Susan Haigney

The COVID-19 pandemic brought on new challenges for the pharmaceutical industry, prompting regulators to quickly develop temporary guidelines to address pharmaceutical manufacturing during the health crisis. When it comes to sterile manufacturing, the urgency of COVID-19 vaccine production has showed how important the use of technology is to add capacity when needed, according to the Parenteral Drug Association (PDA) COVID-19 Task Force, including the use of mobile manufacturing platforms. So, how will these production challenges and short-term regulations impact the future of the industry?

There are principles found in these guidance documents that may be applicable to pharmaceutical development and manufacturing after the pandemic has ended, according to the PDA COVID-19 Task Force. Specifically, FDA’s Remote Interactive Evaluations for Oversight of Drug Facilities During COVID-19 may be useful in the long term for fast-tracking medicines that fulfill unmet needs (1). Data gained from the agency’s guidance on container closures (2) may be used to gain insight on how efficiencies and principles could be more widely applied, according to the Task Force, leading to revised or new guidance documents.

FDA’s guidance on potential transmission of COVID-19 in cell and gene therapies (CGT) (3) raises risk assessment and cross-contamination questions that may need to be answered because of supply chain changes, the Task Force noted, especially the use of sterile fill/finish facilities that manufacture live viral vectors. Cross-contamination from a variety of areas (e.g., employees, materials, and equipment) also should be reviewed.

Kelly Davis-Claeys, director, regulatory affairs at Catalent Bloomington, and Mo Heidaran, vice president, technical at Parexel Consulting, provide additional insight into the future impact of these pandemic challenges and short-term regulations in the following.

Pharmaceutical Technology's Biologics and Sterile Drug Manufacturing


eBook: Biologics and Sterile Drug Manufacturing, May 2021
May 2021
Pages: 34-37

When referring to this article, please cite it as S. Haigney, “The Impact of COVID-19 on Biologics Regulations,"

 Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook 

Articles

Industry experts discuss how FDA’s response to COVID-19 and related pandemic-related guidance documents may impact the biologics industry long term.

The Impact of COVID-19 on Biologics Regulations

When FDA oversight detects violations of current good manufacturing practices (CGMPs) at a drug manufacturing facility, the owner is expected to respond with a corrective and preventive actions (CAPA) plan outlining steps to remedy the problem. The timeliness and thoroughness of this response—as well as implementation, documentation, verification, and monitoring to remedy the problem—are crucial to ongoing production and the safety of the drug product.

A key component of an effective quality system, a CAPA plan should identify and investigate product and quality problems and indicate actions needed to correct and/or prevent those problems from reoccurring. Delayed, rushed, or incomplete responses can doom initial remedial actions, leading to a succession of ongoing, unresolved problems, and additional scrutiny from FDA.

When FDA identifies a CGMP violation and calls for a CAPA, the facility owner should have two primary concerns: responding to the agency and identifying actions to ensure product quality and safety. Aloka Srinivasan, principal and managing partner, Raaha LLC, recommends companies first acknowledge the agency’s request in writing and commit to a timeframe for providing the CAPA plan. Then, says Chris Moreton, partner, FinnBrit Consulting, companies should invest time to fully understand the request and the situation and determine the cause of the deficiency and necessary actions to resolve the problem.

“Make sure the citation is understood, and have a teleconference with [the] regulatory body, if necessary, to fully understand the citation and any expectations of a desired corrective action,” says Heath Coats, principal consultant, Regulatory Consulting Services, Parexel. A robust solution to manufacturing problems instead of a quick fix is important, says Coats. “Depending on the activities required, a long-term plan may need to be created with ongoing updates provided to the regulators.”

To further understand the situation, Steve Lynn, vice-president of Pharmaceuticals, Regulatory Compliance Associates, suggests that companies conduct their own investigation into the cited deficiency and follow the problem management system defined in the company’s quality management system (QMS). “Further I’d suggest that when defining the problem statement that the company think breadth, as well as depth. Don’t just fix what is right in front of you. Think critically about what else may have a problem and how far back you need to dig to adequately bracket off whatever the problem may be. The CAPA/compliance/improvement plan should indicate all the areas that are deemed out of compliance and should address the immediate action the company will take to correct the violation and identify the plans they are developing to prevent the violations from happening in the future,” says Lynn.

