API: reshoring and regulatory complexity


Pandemic emergency hit vigorously pharmaceutical production, by highlighting both the strenghts and weaknesses, uncovering future challenges. Two of theese latter are the main topic of the AFI Symposium session, on June 10th, 2021, for API production: relevant aspects for an operative and strategic management. The first of them is about the importance of active pharmaceutical ingredients (API) in the scope of European pharmaceutical strategy; while the second is about production management (with all the fulfilments connected to it), during a crisis.  

Aschimfarma and active pharmaceutical ingredients

Active pharmaceutical ingredients is a strategic field that could have a great development in the next few years, because of actual facts.  

Around this statement, Paolo Russolo, Aschimfarma President, start the discussion in this AFI Symposium session 2021.

Aschimfarma includes 48 Italian and multinational enterprises. Theese are companies invoicing 2 billions €/years, that are involved in active ingredients production, thanks to industrial processes, characterized by an incredible technology. In this field, Italy is at the top in the word market since it exports >85% of its production in >90 countries.

European pharmaceutical strategy

In such a depiction, active ingredients manufacturers are in a key position to assure medicines availability and to tackle deficiencies. However, Asian countries competition determined a weakening in the active pharmaceutical ingredients, in Europe, in previous years, together with an increasing dependency from the availability of the ready-to-deliver medicine.

While in the past, European role in pharma production was globally crucial, now, supply chain depends for more than 74% from supplies coming from Asia. Theese numbers exposed UE to remarkable risks, especially in the first phases of pandemic.

European pharmaceutical strategy identifies a way for healthcare industry autonomy, among the key-goals. To help with this purpose, the Commission launched a target initiative to identify the causes of vulnerability of pharmaceutical supply chain and a solution proposal, in order to increase resilience.

Drugs reshoring and active ingredients in Italy

According to Aschimfarma, European health autonomy will depend largely on its ability to maintain and develop its industrial base, and of course, to invest in innovative and sustainable technologies”  with this in mind, together with some other Italian supply chain famous associations (Egualia and Farmindustria), Aschimfarma presented the medicines and active ingredients reshoring project in Italy, coordinated by ALISEI Cluster.

New regulatory fulfilments

From one side, the urgency of strengthening this field is getting more intense day by day, on the other, regulatory fulfilments keep increasing.

New requirements in quality management lead to a reorganization in operative modalities, which impacted on production structure.

From this point of view, the main regulatory aspect is the one of the application of the risk analysis in the facilities solution choices, since it imposes a validation, both for quality (dedicated or multi-purpose facilities) and for safety (containment), but especially about critical API.

Risk analysis

Last regulatory updates about active ingredients production introduced risk analysis in the management of the facilities choices.

Producers fulfilments include the submission to documents attesting that new production will not impact on production, and vice versa. Luisa Torchio, member of the Quality/Normative Aschimfarma Commission, explains that the intent is to promote a balance between authorized productions and those that still have to be authorized.

Risk analysis is regulated by the May 28th 2018 Health Ministerial Decree, which repealed the 27th May 1999 Decree, and acknowledges its core in the Risk Evaluation Paper.

The special requirement

The regulatory introduced the concept of special requirement, a feature associated to the product whose authorization is requested. The special requirement concerns sterilized products, antibiotics, radiotherapies, living cells, cytotoxic components or any substance associated to particular risks.

To request the authorization of a new space for production of sterilized active substances, biologics or tissues derived, organs or human/animal fluids (even with clinical trial purpose), the producing company must apply with 392/01 Model andsending the required papers, apart from 031/04 Model.

Risk assessment for critical API

For critical substances, risk assessment must be entirely introduced, which means that it cannot be presented just by summary (as requested for substances not included in this cathegory). It has to be drafted by the Qualificate Person encharged.

All the risk factors have to be considered: 

  • solubility
  • impurity profile
  • nature of the reagents to use
  • facility feature
  • pharmacological activity
  • toxicology profile
  • drug type and somministration modality
  • dosage
  • therapeutic usage (eg. If it is for pediatric use)
  • special requirements
  • other parameters (such as staff safety and environmental risk).

