The pandemic has put an immense strain on the biopharmaceutical manufacturing industry, particularly vendors of consumable supplies, to continue to deliver life-saving medical products to the global population. As a result, the industry is generating new science and risk-based approaches to alleviate some of the consequences of supply issues and actively collaborating with regulatory authorities to manage post approval changes.
More than 80% of the respondents in a PDA survey reported critical shortages of consumable manufacturing goods (filters, single use bags, tubing, raw materials). Some have stopped production of critical lifesaving medicines due to these shortages; others are struggling to implement like for like changes or substitute similar materials to keep processes going.
During the pandemic, the U.S. FDA has closely monitored the medical product supply chain with the expectation that it would be impacted by the COVID-19 pandemic, potentially leading to supply disruptions or shortages of drug products in the FDA understands the significant impact that this can have on patient care and is doing everything within its authority to help prevent and alleviate shortages. FDA continues to work closely with manufacturers to mitigate and prevent shortages as the COVID-19 situation evolves.
PDA Webinar Participants
- Denyse Baker, AstraZeneca
- Mark Birse, Parexel
- Cathy Hoath, Merck & Co
- Maik Jornitz, G-CON Mfg.
- Niraj Mehta, Merck & Co
- Morten Munk, Fujifilm Diosynth Biotech
- Emily Thakur, FDA/CDER
The webinar is available on demand. Click here to access.
Emily Thakur, Commander, U.S. PHA and Team Leader, Drug Shortage Staff, FDA/CDER encourages any company facing such issues to contact the Drug Shortages Staff for assistance.
The PDA COVID-19 Task Force sponsored a webinar, held on 7 June, that addressed some of these challenges and how to mitigate impacts on patients. Discussion topics included: understanding shortage risk factors, approaches for logistics and procurement, technical risk assessments, regulator expectations, and use of streamlined regulatory pathways. The expert participants have provided a few highlights for this article that may help you address issues in your own operation and also responses to two questions asked but not answered due to time constraints during the live session.
Considerations for Filter Shortages
One component which became a critical factor in the supply shortage was membrane filters. Such filters are used throughout the bioprocess, from sterilizing cell culture media to the terminal filtration step in front of the filling line. Some options for addressing a filter supply shortage include:
- Change the filter supplier to another with the same membrane filter polymer and membrane configuration
- Change the filter supplier to another with a different membrane filter polymer
- Change to a different filter size, if available
- Reduce the use of filters within the process stream
However, before starting such activities, one must consider the criticality of the filter based on the position and the processing steps following the filter. For example, the terminal sterilizing grade filter in front of the filling line is the most critical filter use, while filters used further upstream may have a lower criticality where a filter type or size change may not have an unfavorable impact on the product. Another option could be the elimination of intermediate filters, like column protect filters, which then could be utilized for more critical processing steps. However, it is important to monitor whether the column lifetime and performance change due to the removal of the filter.
Factors with potential impact on the product (e.g., higher unspecific adsorption, elevated leachables, lower total throughput or flow rates, higher fouling propensity, higher hold-up volumes, lower adsorptive microbial retentivity) require careful evaluation to avoid any impact on product composition or quality. For example, in the instance of cell culture media, unspecific adsorption may not have as high an impact as in the sterile filtration step after compounding. However, in some instances specific cell growth accelerators may be adsorbed during filtration, if the different polymer chosen is highly adsorptive. Or a smaller effective filtration, and respectively the size of filter, may create a higher blockage rate such that filters either need to be exchanged during the course of filtration or membrane fouling influences the product composition.
In any such cases, it would be advisable to work closely with the filter supplier to determine what would be an appropriate alternative within their product portfolio. If there is no alternative, it would be prudent to gain detailed information about the filter used in the past and compare the leachable profile of this filter with a potential alternative of another supplier. Detailed information is needed to evaluate possible comparability from filter to filter; at least it may support abbreviated performance and analytical test needs.
Health Authority Interactions
Any changes made due to a component shortage may require communication with the relevant Health Authorities and/or post approval change filings. Sites should consider the following factors when preparing for these interactions.
GMP is a minimum standard that firms must operate against, and generally, regulators take account of where a company falls on the spectrum of GMP compliance from those falling below the standard (where regulatory action is taken), to those meeting the standard, and then those operating at the higher ends of the compliance spectrum. This is most easily seen in regulatory risk-based inspections programs, with higher compliance being rewarded by some Health Authorities with longer frequencies between inspections.
Companies wishing to take advantage of the opportunities presented by ICH Q12 for post approval change and seek regulatory flexibilities when needed will need to be able to demonstrate they are operating at the higher echelons of the compliance spectrum, coupled with a strong quality management system that can demonstrate effective quality oversight.