An internal investigation should determine which product batches are impacted and if any additional products are also affected, notes Srinivasan. “Depending on the degree of severity of deficiency, take appropriate measures to quarantine/segregate affected batches as needed. If distributed batches are impacted, assess and determine if a field alert is to be filed with [an FDA] District Office. Conduct a health hazard analysis to determine if there is an impact to patient safety and/or effectiveness,” she suggests.

Understanding the impact of all factors on products is essential to determine how the CAPA plan will be developed, says Linda Evans O’Connor, vice-president, chief of staff, Lachman Consultant Services, Inc. “How are you going to assess product that might already have been manufactured, tested, submitted, and/or released, and could this potentially be a systemic issue, and if so, how will you address the issue across products, equipment, systems, facilities, sites, etc.?” says O’Connor. “Even if one or more elements is not applicable, it may be important to state why they are not applicable. What interim controls are you going to put in place if the actions are not immediate?”

Quality consultants recommend that the CAPA plan be developed by members of the department directly associated with the CGMP deficiency, as well as quality departments and other related departments, according to O’Connor. One person with overall responsibility for the plan should manage the process and “orchestrate” interrelated CAPAs.

The quality team should always be involved with CAPA plans, agrees Coats. “When CAPAs are created for operational groups within a company, an owner of the CAPA within the operational group should be identified. Any support groups that will play a role in execution of the plan should be involved at least from a resource planning standpoint. Regulatory affairs personnel may need to be involved if, for example, updates on a long-term CAPA need to be submitted to regulatory bodies.”

The nature of the CAPA may determine the personnel involved, says Srinivasan, with quality, manufacturing, regulatory, engineering/maintenance, validation, technical services, and project management teams typically participating. “However, a company should be flexible regarding who should be part of the CAPA planning depending on the nature of the preventive action anticipated,” she says.

Some experts suggest a wider scope of participation is important. “A good CAPA/compliance plan needs to be developed by the employees involved in the process and systems that are under scrutiny so they understand the issues and the appropriate changes can be implemented. The more employees understand the compliance concerns, the more effective the plan will be when it is being implemented,” says Susan J. Schniepp, Distinguished Fellow at Regulatory Compliance Associates.

Once the deviation has been internally investigated and a team assembled, the CAPA plan can be developed. The development of the plan should not be rushed, and the CAPA should be broad and fully address the problem, says O’Connor.

A key decision is if more than one CAPA is needed to address the problem. One overarching CAPA plan with multiple CAPA subsections; or each problem may have its own CAPA, which are then tied together under one compliance plan, says Seyed Khorashahi, executive vice president, Regulatory Compliance Associates. “Either way the important issue is that the changes are linked together and monitored so the company has a full understanding of the overall compliance of their processes/systems,” he says.

“In my experience I’ve seen firms handle this both as one CAPA—one action or multiple actions captured on one CAPA. When using a system involving multiple actions per single CAPA, will all actions need to be completed before the CAPA can be closed? How will the multiple actions be managed and linked to the CAPA? These are topics to be considered as a company develops its CAPA policy,” says Coats.

Moreton advises that different manufacturing processes may require different approaches to developing the CAPA. “Retraining of the operators will be a common theme, but all processes are different, and there will be difference between API manufacture and product manufacture, and between sterile products and non-sterile products,” he says.Certain areas of consideration may be impacted by different processes, says Srinivasan, and some processes such as sterilization may need a closer look to see if requalification is required or there is potential impact on other product batches or manufacturing processes.

While different manufacturing processes may require different changes, the basic CAPA elements should be consistent throughout systems and process, says Lynn. “For example, if your CAPA changes a standardized process for one manufacturing process, you need to ensure it doesn’t cause issues with other manufacturing processes. There are many perspectives on what constitutes a good CAPA system, but the reality is the quality and thoroughness of the investigations ultimately drive the effectiveness of the CAPA. Thinking through the issue from beginning to end and detailing what other processes may be affected, then documenting your rationale for changing or not changing something will help you make the right decisions,” Lynn says.

Schniepp recommends a three-phased approach to developing a CAPA. “Phase one would be evaluating/remediating and implementing changes to fix the issue. Phase two should define how the changes implemented will be monitored and improved, and phase three should define what the mature state of the system will offer in the way of continuous process improvements,” she says.

