Inside PIC/S: Top GMP Deficiencies

The FDA makes its inspection results available to the public as required by the Freedom of Information Act. However, very rarely are inspection results of European supervisory authorities accessible in any public domain, except for the periodic publication of regulatory and GMP inspection analysis by the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) and the EMA. The Pharmaceutical Inspection Cooperation Scheme (PIC/S) also has never published the inspection findings of its Participating Authorities.

PIC/S develops and promotes harmonized GMP standards and guidance documents; trains competent authorities, in particular inspectors; assesses inspectorates; and facilitates the cooperation and networking for competent authorities and international organizations. PIC/S celebrated its 40^th Anniversary in 2011 and currently has 40 members across six continents.

Background

In November 2011, PIC/S held a workshop designed by the South Africa/Medicines Control Council (MCC) on the similarities and differences in the top 10 deficiencies cited by PIC/S members. South Africa MCC was the first African Participating Authority to host a PIC/S seminar. The authors were invited to design, formulate, and conduct the workshop to help share inspectors' experiences and lessons learned. The workshop, part of a larger PIC/S seminar on Good Pharmaceutical Inspection Practices also served to help document the experiences and lessons learned from performing GMP inspections.

Methodology

Before the workshop, a questionnaire was designed and sent through the PIC/S Secretariat to invite all PIC/S Participating Authorities and PIC/S applicants to share inspection data. The questionnaire requested the following information:

• Top 10 of the most frequently cited categories of GMP deficiencies within a defined period (i.e., the last period for which data was available). Participants were asked not to differentiate between critical, major, and other deficiencies. Participants also were asked to add for each category the percentage related to the total number of deficiencies in the period under consideration.

• The top 5 of the most severe GMP deficiencies (critical and/or major) within a defined period.

The scope of the survey was defined for GMP inspection findings of finished product dosage form manufacturers, including medicines for veterinary use and investigational medicinal products, where applicable. Inspections of API manufacturers were out of the scope of this survey.

Because PIC/S does not have a formal list of categories for GMP deficiencies, the UK's MHRA model was used as a standard template. The template was provided with the questionnaire to the participants. A total of 56 categories of deficiencies were defined and divided into 8 groups. However, flexibilities were given to PIC/S Participating Authorities and applicants which might wish to use their own model of deficiency categories.

Results

Thirty-three out of 39 PIC/S Participating Authorities responded (85%). Seven out of 9 applicants to PIC/S responded (78%). The top most frequently cited categories of GMP deficiencies were:

• Documentation—manufacturing (24)

• Design and maintenance of premises (22)

• Documentation—quality systems (elements / procedures) (20)

• Personnel issues—training (19)

• Design and maintenance of equipment (18)

• Cleaning validation (14)

• Process validation (14)

• Product quality review (14)

• Supplier and contractor audit (13)

• Calibration of measuring and test equipment(12)

• Equipment validation (11).

The total number of deficiencies per group of top 10 most frequently cited deficiencies were:

• Production (99, or 24%)

• Quality system (82, or 20%)

• Quality control (59, or 14%)

• Premises and equipment (58, or 14%)

• Validation (52, or 12%)

• Personnel issues (34, or 8%)

• Materials management (29, or 7%)

• Regulatory issues (5, or 1%)

The top most severe GMP deficiencies were (see Figure 1):

• Design and maintenance of premises (15)

• Contamination, potential for (chemical, physical, microbial) (12)

• Design and maintenance of equipment (11)

• Sterility assurance (9)

• Batch-release procedures (9)

• Process validation (9)

• Cleaning validation (8)

• Investigation of anomalies (7)

• Documentation—quality systems (elements/procedures) (7)

• Regulatory issues—noncompliance with marketing authorization (5)

• Documentation—manufacturing (5).

Figure 1: Most severe cited GMP deficiencies.

The total number of deficiencies per group of the top most severe deficiencies were (see Figure 2):

• Production (44, or 27%)

• Quality system (32, or 20%)

• Premises and equipment (28, or 17%)

• Validation (22, or 14%)

• Quality control (14, or 9%)

• Regulatory issues (9, or 6%)

• Materials management (8, or 5%)

• Personnel issues (5 or 3%).

Figure 2: Top most severe deficiencies by group.

Analysis and outcome

For a comparison between groups (most frequently cited deficiencies and most severe deficiencies), please see Table I. In general, PIC/S Participating Authorities use different GMP deficiency classification models in the following ways:

• Some use the model developed by the UK MHRA.

• Some use a model based on the Chapters and Annexes of the PIC/S GMP Guide.

• Some have their own classification methodology.

• Some members do not have formal analysis trending on GMP deficiencies.

Table I: Comparison between summary of groups.

There is no significant differences among regions in terms of the way GMP deficiencies are inspected and cited. There is, however, a correlation between the most frequent GMP deficiency classes and the most severe GMP deficiency classes. This implies that there is harmonization across all PIC/S Participating Authorities.

The 10 most frequently cited GMP deficiency classes means that the industry is weak in these areas and inspectors should communicate more effectively and efficiently to the industry on such weaknesses.

Different level of details of the deficiency classes model was noted. A model that could be accepted by most PIC/S participating authorities may be required going forward.

Some of the most frequently cited GMP deficiencies may due to ease of detection as part of the inspection process (e.g., documentation–manufacturing was the most frequently cited deficiency). The design and maintenance of premises ranked second, which may relate to aged buildings or saving on maintenance budget.

Recommendations

The following items were recommended and presented to all participants in November 2011.

Data trending. Some agencies did not conduct such GMP deficiencies analysis/trending exercise over a defined period of time. It is recommended that all PIC/S Participating Authorities should implement such an exercise for analysis and trending within a defined period (e.g., annually) and subsequently, for trending across different years.

Common model. It would be useful for all PIC/S Participating Authorities to use a common GMP deficiency classification model. PIC/S should consider developing a PIC/S common GMP deficiency classification model.

Annual reviews. It may be useful to adopt this exercise and discussion on common GMP deficiencies throughout industry at PIC/S level on an annual basis. Data from each PIC/S Participating Authority could be collated for analysis. The collated output may be used to identify common specific GMP areas to be focused on for training and to help pull resources together within PIC/S.

Conclusion

There is a correlation between the most frequent GMP deficiencies classes and the most severe GMP deficiencies classes. This correlation implies that there is harmonization across all PIC/S Participating Authorities.

Hans Smallenbroek is the former PIC/S Chairman and a senior GMP Inspector in The Netherlands with the Health Care Inspectorate. Boon Meow Hoe is a senior GMP Inspector in Singapore with the Health Sciences Authority.

The topic of this article will be presented during the PDA Europe-PIC/S workshop 2012, taking place May 9–10, 2012 in Geneva, Switzerland.