Chris Oldenhof

The Active Pharmaceutical Ingredients Committee (APIC) — a sector group of Conseil European des Federations de l'Industrie Chimique (CEFIC) — first voiced the need for EU GMP API legislation in 1993 to help ensure the safety of medicines. In 2000, the International Conference on Harmonisation (ICH) finalized the harmonized API GMP Guideline Q7, which became legal in the US and Japan in 2001. The EU adopted a directive in March 2004 that includes the requirement for APIs in medicines for the EU market to comply with ICH/Q7A. Member States are transposing the directive into their national law: about half of them have completed this process, seven more are well on their way to completion, while seven others are still in earlier stages of adoption.   

A basic principle of the EU directive is that API compliance for medicines for the EU market should be primarily assured by the qualified person (QP) of the manufacturer and/or importer of the final medicinal product. This strongly differs from US/FDA practice in which inspections of API manufacturing facilities are a key element of the approval process of medicines.  

To be clear, the European Fine Chemicals Group's (EFCG's) concerns are not directed towards the manufacturers and users of APIs for medicinal products that are covered by patents. Instead, they are directed against the manufacture, trading and use of off-patent APIs, for which there is extensive competition in the marketplace and less control of quality standards along the — often long — manufacturing supply chain compared with APIs for medicinal products still under patent. 

It was the 2004 APIC Lisbon conference that galvanized the CEOs of EU producers of off-patent APIs to put their case to the authorities and other stakeholders through the then newly formed EFCG. The presentations by EU medicines agencies made it clear that they were not contemplating inspection of foreign, off-patent API manufacturers as a key part of their compliance enforcement strategy.  

EFCG is aware that the large majority of off-patent APIs in EU medicines are imported, mainly from India and China. We are also aware that the number of European directorate for the quality of medicines (EDQM)-initiated inspections of non-EU API sites over the past decade has been very low indeed (less than 50), and of those that have been inspected, the number of serious noncompliance cases were at a worrying level.  

EFCG believes that to guarantee the safety of EU medicines, serious consideration must be given to a focused inspections programme of off-patent, API manufacturers outside the EU and at the intermediary points inside the EU (importer, trader, broker), prioritized whenever possible by evidence of suspicious behaviour, but also including a random element.  

Given the increasing pressure on prices of off-patent medicines, we feel that their safety is very likely to start presenting unacceptable risks to European citizens. Why? Because GMP-compliant companies know that compliance requires significant investment in people, as well as in equipment. It is unsurprising, therefore, that cost cutting, especially for off-patent medicines, is a factor that increasingly conflicts with compliance. What is less well understood is that the use of safe APIs forms a negligible factor in the cost of healthcare. The costs saved by noncompliance are only of relevance at "API business level" and have little, if any, impact on the price of final medicine to the patient.  

EFCG remains concerned that the potential risk to public health presented by the strong possibility of non-GMP-compliant, off-patent APIs in EU medicines is increasing. It is important to keep reminding all stakeholders that without effective law enforcement, deterrence and sanctions, the quality of our medicines is compromised and the noncompliant operator is likely to continue business in the EU undetected. 

Many thousands of manufacturing plants for off-patent APIs in those non-EU countries are unlikely to have ever been inspected by an EU official. But what we do not know is how many of them are Q7A-compliant. For the majority of EU medicines containing off-patent APIs the authorities have not confirmed (through their inspections of the API manufacturers or traders) that the APIs are Q7A-compliant and safe. Curiously, although most of the APIs come from Asia, the majority of inspections by EU inspectors are conducted in Europe where, according to the results of EDQM's inspections, very little serious noncompliance has been observed. Also, as CEP (Certificate of Suitability)

statistics seem to indicate, EU off-patent API producers trigger the vast majority the API-related "variations submissions". Does this mean Asian producers never change their processes, or that they have inadequate change control procedures?  

EFCG has accepted the challenge to initiate a change of mindset in off-patent API producers, users, regulators and politicians. We have given annual press conferences during CPhI, first in Brussels (2004), then in Madrid (2005) and last year in Paris. We have met with many stakeholders, regulators, politicians, industry representatives, media, nongovernment organizations (NGOs) and others. EFCG has also published several articles

 and has issued its "simple guide" to buying GMP and regulatory-compliant APIs.

