1. Falsification: the general framework
The first case of falsified medicinal product occurred in 1937 when an American pharmaceutical company, for increasing its sale-volumes, used di-ethylenglycol (a toxic solvent) to manufacture a syrup containing sulfanilammide and more than 100 people, including a lot of children, died.
The company was charged of “misbranding”; this term is usually used to mean “inaccurate and false labelling”.
The directive 2011/62/EU introduces the definition of falsified medicinal products and underlines that the mislabelling of a medicinal product and its characteristics must be intentional to defined a medicinal product as falsified; on the contrary a no-intentional mislabelling is caused by some problems occurred during the production process; therefore the counterfeiting is properly classified as one of the criminal activities.
Generally speaking, the production of the falsified medicinal products is usually associated with the brainchild of a production carried out in unsuitable premises and/or taking place in workshops neither authorised nor controlled by the competent authority. On the other hand, the production sites legally authorized are subjected to periodic inspections performed by the competent authority, that through paper-based and on-site inspections ensures that the production is carried out in compliance with the standards of the Good Manufacturing Practices (GMP): GMP are the quality standards internationally established and recognized, that all the manufacturers are requested to meet.
Unfortunately, that is not always the case.
But what does GMP mean?
2. An Italian case study
A recent counterfeiting case was managed by AIFA (Agenzia Italiana del Farmaco, the Italian RA) in cooperation with the Italian police force, Carabinieri NAS; this case highlighted how the on-site inspections can be an effective method for detecting deficiencies related to GMP non-compliance.
In 2011, AIFA received an alert regarding the counterfeiting of a medicinal product for adults, children and infants; this medicinal product was manufactured and distributed by an Italian manufacturing site.
In the preliminary phase, AIFA in cooperation with Carabinieri NAS, on the basis of the data reported in the alert report, sampled some batches marketed in Italy; the samples were sent to the Italian official control laboratory OMCL (Istituto Superiore di Sanità), in order to test the real composition and state if the alert was -founded.
OMCL found a real counterfeiting, therefore AIFA and Carabinieri NAS performed some on-site inspections between the period of June 2012 and September 2013 in order to verify the materials management, the production’s orders, the laboratory test records, the certificates of analysis and the batch releases of the falsified lots.
In June 2013, the inspections outcomes after two on-site audits led to the arrest of three managers of the company, as it was observed an evident counterfeiting and the issuance of false analytical certificates concerning the composition of the medicinal product; AIFA has later suspended the production authorization of the manufacturing workshop where the falsified medicine was manufactured.
Following further investigations, serious GMP deviations were also found in other production workshops. It was observed the lack of a quality assurance system and quality control system (this deviation was classified as critical by the inspectors team according to the European rating) as well as many other deviations concerning documentation and records. For those deviations AIFA issued a suspension of the manufacturing authorization of the manufacturing site as such as and, at the same time, AIFA banned the use of medicines already delivered on the market; a sampling of all batches manufactured in the last three years was also requested to NAS in order to protect the public health.
3. The role of the GMP inspector
Even though one single case is not exhaustive and cannot consider all possible control strategies, this case study is a good example for thinking about how to act when there is a suspected falsification in a pharmaceutical company.
A GMP inspector has to verify the correct implementation of GMP standards in a pharmaceutical plant and he/she has access to data and documents that can allow, in some cases, to assess any suspected falsification; hereafter some examples of inspections strategies based on paper documents.
In case of suspected absence of the active pharmaceutical ingredient (API)/excipient and/or their replacement with other ingredients it is necessary to compare the deliveries and the quantities of the incoming materials with the ones listed in the production orders, in order to verify if the purchased quantities are comparable with the quantities required for the batch production.
It should also be suitable to verify the traceability of the analysis performed for API/excipients approval and to verify the raw data and the calculations.
If the analytical results appears to be anomalous or the data do not meet the specifications (out of trend and out of specifications), it is necessary to verify whether an internal investigation was performed and whether the root causes was identified; it could also be necessary to verify whether some corrective and preventive actions (CAPA) were implemented to remove the problems.
In case of suspected manipulation of graphics and/or laboratory data it is necessary to verify the sharing of responsibilities within the QC laboratory and the method of graphic elaboration (manually or electronically). In case the laboratory is equipped with information technology, it is necessary verify that the challenge tests were rightly performed and whether the analytical data are displayed only in reading and not in writing; moreover all requirements for computerised system validation have to be in compliance with the GMP standards.
This last kind of counterfeiting is becoming more and more frequent in the Indian manufacturing sites, as the American FDA (Food and Drug Administration) highlighted. The US agency settled three bureaus in India in order to inspect the API manufacturers; a lot of warning letters (the so called “483 modules” or no-compliance modules) were issued following the inspections in India and in most cases the 483 modules were related to data manipulation.
In case of suspect that medicinal products to be destroyed have been relabelled in order to be put on the market, it is necessary to compare the shifts in the packaging department with those in the production department and to verify the quantities of the medicinal products manufactured with those packed and stored.
4 – Conclusions
Of course, as above described is a useful starting point for investigations and audits, even if it is far from being an exhausting list including all possible inspection strategies.
Although each strategy has to be studied case-by-case in order to be modified and improved during the inspection according to the evidence, we can argue: “to control what is done with respect to what should be done” and “anything that is not documented is considered as not done”.
The more difficult inspection case to manage is surely the reporting’s falsification.
As already established in September 2012 during the Inspectors Working Group of the European Medicines Agency (EMA), the term falsification in GMP language means: … any wilful misstatement, misrepresentation, manipulation, adulteration, rewriting, hiding, replacing of quality related documents, materials, activities or buildings in order to give an item the appearance of GMP compliance when this is not the case, as these facts are not isolated and/or known, approved/supported by management (e.g. false analytical data checked and approved).
Consequently, if on the one hand the GMP requires that all the activities are documented and that in some cases it is possible to trace back to illegal activities from the documentation’s evaluation, on the other hand when it is the report itself to be falsified it is difficult to detect possible illegal activities.
Regarding that, the personnel has to be technically trained and be aware of its responsibility. It can be helpful to remind what a FDA investigator said during a GMP inspection addressing to the manufacturing operators: “Remind that in the future you or your family might need what you are manufacturing now”.