A CAPA plan should include the following elements, according to Coats:

A statement of the problem to be addressed

A development plan of actions to be taken, such as risk assessments

A list of resources and operational groups involved in performing corrective actions

A list of documentation that will be developed during corrective actions

Criteria for measuring the CAPA’s effectiveness

A list of preventive activities to ensure the event does not reoccur.

Khorashahi adds that tools that will be used to investigate root cause of the problem should be defined, and critical thinking should be used to develop potential changes to processes. “The company should include the measurements or metrics they will use to continually monitor the processes and systems to make sure they are maintained in a state of compliance. A really well-written CAPA plan will also include some discussion on continuous process improvements as the processes and systems mature,” says Khorashahi.

Correcting CGMP deficiencies in a timely manner is important, but the time it takes to implement a CAPA depends on a variety of variables including the type of CAPA and the deficiency itself. Writing and revising standard operating procedures and retraining staff are also factors, says Moreton.

The complexity of the problem also plays a role, according to Lynn. Corrective actions, such as adding an additional signature line to an existing verification document, may take little time to carry out. “Other changes are more complex and may take additional time to implement. Keep in mind that a seemingly simple change in an SOP [standard operating procedure] with a long CAPA date also raises a flag and could yield questions on why it’s taking so long to do a simple task. If the task isn’t as simple as it appears, it is highly suggested that the rationale for the timing be recorded in the CAPA,” says Lynn.

If the CAPA requires new equipment or facilities, implementation will take longer than just updating a procedure, says O’Connor. “This is where interim controls come into to play. It is not uncommon for very large CAPAs to take a year or more, but if the company is continuing to produce for the US market, then there needs to be other controls in place,” she says.

While the time to complete a CAPA is dependent on the depth and extensiveness of corrective actions and can vary significantly from a few days to several months, companies should avoid setting unrealistic timelines for the CAPA that cannot be met or close a CAPA to meet a due date, says Srinivasan. And commitments should not be provided to FDA that are not vetted or are not feasible for commercial production, she recommends. Time frames that are too short and are impossible to meet—as well as those that take too long—are not acceptable to regulatory authorities, note multiple experts; missing a CAPA commitment date is a sign that the remediation is not going well.

Time is not the only concern when it comes to CAPAs. The effectiveness of a CAPA plan should be verified and monitored with effectiveness checks, which assure the issue has been addressed.“Let’s say a change is implemented to fix an observation that there were too many repeat deviations generated from one specific process step. Once the intended change to fix the process is implemented, the deviation system should be monitored to see if the repeat deviation has been remediated,” says Khorashahi. “This monitoring should be done over a period of time. In essence, the company is performing real-time effectiveness checks and continuously monitoring the process. This is a desired state for maintaining compliance.”

“It is often useful as well to have an independent party assess the CAPAs and the effectiveness at a point in time after the CAPAs have been implemented,” says O’Connor.

Companies should thoroughly follow through with a CAPA, says Srinivasan, and a solution should be confirmed through verification and close-out of the CAPA. Opening another CAPA to continue an uncompleted CAPA should also be avoided, says Coats.

If new information about the deviation or process is discovered after a CAPA is developed and sent to FDA, the plan should be revised. “Any CAPA plan that is carved in stone will only result in the company continuing to get observations of non-compliance,” says Lynn.

“CAPAs can be flexible, but it is crucially important to update the agency as soon as you have made a decision to change the CAPA, with an explanation for why it changed. The explanation should be reasonable and scientifically based, and the new CAPA needs to at least address the original observation,” says O’Connor.

“[CAPA] plans should be living documents and change as needed depending on new information discovered during the CAPA process. If the company had committed to ongoing updates to the regulatory agency as part of the original response, then the changes should certainly be communicated,” says Coats. “The bigger issue is to ensure the company’s quality system has a mechanism to introduce, review, and approve the change to a CAPA plan. Therapeutic efficacy and patient safety should always dictate whether a change to a CAPA plan would be required,” says Coats.

A company’s quality system should include processes—management review, internal audits, periodic procedural reviews, annual product reviews, and environmental monitoring—to review and adjust the CAPA on an ongoing basis.

Effective CAPA plans assure regulators that the company has corrected deviations and prevented future occurrences, and the agency expects a timely response to citations such as Form 483 reports.

