Quality Risk Assessment for Excipients: An Industry Perspective

The IPEC Federation has issued a position paper on European Union (EU) guidelines for excipients based on quality risk management. Although supporting risk assessment, the organization raised concerns over timing for a March 2016 deadline for risk assessments as incomplete assessments may jeopardize the availability of excipients.

IPEC issued the position paper earlier this month to put forth several issues for consideration in the implementation of the risk management and good manufacturing practice (GMP) principles of the EU guidelines, including the necessary collaboration and cooperation along the entire supply chain to avoid gaps in a holistic risk-assessment process. A look at the key points raised.

Background on the EU guidelines
The IPEC Federation represents the four existing regional International Pharmaceutical Excipient Councils (IPECs): IPEC Americas, IPEC Europe, IPEC Japan, and IPEC China. Earlier this month, the IPEC Federation issued a position paper of EU guidelines on the formalized risk assessment for ascertaining the appropriate GMPs for excipients of medicinal products for human use. The general principles of the EU guideline are to properly control and track the quality and safety of excipients, throughout the entire supply chain, by appropriate means of quality management. This involves ensuring that GMPs and good distribution practices (GDPs) are in place, used, and evaluated. 

The EU guidelines, which were finalized on March 19, 2015, specify that the manufacturing authorization holder (MAH) is required to ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate GMPs are.The appropriate GMPs for excipients are to be ascertained on the basis of a formalized risk assessment that takes into account requirements under other appropriate quality systems as well as the source and intended use of the excipients and previous instances of quality defects. The MAH is required to ensure that the appropriate GMPs ascertained are applied and to document the measures taken. Under the EU guidelines, the excipient risk assessment/risk management procedure is to be incorporated in the pharmaceutical quality system of the MAH. The MAHs are required to have the risk assessment/management documentation for appropriate GMPs for excipients available on site for review by GMP inspectors. The EU guidelines further state that consideration should be given to sharing relevant information from the risk assessment with the excipient manufacturer to facilitate continuous improvement. The guidelines specify that the risk assessment as set out in the guidelines should be carried out for excipients for authorized medicinal products for human use by March 21, 2016.

In issuing the guidelines, the EU is basing the guidelines on related provisions, including EU GMP requirements and the International Conference on Harmonization (ICH) guideline, Q9 Quality Risk Management. These quality risk management principles should be used to assess the risks presented to the quality, safety, and function of each excipient and to classify the excipient in question, such as low risk, medium risk or high risk, using quality risk management tools found in ICH Q9 and related provisions. For each excipient from each manufacturer used, the EU guidelines specify that the MAH should identify the risks presented to the quality, safety, and function of each excipient from its source (i.e., animal, mineral, vegetable, synthetic) through to its incorporation in the finished pharmaceutical dose form. Areas for consideration include: transmissible spongiform encephalopathy; potential for viral contamination; potential for microbiological or endotoxin/pyrogen contamination;potential, in general, for any impurity originating from the raw materials, e.g. aflatoxins or pesticides, or generated as part of the process and carried over, e.g. residual solvents and catalysts; sterility assurance for excipients claimed to be sterile; potential for any impurities carried over from other processes, in absence of dedicated equipment and/or facilities; environmental control and storage/transportation conditions, including cold chain management, if appropriate; supply chain complexity; stability of the excipient; and packaging integrity evidence. The EU guidelines also specify that the MAH should consider the use and function of each excipient in the the pharmaceutical form and use of the medicinal product containing the excipient.

Having established and documented the risk profile of the excipient, the EU guidelines specify that the MAH is required to establish and document the elements that he/she believes are needed to be in place to control and maintain the quality of the excipient, which will vary depending on the source, the supply chain ,and the subsequent use of the excipient. Among several things to consider, these elements should include the establishment and implementation of an effective pharmaceutical quality system, related training, qualified personnel, and controls, as well as a qualification program of suppliers. The EU guidelines specify that after the determination of the appropriate GMP, a gap analysis of the required GMP against the activities and capabilities of the excipient manufacturer should be performed. The EU guidelines specify that any gaps identified between the required GMP and the activities and capabilities of the excipient manufacturer should be documented, and that the MAH should perform a further risk assessment to determine the risk profile, e.g. low risk, medium risk or high risk, for that excipient manufacturer. Once the appropriate GMP for the excipient and the risk profile of the excipient manufacturer have been defined, the EU guidelines specify that ongoing risk review should be performed.

