Auditing / Qualification of Active Pharmaceutical Ingredient Manufacturers by Accredited Inspection Bodies


Active ingredients for the production of medicnal products have to be manufact-ured according to the principles of good manufacturing practice (GMP). The licence holder has to verify this on site. As only few active ingredients are produced in Europe today, a consider-able burden is induced by this obligation for every single enterprise.

During the last months the responsible competent authorities have intensified their focus in the direction of the controls actually being carried out.

The German legislation as well as the EU regulations provides the allowance for the license holder to delegate the task to competent experts – who will inform him by expert opinion / audit report. The license holder thereby remains responsible for the choice of a suitable expert. Inspection bodies accredited according to ISO/IEC 17020 norm and who have the proven and necessary know-how are especially qualified. The mentioned standard is already incorporated in the design of the own organizational structures and procedures of competent authorities in Europe. The commissioning of accredited inspection bodies simplifies the principal’s choice, reducing his own expenditure of qualification. The following article informs of the possibility to control manufacturers of active pharmaceutical ingredients (APIs) with the help of accredited bodies.

in: Pharm. Ind. 70, No. 12, 1459-1463 (2008)
Dr. Wolfgang Heisig, blue inspection body GmbH, Muenster, and Dr. Uwe Amschler, Schwentinental

The control of good manufacturing practice (GMP) for active ingredients and starting materials has been focused on by the competent authorities during the past months. This applies to the European Union as well as to the United States and was induced by counterfeits of medicinal products - in particular the anticoagulant Heparin – which also increasingly affected the used active ingredients. A concept has emerged through this discussion on both sides of the Atlantic: Audits by independent "accredited bodies". They could assist the competent authorities to protect GMP for APIs and to strengthen the safety of medicinal products.

On the one hand, this raises the question to the qualities an accredited body must possess in order to comply with its intended role; since it is not the independent auditors, but the Qualified Person of the holder of the manufacturing authorization who is formally responsible for securing GMP-conformity. On the other hand it must be queried how the marketing authorization holders can comply with the additional requirements and increasing audit obligations.

In case of detailed consideration of these questions it must be pointed out that GMP-API-audits can be carried out by accredited bodies - and that this could relieve the holder of marketing authorizations as well as the active ingredient manufacturers in many aspects.

Initial situation

Within the European Union the qualified person (QP) of the holder of the marketing authorization is responsible for GMP-conformity of the manufactured medicinal products. He supervises the whole production chain including the used active ingredients and starting materials. The qualification of APIs has to take place by audits on site at the active ingredient manufacturer according to the German law for medicinal product and active ingredient manufacturing (AMWHV) §11 chapter 2.

Indeed, according to article 111 of directive 2001/83/EC the active ingredient manufacturers are also principally supervised by the competent authorities. Never the less, this check of GMP-conformity is, as a rule, only indirectly within the scope of their GMP inspections of the manufacturers of medicinal products. In recent times, more than ever before, they ask for audit reports which have been generated by the qualified person or qualified employees of the pharmaceutical companies of the respective supplier audits. Direct GMP-inspections at active ingredient manufacturers in third countries rarely take place.

In the United States the situation is a different one. There, the competent authority FDA inspects the active ingredient suppliers itself. Inspections already take place in early phases of the registration procedure, the so-called pre-approval inspections, at the sites of the active ingredient manufacturers. The fact that these inspections have not always been carried out, became evident towards the end of January, 2008, when contaminated Heparin batches caused several deaths in America: The FDA had never examined the Chinese supplier of the contaminated active ingredient. Now in March 2008, eight inspectors belonging to FDA have, for the first time, been directly stationed in China. However, in a country in which more than 1,500 active ingredient manufacturers are located it is more than doubtful whether the available number of inspectors will be sufficient.

