06.07.2015 |

LOGFILE No. 39/2015 – Practice Guide for Conducting Audits of Chemical Active Substance Manufacturers

Practice Guide for Conducting Audits of Chemical Active Substance Manufacturers

GMP Series PDF Download

An excerpt from the GMP MANUAL

by Stefan Kettelhoit

Definition of Audit

The US Code of Federal Regulations 21 CFR 820 Subpart A “General Provisions” defines an audit as follows:“(t) Quality audit means a systematic, independent examination of a manufacturer’s quality system that is performed at defined intervals and at sufficient frequency to determine whether both quality system activities and the results of such activities comply with quality system procedures, that these procedures are implemented effectively, and that these procedures are suitable to achieve quality system objectives.”

In Chapter 3.1, DIN EN ISO 19011 defines audits as follows: “Systematic, independent and documented process for obtaining audit evidence and evaluating it objectively, to determine the extent to which the audit criteria are fulfilled.”

It follows that in terms of preparation and execution an audit is not a random process, but rather a systematic, independent one. However, practical experience shows that, especially with regard to active substance audits, the auditors often randomly select not only the audit samples, but also the audited business areas and documentation. This means that the objective of a normal active substance audit, namely examining whether manufacturing is compliant with the EU-GMP regulations, has not been systematically assured.

Preparing for an audit

Regardless of whether or not the audit is conducted internally or by a third-party, the auditor and/or the audit team should answer the following standard questions in preparation for active substance audits:

  • How is the audit process defined in the quality management system?
  • What information or regulations are available to the auditor with reference to the planned audit (e.g. active substance product quality review (PQR), risk analysis/risk management plan, qualification of auditors, forms for the audit documents, etc.)?
  • What are the relevant auditing criteria (i.e. GMP, GDP, ISO, other regulatory frameworks)?
  • What areas (audit scope) are to be included in the audit (general system and/or product audit, for-causeaudit etc.)?
  • Has the company to be audited (auditee) been informed about these areas and are they acceptable to them?
  • What is the schedule for carrying out and concluding the audit?
  • What is the necessary or expected time allotment for conducting the on-site audit?
  • What possible or anticipated problems could appear during the audit, for example, with reference to:
    - Unexpected line stops
    - National holidays
    - Special weather conditions
    - Visa requirements
    - Vaccinations or special health requirements
    - Availability of manpower at the auditee
    - The auditability of production of the active substances during manufacturing
  • What will be the language of the audit? Are competent translators needed for the audit?
  • How much experience has the auditor had with different cultures?

As soon as these questions have been answered and the auditee has confirmed the auditing date and criteria, the next stage of preparation for the audit can begin. The necessary travel arrangements for active substance audits can be very time-consuming and complex and will not be dealt with in greater detail at this time. A mutual non-disclosure agreement should always be concluded prior to active substance audits (if none is already in place). In addition, a pre-audit questionnaire, a proposal for an audit agenda and a reply request should be sent to the auditee well before the date of the audit (at least approx. 14 days before the start). This ensures that while preparing for the audit, in addition to internal information relating to the audit, the auditor and/or audit team will have adequate specific information from the auditee as well as a mutually approved audit agenda before the audit begins.

Conducting the audit

It is advisable to subdivide active substance audits into the following parts:

  • Opening discussion
  • On-site audit (tour of operations)
  • Review of documentation
  • Closing discussion

The opening discussion and the closing discussion together make up the formal framework within which the on-site audit takes place. Their significance is often underestimated. The opening discussion should include an initial statement and introduce the participating companies on both sides (auditee, auditors). It should also define responsibilities and accountabilities, functions and expectations. In addition, the audit protocol should be addressed and adapted as needed to any new information. Finally, any open questions the auditee or auditors may have can be settled during this discussion, if deemed appropriate.

The auditor should not begin the on-site auditing process without adequate information gathered from the audit preparations or at the latest from documentation submitted during the audit. This particularly includes details of the manufacturing process and the location of the areas to be audited, which are often widely scattered over the company site. It is advisable to conduct an on-site audit in accordance with the process flow, either “forwards from start to finish” or vice versa. The latter possibility is especially recommended if the time allotted for the audit is short and the routes of synthesis of the active substances are long. This makes it possible to set appropriate risk-based priorities during the audit.

Socalled “open” questions should be directed to the participants while the on-site audit is in progress. This is the best way to implement the frequently encountered tripartite structure of (GMP) questioning techniques for audits (figure 1).

Examples for GMP questioning techniques
  • What are your duties/responsibilities?
  • How are they performed and documented?
  • Where is it stipulated that they have to be performed and documented in this way?

Figure 1 Questioning technique for audit

The responses received and impressions made should be documented as comprehensively as possible in the form of audit observations and results (auditing proof), after they have also been appropri-ately verified. It is advisable at the same time to look into whether or not these documented audit results fulfil the defined auditing criteria as in the EU-GMP Guide, part II (and/or ICH Q7). If deviations are identified, the results are referred to as audit findings and should be classified and formulated in accordance with previously defined rules. Samples that are as representative and random as possible must be taken during the on-site auditing and the review of documentation in order to obtain meaningful results and a well-founded audit evaluation.

The amount of time allotted for the review of documentation in audits should be roughly equal to the amount scheduled for the on-site part. Risk-based priorities in the review of documentation are useful for active substance audits.

As a rule, the following documents should be reviewed:

  • Manufacturing authorisation
  • GMP certificate
  • Site Master File
  • History of official inspections, incl. results (compliance, non-compliance, warning letters or the like),
  • Other certificates (such as ISO)
  • Org charts (company, production, quality, etc.)
  • Standard operating procedures (SOPs) for core processes, incl. proof of implementation through appropriate records, such as
    - Deviation/non-conformities
    - OOS results
    - Change control
    - Re-use of solvents
    - Supplier qualification/assessment
    - Self-inspection
    - Training
    - Pest control
    - Customer complaints
    - Recalls
    - Reprocessing/reworking
    - Rejects/returns
    - Blending
    - External contractors
    - Transportation


Here’s an overview of what else you’ll discover in this GMP Series PDF Download:

Auditing active substance manufacturers

  • Regulatory requirements and professional prerequisites
  • Active substances from Europe and/or third countries (such as China or India)
  • Third Party Audits
  • Audit Checklists

Chemical active substances

  • What are chemical active substances?
  • Definition of terms
  • Scope of GMP regulations
  • Basic GMP requirements
  • Special Risks
  • Typical GMP deficiencies in chemical active substance manufacturing

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Practice Guide for Conducting Audits of Chemical Active Substance Manufacturers.