Travel Restrictions: Are Remote Audits an Option
One of the tasks required by GMP-regulations, but also as part of business continuity for Marketing Authorisation Holders, manufacturers and so called contract givers is to qualify their suppliers and contract acceptors. One important part of such a qualification process is the performance of an on-site audit. On the other hand, manufacturers and contract acceptors need to maintain their various certifications; GMP, ISO and others. Currently, because of the Corona crises, the fact that an auditor has to visit a site presents a potential risk to all persons involved or might simply not be possible because of travel bans.
However audits or audit reports are only one component of the supplier qualification process. In addition to the audit report, however, further information must also be consulted. For example, other available reports from authorities (like FDA warning letters), non-compliance reports from the EudraGMDP database, or information from the EDQM database. The type of service or purchased goods also plays a role in the overall evaluation, as does a consideration of transport routes.
All information should be included in a risk assessment, with the help of which one can not only plan audits and audit frequency, but also evaluate and qualify suppliers accordingly. Two systematic methods of risk analysis are often mentioned in this context, FMEA (Failure Mode and Effects Analysis) and HACCP (Hazard Analysis and Critical Control Points), which can be used here.
The ICH Guideline Q9 lists a number of points that should be considered during a risk based supplier qualification process. Those are also helpful during final and ongoing assessment and qualification:
- Existing legal requirements;
- Overall compliance status and history of the company or facility;
- Robustness of a company's quality risk management activities;
- Complexity of the site;
- Complexity of the manufacturing process;
- Complexity of the product and its therapeutic significance;
- Number and significance of quality defects (e.g., OOS/OOT results, unexplained discrepancies, recalls etc);
- Results of previous audits/inspections;
- Major changes of building, equipment, processes, key personnel;
- Experience with manufacturing of a product (e.g., frequency, volume, number of batches);
- Test results of official control laboratories."
If an onsite audit can not be performed, this risk-based supplier qualification process can be supported by a remote or virtual audit. Such an audit may be conducted through various communication channels such as video calls or other appropriate tools available. In fact an auditor could be sitting in the office or even at home conducting the audit.
Until today almost all of these audits have been performed on-site. From time to time auditors use questionnaires and check lists. But these are more or less a supplement for the overall qualification process. Most auditors are aware of the fact that there is limited benefit as compared to an on-site audit. The given feedback to questionnaires should later be confirmed in the audit.
Most of the benefits associated with on-site audits are tours of manufacturing facilities, warehouses, and laboratories. However a lot of time is spent with talking to personal, listening to explanations and document review. This could also be done in a remote audit.
What are the regulations saying?
When the rules and regulations were written and implemented nobody had thought about such a situation as a pandemic. Some of the rules are quite clear about auditing, for example:
Article 8 of EU-Directive 2001/83/EC
The application of a marketing authorization shall be accompanied by a "written confirmation that the manufacturer of the medicinal product has verified compliance of the manufacturer of the active substance with principles and guidelines of good manufacturing practice by conducting audits."
EU-GMP Guidelines Chapter 5 (Production):
5.29 "Audits should be carried out at the manufacturers and distributors of active substances to confirm that they comply with the relevant good manufacturing practice and good distribution practice requirements. (…) Audits should be of an appropriate duration and scope to ensure that a full and clear assessment of GMP is made; (…)."
EU-GMP Guidelines Chapter 7 (Outsourced Activities):
7.17 "The Contract should permit the Contract Giver to audit outsourced activities, performed by the Contract Acceptor or his mutually agreed subcontractors."
EU-GMP Guidelines Annex 16 (Certification by a Qualified Person and Batch Release):
1.7.3 "All audits of sites involved in the manufacture and the testing of the medicinal products and in the manufacture of the active substance have been carried out and that the audit reports are available to the QP performing the certification."
2.2 vi "Repeated audits should be performed in accordance with the principles of Quality Risk Management."
Recently MHRA has published their thoughts in a blog on "MHRA Good Practice (GxP) inspections during the COVID19 outbreak "1. MHRA itself will "focus on service continuity by using alternative approaches for routine regulatory oversight, such as office-based assessment and the sharing of information within the international regulatory network", as they stated in their news from 20 March "New arrangements for MHRA Good Practice (GxP) inspections due to coronavirus (COVID-19)2.
In the blog MHRA give further details how remote assessments could look like:
- organisations are asked to provide electronic copies of documents and other information for review off-site;
- teleconferences and e-mail will be used to follow up;
- necessary on-site portions of routine surveillance such as plant tours will be re-scheduled when travel restrictions are lifted;
- make use of available GxP information from mutual recognition partners and other collaborating regulators
MHRA does not directly allow remote audits for companies but acknowledges the fact that "organisations working in the manufacturing and supply of medicines may also need to adapt their procedures to maintain supply chain vigilance and supplier oversight as audits become difficult to schedule".
Even before the crises with the associated travel bans, PIC/S has started to develop a Guidance document on GMP Inspection Reliance to help Competent Authorities (CA) prioritising resources for GMP inspections. The document introduces a process for desk-top assessments of GMP compliance of facilities in other countries. It is a non-binding high-level guidance for ICMRA and PIC/S participating authorities, but the process can also serve as a model for the pharmaceutical industry for their risk based supplier qualification and current auditing activities.
Performance of a remote audit
So how could such a remote audit be performed? As with a "normal" audit, companies have to trust the auditor that their Intellectual Property rights will me maintained. This is already one of the reasons why auditors are not allowed to review documents in advance of many audits. In a remote audit, auditors have to get documents upfront or at least have access. Here, electronic reading rooms could be an option.
During the audit, discussions could be facilitated through technical presentations via virtual meetings. These discussions include interviews and comprise the same content of on-site audits with the exception of tours. A lot of time is dedicated to the review of documents. The audit agenda should include opening and closing meetings and allow sufficient time for discussions and interviews with Subject Matter Experts from all respective areas. Maybe it is even possible to conduct virtual tours of a facility to get a brief overview.
As with any other audit, in a remote audit, the auditor should be well prepared, ask appropriate questions, listen to answers, obtain objective evidence (facts) to confirm the responses, take notes and record findings. Communication skills and questioning techniques are of utmost importance. The auditor needs to understand what is actually happening and not assume what is happening. Therefor the auditor clearly needs to lead and select what he/she wants to see, and not focus only on what is presented.
It is recommended that every company documents the risk assessment undertaken and the outcome achieved by using a remote audit approach. This should also include what plans will be put in place when the current restrictions are removed to ensure a resumption of on-site audits in a timely manner.
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA and GMP.