Ken Maltas – Director of R & D Ian Buck – Director of Sales & Marketing – ThermoSafe Europe
On 7th March 2013, the new EU GDP guidelines were finally released ending much speculation and uncertainty. The six month grace period passed as quickly as expected and since 8th September 2013 the EU GDP have been in full force with regular inspections now occurring both internally and from regulatory authorities.
The updates were heralded as an unprecedented change for the biopharmaceutical industry and all those involved in their supply chain networks. The main changes came in the shape of the requirements for temperature controlled distribution apply not only to cold chain (+2°C to +8°C) but also to room temperature/ambient products. Secondly, the guidelines have increased emphasis on risk based approaches.
Ambient products, or those that are stable at room temperature, are now under the same scrutiny during distribution as their cold chain counterparts. In the eyes of the EMA, it’s no longer sufficient to assume ‘room temperature’ is uniform throughout geographical zones and that medicinal products will be kept within their stability limits during the whole supply chain. Most organisations do have at least some competency in temperature controlled supply chain operation through their cold chain portfolios and there is a strong, specialist infrastructure in place. However, this change to the way all pharmaceutical products are distributed is having a huge impact on the industry, not to mention the added cost for the manufacturer.
So, what is the regulator’s definition of room temperature or ambient? There are no defined temperature limits as there are for cold chain, instead it relies on product stability data. GDP chapter 3.2 states that ‘premises must be designed or adapted to ensure the required storage conditions are maintained’. The required storage conditions are the temperatures stated on the label. Subsequently, chapter 5.5 states that ‘warehouse operations must ensure appropriate storage conditions are maintained.’
The MHRA states that there is no real definition of “controlled room/ambient temperature” – it is whatever the requirements of the specific products stored are.
Outside of the EMA, the United States Pharmacopoeia does clearly define ‘controlled room temperature’ as “a temperature maintained thermostatically that encompasses the usual and customary working environment of 20°C-25°C, that results in a mean kinetic temperature to be not more than 25C and that allows for excursions between 15°C and 30°C…”
The dichotomy between the need for compliance and ensuring patient safety is finely balanced with minimising the cost burden of added supply chain requirements. As such, it is even more crucial to understand the inspection process and the regulators’ expectations so that inspections may take place with little disruption and minimal compliance escalation.
We must first consider the Principle of Chapter 9;
‘It is the responsibility of the supplying wholesale distributor to protect medicinal products against breakage, adulteration and theft, and to ensure that temperature conditions are maintained within acceptable limits during transport. Regardless of the mode of transport, it should be possible to demonstrate that the medicines have not been exposed to conditions that may compromise their quality and integrity. A risk based approach should be utilised when planning transportation.’
This is the introduction to what is arguably the biggest change the industry has seen in years but the industry must now come together to develop a best practice when approaching these new requirements to ensure compliance.
We will now jump to the inspections themselves; preparation requirements, expectations on the day and post inspection follow up and obtaining the all-important GDP certificate.
For the purpose of clarity, we will define GDP in the context of inspections. GDP requires that medicines obtained from the licensed supply chain are consistently stored, transported and handled under suitable conditions, as required by the MA or product specification.
The MHRA are a leading regulatory body in the EMA, they state that they “carr[y] out inspections to check if distribution sites comply with GDP. Inspections are carried out periodically based on risk assessments. Overseas manufacturing sites are also inspected.”
There are two main approaches when deciding who and where to inspect, the risk-based compliance programme and triggered inspections. Inspections under the risk-based programme relate to a risk rating or score, which every manufacturer and wholesaler has, it is the basis for prioritising inspections. The notification period, according to the MHRA is thus “You will be told about these inspections in advance, although under the short-notice inspection programme we may send little or no notification.”
The risk score is based on what activities take place on site and the number and type of deficiencies observed. It’s important to note that you cannot appeal against your rating. These will be the types of inspection we will examine most closely during this article.
Triggered inspections are undertaken on a more critical basis. Regulatory authorities may inspect you if they are informed about possible GDP breaches by:
- a whistle blower
- other internal departments
- another regulatory authority
You will probably receive little or no notification of these inspections in advance.
It is important to note that a GDP compliance report must be completed before a routine inspection. An example of a compliance report is shown below from the MHRA’s website
- GDP compliance report (MS Word Document, 331KB)
2. The Inspection
No one inspection is alike making it challenging to describe a typical inspection or gauge the inspectors’ expectations. However, there are certain basic procedures you can expect from the inspection team:
- interview of relevant personnel
- review documents
- conduct site visits
Site visits may include any facility or process involved in producing, purchasing and distributing medicines, so thorough preparation and communication is essential.
Furthermore, you may be asked for additional documentation and samples for testing during the inspection, the focus may also change if serious non-compliance is suspected.
There will, however, always be a closing meeting, where you will have the opportunity to interact with the inspection team. They will provide feedback, discuss any deficiencies and agree upon timelines for corrective actions. This is where you will receive the grading of your inspection and how serious any deficiencies might be.
Deficiencies found during inspections are graded at 3 levels; critical deficiency, major deficiency and other. Other is defined as ‘A deficiency which cannot be classified as either critical or major or there is not enough information to classify it as critical or major but which indicates a departure from good manufacturing and distribution practice.’
3. Post inspection
There are three potential courses of action that will occur post inspection.
Firstly, a response is required to the post inspection letter to confirm proposed corrective actions and dates for completion. If the inspectors accept it, you will receive a GDP certificate with your inspection report
Secondly, if compliance is found to be poor but has not hit the threshold for regulatory action the other option is to go through the compliance escalation process. The aim of this process is to support companies to achieve compliance before regulatory action becomes necessary.
Once the escalation process has been completed you are returned to the routine risk-based inspection programme. However, there is still risk of regulatory action if the necessary improvements are not made.
The compliance escalation process consists of:
- making recommendations on close monitoring of compliance improvement work through inspection
- meetings and correspondence with company senior management clearly outlining the consequences of continued non-compliance
Thirdly, and the most isolated course of action, is a suspended license. If the inspector finds critical deficiencies or that agreed action plans from previous inspection deficiencies have not been resolved they will contact the Inspection Action Group (IAG). The IAG can refuse or suspend licences, increase inspection visits or request a meeting with the licence holder.