The FDA is already considering certain solutions. Additional to the establishment of foreign offices the carrying out of audits through other competent authorities and independent accredited bodies should be considered more strongly: "FDA is pursuing the use of third party certification to verify compliance with FDA requirements. These third parties may include foreign government agencies and independent entities who have been accredited by FDA or accreditation organizations recognized by FDA ." Although these reports cannot substitute own inspections, they should serve the profit of information and help the authority to prioritize. This way the FDA is carefully moving towards the European model of two-stage supervision.

In the light of increasing counterfeits of medicinal products the European commission has also presented strategies to how the protection of patients can be guaranteed. Beside a stronger formalisation of inspection duties it also suggests to recruit accredited bodies for the qualification of suppliers: "Audits are an important means of ensuring that economic operators act with reliable partners. These audits should be mandatory. […] to rationalise acceptance of third-party audits by accredited companies could be considered “.

Accredited bodies

What is the idea behind this actual discussion? The term "Accreditation" describes the certificate of competency that an organization - the accredited body - is qualified to confirm to a third party by certificate, that this third party complies professionally and formally correct with an official standard. The accredited body gains the certificate of competency through a formal inspection and approval of a super­ordinated, authorized organization - the accreditor. It checks whether the accredited body possesses the necessary technical know-how in its field of activity, whether it has an infrastructure suitable for its tasks and whether it can guarantee through valid procedures the quality of its services on a long term basis. The accreditor additionally carries out annual inspections of the accredited body and is also responsible for the re- accreditation in up to quinquennial intervals. Germany disposes of a total of eleven accreditors which are united in the German accreditation-council (DAR).

Indeed, accredited bodies are established worldwide and are needed in a huge number of areas. Material testings and type checks belong in the technical area - from the fire prevention classification for plastics up to EC-type check for vehicle parts. In the pharmaceutical field, for instance, analytical laboratories which carry out toxicity studies are regularly accredited according to DIN EN ISO/IEC 17025. In the adjoining field of medical devices the so-called “Notified Bodies”, which carry out the required evaluation of conformity by EC directive 93/42, must be accredited according to DIN EN ISO/IEC 17011.

However, in the area of GMP inspections and qualification of active ingredient manufacturers the number of accredited bodies is still extremely clear in Europe. The relevant norm here is DIN EN ISO/IEC 17020. The German contract auditor blue inspection body GmbH is accredited according to this norm for the scope ”Inspections of excipient and active pharmaceutical ingredient manufacturers for pharmaceutical products and determination of the conformance with international GMP rules“  - nowadays, still being the only service provider in the European Union. Apart from blue, only the Swiss competent authority Swissmedic is accredited for "Inspections of manufacturers and wholesalers of medicinal products according GMP-and GDP guidelines ".

ISO 17020 defines the criteria for the conduction of different types of bodies which carry out inspections. Accordingly, the organizations accredited according to this norm are called “Inspection bodies”.

European competent authorities responsible for GMP inspections are also acting on the basis of this norm. It forms the basis of the "Quality Systems Framework for GMP Inspectorates", the common collection of procedures for inspections and information exchange published by the European commission.

Swissmedic explains the purpose of the accreditation according to ISO/IEC 17020 as follows: "An accreditation according to this norm increases the acceptance of the Swiss inspection system from other competent authorities for medicinal products (EU, Canada, Australia, etc.). […] a missing international acceptance could imply a substantial additional expenditure for the exporting local manufacturers because these would be inspected, in addition, by different competent authorities of the individual importing countries."

The possibility of such an international acceptance is based on the certificate of competency which the inspection body gains with the accreditation. Amongst others, the professional competence of the auditors of the inspection body is examined. In addition, the natural requirement of the nominated auditors must be qualified, e.g., by the qualification as a qualified person, witness-audits must be graduated. These

are examinations during audits conducted by the accredited body performed by approved professional GMP experts of the accreditor itself, e.g. inspectors of competent authorities for medicinal products.