Toxicology profile

Toxicology profile is defined by the concept of Permitted Daily Exposure (PDE). This is a parameter initially used to quantify the staff safely level, and now it has become an important criterion to establish the molecule-associated risk.

The lower is its value, the higher is its risk, and therefore it could be required additional papers.

The toxicology profile is established by a toxicologist.

The facility choice

The evaluation outcome establish whether the product is adequate to be manufactured in a multi-purpose facility (in order to respect the balance) or if there is the need for a dedicate structure for that production

Of course, the constraints imposed by the regulatory, for the special requirements of active ingredients that have not been authorized yet, are higher than the authorized ones.

COVID-19 emergency

COVID-19 emergency represented a great challenge for regulatory agencies.

Because of the limitations imposed by pandemic, health authorities established remote inspections modalities, that allowed to continue with checking praxis, in order to safeguard the drugs production and distribution activity, and comply to the public health protection instances.

Regulatory flexibility

In order to manage critical stages during pandemic, the drug agencies recognized the need for a certain regulatory flexibility that could not affect the medicines efficacy and safety standards. Marisa Delbò (AIFA) will talk about this during the AFI Symposium 2021 in the active ingredients production session.

In the remark “Questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic“ published on April 10th 2020, several regulatory flexibilities appear. Among them, GMP validity certificates automatic extension prolonged untill 2021, postponing inspections, except in particular cases.

The very same paper introduced the concept of “distant assessment” too.

What do we mean by “distant assessment”

Distant assessment concerns compliance evaluation of a production site to GMP/GDP principles, even with no physically present inspectors.

In theory, this could be applied to any sites, but actually it is only applied for simple production. In any case, on-site inspections is just postponed to the end of pandemic.  

Remote inspections have gradually applied EMA guidelines: beforehand, it provided just a papers presentation, and then, it added a virtual tour, untill the distant assessment itself.

When does the distant assessment could be stipulated?

In the pre-evaluation phase it is established whether the specific case is appropriate for distant assessment practice.

Marisa Delbò reminds what the evaluated parameter during this stage are:

  • manufactured product criticality
  • site complexity
  • risk level
  • type of product
  • possible deficiency risk

Even on-site production aspects are included:

  • previous inspection history
  • detected deviations number and level
  • evenctual penalties or claim for failing in complying to the GMP rules
  • transmission of incorrect information to the agency.

Lastly, we have to consider those factors that are about the inspection modalities themselves, such as the effectiveness of compliance remote inspections, especially where the production site in located abroad.

It evaluates the presence of the inspection report, drafted by another regulatory agency, that the inspected company has mutual recognition with (eg. FDA or Health Canada).

Distant assessment fulfilments

If the place is considered adequate according to the remote inspections, a paper submission is the requested to the company. Afterwards, they will send the request for availability to the manufacturer for distant assessment and, in case of positive response, they will also send pre-inspection papers that they had not been sent before.

At the end of the remote inspection, the encharged team will anyway end up establishing that there is still need for an in-site inspection.

Remote inspection challenges

As dr. Delbò specified, the main challenges are about digital communication difficulties.

They must verify connection to be stable and lead by means of safe digital platforms and staff must be qualified for their use.

Furthermore, papers exchange must be properly organized.

One of the main limitations for remote inspections, is the impossibility to smell the air, which could help in recognize potentially risky processes. And of course, the impediment to interpret body language: interlocutors are not always visible, and that is undoubtedly penalizing.

There are also some problems connected to the distance itself when the production site il located abroad. The time zone could constraint videocalls to be scheduled at very uncomfortable moments.

All theese aspect could elongate the inspection duration, which could be prolonged for even 3-4 months , a lor more than any in-site inspection.

AIFA remote inspections

Since March 2020, the Italian Drug Agency (AIFA) conducted 16 distant assessment in workshops with medium-low risk (non-critical productions) or in workshops producing drugs used in COVID-19 emergency.

All the inspections had positive outcome, except for a single one, because of the company waiver (5 inspections are still in the follow-up stage).