PS 9100:2002 Pharmaceutical Excipients - An Updated GMP Standard for Excipients Suppliers

Jan 01, 2003
Volume 15, Issue 1

An excipient is any starting material used in the formulation of a medicine that is not an active pharmaceutical ingredient (API). It can include constituents that are later 'lost' from the medicine, such as solvents. Excipients can have a range of effects on consumer acceptance, safety and the efficacy of medicines. These effects can be as basic as improving the organoleptic qualities of the medicine through to influencing its effectiveness during use.

Table I: Low level risks, potential consequences and associated foundation level GMPs.
Excipient controls Excipients are available from a wide range of sources and have a large number of applications, which presents a significant challenge to pharmaceutical companies. Once a manufacturer understands the potential risks to a product from excipients, it can develop a combination of inter-related controls both internally and for the supplier. Many manufacturers have developed their own protocols for assessing risks and then work with excipient suppliers to appropriately align the good manufacturing practices (GMPs) adopted in the supplier's facility.

Mistake prevention is the prime reason why stringent controls must be implemented. A pharmaceutical manufacturer must ascertain whether the supplier produces any other excipients that could be mistakenly mixed with, or substituted for, the intended material. The Haitian incident2 is a well-reported occurrence of a fatal mistake involving similar chemicals. At least 59 children died as result of being given paracetamol oral syrup in which glycerol had been partially substituted with the chemically similar but highly toxic diethylene glycol.

Defining controls Whereas pharmaceutical companies work within a highly regulated environment, the controls for starting materials are not clearly defined. The European Union (EU) Guide to Good Manufacturing Practice for Medicinal Products emphasizes the need for the control of purchasing starting materials. Regular audits of a manufacturer's quality system are a key consideration in the validation of reduced sampling of starting materials in Annex 8 of the guide. The UK Medicines Control Agency (MCA) also provides specific guidance on Certificates of Analysis. The International Conference on Harmonization (ICH) has recently given a clearer definition of API GMPs that are now internationally accepted and have been incorporated into EU GMPs as Annex 18.

The US Food and Drug Administration's (FDA's) Code of Federal Regulations 21 also examines the control of starting materials through specification, sampling and testing, although there are no references to control the manufacture of excipients. FDA has also accepted and issued ICH's API GMPs. However, the recent Compliance Program Guidance Manual,3 which covers system inspections, emphasizes that current good manufacturing practice (cGMP) regulations are not direct requirements for the manufacture of APIs, but act only as a guide.

Table II: Additional risks, potential consequences and associated intermediate level GMPs.
Need for GMPs During 1990, it emerged that a better definition of GMPs for starting materials was required. In response to this, the The Pharmaceutical Quality Group (PQG) developed and published a code of practice (CoP) for manufacturers of APIs and excipients. This CoP, together with two related CoPs for packaging materials, formed the basis for a third party certification scheme linked to the ISO 9000 international quality system standard. This CoP was revised during 1995 in line with the changes to ISO 9002:1994 and has been revised during the last year to align with ISO 9001:2000 and the increased GMP expectations of suppliers. The new document is PS 9100:2002 Pharmaceutical excipients4 and was launched in June 2002. In the standard, John Turner, representing the MCA, states that: "The quality of excipients is best assured by following appropriate GMPs."

Other organizations have also recognized the need to define "appropriate GMPs." The International Excipients Council (IPEC) introduced a guide in 1995, which was revised in 2001. The World Health Organization (WHO) is currently developing a voluntary certification scheme,5 which encompasses excipients and is linked to a set of defined GMPs. In addition, GMPs for food ingredients can be directly applied to pharmaceutical excipients; the most comprehensive of these is the Institute of Food Science and Technology GMPs.

PQG agrees with Anisfeld7 when he strongly argues that pharmaceutical manufacturers must know the manufacturing source of excipients, otherwise relevant controls cannot be implemented. He also maintains the importance of Certificates of Analysis. Certificates are a very important part of the supplier assurance process and most suppliers now provide them, but with varying levels of quality.

The PQG recognized the inconsistency, and in 1990 introduced a standard in the first edition of the CoP, which is now included in the latest standard (PS 9100:2002). This is coupled with associated requirements for traceability and communication throughout the supply chain in a section dealing with agents, brokers, traders, distributors, repackers and relabellers.

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