There are many reasons for the deviations from quality standards. For example, physicochemical properties may have changed; the stability of the substance or the pharmacological activity might have been impaired or the impurity profile may have been aggravated.
Extensive analyses of the finished API cannot sufficiently address these problems as they cover “expected” deviations and impurities and only detect specified items. In 2008, the Heparin product scandal was caused by oversulphated chondroitine sulphate that avoided detection as a contaminant in quality control tests.
European manufacturing authorization holders are obligated to ensure Good Manufacturing Practice (GMP) compliance of their medicinal products. This is laid down in Article 46f of “Directive 2001/83/EC”, which has been transformed into the national legislation of the European member states. Corresponding regulations in the US can be found in section 501(a)(2)(B) of the “Federal Food, Drug and Cosmetic Act”.
GMP compliance has to be ensured by onsite audits of API manufacturing facilities in accordance with European legal provisions. Even GMP certificates provided by competent national authorities, for example from the Chinese State Food and Drug Administration (SFDA) or Indian regulatory authorities, are not sufficient enough to replace API audits.
Asian API manufacturers that supply their goods to regulated markets should therefore expect related GMP audits of their quality systems and manufacturing processes. These audits have to be performed under the responsibility of a Qualified Person or through contracted third-party auditors.
GMP regulations vary worldwide. The World Health Organization (WHO) has created a globally consistent basis for quality standards with the compendium “Quality Assurance of Pharmaceuticals.” Chapter two describes the GMP requirements for “APIs (bulk drug substances)”.
The US, Europe and Japan have adopted the “International Conference on Harmonisation (ICH) Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients,” representing their own regulations for the manufacturing of APIs. These regulations substantiate and even extend the WHO requirements in several topics.
Within the European Union, the ICH Q7 regulations have been established as “EU GMP Guideline Part II,” with (nearly) identical wordings. Other countries such as Canada, Australia and Singapore have also adopted the ICH regulations – the latter via the “Pharmaceutical Inspection Co-operation Scheme” (PIC/S).
Most of Asia portrays a mixed image: whereas Japan and Singapore follow the ICH Q7 regulations, India and China – the major API manufacturing countries, have approved their own GMP regulations (although representatives of both countries were invited participants of ICH Q7 expert working groups). These GMP regulations simultaneously cover active pharmaceutical ingredients and medicinal products.
India has laid down its own GMP requirements in Schedule M of the “Drugs and Cosmetics Rules”. In China, the rules from “GMP for Pharmaceutical Products” which have been issued by the SFDA are in force. Unlike the ICH Q7 which deals exclusively with APIs, the Chinese and Indian GMP regulations do not distinguish between GMP for medicinal products and GMP for APIs. Part 1-F of the Indian Schedule M is for API manufacturing while the SFDA GMP guideline has a corresponding appendix 4.
However, in both cases the number and complexity of rules are comparatively low. This may create problems for API manufacturers in these two countries. For instance, auditors from ICH may still find these manufacturers non-compliant even if the latter have adhered to their respective national GMP regulations.
Pharmaceutical companies that sell medicinal products within the ICH region have to comply with the valid ICH Q7 guideline, or the valid identical national regulations. GMP audits conducted in Asia by these companies must primarily be geared towards the legal requirements of the target market rather than those of the API supplying country.
As a general rule, such an audit will follow the structure and the requirements of the ICH guideline. The guideline is structured into 19 chapters Table 1 , with a number of audit topics. The differences between the effective GMP standards of the supplying countries and the receiving countries may therefore result in ambiguities and difficulties relating to GMP compliance.
From a fundamental standpoint, the differing structures between the CH Q7 and the Schedule M or the SFDA can cause difficulties in finding the required information. This opens up the possibility of misinterpretation by the auditor as the country or company specific GMP documents may not be presented in a way that he is familiar with.
This risk can be avoided by employing experienced auditors who are familiar with the regulatory guidelines in India and China. This means that the buyers of APIs have to ensure that the auditors are suitably qualified for the job.
Following the Rules
The differing requirements of the underly the GMP guidelines may also lead to real noncompliance. This for instance is the case, if topics defined within the ICH Q7 are not (or are only superficially) covered in national GMP guidelines.
Eg, topic 1.3 of the ICH Q7 (and topic 1.2 of the EU-GMP guideline, part II and topic 1.2 of the PIC/S GMP Guide for Medicinal Products part II) suggests the stage (starting point) within the manufacturing process where GMP requirements need to be fulfilled for different kinds of API starting materials.
During the auditing of the process validation and manufacturing flow according to ICH standards, an auditor will emphasize on the adherence of the early stages of the manufacturing process to essential GMP requirements. With subsequent process steps up to the point of the purified, finished API, the auditor expects increasing GMP compliance.
