27.10.2014 |

LOGFILE No. 24/2014 - Risk Assessment of Excipients

Excipients – Risks and their Assessment

by Dr. Stephanie Blum

Viewed in terms of the way a medicinal product works, excipients have a wide variety of tasks to perform and are essential to the quality of the product. Since the beginning of 2013, legal requirements for medicinal product manufacturing have more strongly reflected this development. Every manufacturer of medicinal products since then has been required to ensure the suitability of excipients for the manufacture of medicinal products for human use by performing a risk assessment.

Excipients – Qualification of Suppliers and Risk Assessment

Section 11, Subsection 2 of the AMWHV (German ordinance on manufacturing medicinal products and active drug substances) [1] stipulates: “To ensure that excipients are suitable for the manufacture of medicinal products intended for human use, the supplier qualification process shall provide for a formalised risk assessment by the manufacturer of the medicinal product. Specifically, the risk assessment must include checking for compliance with the regulations on appropriate good manufacturing practice in the manufacture of excipients, their origin and intended use, as well as any information on past incidents.”

Even though concrete requirements for this risk assessment have not had binding force up to now, Section 3, Subsection 2 of the AMWHV already mentions corresponding guidelines. Even more than a year after they were published in February of 2013 by the European Commission, these guidelines [2] are still available only as a draft. However, that should not by any means be taken as a reason to postpone the required risk assessment. Even if the guidelines themselves have not yet gone into effect, the amended AMWHV has been in force since 2nd January 2013. Thus, the “formalised risk assessment” called for in this document is binding. What now has to be done? Fortunately, the draft guideline provides excellent support for making risk assessments.

Risk Assessment

The draft guideline includes the following fundamental requirements for the risk assessment of excipients for the manufacture of medicinal products for human use:

  • The procedure for the risk assessment of excipients must be an integral part of the quality management (QM) system of the medicinal product manufacturer.
  • The risk assessment must be carried out for each excipient.
  • The risk assessment should be in conformity with the principles described in ICH Q9 “Quality Risk Management” [3].

In the first step of the risk assessment the medicinal product manufacturer identifies conceivable risks relating to the quality, safety and function of an excipient. The draft guideline also suggests specific examples of this:

  • transmissible spongiform encephalopathy (TSE)
  • potential contamination (of viral or microbial nature or with endotoxins or pyrogens)
  • potential impurities from the raw materials used to manufacture the excipient
  • potential process contamination (e.g. residual solvent or catalysts)
  • assurance of sterility, where applicable
  • production in special areas or use of dedicated equipment and facilities
  • monitoring ambient conditions and storage conditions.

In view of the use and function of the excipient, the following aspects should also be taken into consideration:

  • dosage form of the medicinal product
  • function of the excipient within the formulation (e.g. lubricant/compression additive of a tablet or preservative of a liquid dosage form)
  • quantitative proportion of the dosage form
  • daily intake of the excipient by the patient
  • quality defects of the excipient that are already known (on a company level or worldwide)
  • single substance or composite
  • potential impact on critical quality attributes of the medicinal product.

Thus, the risks taken into account in the course of the risk assessment include not only those that are directly associated with the excipient itself, but also those that arise from the intended use of the excipient.

Risk Control

In the next step, risk control, the medicinal product manufacturer now defines GMP elements that are suitable for controlling the risks that have been identified. According to the draft guideline, the following GMP elements should be considered:

  • effective quality management system
  • competent and qualified personnel in adequate numbers, job descriptions, training programmes
  • appropriate facilities and equipment
  • documentation system for processes and specifications of all production and quality activities, including archiving records
  • system for encoding and identifying starting materials, intermediates and excipients to allow full traceability
  • independent quality control
  • storage of retention samples of the excipient
  • contracts for outsourced activities
  • effective system for management of complaints and, where applicable, necessary product recalls
  • regular self-inspections

After the required GMP elements have been defined, a gap analysis is conducted. The medicinal product manufacturer evaluates the manufacturer of the excipient to verify compliance with these GMP elements, thus defining the manufacturer’s risk profile. The gaps that are discovered must be documented. This forms the basis on which the medicinal product manufacturer then sets up a risk mitigation strategy, including the relevant control measures. These measures range from approval of the excipient manufacturer on the basis of appropriate controls to terminating dealings with the excipient manufacturer due to unacceptable failures. The controls proposed by the draft guideline include elements such as audits, document retrieval or in-house analysis.