“If an extensive corrective action is planned, the firm should acknowledge the CAPA requirement in the initial Form 483 response, indicate the CAPA is under development, and provide a commitment to submit the proposed CAPA in a follow-up response within a reasonable time (i.e., no more than two weeks later),” says Srinivasan. “Any initial CAPA submitted should include milestones (timeline) for providing progress reports to the Agency, the timing of which depends on the actions needed.”

As the CAPA implementation process progresses, routine updates should be provided to FDA, according to Schniepp, including completed commitments, those still in progress, and changes that may be needed to the original plan. “Providing data that demonstrates that the completed commitments remediated the problem should be provided as direct evidence the process/system was effectively remediated,” says Schniepp.

“The verification portion of a CAPA provides the assurance the CAPA is working, and the periodic milestone reports submitted to the agency provides the reporting required. There is a possibility that FDA will revisit to assure the CAPAs are being followed,” says Srinivasan. “The amount of vigilance on part of FDA depends on the severity of the deficiencies noted. The agency may make a special return visit to verify implementation of specific CAPAs. In most cases, FDA will wait until the next GMP inspection to review the CAPA progress.But be assured the agency investigators will have the CAPAs in hand to double check the information a company provided during their visit.”

When referring to this article, please cite it as S. Haigney, “Responding to FDA CAPA Requests,” 

Understanding an FDA corrective and preventive actions request is step one in developing a robust plan to address CGMP deficiencies. 

Responding to FDA CAPA Requests 

For the bio/pharmaceutical industry, 2020 was a challenging year, as industry worked to develop and manufacture vaccines and treatments for the COVID-19 pandemic. Despite an increased workload and travel restrictions precipitated by the pandemic, FDA continued to meet goals and approve new drug products. As the effects of the pandemic continued in the first quarter of 2021, FDA’s two bio/pharma sectors, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), have announced their guidance agendas for the year.CDER has plans for new or updated guidance documents in a variety of areas, especially for generic drugs and procedural updates; CBER is focused on tissues and advanced therapies.

Pharmaceutical Technology's Regulatory Sourcebook 


eBook: Regulatory Sourcebook, March 2021
March 2021
Pages: 6–9

When referring to this article, please cite it as S. Haigney, “FDA 2021 Guidance Agenda Sees Focus on Generics,"

 Pharmaceutical Technology Regulatory Sourcebook eBook 

The agency’s focus appears to be on generic drugs for the upcoming year. 

FDA 2021 Guidance Agenda Sees Focus on Generics

The COVID-19 pandemic tested the R&D capabilities of bio/pharma companies and highlighted some of the challenges present in the bio/pharma industry before the crisis hit. Among the lessons learned from the pandemic response are changed perceptions within the industry regarding flex capacity, risk management, supply chain, and inventory control, according to Eric Langer, managing partner at BioPlan Associates.

“These are not ‘new’ factors by any means. But the pandemic has demonstrated how critical they are, not just in normal times, but during crisis as well,” says Langer.

Is the industry up for the challenge of handling the pandemic? “…the industry has in many ways known [that a pandemic response] would be possible, and all the ‘moving parts’ have generally worked at the remarkable speed needed to develop vaccines and therapeutics around the world,” Langer says.

Contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs) proved integral to the biopharmaceutical industry’s ability to handle the pandemic, providing expertise, facilities, and manufacturing capacity sponsor companies did not have. COVID-19 has emphasized the benefits of CMOs and CDMOs. So how did these organizations fare in 2020 and what is their outlook for 2021?

Capacity has been a challenge in the past year, says Langer. “CMOs and manufacturers have been managing their capacity since the beginning of this crisis, from vials to stoppers, from single-use devices to fill/finish lines, and all the accompanying logistics. Many non-COVID projects have reportedly been shifted to other facilities, and even other partners, which has created bottlenecks in other adjacent segments, as well. But by managing existing capacity, we’re already seeing a smooth transition from R&D and clinical production, to large-scale manufacturing,” he says.

Fiona Barry, associate editor at PharmSource–GlobalData, agrees that there is insufficient capacity for the level of demand caused by the pandemic but doesn’t see the industry being able to catch up to the demand in 2021. “Eventually there will be a few different vaccine types on the market, and these will require different technologies/processes to manufacture, and so capacity will be specific to which vaccine types gain approval,” she says. “A number of promising vaccine candidates in late stage use newer vaccines technologies such as mRNA-based products. As these become approved—the UK [United Kingdom] issued an emergency approval of Pfizer/BioNTech’s mRNA vaccine BNT162b2 on [Dec. 2, 2020]—then repurposing more traditional vaccine facilities will not help capacity issues.”