The suitability and implementation of the quality management system of the inspection body is examined during the accreditation. The confidentiality, impartiality, integrity and independence are also checked. ISO/IEC 17020 identifies three classes for inspection bodies, from which the highest, type A, implicates a total objective and economic independence from the contract giver and the object of the audit: Auditors of an inspection body type A should not experience conflicts of interest, neither to the contract giving manufacturer of medicinal products (= Marketing authorization holder; MAH) nor to the manufacturer of active pharmaceutical ingredients, through possible business connections, investments, former (or following) employment contracts. An overview of all test criteria for an accreditation has been published by the German accreditation system inspection department (DAP).

Duties of the qualified person

According to article 46f of directive 2001/83/EC the holder of the manufacturing authorization is responsible for GMP compliance. He and his qualified person, respectively has to assure that all active pharmaceutical ingredient manufacturers accepted by him comply with requirements of the EU GMP-guide part II. In Germany this binding demand is defined in the AMWHV §13, clause 3: "For the manufacture of medicinal products only active ingredients and certain excipients […] are to be used as starting materials which have been produced according to the rules of good manufacturing practice. "

Concerning the confirmation of GMP compliance, competent authorities really do not accept every kind of document presented to them. EMEA explicitly points this out in their Questions & Answers to GMP inspections: ISO or GMP certificates from third countries, certificates of suitability (CEP) or so-called paper-audits are not sufficient to demonstrate GMP compliance of the manufacture of an active ingredient. They can merely be used as an "interim and temporary measure" between audits. Only audit reports generated from professional (qualified) persons concerning active ingredient manufacturers audited on site and with special focus on the respective active ingredient will find mercy in the eyes of the official inspectors. These audits should - when necessary be chronologically scheduled according to risk assessment on the basis of available CEPs, ISO or GMP certificates – be carried out at regular intervals, possibly every two to three years (cf EMEA/INS/GMP/313538/2006).

Previous to the AMWHV coming into force in November 2006, GMP-audits for active pharmaceutical ingredient, briefly called API-audits, were not binding in Germany. Many manufacturers of medicinal products have avoided this type of supplier-qualification. In other European countries the situation was similar. Now these audits have to be carried out: Whether the manufacturers of medicinal products or contract manufacturers comply with this requirement or not is currently being more and more intensely checked by the competent authorities during their regular GMP-inspections. Besides, the use of active ingredients produced under non GMP conditions, or the presentation of invalid audit reports and assessments represent a critical finding.

The GMP/GDP-inspectors workgroup of the EMEA nowadays prepares an amendment for chapter 5 of the EU GMP guide which should define the supplier qualification even more exactly. The procedure to do so should be described more definitely.

It is therefore the only way for the MAH to assure himself of the GMP-compliance of the production of his active ingredient manufacturers on site, e.g., in India or China, Italy or Spain - or to delegate this obligation to a contract auditor. In the market several service providers are established who carry out such contract audits. This practice is explicitly permitted by the EMEA as well as - for Germany - through §11 clause 2 AMWHV: "Instead of own audits the manufacturer of medicinal products can revert on suitable information from third parties as long as the requirements for the execution of the audits are equivalent to those of the own QM-system."

EMEA defines a row of preconditions for this. Thus, the MAH must verify the competence, quality and independence of the assigned auditor to be allowed to accept his audit reports. Strictly speaking, it requires that the qualified person of the manufacturer of medicinal products formally approves the contract auditor and his qualification.

Audits executed by accredited inspection bodies

At this interface of the qualification of auditors the specific advantage of accredited bodies is based for the MAH or his qualified person. As described, the accreditation by an accreditor covers exactly those requirements which a qualified person also has to prove if he wishes to accept contract auditors. The verification of the professional competence, to secure independency concerning conflicts of interests etc. is the central element of the inspection by the accreditor. The enforcement of witness-audits (external revision of the audit execution by third parties) as an instrument for quality assurance purposes by the accreditor is another distinction compared to other contract auditors and own audits. An accreditation reduces the expenditure for qualification for the contract giver and for the manufacturer of medicinal products.

