Ashley McCraight

Within the premises of European Union (EU) pharmaceutical manufacturers, there is typically up to 3 weeks' worth of supplied materials inventory waiting to be tested. This is consistent with available US data reported during a benchmarking exercise regarding pharmaceutical manufacturing performance.

 Quality control (QC) waiting times such as these contribute significantly to the typically low stock-turns (5-10 per annum) prevalent for pharmaceutical materials. These high inventories and associated QC costs represent a pressure point as businesses strive to stay competitive.	

One well-proven method of containing costs is to expedite the QC testing process for such materials. This may be done by accepting supplier-provided data at the point of receipt into the pharmaceutical facility that confirms the batch's compliance with specifications. The frequently expressed argument "Why is it necessary to test the batch a second time before it is released for use within the pharmaceutical plant?" is a strong one; however, there are many obstacles to overcome to achieve the high level of supplier certification sought by pharmaceutical manufacturers. 	

One obstacle to efficient QC testing is that requirements associated with this process are poorly defined in the EU good manufacturing practice (GMP) rules,

 which do not even contain a specific reference to Certificates of Test (CoTs). Although the UK's Medicines and Healthcare products Regulatory Agency (MHRA) has issued guidance concerning what a certificate should contain,

 this only represents one part of a series of otherwise unwritten GMPs on this subject. 				

This absence has led to differing interpretations by national and regional inspectors, resulting in different economic impacts. This represents a potential quality pitfall - the national GMP requirements are relatively undemanding and are seen as unfair competition in countries where the regulatory authorities apply stricter standards.	

This article explains why pharmaceutical manufacturers should actively engage in this process and when they should be careful. Examples are provided of typical GMP requirements for acceptance of CoTs and the article discusses how they vary in different European countries. The authors have developed a recommended process for acceptance of certificates, based on experience of managing supplier development programmes, surveys conducted amongst quality professionals around Europe and interaction from participants on training courses. The article concludes by suggesting a framework for GMPs that are compatible with defined US requirements and could be incorporated into the EU GMP rules for finished pharmaceutical products.

Figure 1:  Process for reducing QC testing based on acceptance of certificates of test.	

The pharma industry typically purchases the majority of the materials that are used to manufacture and package its products, such as excipients, active pharmaceutical ingredients (APIs) and primary and secondary packaging. Therefore, as 95–100% of raw materials are purchased, the expertise for making and testing these materials resides with the manufacturer and not with the purchasing pharmaceutical company. 				

However, regulations and registered requirements place responsibility for ensuring the quality of raw materials used with the pharmaceutical manufacturer. Consequently, companies routinely perform chemical, microbiological and physical testing on samples of purchased materials that are often small and possibly not representative of the batch. Similarly, the tests may not be the most suitable to determine the overall quality of the materials because the purchaser does not have the specialized equipment necessary to measure the appropriate parameters.	

Producers of materials often take many more representative samples throughout the manufacturing process and use well-established test methods to determine the quality of their products. They also appreciate the implications of subtle variations in test results that the purchaser might not. The majority of manufacturers will also provide the data to their customers with the goods in the form of CoTs, if asked.				

The appropriate use of manufacturer's data in the form of a CoT can benefit both the supplier and the purchaser. The buyer can reduce the amount of testing done upon receipt and the supplier knows that the materials are less likely to be rejected because the client has confidence in the data provided.	

Additional benefits are present that are both intuitive and borne of experience and research. Time invested by the pharmaceutical company to achieve the understanding and assurance levels required pays dividends in terms of reduced errors and fewer suppliers. Overall, these benefits facilitate lower inventories. 	

Although EU GMP rules are common to all countries, specific GMPs appropriate to the acceptance of CoTs are not clearly defined. Consequently, GMP interpretation can be different in each member state. All countries expect that purchased materials will meet the required standards and most will accept that data from CoTs can be a substitute for additional testing if additional controls are in place. However, research shows that this approach is not universally accepted across the EU. In France, for example, inspectors currently expect full testing to take place for all APIs and excipients, and are not amenable to the use of CoTs. This, however, may change during 2004.				

To use CoTs, a pharmaceutical company must know how the manufacturer makes, samples and tests the products, and what systems are in place for controlling production, distribution and quality. In addition, a good history of the product's supplies must exist. This type of information is usually gathered by questionnaire and/or by audit of the facilities concerned. It is not be advisable to use data from certificates without this minimum level of assurance.				

Arranging audits and collecting data is both time and resource intensive. Before embarking on such a course, it is advisable to consider from where the most benefit can be obtained. Materials such as packaging items (for example, labels and cartons) tend to be purchased in large numbers and their acceptance testing is usually repetitive. In this instance, the economic benefits gained by using supplier's data is high. Conversely, materials such as APIs are purchased in smaller amounts; testing can be complex and the benefits are usually less. As an example, a pharmaceutical company that manufactures products that are sensitive to certain parameters in an excipient might want to exclude that particular test from its reduced testing programme. This policy might also extend to materials for sterile applications because of their mode of use.	

The current stated GMP requirements for the acceptance of certificated data from suppliers is not extensive. There is no specific mention of the acceptability or otherwise of CoTs within current EU GMP rules for secondary pharmaceutical products. There is a mention in Annex 18, which covers GMPs for APIs, but this Annex has not yet been implemented by regulation. Useful guidance is provided by the MHRA regarding the content of certificates, but this does not enjoy EU-wide acceptance, nor is it supplemented by any guidance covering the nature of the system that should be put in place to support the use of such information. 	

Table I:  Cost/benefit analysis of supplier/material combinations.				

