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Medicines and excipients are inseparable, with few exceptions - one cannot exist without the other. The Pharmaceutical Quality Group and other international bodies have developed good manufacturing practice (GMP) standards and guidelines to facilitate the effective supply of excipients. This article discusses the definition and significance of excipients, and highlights the importance of implementing the correct excipient manufacturing controls and standards.
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.
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.
Table I: Low level risks, potential consequences and associated foundation level GMPs.
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.
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.
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."
Table II: Additional risks, potential consequences and associated intermediate level 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.
The need for suppliers to adopt wide variations in GMPs reflects the realities of the current situation. A set of common GMPs for all suppliers, regardless of application, will inevitably increase costs and may lead to an adverse reaction.
PS 9100:2002 has included a risk assessment process to counter this problem and to target an appropriate level of GMP for an excipient, based on its application. This formalizes the different approaches that an auditor would take to assess, for example, a manufacturer of a sweetener for an oral product compared with a manufacturer of a critical excipient for a parenteral product. The appropriate level of GMP is set after giving consideration to these key risk areas:
The following examples highlight how PS 9100:2002 Pharmaceutical excipients could be implemented.
Example 1: sucrose as a sweetener in an oral syrup. Sucrose is included in many oral medicinal syrups as a sweetener to improve the taste of the product and improve patient compliance. This may be particularly important to ensure children do not reject the dose. Using the matrix on page 70 of PS 9100:2002, the excipient is considered as low risk and requires a minimum level of GMPs, which are referred to as the foundation level.
This scenario involves a range of potential risks to the quality of the excipient, which are listed in Table I together with the potential consequences of these risks. This understanding has led to a judgement, through an extensive consultation process, as to the nature of the GMPs that are required to control such risks at the foundation level. These GMPs are also illustrated in the table.
Table III: Additional risks, potential consequences and associated high level GMPs.
In addition to specific GMPs, PS 9100:2002 also requires the development of a quality system in more general areas to protect the quality of the excipient and the customer's subsequent use. One example is change control, where PS 9100:2002 Part 1 clause 7.2.3 requires that changes to established process controls need communication with the customer. Another example is training in GMP, where Part 1 clause 6.2.2 requires training in the contents of PS 9100:2002 to help minimize the risks described.
The risks associated with obtaining excipients through agents are covered in several clauses, such as 7.5.3, where complete traceability is required, and 7.2.3 where communication of quality related information is required.
Example 2: clioquinol used as a preservative in a topical cream. Clioquinol is used as a preservative in many topical creams to control microbiological contamination during use. This may be particularly important where the product is used to treat conditions involving damaged skin. Using the matrix on page 70 of PS 9100:2002, the excipient is judged to be of intermediate risk and requires intermediate level GMPs. The potential additional risks associated with this scenario, the consequences of the risks and the additional GMPs controlling the risk at intermediate level are illustrated in Table II. These build on the risks, consequences and foundation level GMPs listed in Table I.
With these GMPs, the level of monitoring quality related subjects is increased to reflect the greater perceived risks. For example, the requirement to have a quality unit is increased in Part 1 clause 5.5.1 to ensure that this unit is independent. This unit also has to become involved in reviewing deviations (clause 7.5.1), the approval of critical parameters (clause 7.5.1) and the batch release process itself. The practice of asking the quality unit to review the quality performance of the excipient is also introduced in clause 8.4. Increased traceability of production information is enhanced by extending the requirement to record deviations (clause 7.5.1).
Example 3: cyclodextrins as solubulizers in parenteral products. Cyclodextrins are used as solubulizers in some aqueous parenteral products, which would otherwise require non-aqueous solvents. The API forms a complex with the cyclodextrin and remains in solution. Using the matrix on page 68 of PS 9100:2002, the excipient is deemed as high risk and requires high level GMPs. The added potential risks, the consequences of these risks and the additional GMPs controlling the risk at a high level are illustrated in Table III.
Building on the introduction of quality reviews at the intermediate level, this requirement is increased annually to reflect the potential criticality of this type of excipient (clause 8.4). The assurance process has also been extended to suppliers, requiring their audit (clause 7.4.1) and monitoring the results they provide on certificates of analysis (clause 7.4.3).
The total set of foundation, intermediate and high level GMPs defined in PS 9100:2002 Part 1, including the essential base level requirements of the international quality system standard ISO 9001:2000, are directly comparable with the requirements of ICH GMPs for APIs, now incorporated into Annex 18 of the EU GMP.
It is important that manufacturers and users of excipients establish the highest risk area and agree the appropriate GMP level.
The PQG's risk assessment shares some similarities with the British Retail Consortium's Food Industry Scheme.8 In the food industry, the use of hazard analysis (HACCP) is now mandatory following the implementation of the EU Directive on the Control of Foodstuffs (93/43/EEC). Evidence of implementing HACCP is required by certification schemes, such as the scheme managed by the UK's Royal Society for the Promotion of Health, for example.9 In the EU's GMPs for Medicinal Products,10 annexes are used as the standard method of defining additional requirements for specific applications, and risk assessment is a fundamental approach used within many specific GMP processes, such as cleaning validation and environmental control.
Whereas the IPEC Americas/Europe excipients GMP guide11 has much similarity and overlap with PS 9100:2002, it does not outline a specific structured consideration of risk. Instead, it states in its introduction that "each manufacturer should consider how the guide might apply to their products and processes." This clearly covers the excipient manufacturing process but does not give due consideration to the application. The IPEC guide is very flexible because it suggests that the requirements are not necessarily 'musts' and that 'common sense' should be used in the application.
PS 9100:2002 consists of two parts. The first is an application standard based on ISO 9001:2000, which is the commonly applied quality system for excipient manufacturers and includes additional specific GMP requirements. Part 1 is the new standard that excipient manufacturers can be assessed against for a sectoral certification scheme to gain recognition of achievement of a particular level of GMP. The second part of PS 9100:2002 provides GMP guidance in an ICH format that provides detailed information regarding the clarification of the GMP levels.
PS 9100:2002 Pharmaceutical excipients is designed to meet the needs of the British Pharmaceutical Industry and was launched at the Royal Pharmaceutical Society of Great Britain (London, UK) in June 2002. The PQG recognizes the importance of this subject and in response has discussed with its representative European trade association (EFPIA) how it may develop a common GMP guide, in conjunction with IPEC, that meets the needs of the wider European manufacturing industry. With this objective in mind the PQG and IPEC agreed in June 2002 to produce a joint guide that utilizes the experience of both groups. The development process for this is now under way. Recognizing the importance of communicating this subject, the PQG also intends to develop a training guide to the application standard that will provide explanations for the need for the GMPs that it has specified.
Whereas there is a recognized need for appropriate controls, there is little regulatory definition of which GMPs should apply to suppliers of excipients. Consequently, different representative organizations have developed guidance on GMPs for such suppliers. The PQG (
) was the first organization to do this with the objective of satisfying the needs of the British Pharmaceutical Industry. It has updated these GMPs and integrated them with the new ISO 9001: 2000; the resulting document, PS 9100:2002 Pharmaceutical excipients, is an application standard for suppliers, and second and third party auditors combined with a GMP guide. It encompasses a rational risk assessment process that defines the appropriate level of GMP for excipient manufacture, which is an important differentiator.
A significant implication of this process is that it should prevent cost escalation that may otherwise be caused by the introduction of unnecessary controls and over embellishment of a supplier's quality system. Integration of this standard with other standards, such as the IPEC and WHO guides, would be a desirable objective for the future.