In 2005/2006, we performed a benchmarking exercise across the EU to assess the extent of readiness of the medicines agencies to enforce API compliance. The head of the Spanish Medicines Agency opened our Barcelona conference in April 2006 by announcing that her agency would be doubling the number of inspectors in 2007, which was very good news, but she was unwilling to commit to an increase in the number of overseas inspections. At that event, EFCG reported the results of the benchmarking exercise. It was concluded that there was a common understanding of the issues, a common shortage of inspection resources and there were only limited intentions to inspect outside of the Member States' jurisdiction. 

A German lawyer speaking at the conference believed that the QP's personal legal liability is much less than what is generally understood. If this is so, the QP appears to be less accountable than a certified accountant who signs off the financial statements of public companies. In our opinion, this contrasts sharply with the importance of securing the safety of EU medicines.  

During 2006, more information became available on the 1990s Biochimica Opos API affair on illegal APIs.

  More than € 100 million have now been paid in fines and damages. An account on FDA's investigation showed that cefaclor manufacturing steps were secretly performed in unapproved facilities in Italy, France and Romania while fake production records were kept.

  Manufacturing processes were very different from the original, authorized drug applications. 

In 2005, a former manager of Biochimica Opos was arrested by the US authorities on entering the US at Miami airport. He was held in detention for 13 months and personally fined $16 million. The system in Europe heavily relies on individuals and companies obeying the law and much less on its enforcement. We have been unable to find significant examples of API-related sanctions within the EU that would deter determined, noncompliant manufacturers. 

We were pleased to note that in 2006, the European Agency for the Evaluation of Medicinal Products (EMEA) started an EU-wide API programme that, 

, provides all the medicines agencies with a checklist for inspectors. EMEA stated that this initiative serves two purposes: 

 To support and harmonize training on how to enforce and verify API compliance when inspecting dosage form manufacturers. 

 To gather information to assess the compliance situation regarding APIs. 

We are eagerly awaiting the outcomes of this data-gathering exercise and look forward to EMEA sharing any available data with us. 

The APIC Audit Program has been completely revised to bring it in line with EMEA's guidance on the responsibility of auditing active substances manufacturers by the Manufacturing Authorization Holders for medicinal products in Europe. This audit programme now provides a third party option for auditing active substance manufacturers and is developing very well. 

In 2006, another US initiative attracted our attention: the United States Pharmacopeia (USP) has launched its "Pharmaceutical Ingredient Verification and Qualification Program".

  The USP website claims that "USP has established the world's most rigorous third-party verification programme for APIs and excipients". This essentially comes down to the USP granting its seal of approval after having performed a thorough, product-specific audit covering both GMP and — possibly — regulatory compliance (this latter aspect remains as yet unclear). 

The leading US trade association representing API producers, Synthetic Organic Chemical Manufacturers Association (SOCMA),

  joined EFCG last summer to develop a joint position paper arguing for the need of a level playing field to enforce GMP and regulatory compliance of APIs.

  Whereas FDA is very tough, and sets high regulatory standards and hurdles for the APIs for prescription medicines, there is very little regulatory control over APIs for over the counter (OTC) products. There is neither a requirement for a preapproval inspection nor for regulatory (DMF) submissions. Therefore, for OTC products, any supplier that meets the specification seems acceptable. In contrast, APIs for OTC products in the EU must meet similar standards as those for prescription medicines.  

The most recent development to recognize the lack of effective enforcement of European laws governing GMP compliance for APIs, has been the approval of the Written Declaration (0061/2006) in November 2006 by a majority of EU Parliament members. This states that worldwide GMP inspections of API manufacturers by European inspectorates should be mandatory for every API included in a medicine marketed in the EU, and that every such API should have a Certificate of GMP Compliance issued by an EU member state. The Written Declaration has been forwarded to the European Commission, the Council of the EU and the Member States for further action. This official position taken by the elected representatives of around 250 million Europeans is very similar to the one included in the APIC position paper of 24 December 2004 and adopted by EFCG as the cornerstone of its advocacy programme.

In conclusion, EFCG believes that it has helped to advance the agenda on the need for the effective enforcement of GMP compliance of off-patent APIs, but there is still much more to do to convince the authorities to take further action. We see support for our actions from many quarters, particularly the EU Parliament through its Written Declaration, but we still do not have tangible progress on enforcement. Consequently, we would welcome the following recommendations by the EU authorities:   

To create an EU Foreign Inspection Service in concert with the EU medicines agencies with a capacity to inspect at least 100 non-EU API manufacturers per year for both GMP and regulatory related compliance. It also seems reasonable that those intending to export APIs to the EU should pay fees towards the costs of this service. 