It is anticipated that national legislation will be put into effect in France this year that will permit the use of CoTs. The authors understand that the suppliers involved must either be based within the EU or linked by a mutual recognition agreement (MRA) and will also need to submit to a regulatory GMP inspection. Not surprisingly, compliance with the marketing authorization would be expected. 	

Importantly, there is an implicit requirement that when data (provided on a certificate) are used by the pharmaceutical company to make decisions relating to the suitability of the batch, then a contract must be in place between the parties involved. This is because the act of accepting a supplier's data represents the contracting out of an analytical service, which is governed by Article 12 of Directive 91/356/EEC.

 This requires that "Any . . .  operation linked with the manufacture, which is carried out under contract, shall be the subject of a written contract." However, the guidance provided in the appropriate related section of the GMP rules is insufficiently specific for this situation. 				

The Code of Federal Regulations (CFR) is much more specific and helpful in this matter because it specifically states in clause 211.84(d) that "a report of a test may be accepted from the supplier of a component . . .  provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals."

 Although Annex 18 of the EU GMP rules does not yet have a legal basis and applies only to APIs, it does contain some helpful guidance in Section 7.30. "A supplier's CoT can be used in place of performing the tests, provided that the manufacturer has a system in place for evaluating suppliers." This is usefully expanded on in section 7.31 where a requirement to evaluate the reliability of the quality history - and also to validate at least three sets of the supplier's results - is introduced. Full analysis must be performed "at appropriate intervals" and the supplier's certificates checked for reliability.				

The World Health Organization (WHO) draft guidance on 

Good Trade and Distribution Practice of Pharmaceutical Starting Materials

 outlines the standards to be adopted by suppliers concerning the content and provision of Certificates of Analysis, skip lot testing by the manufacturer, traceability and the controls required should batches become mixed.

 These should be incorporated into the evaluation process employed.				

The authors' recommended approach for the acceptance of supplier's data is based on experience and surveys conducted amongst companies throughout Europe. This core process, which is outlined in blue in Figure 1, defines the necessary sequence of activities. 				

 This five phase process is interlinked with the three groups that have a stake in a successful outcome: regulatory bodies requiring compliance with appropriate regulations; suppliers whose data is destined to be used on trust; and the pharmaceutical company's management who are seeking to improve efficiency and maintain the confidence of regulators and patients. This is a complex mix that requires a high level of understanding and focus, but a mix that can enhance both the efficiency and quality of supplied materials.	

The five phases of activity and the important principles that underpin each one are given in detail below: 	

Phase 1:Understanding the current performance of each material/supplier combination received and the relevant regulatory requirements.

The current QC system reflects the registered requirements precisely and gives an understanding of whether any specific constraints on reducing testing are defined in the marketing authorization. For example, there may be a specific requirement defined to perform QC testing on each batch for a sensitive parameter. 

Measurement processes are in place for both the supplier's quality system and the quality of the material supplied. These must be considered separately as both are important when deciding whether or not to proceed. The measurement for the quality system would be qualitative and should address the question "Is this system well enough developed to initiate or continue supply?" The measurement for the material quality should be quantitative and should incorporate batch reject rates, concession rates and complaints from external and internal customers (for example, production). It should also enable comparison between different companies by normalizing the number of batches (or volume) received and allocating a specific score for each type of deficiency. Available process capability data should also be reviewed. 

Phase 2: Identify potentially cost-effective material/supplier combinations where the acceptance of supplier's data would be acceptable to regulators and suppliers.

 This phase involves identifying suitable candidate supplier/material combinations such as	

Understanding the constraints placed by national/state inspectors regarding the acceptability of reducing QC testing. These constraints represent the unwritten GMP requirements and the next section shows how these can vary within the EU.

Performing a cost/benefit analysis for each supplier/material combination. This should consider factors such as the cost of QC and holding stocks of materials, together with the increased costs of higher level evaluation of a supplier's system and performance measurement process maintenance. The matrix shown in Table I illustrates that supplier/material combinations in Box 2 are ideal for reducing QC testing; it also shows appropriate strategies for other scenarios. 

Evaluation of the supplier's quality system and management attitude to understand whether it has the capability to develop its system to the level required. This demands a listening approach and checks for coherence between declared intentions and delivered performance.

Phase 3: Develop and validate the acceptance process in conjunction with the supplier and internal customers.

The discussion of a draft contract with the supplier to define parameters such as sampling frequencies and locations, test methods, format of the certificates and change notification.

Obtaining draft contract agreement with internal stakeholders such as production management and the qualified person. Note that this will probably require progression through the change control process.

Validation of the supplier's results using a conventional approach when the accuracy required for the test results is defined in advance of the validation study. This might highlight that the supplier is achieving more accurate results than the QC laboratory in the pharmaceutical company.

A procedure is written to define how the system will work. The monitoring frequency and process should be defined, for example, as should the situations wherein full testing should be reinstated. It is particularly important that such 'alarms' are clearly defined at this stage because once QC testing has been reduced and analysts redeployed it is often difficult to revert back. An alarm could be, for instance, a significant difference between the supplier's reported result and a monitoring result. Another example is a drop in the supplier/material score to below a preset value. 

Analysts are trained in the new monitoring process and also made aware that this change is completely separate from any reduction in identity testing that may or may nor be implemented in accordance with Annex 8 of the EU GMP rules. 

Articles

This article examines European differences in GMP requirements for the acceptance of Certificates of Tests. The authors look at how pharmaceutical manufacturers can address the issues and suggest a US-compatible framework for GMPs that could be incorporated into EU requirements.

Certificates of Test - What are the European GMP Requirements?

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 route of administering the medicinal product

the toxicity or other inherent risk of the excipient

the potential for cross-contamination during excipient manufacture. 

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.	

Other standards incorporating risk assessment

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.	

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.