The pandemic has created another challenge: maintaining the manufacturing of non-pandemic drugs in addition to needed COVID-19 treatments. In 2021, Langer says, CMOs and CDMOs will continue to balance pandemic and non-pandemic-related programs by shifting projects from facility to facility. “The cascade of scheduled pre-pandemic, non-COVID projects are necessarily continuing, since these, too, are lifesaving, and must be moved forward, despite the challenges to R&D and clinical trials during these times,” he says.

COVID-19 vaccine developers are contracting with CMOs and CDMOs at a rate not seen before in the industry, says Barry. “Consequently, infectious disease drugs have already overtaken perpetual leader oncology as the year’s top therapy area for contract manufacturing service agreements, since many of these vaccine-developer companies are small and lack manufacturing capabilities. Even the largest companies require extra resources to supply billions of doses with AstraZeneca and Inovio having the largest number of contract service agreements to date. Pharma companies such as Pfizer are also pushing internally manufactured drugs out to CMOs to free up space for COVID-19 vaccine manufacture,” she says.

Barry agrees, however, that manufacturers will continue to juggle the needs of non-pandemic therapies and COVID-19 medicines and vaccines. “More than 1000 clinical trials worldwide were disrupted in 2020 by COVID-19 due to suspended or slow enrollment or delayed initiation (1). Resumed trials and delays in manufacturing of advanced biologics, many of which require the same capabilities as vaccines, will cause even greater demand of these already scarce resources in 2021,” she says. Cell and gene therapies have also been affected by the pandemic, according to Barry. She notes that a bottleneck in viral vector manufacturing was already a problem prior to the onset of the COVID-19 pandemic (2).

This past year saw a 3% increase in contract manufacturing agreements between January to November 2020, according to Barry. “We know from previous years that these agreements are often revealed in hindsight, so the increase is probably much larger. What is more notable than the change in volume is the shift in therapy area covered by these agreements: while oncology dominated in 2019, infectious disease is the top area in 2020,” she says.

There was also an increase in private companies and institutions outsourcing to CMOs in 2020, says Barry. “From January to November 2019, approximately 36% of contract manufacturing agreements were outsourced by private companies or institutions. Over the same 11 months in 2020, this number increased to 47%,” she says. “Smaller companies that are unable to invest in their own facilities are more likely to outsource products than larger companies. This is especially true for products in accelerated development such as COVID-19 vaccines.”

And, according to Langer, the pandemic is expected to increase the amount sponsor companies outsource in 2021. “We found that 70% of innovator/sponsor companies expect to outsource more as a result of the pandemic. This is likely due to the recognition that human capital is going to continue to be in short supply. Finding reliable outsourcing partners able to address these shortages in staffing will be an ongoing concern, well after the pandemic is resolved,” he says.

The industry is preparing for the continued COVID-19 vaccine demand in 2021, says Barry. “Pharma companies and CMOs are engaged in a wide variety of investments to better prepare for COVID-19 vaccine demand, which includes increasing captive capacity (building or acquiring) and engaging in collaborations to expedite vaccine development and approval. We will see this continue into 2021, as well as investment in cold chain storage required for mRNA vaccine transportation and distribution. In addition, there will be a large population of COVID survivors who will require new treatments with unique dosage forms,” says Barry.

Outsourcing companies prepare for new year

In 2020, several CMOs and CDMOs announced plans to expand their facilities and services in 2021. Thermo Fisher Scientific announced in December that it is expanding sterile drug product development and commercial manufacturing in North America and Europe (3).

The company is planning to expand facilities in North Carolina, the UK, and Italy and will add 15 development and current good manufacturing practice (CGMP) commercial production lines to support live virus, aseptic liquid, and lyophilized vial filling capabilities.

The company also announced a new sterile manufacturing facility in Singapore and a new integrated biologics and sterile drug development and manufacturing site in Hangzhou, China (3).

Lonza announced in late November 2020 that it is expanding its particle engineering and drug product capabilities at its Bend, OR site. The expansion will include new suites for the development and clinical manufacturing of drug product intermediates and drug products using spray-drying, hot-melt extrusion, and melt-spray-congeal processing and CGMP suites for early-phase CGMP manufacturing featuring added storage, gowning, and a customer in-plant viewing corridor (4).

