In February of this year the US Food and Drug Administration (FDA) released a 27-page draft guidance, ‘Quality Considerations for Continuous Manufacturing’. The FDA is seeking to encourage the adoption of continuous manufacturing as the agency believes it can improve consistency and potentially reduce the risk of drug shortages.

In this draft guidance, the agency provides insights on its current stance on critical quality issues in NDAs, abbreviated NDAs (ANDAs), supplemental NDAs, and ANDAs for small molecule, solid oral drug products produced using continuous manufacturing methods. However, while some of the recommendations made in the guidance may apply to other types of pharmaceuticals, the FDA states that it does not provide recommendations for biological products.

For several decades, manufacturing industries, from petroleum to food processing, have employed continuous manufacturing processes. In stark contrast, pharmaceutical companies have been much more conservative to adopt new continuous manufacturing approaches and the majority have opted to remain with traditional production methods, moving materials through each step of the manufacturing process in single large batches. Continuous manufacturing processes produce drug ingredients or finished drug products continuously, without having to wait for each batch to finish before commencing a new batch.

The Office of Pharmaceutical Quality (OPQ), which is located within the Centre for Drug Evaluation and Research (CDER), has used its Emerging Technology Program to encourage and support companies in implementing continuous manufacturing. Drugmakers may communicate with the FDA to understand and navigate through scientific and policy issues that might arise with emerging continuous manufacturing technologies. The guidance document released by the FDA provides quality system considerations for companies seeking to adopt continuous manufacturing.

Within the guidance document, the agency advises each manufacturing site to evaluate their quality system design to determine if modifications are required to support continuous manufacturing. Such considerations include equipment qualification and maintenance, in-process material diversion strategy including criteria for rejecting batches, handling of unplanned process disruptions which occur, raw and in-process material investigations, and more.

Dr Janet Woodcock, Director of FDA’s CDER, commented, “Right now, manufacturing experts from the 1950s would easily recognize the pharmaceutical manufacturing processes of today. It is predicted that manufacturing will change in the next 25 years as current manufacturing practices are abandoned in favor of cleaner, flexible, more efficient continuous manufacturing.” The FDA stated that potential benefits of continuous manufacturing may include:

Integrated processing with fewer steps

• Reduced manual handling, increased safety
• Shorter processing times
• Increased efficiency

Smaller equipment and facilities

• More flexible operations
• Reduced inventory
• Lower capital costs, less work-in-progress materials
• Smaller ecological footprint

On-line monitoring and control for increased product quality assurance in real-time

• Amenable to Real Time Release Testing approaches
• Consistent quality

‘Quality Considerations for Continuous Manufacturing’ draft guidance document examines three stages of process validation: process design, process qualification, and continued process verification. Given that continuous manufacturing systems involve many variables, the three stages outlined by the FDA are imperative to focus on if companies are seeking to improve operational and quality efficiency. Adopting continuous manufacturing is highly technical and incurs great costs. However, taking into account the possible benefits and long-term savings of continuous manufacturing, this transition may be worthwhile for many companies due to fewer interventions and the expectation of increased quality. The draft guidance document can be viewed here.

To discuss this further or any HiTech Health services you can contact us today.

References

1. FDA, Office of Pharmaceutical Quality 2018 Annual Report, available at https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM632265.pdf; see also Statement from FDA Commissioner Scott Gottlieb, M.D., and Janet Woodcock, M.D., director of the Center for Drug Evaluation and Research on FDA’s modern approach to advanced pharmaceutical manufacturing, Feb. 26, 2019, available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632043.htm.
2. FDA, Office of Pharmaceutical Quality 2018 Annual Report, available at https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM632265.pdf.
3. FDA, Quality Considerations for Continuous Manufacturing, Draft Guidance, February 2019, available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM632033.pdf.

The UK life sciences industry contributes over £30bn to the UK economy, and supports almost half a million UK jobs. The UK is a leading centre of medical research and biopharmaceutical innovation, and is at the forefront of the drug development and approval process in Europe. With the date of Brexit less than six months away, the UK pharmaceutical industry is increasingly focused on taking actions to ensure the continuity of supply of their products to patients during this transition, and to ensure their companies’ long-term access to markets and customers throughout Europe.

On March 29th 2019, the UK becomes a “third country” from the EU, and will transition to a new relationship. The impact of Brexit on the pharmaceutical industry continues to evolve, but UK companies who develop or supply product for sale or clinical use in the EU/EEA will likely face regulatory complexity, added costs, disruption in their supply of raw materials and finished-goods, and risk long-term loss of revenue and customers.

The European Medicines Agency (EMA) is currently headquartered in London, but as a consequence of Brexit will be transitioning to a new home in Amsterdam by January 2019. Post-Brexit, slower marketing approval of drugs in the UK is expected regardless of what deal, if any, is implemented. The UK government is hoping to retain an arrangement almost identical to the current situation for drug approvals. However, the European Union has indicated they will not accept such an arrangement following the departure of the UK from the union. With uncertainty remaining over the final state, as well as the likelihood of a final agreement that is inferior to the current state, it is unsurprising that drug approval and regulatory issues are posing major concerns for pharmaceutical companies.