Risk Communication

Risk communication is an essential component of all risk management processes. (The draft guideline contains no specific regulations for this.) If the defined risk controls are to be successful, of course it is imperative that they be communicated to the appropriate places. These are, first and foremost, those persons who are responsible for implementing these measures. That would be Quality Control, if certain tests or analyses were specified for inspecting incoming excipients, or Goods Received, if specific documentation of delivery is to be routinely attached to the delivered excipient. And then, of course, the excipient manufacturer should be directly approached and called upon to implement appropriate corrective actions to ensure that any gaps discovered have been closed.

Risk Review

In the final step, risk review, the effectiveness of the risk control measures is continuously verified. The draft guideline suggests taking the following factors into account:

  • number of defects in excipient batches received
  • type / severity of the defects
  • loss of existing QM certification of the excipient manufacturer
  • trends observed, where applicable, in the quality attributes of the medicinal product
  • results of audits of excipient manufacturer

It also appears advisable to take the opportunity to verify one’s own risk strategy. For this purpose, the originally defined necessary GMP elements and the company’s own control strategy should be reviewed and adapted, if necessary.

Good manufacturing practice for excipients - but which one?

The draft guideline does make clear which elements of a QM system should be taken into account in a risk assessment. However, there are no rules governing the specific form of these elements. To some, this may appear to be an unfortunate failure. To medicinal product manufacturers, however, it essentially opens up valuable leeway for decisions, which should be put to good use. A wide variety of regulatory works is available for this purpose.

The first item to be mentioned is certainly “The Joint IPEC-PQG Good Manufacturing Practices Guide“ [4]. This document was published jointly in its present form by IPEC and PQG (Product Quality Group) in 2006. On this basis and under the auspices of the IPEC, the EXCiPACT certification guidelines [5] were developed in an additional step, thus enabling appropriate certification of the excipient manufacturer by an independent accreditation body.

The IPEC-PQG guidelines, which were developed in an industrial environment, have gained wide acceptance over the years amongst manufacturers and users of excipients and have even won over the authorities of the United States: They were published with only a few editorial changes as the informative Chapter <1078> of the USP [6]. The IPEC has issued a number of additional publications [7] that are also helpful. And, of course, it is always possible to fall back on the corresponding WHO guidelines [8].

Furthermore, of course the medicinal product manufacturer can also rely on individual requirements of the EU-GMP Guide (Parts I - III). (At any rate, the draft guideline explicitly refers to Parts I and II and to individual annexes of the EU-GMP Guide. In their guideline, IPEC and PQG also make it clear that excipients for some special applications lie outside the scope of the IPEC-PQG Guideline. These include excipients for parenteral drugs, ophthalmic products, medicinal products for inhalation and for use on open wounds, as well as all excipients declared as being sterile and free of pyrogens. In this case the IPEC and PQG expressly recommend consulting the guidelines that apply for the particular medicinal product and adapting them in the appropriate form to the relevant excipient.)

Defining the GMP requirements

Within the scope of risk evaluation the medicinal product manufacturer has the duty, but also the freedom, to define those GMP requirements for excipients and their manufacture that are appropriate from the point of view of the manufacturer. It follows that this freedom should be used wisely and that precisely those customised GMP standards should be defined which ensure the safety and quality of the relevant excipient. Thus, the focus is on patient safety, without the excipient manufacturer being unreasonably burdened with excessive demands. Good manufacturing practice is appropriate precisely whenever specific measures ensure that high-quality excipients are being manufactured, thus ensuring the patient’s safety as well.


[1] Arzneimittel- und Wirkstoffherstellungsverordnung vom 3 November 2006 (BGBl. I S. 2523) last modified by Article 3 of the Ordinance of 11 February 2013 (BGBl. I S. 188).

[2] Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use, SANCO/D/6/SF/mg/ddg1.d.6(2013)17926.

[3] ICH Harmonised Tripartite Guideline Quality Risk management Q9, 09.11.2005.

[4] The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients, IPEC, 2006. http://www.ipec-europe.org/page.asp?pid=59

[5] Certification Standards for Pharmaceutical Excipient Suppliers: Good Manufacturing Practices, Good Distribution Practices, Requirements for Auditor Competency and 3rd Party Audit Organizations Providing Certification of the Management System, 2012.

[6] USP-NF <1078> Good Manufacturing Practices for Bulk Pharmaceutical Excipients.

[7] http://www.ipec-europe.org/page.asp?pid=59

[8] Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients. WHO Technical Report Series No. 885, 1999, Annex 5.

All URL information is dated 30 March 2014.


Dr. Stephanie Blum
cirQum, Frankfurt

E-mail: stephanie.blum@cirQum.de

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