Assistance Available from the FDA
In the United States, the Center for Drug Evaluation and Research (CDER) is working to address drug shortages and to proactively prevent future shortages of needed drugs. CDER is conducting this work in close collaboration with manufacturers, compounders, distributors, health care professionals, health care associations, and the National Association of Boards of Pharmacy, international regulators, and government counterparts. CDER assists in the following ways:
- Monitoring the quality and security of the nation’s drug supply chain
- Monitoring potential disruptions across the drug supply chain and proactively working with manufacturers to evaluate supply chains
- Actively monitoring potential drug product shortages and working collaboratively to make sure shortages don’t impede patient care
- Offering temporary regulatory flexibility for certain critically needed drugs
Opportunities for Expedited Approval of Global Changes
Many manufacturers provide products globally and not all countries have the same requirements for reporting changes to manufacturing components. In non-emergency situations, global approval of a single change could take months or years, causing significant product supply challenges. Clearly something else is needed in response to pandemic conditions.
A greatly streamlined process for post approval changes is outlined in WHO TRS 1019 Annex 6: Good practices of national regulatory authorities in implementing the collaborative registration procedures for medical products. Reliance approaches for National Regulatory Authorities (NRAs) and companies are also discussed in WHO TRS 1033 Annex 10: Good reliance practices in the regulation of medical products: high level principles and considerations, and WHO TRS 993 Annex 4: Guidelines on procedures or data requirements for changes to approved vaccines.
Combining recommendations from these sources produces a process for implementing post approval changes that promotes maintenance of high standards for safety, efficacy and quality, without risks to product supply to patients (see Table 1).
Table 1 Current and proposed post approval change processes
||Current NRA Requirements
|Major or Moderate
||Approval required prior to implementation, which may take 8 years or more
||Implement immediately following reference authority and WHO approval with notification provided to NRAs within 30 days
||Approval may be required prior to implementation, which may take 8 years or more, or no regulatory action may be needed and the change may be implemented immediately
||Implement immediately and provide notification annually via WHO PQVAR
Type Current NRA Requirements Proposed
Major or Moderate Approval required prior to implementation, which may take 8 years or more Implement immediately following reference authority and WHO approval with notification provided to NRAs within 30 days
Minor Approval may be required prior to implementation, which may take 8 years or more, or no regulatory action may be needed and the change may be implemented immediately Implement immediately and provide notification annually via WHO PQVAR
Webinar Questions Not Addressed Live
For those of you who attended the webinar, here are a few important questions asked that could not be addressed at the webinar due to time constraints, together with brief responses.
- Question to Maik Jornitz: Would the reduction in safety factor for effective filter area (EFA) based on a batch specific scale down study be considered a low-risk change?
It depends in what part of the process the filter is used. If the filter is the final sterilizing grade filter in front of the filling line, the change to a lower EFA would be considered a major change and a major risk in some jurisdictions, as such a filter cannot be exchanged mid batch and if it blocks, only the filled volumes can be safely recovered. However, in other processing steps such change to a smaller EFA may be considered a lower risk, especially in the buffer area. Most filters are sized with an upside capacity to avoid filter blockage in the first place, therefore lowering the EFA may work well, especially when the fluid has a low foulant propensity. Cell culture media filtration is a high foulant fluid, which would definitely require checking the filterability tests performed and checking with the filter supplier whether or not it is advisable to lower the EFA to avoid mid filtration changes.
- Question to Morten Munk: During the webinar, Morten talked about possibility of “borrowing raw materials (RM) from each other”. If this would be cross company, how do you deal with transfer of ownership/liability?
As a Contract Development and Manufacturing Organization (CDMO), we have experience with a setup where our customers have provided the raw materials that we were not able to source ourselves. In this case, we have followed QC procedures similar to our normal procedures for RM acceptance testing. In addition to the standard procedures, the QA functions at both companies have been involved a bit more than normal to handle the situation.
- WHO TRS 993 Annex 4: Guidelines on procedures or data requirements for changes to approved vaccines (2015) Available at: Annex4_Guidelines_changes_to_approved_vaccines_eng.pdf (who.int) (Accessed: 8-Jun-2021)
- WHO TRS 1033 Annex 10: Good reliance practices in the regulation of medical products: high level principles and considerations (2021) Available at: TRS 1033 - 55th report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations (Accessed: 8-Jun-2021)
- WHO TRS 1019 Annex 6: Good practices of national regulatory authorities in implementing the collaborative registration procedures for medical products (2019) Available at:
WHO_TRS_1019_Annex6.pdf (Accessed: 8-Jun-2021)
About the Author
Denyse Baker is Senior Director of Global Regulatory Policy for AstraZeneca and engaged in building external advocacy strategies on a variety of topics including COV19 therapeutics, post approval change management, quality culture, clinical trial transparency, and e-labelling.
She has more than 30 years pharmaceutical industry experience in leadership roles across advocacy and policy, regulatory affairs, quality systems, parenteral manufacturing and engineering in industry, health authority and association settings.