What we know so far is that, after March 29th 2019, the following will occur:

• Marketing Authorisation (MA) holders, if held in UK, will have to be transferred to an EU or EEA country.
• Each consignment of UK-manufactured Active Pharmaceutical Ingredients (APIs) to the EU/EEA needs to be accompanied by an MHRA certificate of conformation to EU GMPs.
• Each batch of drug product will need to be released by a QP within the EU/EEA.
• Pharmacovigilance will need to be managed from a location within the EU/EEA.
• There will no longer be unrestricted transport of goods between the EU and the UK.
• Expect added paperwork, transport delays, and likely customs duties.

HiTech Health has developed a range of strategies to enable healthcare companies to successfully navigate Brexit. Our support will be tailored to your company’s needs. Please email us at info@hitech-health.com to request further information on the range of services we can provide.

A BioPharma product may go through a scaling process multiple times during its life cycle. The product owner may decide to either select a Contract Manufacturing Organisation (CMO) to manufacture a product or manufacture in-house. The first batches manufactured in a small-scale laboratory may be scaled-up to produce larger batches for clinical trials. Following this, a further scale-up process is typically needed to progress to pilot-scale and ultimately to full-scale commercial production scale for market entry. Quantities manufactured during the early laboratory development are typically 100 to 1,000 times smaller than the amounts produced during the pilot and final production stages. It is essential that an organisation places emphasis on making optimal strategic decisions from an early stage in the scale-up process to facilitate successful product entry to the market. Here are four key considerations during the scale-up process:

1. Are you choosing the best location?

With global economic and political uncertainties, as well as ever-changing regulatory environments, it is imperative to ensure the optimal location is selected to manufacture your products on a commercial scale. Irrespective of whether products are being manufactured in-house or outsourced to a CMO, selecting a problematic manufacturing location can have a detrimental impact on an organisation. Transferring from laboratory-scale to commercial production also brings to the fore the area of logistics that may not have been previously considered in-depth. Especially with temperature-sensitive drugs and biotechnologies, the expense of transporting between manufacturing sites and from manufacturing to market could be very significant and pose extra risks to supply chain security.

2. Are you selecting the right partners?

Scaling-up to commercial production typically means new partnerships will be formed to support the manufacturing and distribution of your products. Partners may be required to support several aspects of the production, such as manufacturing, packaging, analytical testing, stability testing, transportation and/or distribution. Start by assessing whether your partners have the right expertise and capabilities to meet product requirements. You may want to prevent your partners from further outsourcing activities they cannot complete themselves as this can bring an extra layer of complexity and new challenges to market entry. If you chose to select a CMO for commercial production, have clearly defined agreements in place that outline quality, safety and efficacy expectations, as well as a transparent legal and financial breakdown. Critical quality attributes for the product should be identified and agreed upon internally before being shared with your partners. How will you communicate with your partners and ensure everyone is streamlined?

3. Is the required equipment available?

When it comes to biopharmaceutical scale-up, the ultimate goal is to mass-produce a product that is consistent in quality, safety and efficacy for supply to patients. Assessing and confirming that your processing equipment is fit-for-purpose is essential to ensuring the scale-up process is efficient and robust. The end-to-end scale-up process must be validated every time the process is scaled-up by a factor of 10 or more according to the FDA’s Scale-Up and Post-Approval Changes (SUPAC) guidelines. It is recommended that the team involved in scaling-up a new product(s) from clinical batches to full scale commercial production assess the equipment intended to be used, including line capacity, speed, size and more. Calibrated equipment that has been qualified for use will help with ensuring a smooth transition during the scaling process. If outsourcing to a CMO, will the equipment be shared with other products? If so, what impact may this have on your product? Employing equipment that excels at yielding tightly controlled particle size distributions (PSDs), regardless of batch sizes, is highly beneficial in comparison to the use of unsuitable equipment that does not truly meet product expectations and may result in quality concerns and yield loss.

4. Have you assessed ‘Robustness’ of the product, processes and systems?

During small-scale laboratory production, you may have carefully refined processes so they are efficient, repeatable and high quality. Are these processes scalable? A key consideration here is the ability of a process to demonstrate acceptable quality and performance, while tolerating variability in inputs. Before scaling up, a cross-functional team should meet to discuss formulation and process design to ensure controls are in place over the variability of parameters. Verification is needed that the defined parameters in early stage product development will stay within the determined design space post scale-up. In addition to this, proactive process monitoring and implementing continuous improvements approach can allow for robustness to be maintained following scale-up.
Operating internationally, HiTech Health supports healthcare companies from the development to the launch and supply of products. At HiTech Health, we are uniquely positioned to offer services and technologies from a multi-disciplinary team during the scale-up process. We can help you select optimal partners to maximise growth ensuring that you bring products to market successfully with security of supply. For more information about HiTech Health’s solutions, call or email us today!