Shortly after the entry into force of the Good Manufacturing Guide for Active Pharmaceutical Ingredients ICH Q7 in the year 2000 the Active Pharmaceutical Ingredients Committee APIC wrote the "How to do" document which clarifies the requirements of the guideline on the basis of experience gained from operational practice. The present document aims at providing practical advice for the implementation and maintenance of GMP standards during the production of active pharmaceutical ingredients concerning those provisions of ICH Q7 that require further interpretation. The "How to do" document is a "living" document as it is revised in irregular intervals in order to keep pace with the constantly changing state of scientific and technical knowledge.
The recently revised version of the document was published as "Version 8" on the APIC publications website in August 2015. As compared to the last revision (August 2012) the chapters 10 "Storage and Distribution", 11 "Laboratory Controls", 12 "Validation" and 15 "Complaints and Recalls" were revised. The following is a selection of the most important changes:
Chapter 10 Storage and Distribution
This chapter points out the importance of controlling the temperature distribution in warehouses taking into account seasonal temperature changes. The document indicates sets of rules that describe concretely how to perform a temperature mapping (section 10.10.).
It stresses the necessity of physical separation between released and returned material, preferably by storing them in different rooms. Storage conditions for intermediates are based on development data and knowledge (section 10.11).
The document points out that logistics companies should be qualified (quality agreement). The shipping conditions records should be reviewed. If deviations occurred an investigation should be initiated and appropriate measures be carried out and documented (section 10.21).
Chapter 11 Laboratory Controls
This chapter expressly points out that analytical methods have to be validated and that the integrity of analytical data has to be ensured by means of controls (section 11.11).
Rounding rules and the process used for averaging should be described in a SOP (section 11.11.).
In chapter 11.13 ICH M7 and ICH Q3D have been added to the list of ICH guidelines. Furthermore, it is pointed out that the design of experiments approach can also be used within the framework of design space when defining specifications.
Chapter 11.15 contains detailed guidance on the FDA requirements for active pharmaceutical ingredients that are exported to the USA and sold there, especially on the handling of OOS results.
Chapter 12 Validation
Chapter 12.11 explains more in detail the handling of critical parameters and quality attributes referring to the actual ICH guidelines ICH Q8 and Q11 as well as to FDA and EMA guidelines.
It indicates that the 3 consecutive validation batches should be considered as an orientation. The actual number of validation batches has to be pre-defined and to be justified (section 12.50).
The process validation report has to contain all critical quality attributes compared to the reference batches. These attributes should be comparable to or better than the reference batches. The rationale for selecting the reference batches must be justified (section 12.52).
Chapter 15 Complaints and Recalls
This chapter refers to the necessity to include other batches potentially connected with the batch affected by the complaint or recall in the complaint investigation and to define a period to close complaint investigations (section 15.10).
It points out that a recall cannot be carried out by the API manufacturer himself. This is the responsibility of the finished dosage form manufacturer. The notification of the authorities (such as public health departments) can also only be carried out in close cooperation with the finished dosage form manufacturer (section 15.10).