Continuous Manufacturing: Industry reacts to new FDA guidelines

Continuous Manufacturing: Industry reacts to new FDA guidelines

In February of this year the US Food and Drug Administration (FDA) released a 27-page draft guidance, ‘Quality Considerations for Continuous Manufacturing’.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In this draft guidance, the agency provides insights on its current stance on critical quality issues in NDAs, abbreviated NDAs (ANDAs), supplemental NDAs, and ANDAs for small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.


  1. FDA, Office of Pharmaceutical Quality 2018 Annual Report, available at; 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
  2. FDA, Office of Pharmaceutical Quality 2018 Annual Report, available at
  3. FDA, Quality Considerations for Continuous Manufacturing, Draft Guidance, February 2019, available at

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Key Serialisation Considerations for Orphan Drugs

Adapting company strategies to serialisation

Falsified medicines are counterfeit drugs that reach the market illegally. They have not been approved and may contain ingredients which are of poor quality and/or at the incorrect dose. Notably, falsified medicines pose significant health risks to patients, as well as jeopardise the legitimacy of pharmaceutical companies, tarnishing consumers’ trust and prospective generated revenue. In this article, HiTech Health takes a look into the serialisation requirements and key considerations for orphan drugs used to treat rare diseases.

As of 9th February 2019, the European Union Falsified Medicines Directive (FMD) came into effect. Marketing Authorisation (MA) holders of approved medicines are now required to place two new safety features on the packaging of their products; a unique 2-dimensional barcode which allows for identification of the medication and an anti-tampering device on the packaging of the product. Similarly, in the United States, the Drug Supply Chain Security Act (DSCSA) was brought into effect by the FDA in November 2018 to ensure serialisation of all medications. The introduction of FMD and DSCSA requires each party involved in the supply chain process to verify the authenticity of the product, preventing the entry of falsified medicines into the marketplace.

Overall, companies have started adopting a strategic business view for serialisation, identifying benefits beyond regulatory compliance, such as an approach to safeguarding brand reputation, ensuring patient safety and actively contributing to an effective management of the supply chain.


5 key parameters to serialise, verify and store your product

Orphan drugs must comply with current serialisation regulations in the same manner that any other authorised pharmaceutical product is required to. However, orphan drugs face several unique challenges when it comes to serialisation compliance. They are typically of very high value and they are often distributed in small quantities directly to hospitals, speciality practices or patients’ homes. All drugs must now be serialised at the package level using a 2D DataMatrix barcode that provides accurate and contemporaneous information on the drug product identifier, lot number and expiration date. Generally, hospitals, pharmacies and distribution centres will scan the 2D DataMatrix barcode when the drugs arrive at their facility or at the point of dispensing. The quantity of orphan drugs that enter legal supply chains may be much less than other medicines and, generally, the supply chain is patient-centric focused, with a more direct access to the final consumer.  As orphan drugs are often shipped in small quantities direct to patients or their primary care physicians, there may be challenges in ensuring the required serialisation hardware and software are available to verify if the medicine is legitimate or could potentially have been falsified.

Being involved in the development, manufacturing and distribution of orphan drugs, one must be aware of how and where patients will receive the medication. In order to comply with FMD and DSCSA, orphan drug serialisation must follow a process that aligns with the key parameters of serialisation, verification and storage:

  1. Secondary packaging serialisation uses a 2D DataMatrix barcode. If required, serialisation is completed at the sealed case level, using a 2D DataMatrix or linear barcode. Data must be machine and human readable that include orphan drug product identifier, lot number and expiration date.
  2. Cold-chain distribution needs to be successfully controlled and managed with anti-tampering devices.
  3. The orphan drug product received by the patient, doctor, pharmacy or speciality distribution centre will have the 2D DataMatrix barcode scanned at arrival or at the point of dispensing.
  4. The serialisation software will verify the orphan drug product identifier and ensure that the drug is not falsified. The software should respond to requests for verification from authorised users to verify the product identifier, including the serial number, within 24 hours at most.
  5. Serialisation data on all orphan drugs must be stored in an active, readily available location for a minimum of five years past the date of manufacture.


Many orphan drugs, like immunotherapies, are fragile in their composition and have specific packaging requirements as well as temperature-controlled shipping and storage needs. When selecting a packaging partner for orphan drug products, it is critical to conduct due diligence processes to ensure your selected partner can comply with serialisation regulations and the challenges of handling small quantities of sensitive products.


Identify the most appropriate solution for your unique needs

For orphan drugs, where product flexibility is paramount, effective packaging solutions are key in the EU multi-lingual market. Traditional packaging and labelling might result in product waste. Limited shipments of material to several countries could be facilitated using multi-lingual packaging. Further, if you are manufacturing a drug for a small patient population, it is imperative to have controls on your inventory and effective management of the supply chain. During distribution, will the serialisation hardware and software be usable in every destination that the orphan drug is distributed to? By targeting orphan drug providers, counterfeiters can possibly take advantage of newly introduced serialisation systems and create new revenue streams from high value orphan drugs. The validation and qualification of your chosen serialisation software and hardware units is a paramount step in ensuring you have a robust supply of orphan drugs to patients.


It is apparent that applying a unique identifier at the level of the individual product unit is now a core requirement for all medicines with no distinctions. Overall, the primary drivers for serialisation include the ability to control and monitor a highly complex distribution network from manufacturer to consumer, in which products possibly change hands several times. Authentication of orphan drugs at various levels in the supply chain becomes very difficult without data sharing across the supply chain. From our experience, process flexibility is key in the supply chain of orphan drugs and, therefore, there is the need of an integrated cross-functional process and systems at every stage of the supply chain to allow for clear and effective delivery of high quality orphan drugs to patients.

At HiTech Health we focus on strategies that can optimise the process, continuing to promote product quality. Get in touch if you wish to discuss your orphan drug development processes and supply chain models with one of our experts.

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What will Brexit mean for the pharmaceutical sector?

What will Brexit mean for the pharmaceutical sector?

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 to request further information on the range of services we can provide.

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FOUR Key Considerations for Scaling-up BioPharma Products

FOUR Key Considerations for Scaling-up BioPharma Products

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!

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