What are the current Rules for Supplier Qualification?

Supplier Qualification is more than auditing. Supplier qualification can be seen as a risk assessment tool. But what are the exact requirements for qualifying suppliers?


Supplier Qualification is more than auditing. Supplier qualification can be seen as a risk assessment tool. It should provide an appropriate level of confidence that suppliers, vendors and contractors are able to supply consistent quality of materials, components and services in compliance with regulatory requirements. An integrated supplier qualification process should also identify and mitigate the associated risks of materials, components and services. But what are the exact requirements?

They are wide-ranging and complex. There are different directives and regulations for medicinal drug products for human or veterinary use and for investigational medicinal drug products. Certain requirements in different directives and the EU-GMP Guidelines define expectations. Here are some examples:

Article 8 of EU-Directive 2001/83/EC
“The application [of a marketing authorization] shall be accompanied […] by […] a written confirmation that the manufacturer of the medicinal product has verified compliance of the manufacturer of active substance with principles and guidelines of good manufacturing practice by conducting audits.”

Article 46 of EU-Directive 2001/83/EC
“The holder of a manufacturing and/or import authorisation shall at least be obliged […] to use only active substances, which have been manufactured in accordance with GMP for active substances and distributed in accordance with GDP for active substances and … to ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate GMP is.”

Article 46b of EU-Directive 2001/83/EC
“Active substances shall only be imported if they have been manufactured in accordance with standards of good manufacturing practice at least equivalent to those laid down by the European Union”. This can be shown by a written confirmation, or the exporting country is included in the so called white list, or a waiver has been granted.

EU-GMP Guidelines Chapter 5:
5.25 “The purchase of starting materials is an important operation which should involve staff who have a particular and thorough knowledge of the supplier.”
5.26 “Starting materials should only be purchased from approved suppliers …”
5.40 “…printed packaging materials shall be accorded attention similar to that given to starting materials.”

The revised Chapter 7 of the EU-GMP Guidelines describe the responsibilities of the Contract Giver when it comes to contract manufacturing and testing. He needs to assure the control of the outsourced activities, incorporating quality risk management principles and including continuous reviews of the quality of the Contract Acceptor’s performance. Audits are a helpful tool to asses the “legality, suitability and the competence of the Contract Acceptor“. The new Chapter 7 was obviously designed to intensify the control of Contract Acceptors by the Contract Giver and extend those controls to subcontractors.

The holder of the manufacturing authorisation is responsible for the supplier qualification by law but in fact the supplier qualification is one of the duties of the Qualified Person (which can be delegated) as defined in Annex 16 of the EU-GMP Guidelines. The QP of the marketing authorisation holder is responsible for certifying the drug product for the market place and is now being held accountable to ensure that all aspects of the supply chain have been made under the appropriate GMPs. However, according to Chapter 2 of the EU-GMP Guidelines, the heads of Production, Quality Control and Quality Assurance share the responsibility of approving and monitoring suppliers of materials (2.9).

So how to proceed? At the beginning of a supplier qualification process, the regulatory requirements regarding the type of material, component or service and the type of product (human/veterinary drug product or IMP) should be identified and specified. Audits, if required, should be planned and executed. The compliance of the selected supplier(s) with the requirements and user requirement specification should be demonstrated. The scope of an audit should cover this. But a successful audit is not the end of the qualification process. After finalising the contract, the compliance of the selected supplier(s) with the applicable requirements should be evaluated periodically. Changes at the supplier´s site (for example manufacturing process etc.) that pose a particular risk to the compliance with the requirements should be assessed. There needs to be a mechanism in place so that any change made by the supplier which could have an impact on the GMP status or the production or testing parameters have to be agreed to before any such changes are implemented. A supplier must also notify the contract giver immediately upon discovery of any deviation/non-conformance/complaint that may have an impact on the services provided. Those need to be assessed and respective actions need to be defined.

The use of Brokers:
Some raw materials are only available at reasonable costs if purchased through an intermediary, i.e. a Broker. If the material is critical to the process, e.g. an API or a key excipient this can give an added complexity to the process and this must be fully investigated with the Quality and Regulatory units being involved, before any orders are placed.


FDA Guideline on Dissolution Testing

The FDA has presented the draft of a revised guideline on dissolution testing for immediate release. Under certain conditions, the tests can now be standardised. Read on to get more information about FDA’s Guideline on Dissolution Testing.


In August 2015, the FDA published the draft of a guideline on dissolution testing for immediate release solid oral dosage forms. It is planned that after its finalisation, a part of this guideline will replace the current guideline from August 1997.

The Biopharmaceutics Classification System (BCS) distinguishes 4 different classes of APIs depending on their  solubility and permeability.
On the basis of this classification, a decision can be taken for determining when bioavailability or bioequivalence studies are required, or when a successful in vitro-in vivo correlation (IVIVC) is likely.

The BCS proposes that, for certain medicinal products which contain a high soluble API, dissolution testing can be standardised. Due to their high solubility, medicinal products in the BCS classes 1 and 3 have a relatively low risk with regard to the impact on dissolution, provided that the in vitro performance meets or exceeds the recommendations given.

If these conditions are met, the new guideline will provide concrete provisions regarding the methods which can be standardised: USP apparatus 1 (basket method) or 2 (paddle method) with fixed parameters for stirring rate, medium and temperature. For this, the permitted limits for the specifications are laid down. In addition, the possibility is granted that, under certain conditions, disintegration testing can be used as alternative method.

You can access the complete document of the FDA “Dissolution Testing and Specification Criteria for Immediate Release Solid Oral Dosage Forms” here.

The new Elemental Impurities Database for Excipients – ECA offers a meeting at no costs

A step-wise integrated risk-based approach to determine a control strategy for according to ICH Q3D has to consider data from all kinds of potential sources for elemental impurities in particular from excipients. Read more about the newly created Elemental Impurities Database as a valuable support for performing risk assessments for drug products.


The new ICH Q3D Guideline on Elemental Impurities strongly advocates the use of risk assessments in order to define a final control strategy. Specific challenges appear when risks associated with production equipment, packaging material and excipients have to be determined, and quantified. In particular the contribution of elemental impurities from excipients is not easy to assess due to their big variety and the lack of information from excipient vendors.

Quite recently a pharma consortium started an initiative which aims to collect and share data from pharmaceutical excipients by establishing a database. This Elemental Impurities (EI) Database provides information required for performing a comprehensive risk assessment of a drug product with respect to elemental impurities. Interested companies can contribute to this database by providing information about excipients and may also benefit from this database by taking out information needed for their risk assessments.

The “Impurities Workshop” from 14-16 June 2016 in Heidelberg, Germany provides a comprehensive and practical oriented review of impurities analysis and characterisation in drug substances and drug products. Part III of the workshop on 16 June 2016 is specifically dedicated to Elemental Impurites. In the subsequent post-Conference Workshop on 17 June 2016 the above mentioned EI Database will be explained. The following questions will be discussed:

  • What is the procedure of providing data for the Database?
  • How can information be obtained from the Database?
  • What has to be considered in terms of confidentiality when data will be received or submitted to the Database?

This post-Conference Workshop is free of charge. It ideally complements the previous parts of the “Impurities Workshop” and can be booked in combination with either Part III or all Parts of the “Impurities Workshop”. As we expect a high interest in this post-Conference Workshop participants joining the “Impurities Workshop” (one day or all three days) will be registered first