At the beginning of every third-party-audit – in case of non-accredited service providers or by inspection bodies – the specific requirements of the MAH always have to be defined concerning the manufacturing plant and the particular active ingredient to be audited. As a result the auditor generates, if necessary together with the MAH, a suitable audit plan and carries out the audit. After the audit the active ingredient manufacturer receives a report defining the audit results to comment the findings. Corrective actions and a relating time schedule to clear deficiencies are defined.

In the case of an accredited audit, the reports of the auditors are internally reviewed from the inspection body itself. This is carried out by a specially assigned functional unity of the QM system of the inspection body, the Inspection Review Board. The MAH or his qualified person receives the report released according to this procedure for his own evaluation and release or suspension of his supplier.

Request of competent authorities - advantage for manufacturer of medicinal products?

Audits by accredited bodies (also called "accredited audits“) facilitate the tasks of the qualified person of the MAH, because the qualification of the GMP inspectors / auditors is guaranteed by ISO 17020.

Nevertheless, it must be underlined that ISO 17020 is no legal regulation. An accreditation has formally the identical relevance as for example the ISO 9001 certificate for a quality management system: Both are only confidence-building procedures. For this reason the qualified person of the MAH has to evaluate the audit report according to his own estimation. It is his responsibility to release the active ingredient manufacturer and to define at which time a follow-up audit has to be conducted. Nevertheless, de facto the ISO norms like accreditations prove themselves as important quality standards in numerous areas worldwide. In this context the announcement of the European commission is also to be regarded, to include GMP inspections of accredited bodies in its own evaluation procedures.

Accredited inspection bodies gain their extraordinary importance for competent authorities through their independency which is guaranteed - at least in case of the inspection body type A - not only towards the active ingredient manufacturer to be audited, but also towards the contract giving MAH. This independency also exceeds the independency of the qualified person of a MAH. The QP will also always feel obliged on account of personal (terms of employment) and economic circumstances of the enterprise towards his employer.

In the case of active ingredients being used by several MAHs a shared audit will be preferred. This "sharing of audit reports between different manufacturing authorisation holders"  is specifically permitted by EMEA should the shared audit report cover the relevant subjects - possibly concerning the specifications for the manufacturing procedures - for each of the participating MAHs. The audit expenditures can hereby be shared between several enterprises and the costs for the single MAH or contract manufacturer will be clearly reduced.

Future prospects

The purchase of starting materials and active ingredients from third countries is a current practice, in particular in the production of generics. According to estimates nearly 80 percent of all in the EU and in the USA handled active ingredients originate from third countries. Main exporting countries are India and China. Official inspections of these active ingredient manufacturers alone are obviously no solution if one regards the huge amount of manufacturing plants and the restricted number of official GMP inspectors. An example has been shown during the previous months through the Chondroitin Sulfate contaminated Heparin.

But the practice of the European Union also implicates disadvantages. Here, under the responsibility of the QP of every MAH all active ingredient manufacturers are to be audited:

- Firstly, the audit reports have a lack in independency, because a QP is also bounded at all times to the economic welfare of his MAH.

- Secondly, this practice leads to considerable additional expenditure for the active ingredient manufacturers: If a manufacturer supplies the same active ingredient to ten manufacturers of medicinal products in Europe, he will be audited as a rule 10 times from different QPs in regular intervals, possibly every two to three years.

- Thirdly, relating to this, a considerable burden is also induced for the MAHs themselves, because they must also send their qualified staff on inspection tours to all their active ingredient manufacturers worldwide every two to three years – if the QPs take over these duties themselves, they cannot simultaneously guarantee the correct production of finished medicinal products in their own enterprises.

Therefore, it is in the interest of the MAHs to promote a system of accredited audits. An efficient control for GMP compliance would be guaranteed regarding active pharmaceutical ingredients. These audits should, where ever possible, be carried out, as shared audits so reducing costs for all manufacturers of medicinal products.


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7) ;

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blue inspection body GmbH
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