January 2023 Pharma News Update

On May 31, 2022, the Medicines and Healthcare Products Regulatory Agency (MHRA) launched a consultation on “The future strategy for batch testing of medicinal products in Great Britain.” This consultation closed on July 26, 2022, and offered four options:

1. No import testing or UK QP certification/release for listed countries
   (This maintains the current position that has been in place since January 1, 2021.)
2. No import testing, but implement UK QP certification/release for listed countries
3. Full quality control batch testing, and implement UK QP certification/release for all non-MRA countries
4. Reduce the number of import tests and implement UK QP certification/release for all listed countries

On December 15, MHRA published the outcome of this consultation, which is that the government has decided to make permanent the approach of maintaining a list of approved countries for import that require no import testing or UK QP certification (i.e., option A in the consultation).

On November 30, 2022, the European Commission issued a new draft regulation on packaging to replace the current 1994 Directive 94/62/EC, which is intended to apply to all industry sectors. This draft seeks to introduce wide-ranging new requirements for the recycling and reuse of packaging materials to lessen their environmental impact.

The draft regulation proposes to mandate minimum amounts of recycled content that plastic packaging must contain. However, these requirements will not apply to the immediate packaging of human or veterinary medicinal products, or to the outer packaging in cases where the packaging has to “comply with specific requirements to preserve the quality of the medicinal product.”

The draft also seeks to set limits on the recyclability of packaging but gives a derogation for the immediate packaging of medicines that will apply until January 1, 2035.

EFPIA, the European research-based industry trade association, has expressed concern about the impact of the draft regulation on the pharmaceutical industry and warned that the 2035 recyclability deadline would be difficult to meet.

Lynne Byers, Global Managing Director of Pharmaceuticals and Dietary Supplements Consulting and Training at NSF, spoke with Healthcare Brew on the issue of shortages in the U.S. pharma industry. You can read the full article on Healthcare Brew here.

ICH Q13 - Continuous Manufacturing of Drug Substances and Drug Products received step 4 approval at the ICH Assembly on November 16, 2022. The text of the final version, which has not changed too much from that of the draft published in July 2021, is now available on the ICH website.

As the title states, Q13 is intended to apply to both drug/medicinal products and drug substances/APIs for chemical entities and therapeutic proteins. The principles may also apply to other biological/biotechnological entities. Continuous manufacturing (CM) applies to new products and the conversion of batch manufacturing to CM for existing products.

The guideline describes three different models of continuous manufacturing:

1. A combination of approaches in which some unit operations operate in a batch mode while others operate in a continuous mode
2. An approach in which all unit operations of a drug substance or drug product manufacturing process are integrated and operate in a continuous mode
3. An approach in which the drug substance and drug product unit operations are integrated across the boundary between drug substance and drug product to form a single continuous manufacturing process

The guideline uses the ICH Q7 definition of a batch for both drug substances and drug products. Based on this definition, the size of a batch produced by CM can be defined in terms of one of the following:

• Quantity of output material
• Quantity of input material
• Run time at a defined mass flow rate

Other approaches to defining batch size can also be considered if scientifically justified. The batch size can be defined as a range as well.

Section 3, Scientific Approaches, has the following subsections:

1. Control Strategy
2. Changes in Production Output
3. Continuous Process Verification

Section 4 is on Regulatory Considerations, and Section 5 is a glossary.

Part 2 of the guideline, which is the majority of the document, is a series of five annexes, as follows:

1. Continuous Manufacturing of Drug Substances (Chemical Entities)
2. Continuous Manufacturing for Drug Products (Chemical Entities)
3. Continuous Manufacturing of Drug Substances (Therapeutic Proteins)
4. Integrated Drug Substance and Drug Product Continuous Manufacturing
5. Perspectives on Managing Disturbances

The requirement in EU Regulation 536/2014 (Clinical Trials Regulation), Annex VI for the immediate packaging of investigational medicinal products (IMPs), to always have to carry an expiry date for the product has been controversial since the regulation was first published in 2014. The problem with this requirement is that product stability data is often limited when clinical trials commence, and it is fairly common for the expiry date of IMPs to be extended during their use in a trial as additional stability data becomes available. The industry has argued that the act of relabeling IMPs already in use in a clinical trial introduces unnecessary risks, such as damage caused by opening outer packaging that can cause risks to the product and to the potential for unblinding a trial.

On September 6, 2022, the European Commission adopted a revision to the Annex VI label text requirements. The commission stated, “The aim is to prevent additional safety and quality risks associated with the relabeling procedure and the need for more frequent resupply, which may lead to delays in clinical trials.” This amendment to Annex VI is fully applicable from December 5, 2022, 20 days after it was published as delegated Regulation 2022/2239 in the Official Journal of the European Union on November 15, 2022.

The revision allows the expiry date to be omitted from the immediate container in specific situations:

• When the immediate container will remain with the outer container
• When the immediate container is small and has limited space for label text

In both cases, the immediate container must be provided with an outer container that has the expiry date printed on the label.

This revision will make management of expiry updates significantly easier whenever the immediate container is packaged and supplied with a labeled outer container; it will likely be possible for the sponsor to justify the omission of the expiry date from the immediate container.