by Robert M. Tribe

As explained in Regulatory Review of November/December 2004, the Pharmaceutical Inspection Cooperation Scheme (PIC/S) is a cooperative arrangement between 27 regulatory authorities that enables active and constructive cooperation and sharing of information in the field of GMP¹.

PIC/S member authorities prepare GMP inspection reports according to a standardized format in order that the information held on file and/or exchanged with other regulatory authorities is consistent. The PIC/S standard operating procedure describing the inspection report format, which is available on the PIC/S web site, also provides definitions for three different categories of GMP deficiencies². These deficiencies, and their definitions, are as follows:

1. Critical Deficiency
   • A deficiency that has produced, or may result in a significant risk of producing, a product that is harmful to the user.
     
     Examples of critical deficiencies:
     • Grossly inadequate air filtration to minimise airborne contaminants.
     • Falsification of analytical results
   
   
2. Major Deficiency
   A non-critical deficiency that:
   • has produced or may produce a product which does not comply with its marketing authorisation; or
   • indicates a major deviation from the PIC/S GMP Guide; or
   • indicates a major deviation from the terms of the manufacturing authorisation (eg. Manufacturing licence); or
   • indicates a failure to carry out satisfactory procedures for release of batches; or
   • indicates a failure of the person responsible for QA/QC to fulfil his/her duties; or
   • consists of several “other” deficiencies, none of which on their own may be major, but which may together represent a major deficiency and should be explained and reported as such.
     
     Examples of major deficiencies:
     • Insufficient manufacturing space that could lead to mix-ups.
     • Reduced QC testing of raw materials without data to certify suppliers
   
   
3. Other [Minor] Deficiencie
   • A deficiency that cannot be classified as either critical or major, but indicates a departure from good manufacturing practice.
     
     Examples of other [minor] deficiencies:
     • Use of white out correction fluid on manufacturing documents.
     • Equipment not calibrated by due date.

Classification of deficiencies in this manner enables PIC/S member authorities to more easily apply a risk management approach to regulating medicine manufacturers, thereby facilitating the protection of public health. For example:

• A manufacturer where several critical deficiencies are detected could warrant suspension or revocation of the company's manufacturing licence.
• A manufacturer showing a significant increase in the number of major deficiencies since the last GMP inspection could warrant suspension or conditioning of the company's manufacturing licence.
• A manufacturer with a consistently low number of minor deficiencies over several GMP inspections could be rewarded with less frequent inspections.

Some PIC/S member authorities undertake detailed analysis of GMP deficiencies in order to help identify the most common GMP problems across the industry in that country. For example, for the period 2001-02 the United Kingdom Medicines Control Agency, or MCA (now known as the Medicines Healthcare Products Regulatory Agency, or MHRA), found that the top three GMP deficiencies observed for that period of time were:

1. Potential for non-microbial contamination.
2. Deficient manufacturing documentation.
3. Deficient design and maintenance of premises³.

This approach gives these regulatory authorities the ability to not only focus their attention on specific problem areas during routine regulatory inspections but also to work constructively with industry to find solutions to help improve GMP compliance across the whole industry. One such solution is for industry Seminars to be arranged to provide education on specific topics, with active participation by GMP regulators.

The use of a similar system of deficiency classification within a company's internal audit program can be useful in:

• Proactively identifying problems prior to an anticipated regulatory inspection;
• Establishing priorities for corrective and preventative actions;
• Providing confidence to management that GMP compliance is on track.

References:

1. Pharmaceutical Engineering, November/December 2004; page 110.
2. Standard Operating Procedure PI 013-2, 1 July 2004. PIC/S Inspection Report Format. Obtainable from the PIC/S web site address; publications page: www.picscheme.org/pubs/pubs.htm  
3. J. Taylor, G. Munro, G. Lee & A. McKendrick, MHRA, UK. The Pharmaceutical Journal; Vol. 270; 25 January 2003; pages 127-129. Obtainable in PDF format from the Pharmaceutical Journal web site address at the following location: www.pharmj.com/ContentsPages/Contents20030125.html  
   

About the Author
Bob Tribe is ISPE’s Regulatory Affairs Advisor for the Asia Pacific, based in Canberra, Australia. He joined ISPE from the Therapeutic Goods Administration (TGA) in Australia, where he served as Chief GMP Auditor for 23 years. During that time, he not only enhanced the TGA’s reputation as a leading GMP regulator internationally but also held leadership positions with the Pharmaceutical Inspection Cooperation Scheme (PIC/S), serving as vice chairman in 1998-1999 and chairman in 2000-2001. Recently, Tribe founded a company to provide consulting to GMP regulatory authorities around the world.