 The European medicines agencies should harmonize and coordinate the courses of action to be taken when a seriously noncompliant API is identified. This should include measures to block the import of such APIs into the EU by involving the EU Customs services. As a strong deterrent to others, effective sanctions must follow so that it becomes widely known that it does not pay to break EU law. EFCG is unaware of any progress on coordinated action by the European medicines agencies to deal with the consequences of suspended CEPs.

EFCG urges the Commission to recognize that legislation without full implementation and enforcement (via inspections), and without tough, appropriate deterrents and sanctions, is ineffective and a cause of increasing the risk to EU citizens, as well as leading to market distortions. Without proper enforcement and deterrents in place, GMP and regulatory noncompliance by manufacturers of off-patent APIs will continue to threaten the safety of European medicines containing them and will remain a major competitive advantage to overseas suppliers. A recently published Chinese article on the API compliance situation in China would seem to support this view.

An additional concern is the information given in a recent article reporting on corruption within the Chinese SFDA during the period 1998–2005.

  It appears 170000 GMP and production licences may have been granted improperly with possible implications for public health.  

is a board member of APIC and EFCG (Portugal).			

www.gmpapi.migg.com/download/asp/lasp_17508_2_21810.asp?MENUID=2

3. Hoechst 1997 Annual Report, p 71, note 8. 

4. Investigators' Reports: Foreign Drug Firm Pleads Guilty to Felony Charges 

7. Uneven Enforcement Leads to Sub-par Drugs and National Security Risk http://

8. No Safe Medicines Without Safe Ingredients 

10. China's State FDA fights for its future, 

Articles

The Active Pharmaceutical Ingredients Committee (APIC) - a sector group of Conseil European des Federations de l'Industrie Chimique (CEFIC) - first voiced the need for EU GMP API legislation in 1993 to help ensure the safety of medicines. In 2000, the International Conference on Harmonisation (ICH) finalized the harmonized API GMP Guideline Q7, which became legal in the US and Japan in 2001. The EU adopted a directive in March 2004 that includes the requirement for APIs in medicines for the EU market to comply with ICH/Q7A. Member States are transposing the directive into their national law: about half of them have completed this process, seven more are well on their way to completion, while seven others are still in earlier stages of adoption.

Enforcing GMP compliance for APIs in EU medicines

The safety of medicines concerns us all. Everyone is confronted sooner or later with situations where a medicine can make the difference between life and death for ourselves or for those who are close to us. The possibility of a quality defect of the medicine that may lead to unexpected, detrimental effects in such situations may be something that would not normally cross our minds. Nevertheless, especially regarding older, well-established medicinal products, there are indications that such possibilities may be increasing. 

"...it is estimated that annually about 70000 tons of paracetamol (acetaminophen) are consumed worldwide, representing a total of 150 billion tablets. A sub-standard product could have a more lethal impact than an atomic bomb in such cases!"

Active pharmaceutical ingredients (APIs) give medicines their pharmacological activity. If it were not for the API a medicinal product would be as likely to cure a patient as a placebo. Several synonyms of the acronym 'API' are in use today: 'drug substance' is the traditional term in the US, and 'starting material' and, more recently, 'starting material used as an active substance' is preferred in Europe. However, the world seems to have adopted 'API' as the unofficial, but harmonized term. 

APIs are manufactured worldwide using many types of production processes to a precise specification agreed with national governments. APIs may be produced by  				

 extraction from plants or other natural sources 

Substandard APIs either result from poorly controlled, though approved manufacturing processes or from processes, that have not been approved by national authorities. 

To help protect EU citizens from such APIs, the rules governing the manufacture of APIs destined for the EU market have just been tightened to ensure they are made to the highest possible industry standards, a quality management system in the pharmaceutical industry known as good manufacturing practice (GMP). The quality of the API is fundamental as it predetermines the essential, approved pharmacological properties of a medicinal product, especially its safety and efficacy at prescribed dosages. 

To make the final medicine (powder, pill, injectable etc.), the API is mixed with other pharmacologically inactive substances (called excipients). As excipients do not normally change the intrinsic properties of the API, provided the quality of the API is as specified, the patient will be safe at the prescribed dose. However, if the quality of the API is not as specified (is substandard) then the patient's health could be affected. For example, the substandard API may contain a nonspecified toxic substance. The medicinal product containing the API would then be unsafe to prescribe, if not lethal. The question is how would a doctor know that? 

