Formal layout of the report
A specified and accepted standard for the contents of audit reports is not (yet) available. In practice, different layouts such as structured text, tables, tick boxes and also mixtures thereof are used. Preferred are reports, which are formally derived form the “GMP Inspection Report – Community Format” of the EMEA . The competent health authorities are familiar with this report format, which will allow them to quickly get an idea about the underlying audit. This “Community Format” of the EMEA contains the following elements:
- Inspected site(s)
- Activities Carried out
- Inspection date(s)
- Brief report of the inspection activities undertaken
(Scope of Inspection; Inspected area(s))
- Activities not inspected
- Personnel met during the inspection
- Inspectors findings and observations relevant to the inspection; and deficiencies
(Headings to be used: Overview of inspection findings from last inspection and the corrective action taken, Quality Management, Personnel, Premises and Equipment, Documentation, Production, Quality Control, Contract Manufacture and Analysis, Complaints and Product Recall, Self Inspection; Distribution and Shipment; Questions raised relating to the assessment of a marketing application; other specific issues identified; Site Master File)
- Annexes attached
- List of Deficiencies classified into critical, major and others
- Summary and conclusions
- Name(s), Signatures(s), Organisation(s), Date
However, the report format employed by authority inspectors is not ideally suited for API-specific GMP audits within the pharmaceutical industry. First of all, the specifications for the narrative key part of the audit report, the “Inspectors findings and observations relevant to the inspection; and deficiencies” are rather directed to finished medicinal products than APIs. This item will be covered later in this article. Furthermore some topics, which should in fact not be missing in every audit report, are not covered. In particular:
- the illustration of the on-site audit extent,
- the different product quality grades manufactured,
- the manufacturing activities performed during the course of the audit,
- the documents reviewed during the audit including their respective revision version, and
- the qualification of the auditor(s).
These aspects are eminently important for the subsequent assessment of the audit report. Therefore the extent of the on-site audit part should be phrased as accurately as possible. Within the EMEA documents it is only stipulated that “Activities not inspected” should be indicated, if this is deemed to be necessary. This potentially selective description of areas (not) audited would, however, not allow subsequent readers of the audit report to appropriately review the audit extent.
Manufacturing of several different product quality grades at a certain production site takes immediate effect on the preparation of the audit and the priorities selected for the audit. An evident example can be derived from the field of excipients, which are frequently produced by one manufacturer for many different applications. Lactose is used in Dry-Powder-Inhalers (DPI) as a carrier for APIs but tons of Lactose are manufactured at the same time as a filler for oral solid dosage forms. In addition, even higher amounts are used for non-GMP regulated applications. The first application mentioned bears of course much higher quality requirements concerning e.g. purity, microbial load or particle shape and particle size distribution. Special attention should consequently be given to packaging, labelling, storage and re-use of material. If the audit report does not contain any reference to different material quality grades and/or specifications, a subsequent reader may not be able to understand whether the audit scope fully covered the existing risks.
It is also of major relevance for the audit report whether the audited API was being manufactured during the course of the audit at all and, if yes, which steps of the synthesis. From article 46(f) of Directive 2001/83/EC arises that supplier audits, as a matter of principle, have to be conducted specifically for every single API. It is therefore in any case recommended to audit a manufacturer when the respective API production is running. In practice, this will not always be possible and an exhaustive audit of the entire synthetic process flow may not be accomplished at all, since the single, sometimes quite complex manufacturing steps, will usually be executed sequentially and in a multi-shift operation. Rather frequently during audits the respective equipment of the site is “accidentally” just being cleaned, which allows for the auditing of the cleaning processes but not the good manufacturing practices. It is therefore mandatory that the audit report contains a description about the production status, the intermediates and APIs manufactured during the audit and the audited areas.
Besides the implementation level of cGMP requirements at the „shop floor“ level, the relevant GMP documentation, such as Standard Operating Procedures (SOP) of the auditee, has of course to be audited randomly. The documents reviewed should be clearly referenced in the audit report under the relevant report chapter –thus the SOPs covering training of personnel under the chapter “Personnel”, SOPs covering the materials management of raw materials under the chapter “Materials Management” and so on. In addition to (key) SOPs there are further important documents and records to be audited with regard to this:
- the often very comprehensive documentation concerning qualifications and validations (such as the qualification of the cleanroom, qualification of the water system, process validations, cleaning validation and validation of analytical methods etc.),
- (master)production instructions and (master)batch records,
- the Product Quality Review(s) including randomly exemplarily chosen records concerning Change-Control-activities, Failure Investigation, Corrective and Preventive actions,
- physicochemical and microbiological monitoring data (water, resp. other media, clean rooms/controlled areas) and
- GMP training records,
- the audit report should not only contain the title of the audited documents but also the document number and revision number.
The qualification of the auditor will be of minor importance in case of an audit being performed by the Qualified Person of the pharmaceutical manufacturer.
This question is, however, of more importance in the light of increasing amounts of Third-Party-Audits since the Qualified Person has to ensure by written documentation that the Third-Party-Auditor has the required competence, quality and independence to perform the audit. For Third-Party-Auditors belonging to an accredited (inspection) body, these qualification confirmations are part of the accreditation. Therefore this process of qualification is remarkably facilitated. Otherwise the Third-Party-Auditor is due to be audited (including audit report!) before performing the supplier audit.