacturers &
  2. Additional GMP elements based on excipient risk profile along with identification of the significance of the risk element as High or Low.
• Perform Gap analysis on the GMP elements to assess whether the current GMP controls adequately address the identified risks
• The gap analysis shall be performed based on information collected from Excipient Manufacturer/ Vendor through questionnaire, declarations, excipient information package documentation, certification of excipient quality systems and / or GMP certificates, vendor audits.
• Document the adequacy of each GMP system element as: Adequate (A); Inadequate (IA); Not Applicable (NA); Additional Information Required (ANF). Provide a rationale for each rating.
• After this perform a Further Risk Assessment specifically focussing on the High /Medium risk elements to determine the excipient risk profile based on adequacy of GMP elements and controls and information provided. For each risk element assign a risk profile as High / Medium / Low. At this stage
  • A High / Medium score of source or functional risk of an excipient may be brought down to Medium or Low if adequate GMP controls and systems are in place
  • A Low / Medium risk profile may also be elevated to Medium/ High based on additional information or lack of information.
• Based on the Gap Analysis on the GMP Elements and Further Risk Assessment establish the Control strategies for the excipient. The strategies could range from (but not limited to):
  • acceptance based on COA and documentation support,
  • acceptance testing,
  • prequalification audit
  • prequalification audit and routine audits
  • Unacceptable / Discontinue to excipient / excipient source
• Further perform periodic Ongoing risk review of the risk profile of the excipient and excipient manufacturer by monitoring performance of excipient quality, impact on drug product performance, continuation of GMP systems and certification of the excipient manufacturer, organisational, procedural or process changes at excipient manufacturer, supply chain, audit outcomes. The input data for this assessment could come from product quality reviews, raw material trend reviews, vendor questionnaire, certification updates, information packages and declarations from excipient manufacturer. Based on the review, make conclusions on whether control strategies applied are sufficient or Control strategy need to be revised.

Qvents Templates

References

1. EU Guideline for Risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use (2015/C 95/02)
2. Excipient risk assessment: possible approaches to assessing the risk associated with excipient function; Olena Ruban et al; Journal of Pharmaceutical Investigation · August 2017
3. EU Excipient Risk Assessment Guidelines – Practical Implementation Experience; Frithjof Holtz, Advocacy & Surveillance, Life Science Regulatory Management, Merck KGaA, Darmstadt, Germany