Examples of major API quality defects that may occur are the presence of dangerous quantities of toxic impurities, inadequate physical properties or insufficient stability. Each of these quality defects may give rise to health problems for the patient taking the medicine: 			

Toxic impurities may result in short- or long-term side-effects that may range from minor to lethal. 

Inadequate physical properties, such as incorrect particle size or crystal form, may either impede the action of the medicine or result in dangerous overdosing, because the API either dissolves too slowly/quickly directly impacting the rate of absorption in the organism. 

 If the API is not sufficiently stable, it may have degraded by the time the patient takes the medicine, resulting in too low a dose of the API and the possible presence of dangerous quantities of toxic degradation products.

To protect patients against possible API-related health risks, the EU authorities have developed and implemented a large number of laws and regulations with supporting guidelines for the pharmaceutical industry. These are extensive and very detailed. They include the requirement for thorough documentation — on site as well as to be submitted to the authorities — running from many hundreds to even thousands of pages. To comply with the laws, a producer needs to employ an appropriate level of skilled staff. In the case of API manufacture, the law aims to ensure that APIs are manufactured in a way that will consistently guarantee their high quality. 

EDQMÃÂ´s API inspections: the results are reason for concern			

Regulatory compliance in API manufacture is fully auditable by a qualified party and should normally be audited and inspected regularly. 

The manufacturing process used for an API's production is a crucial factor determining its quality. An API of the required quality and specification can only be produced based on in-depth knowledge and rigorous control of this process and its capabilities. If either a different or an uncontrolled process were used, deviations from the desired result would probably occur and the API may have — detected or undetected — quality defects. It is important to emphasize that such uncontrolled situations may pass completely unnoticed despite the analytical quality control testing of the API: the analytical testing for impurities is performed with methods that have been developed and chosen because of their suitability to detect the impurities that are expected to be present in the API. However, they can easily miss any unexpected impurities. Therefore, because uncontrolled processing and processes have a high chance of giving rise to unexpected impurities, the resulting API will be of an unknown, undefined quality even after analytical testing and can, therefore, be a danger to the patient.  

The rules that are in place to protect an EU patient against these risks can be divided into two essentially different categories: 

 Rules for the registration and authorization of the final medicinal product, including the API. 

. Rules for the systems to be used to ensure controlled and consistent manufacture of the API. 

The API manufacturer has to submit a document to the health authorities (in many cases a so-called Drug Master File [DMF]) that describes in full detail all the manufacturing aspects of the API. This includes analytical testing methods, product specifications, raw materials specifications, in-process controls and API stability. The information is to be assessed by expert reviewers from the health authorities. They will only approve use of the API if the submitted information complies with all the rules. The time between filing of the document and approval can range from one to a few years.  

Any changes to the manufacturing process and/or operations require the API manufacturer to provide the authorities with an amendment to the DMF while at the same time the holder of the marketing authorization for the medicinal product must submit a 'variation' document to the authorities. Many variations require assessment and prior approval from the authorities before the change is allowed to be implemented. In conclusion, difficult regulatory hurdles first have to be overcome before the implementation of a change in API manufacturing operations is permitted. 

The API manufacturer has to execute its operations in full compliance with a specific GMP. In October 2005, the EU adopted this principle into law for API manufacture — a principle already applied by FDA since the early 1960s.

  A harmonized standard for API–GMP now exists in the form of the so-called ICH/Q7A Guideline.

Compliance with these regulations requires additional costs. Studies published in recent years have concluded that the 'cost of compliance' forms an important part of pharmaceutical production costs. The cost of reaching and maintaining the required Category 1 and Category 2 compliance level for the API operations may be 20–25% of a site's operating cost, less the cost of raw materials.

  In addition, depending on the types of technologies involved, over time, the high registration-related thresholds to implement improvements in API manufacture will increase the cost gap between APIs manufactured in full compliance of GMP rules compared APIs manufactured without full compliance with the rules. So strict adherence to compliance also implies significant inflexibility to change and reduces time-to-market — so it provides 'noncompliers' with significant competitive advantages. 

We need to compare the additional cost of GMP and regulatory compliance with the 'costs' of noncompliance. The latter may vary from just replacing 'rejected' material to multiple fatalities.

  The issue may be a matter of negligence, but may sometimes be one of wilful misconduct. Indeed, the profit motive should not be ignored. The API contributes a small percentage of the overall cost of the medicine, a level out of all proportion with its enormous quality impact. So the higher costs of using better quality, compliant APIs ought not to be a deterrent to their use. But for APIs that have become 'commodities', the cost and price differences are of great importance. 