Also in late November, Baxter BioPharma Solutions announced a $50 million expansion of its sterile fill/finish manufacturing facilities in Bloomington, IN.

The expansion will include a new 25,000-sq.-ft. warehouse, a filling line for flexible plastic containers, an automated syringe fill line that can fill up to 600 units per minute, and an automated visual inspection line (5).

Sector Impact: The COVID-19 Pandemic Impact on Clinical Trials

Gene Therapy Market Opportunity for CMOs–2019 Edition

Thermo Fisher Scientific, “Thermo Fisher Scientific Further Expands Global Footprint for Drug Product Development and Commercial Manufacturing,” Press Release, Dec. 9, 2020.

Lonza, “Lonza Expands Development and Manufacturing Capabilities at Bend (OR) Site,” Press Release, Nov. 30, 2020.

Baxter BioPharma Solutions, “Baxter BioPharma Solutions Announces $50 Million Investment to Expand Sterile Fill/Finish Manufacturing Site in Bloomington, Ind.,” Press Release, Nov. 24, 2020.

Susan Haigney is the managing editor at Pharmaceutical Technology. 


Vol. 45, No. 1
January 2021
Pages: 50-52

When referring to this article, please cite it as S. Haigney, "Supporting the Industry During a Pandemic," 

Outsourcing increases as the industry balances development and manufacturing of both COVID-19 treatments and non-pandemic-related medicines.

Supporting the Industry During a Pandemic

The race for the development and approval of treatments and vaccines for COVID-19 is well under way, and regulators and other organizations are working with the bio/pharmaceutical industry to get these products into the hands of the public. As ever, pharmacopoeias play a role in providing a standards framework for the development, manufacture, and quality of these life-saving medicines.

With the current challenges facing industry and regulators, how has the US Pharmacopeia (USP), which publishes the 

United States Pharmacopeia–National Formulary

), been assisting in the development of COVID-19 treatments and how has the pandemic affected the organization’s operations?

USP, like many other organizations, has been ensuring the safety of its staff and shifted the majority of its staff to working remotely in March 2020, according to Jaap Venema, PhD, chief science officer at USP.“Critical lab functions continued in a way that minimizes the risk to on-site staff,” says Venema. “Similar measures were taken for USP’s expert volunteers, who now regularly meet virtually to advance their standard-setting work.”

For USP, building trust in the effectiveness of COVID-19 vaccines and treatments, ensuring global access to these treatments, and combating falsified and substandard medicines are the focus, according to Fouad Atouf, PhD, vice president, USP Global Biologics. USP has been offering free resources and technical expertise to developers of COVID-19 vaccines and treatments since early 2020, says Atouf, including free and discounted education, limited-time free access to the

, and free samples of USP monoclonal antibody reference standards.

“Scientists and manufacturers working on developing new vaccines and treatments, increasing the production of approved drugs, and advancing other projects to tackle COVID-19 can access the 

 Online free for six months. Also, we have extended implementation dates and comment periods for our compendia, recognizing the challenges that the pandemic has brought to drug developers and manufacturers,” says Atouf.

“USP’s role in the wake of COVID-19 is multi-pronged: we are helping to accelerate the work of scientists and manufacturers in developing vaccines and treatments; supporting front line workers who will administer COVID-19 vaccines and treatments and who have been affected by shortages of critical drugs and personal protective equipment; and working on developing insights on current supply chain vulnerabilities and ways to strengthen it,” says Atouf. “Our expert volunteers and scientific staff can advise on novel vaccines, monoclonal antibody therapies, antiviral and cell therapies, and immunoglobulins or convalescent plasma treatments. And for existing and new therapies, 

 compendial tests and methods address common issues shared by all drug manufacturers, such as suitability, validation, contamination control, stability testing, and qualification of raw materials,” he adds.

One of the key topics USP is planning to address in 2021, according to Edwin Gump, PhD, vice president, USP Small Molecules, is the detection and control of nitrosamine impurities, which are known carcinogens that have been found in some medications. USP has proposed General Chapter <1469> Nitrosamine Impurities that identifies sources of nitrosamines and risks associated with each source. The proposed chapter, says Gump, will give recommendations on a nitrosamine risk assessment and control strategies. It will also provide different test methods for controlling nitrosamines at levels below acceptable intake limits in angiotensin II receptor blockers.