The SFDA GMP rules on the other hand, are primarily focused on the final manufacturing steps. For the API manufacturing process, batch records are (only) required starting from the “refinement from crude” step (appendix 4, topic 10 of SFDA-GMP). Since regulations for the early manufacturing steps are not contained within the guideline, Chinese companies may be non-compliant according to ICH criteria – depending on their selection of the API starting material. The subject of “change control” is covered in chapter 13 of the ICH Q7. Every change that is related to the production process that “may affect the production and control of the intermediate or API” has to be identified, documented, assessed and approved. This means that the API purchaser has to be informed about changes in the production process based on the ICH Q7 requirements.
However, local GMP regulations may not require API manufacturers to inform their purchasers about such changes. The Chinese SFDA GMP guideline does not explicitly dictate change control procedures. The Indian schedule M covers the changes in the manufacturing process in chapter 26.5. However, these changes are only regarded as a task for validation: “Significant changes to the manufacturing process, including any changes in equipment or materials that may affect product quality and/or the reproducibility of the process, shall be validated.”
Changes in the manufacturing process may potentially lead to extremely altered properties of APIs, eg, the bioavailability and the resulting efficacy – the API exhibits identical chemistry properties with different eventual polymorphic forms. Therefore, unqualified and undocumented changes in the production process can result in serious consequences for the marketing authorization holder to the point of a termination of the manufacturing authorization.
Manufacturers from Asia should therefore align their quality management systems and manufacturing processes not only to their respective national standards but also to the requirements of ICH Q7. Otherwise, European and American companies cannot accept the APIs. In most cases, the adaption of the quality systems is feasible. The topics are covered in the respective guidelines, but with different levels of complexity in the rules. The guidelines can be combined by implementing requirements from ICH as an extension to the national legislations.
Intentional non-compliance can also occur and are usually due to economic reasons. Strict adherence to compliance implies a significant inflexibility to change, providing noncompliers with significant competitive advantages.
Compliant manufacturers are placed at a disadvantage because of these “black sheep”: after incidents of intentional non-compliance, exported APIs from that country will be under the general suspicion of purchasers and regulatory authorities, leading to impeded market penetration. For instance, after contaminated Heparin from China led to more than 80 cases of death in the US, the affected pharmaceutical manufacturer Baxter started an immediate review of its China-based suppliers and their sources.
Additionally, companies have even added on their Bovine Spongiform Encephalopathy/ Transmissible Spongiform Encephalopathy (BSE/TSE) certificates, a phrase that states that their APIs and excipients are not manufactured in China.
As a consequence of such incidents, the legal or company specific compliance regulations are frequently and reflexively tightened. In the worst case scenario, such measures primarily serve to aggravate the economic conditions of honest market participants.
However, the problem cannot always be resolved with tighter regulations but with the continuous and professional auditing of the entire supply chain. GMP requirements need to be veritably fulfilled, starting with the manufacturer of the medicinal product to the related API trader, up to the manufacturer of the API.
While APIs and excipients have evolved into globally traded goods, GMP regulations have not kept pace with this development. Differences, particularly between the ICH region on one hand and China and India on the other, slow down the development of the market. In addition, these differences complicate the monitoring of successful GMP compliance. Achieving an international harmonization of the standards will take time.
Manufacturers of APIs that desire to take advantage of export opportunities should therefore not merely align their manufacturing processes according to the respective national regulations. Rather, they should consider the ICH Q7 requirements pertaining to their quality management system and documentation structure – and the additional expenditure is usually justified. Those that are not willing to adapt may end up facing closed doors to the American, Japanese or European markets.
1) vgl. z.B. in Deutschland: "Verordnung über die Anwendung der Guten Herstellungspraxis bei der Herstellung von Arzneimitteln und Wirkstoffen" (AMWHV), §11 Absatz 2.
2) WHO (2007): Quality assurance of pharmaceuticals. A compendium of guidelines and related materials, Volume 2: Good manufacturing practices and inspection.
3) ICH (2000): ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. www.ich.org/LOB/media/MEDIA433.pdf
4) Therapeutic Goods Administration (2002): Australian code of good manufacturing practice for medicinal products. www.tga.gov.au/docs/html/gmpcodau.htm
5) The Drugs and Cosmetics Rules (India), Schedule M.
6) Drug Administration Law of the People's Republic of China (China), Art. 9
7) Heisig Wolfgang / Amschler Uwe (2008): "Auditierung/Qualifizierung von Wirkstoffherstellern durch akkreditierte Stellen" (Auditing/Qualification of Active Pharmaceutical Ingredient Manufacturers by Accredited Inspection Bodies). Pharm. Ind. 70, Nr. 12, 1459-1463.
8) Oldenhof, Chris (2006): APIs: Why EU authority oversight is vital, Pharmaceutical Technology Europe Nr. 3/2006, 32-35.