This cost difference, therefore, puts a heavy responsibility upon the competent authorities. The new law on GMP compliance requires the EU inspection, enforcement and penalty system should provide for the guaranteed protection of the EU citizen against the supply of medicines made from illegal, nonGMP-compliant APIs. Otherwise, such noncompliant APIs would continue to have the competitive advantage of being available in the EU at significantly lower prices! 

The adoption into law of the API–GMP standard ICH/Q7A is a major milestone for making available to the EU patients safe, reliable, effective and affordable medicines. However, to judge whether this will be sufficient it is important to first assess the situation in today's EU API market. 

Until October 2005 only Category 1 rules were in force for medicines sold in the EU and no adequate API manufacturers' inspection system was in place. Consequently, until October 2005, the EU system was based almost solely on assessing paperwork, and trusting the authors of the DMFs that they reflected what actually occurs in the manufacturing plant. This meant that there was little incentive for API manufacturers, API brokers, traders and users of APIs to comply with the rules. However, many API manufacturers in the EU were already complying with the GMP standards because FDA required them before their products were approved for sale in the US. FDA not only demanded high standards, but it provided the necessary regulatory oversight and inspections to ensure their enforcement. 

Unsurprisingly, for those APIs not covered by FDA oversight there is a relatively high incidence of noncompliance with such strict GMP standards. In the past few years, evidence has begun to emerge confirming that a significant percentage of, in particular, the older medicines in the EU market may contain noncompliant APIs from obscure and/or unknown origin. They present a significantly increased risk of containing potentially dangerous impurities. 

Quantitative estimates are difficult to make. However, as a first example that would indicate that the situation is quite serious, published scientific research results on the fingerprinting of samples of the antibiotic API gentamicin are now available. This product is known to have caused fatalities in the US as a result of the use of substandard API material.

  The published results suggest that in the EU market the percentage of gentamicin API from unknown origin is significant.

  This conclusion has been confirmed to be a representative picture for many older APIs on the EU market, by presentations and publications on fraudulent and grossly negligent API practices, published by API traders during 2004 and 2005.

  In conclusion, estimations made by some sources that for older medicinal products 'at least 33% of the total API volume in the EU may be from unknown sources' do not seem exaggerated.

The EU has now created the legal basis for the worldwide inspection of API manufacturers whose products are destined for the EU market. However, the directives and guidelines make clear that API inspections will not be performed on a routine basis. Inspections will only be triggered either by suspicion of noncompliance or by a request of the API manufacturer. Without a random factor and a high enough probability of inspection the law has no teeth. EU law now places the prime responsibility and burden of proof that GMP-compliant APIs are being used, on the holders of the EU manufacturing — and of marketing authorizations for medicinal products. This responsibility will be challenged during inspections at their sites. The question is whether this new law will effectively lead to the use of only GMP-compliant and safe APIs in EU medicines. It seems likely that this can only be achieved if strong enough deterrents and potentially business-damaging sanctions as well as penal sanctions against the responsible individuals are put in place by the health authorities.  

Numerous publications during the past have described the very serious problems that exist regarding fake and counterfeit medicines.11–19 The World Health Organisation and other reliable sources have estimated the annual worldwide turnover for these fake and counterfeit medicines to be approximately $35 billion (â¬29.2 billion). They expect this to nearly double by 2010.  

Publications also agree that the majority of these fake medicines are being manufactured in and exported by China and India, most of it to developing countries (especially in Africa), but also to the Western markets, either directly or indirectly. Taking this into account, it is of great concern that today more than 70% of the API volume contained within the medicines on the EU market originates from China and India. Without an FDA-style approach to significantly reducing the risk of nonGMP-compliant APIs entering the EU market (by implementing a programme of thorough frequent regulatory oversight, inspections and enforcement by our European competent authorities) the threat to the health of the EU citizens is certain to increase. 

Medicines have always had to include some level of risk. This risk has traditionally been kept at an acceptable level. However, this has now changed: the intensity of competition — especially regarding 'commodity-type APIs' — triggered by accelerating globalization has driven the risk to unacceptable levels. The rate of change in the industry has been dramatic, the regulators have not kept with the pace, they possibly are not even fully aware of it.  

The manufacturing process used for an API’s production is a crucial factor determining its quality.