IPEC’s position
Although favoring risk assessment for excipients, IPEC raised concerns over the feasibility of implementing the provisions by the March 2016 deadline. “IPEC is convinced that the application of appropriate GMP and GDP throughout the entire pharmaceutical excipient supply chain will enhance patient safety,” said the organization in its position paper. “This can, however, only be achieved if the risk-based approach is always scientifically sound and risks are evaluated in collaboration with all relevant parties in the supply chain. IPEC is concerned that there is not enough time to complete risk assessments for all excipients by the March 21, 2016 deadline, and that incomplete assessments may jeopardize the availability of high-quality excipients that have been in use for many years.”

The IPEC position paper pointed out that the risk-management principles and other related measures are already in use for excipients and raised concerns over how current measures and practices would align with the EU guidelines. “The ‘excipient industry’ does not exist as such because the ingredients produced are not only targeted for use in pharmaceuticals but also in food, cosmetics, or as general chemicals,” explained IPEC in its position paper. “The supply of ingredients for use as pharmaceutical excipients is often minor compared to their use in other applications; however, the availability of the ingredients for use in the manufacture of medicinal products may be essential to the performance and delivery of a drug product. Quality systems applied during the manufacture of pharmaceutical excipients are diverse and usually [are] based on their use in a specific application, thus by necessity, they often already include risk-management principles,” said IPEC in its position paper. “Adjusting current quality systems to “pharmaceutical quality systems” according to 2.6 (i) of the guidelines may be difficult and conflict with other requirements. Furthermore, specific criteria has not yet been defined for what is a pharmaceutical quality system; therefore, additional clarification of the specific expectations by the regulators is necessary. IPEC is happy to provide experts to collaborate with regulators as they work to develop and define future requirements. Inappropriate requirements could jeopardize the availability of high-quality excipients that have been used for many years and potentially lead to drug shortages.”

In its position paper, IPEC said that many elements of GMP and GDP were implemented by excipient manufacturers and suppliers and historically other voluntary GMP guides and standards have been available and used by excipient suppliers to facilitate implementation of excipient GMPs. “IPEC believes these guides and standards have appropriately defined and support pharmaceutical GMP requirements for excipients according to the EU regulation,” said the organization.

The IPEC position paper explains that the EU guidelines set out a number of high-level GMP principles for excipients that excipient suppliers will be required to comply with. It points out that historically a significant number of these principles have not been embraced and implemented by excipient suppliers for the reasons previously outlined, and that as a result, a MAH may conclude that an excipient manufacturer and its excipient are “high risk,” and if mitigation measures are not possible, would require the MAH to stop using that excipient. “This action will result in the shortages or lack of availability of existing medicines which, until the publication of these guidelines [the EU guidelines on risk assessment for excipients] were accepted by all as safe and effective.”

IPEC said it would like to contribute to the implementation of the risk management and GMP principles of the EU guidelines and related measures, and in doing so, the organization enumerated some points for key stakeholders.

  • The assessment of all associated risks of an excipient and its suppliers can only be achieved by the MAH through open communication, collaboration, and flow of information between all parties in the excipient supply chain.
  • The risk-assessment application process, as described in the guidelines, could lead to situations in which an excipient from a single manufacturer could be classified by different MAHs into different risk classes (low, medium, high), depending, for example, on its intended use and application. This could result in differing expectations relating to the appropriate GMPs necessary in the manufacture of the same excipient. It would be impossible to comply with these different expectations in one quality system unless the highest level of GMP were to be implemented. IPEC sees this as a major concern and topic for further discussion between excipient users, excipient suppliers, and authorities.
  • As the evaluation of the “supply chain complexity” is required in 2.3 (viii) of the EU guidelines, communication, collaboration, and cooperation along the entire supply chain is critical to avoiding gaps in a holistic risk-assessment process.
  • IPEC views third-party auditing and certification schemes, such as EXCiPACT, and national standards, such as NSF/IPEC/ANSI 363-2014, as playing an essential role to achieve compliance with new requirements for the qualification of excipients and their suppliers. Without additional information concerning GMP and GDP compliance of the excipient supply chain through independent third-party audits, it will be nearly impossible for MAHs on their own to gather all the necessary data required. IPEC is committed to developing a document which traces the links between the EU guidelines and IPEC’s own recommended good practices.

In concluding, IPEC said that “considerable effort will be required by the industry in order to complete all excipients risk assessments by March 21, 2016, as required by the EU guidelines. The implementation of appropriate excipient GMPs by suppliers will require more than a year, and may be difficult to achieve for manufacturers of certain substances not typically produced as pharmaceutical excipients. MAHs may need to collaboratively establish realistic timelines with their suppliers to achieve the appropriate level and timing for implementation. IPEC will share their views with the EC on the challenges to complying with the current compliance timeline and request collaboration with them to help establish more realistic goals and timelines.”

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