According to Horacio Pappa, PhD, director of USP General Chapters, USP is also developing a chapter on supplier qualification that will provide a quality risk-based approach to the selection, assessment, approval, and monitoring of suppliers. “Suppliers for pharmaceutical ingredients, medical devices, as well as dietary supplement manufacturing companies and compounding pharmacies will be within the scope of the chapter,” says Pappa. “The current thinking is to develop the chapter around the supplier qualification lifecycle—a five-step process that includes identification/selection, evaluation/acceptance, performance, monitoring, and disqualification—along with discussions about expectations and a rationale for each step,” he says.

 General Chapter <1220> Analytical Procedures Life Cycle offers “an alternate framework for analytical procedures that holistically incorporates the events that take place over the procedure life cycle,” says Pappa. “It is designed to demonstrate that a procedure is, and remains, fit for the intended purpose.”

The proposed chapter also seeks to build the connections between validation, verification, and transfer through the life cycle approach, says Pappa. At the same time, the International Council for Harmonization (ICH) has started the revision of the

 Q2 Validation of Analytical Procedures: Text and Methodology

 guideline on validation and proposed the creation of a complementary guide (

) on the development of analytical procedures. “These guidelines will incorporate some of the concepts presented in <1220>,” says Pappa.

In 2021, USP also will propose procedures based on inductively coupled plasma spectroscopy (ICP) to element-specific general chapters, which impact 

 General Chapters <206> Aluminum, <211> Arsenic, <241> Iron, <251> Lead, <291> Selenium, and <261> Mercury, according to Pappa. “This will give our stakeholders the option to continue using the classical wet chemistry tests as currently included in these chapters, or to adopt the use of an ICP-based procedure for analysis of the element in question, as similarly outlined in 

 <233> Elemental Impurities—Procedures. This ensures the same approach is used throughout 

 regarding the analysis of individual metals with elemental impurities. This revision will provide stakeholders with an option for a single analysis to meet both monograph and chapter requirements, rather than multiple procedures,” says Pappa.

USP also is planning a chapter on batch release testing. “USP is aware that many of our tests are commonly used for batch release, but the procedures and acceptance criteria in General Chapter <905> Uniformity of Dosage Units refer only to the units tested, so any passing results should not be extrapolated to larger populations. The approach to release the batch (with respect to content uniformity) based on passing the <905> requirement is neither appropriate nor acceptably rigorous,” says Pappa.

When it comes to large molecules, USP added additional performance standards for monoclonal antibodies, according to Atouf. “These reference standards can be used as independent control materials for method development, training, method transfer, and internal assay control support, standardization of physicochemical testing, such as intact mass, charge heterogeneity, size variants, purity, and glycan analyses. These types of standards will have a positive impact on access to these critical drugs,” says Atouf.

In addition, a Plasmid DNA Expert Panel has been formed under USP’s Advanced Therapies Expert Committee to develop a new general chapter on the use of plasmid DNA in cell and gene therapies, according to Atouf. USP will also be developing a lentiviral vector copy number standard to “standardize the quantitation of viral vectors in cellular genomes. This is important because the number and persistence of inserted genes in patients may lead to health complications, and quantifying vectors efficiently in preclinical studies for gene therapies and vaccine development may prevent adverse events in patients,” says Atouf.


Vol. 44, No. 12
December 2020
Pages: 42–46

When referring to this article, please cite it as S. Haigney, "USP, COVID-19, and Plans for the Future," 

USP is preparing for 2021 while also supporting the development of vaccines and treatments for COVID-19.

USP, COVID-19, and Plans for the Future

The race for the development and approval of treatments and vaccines for COVID-19 is well under way, and regulators and other organizations are working with the bio/pharmaceutical industry to get these products into the hands of patients. As ever, pharmacopoeias play a role in providing a standards framework for the development, manufacture, and regulatory approval of these life-saving medicines.

With the current challenges facing industry and regulators, how has the European Directorate for the Quality of Medicines and HealthCare (EDQM), which publishes the 

EDQM has revised its production planning to adapt its approach as the pandemic crisis develops, according to EDQM Director Susanne Keitel. “We also reorganized our production process. These changes have enabled us to maintain an uninterrupted supply of reference standards throughout the crisis, which I consider to be a significant achievement since our portfolio covers more than 3000 different standards,” Keitel says.

EDQM has relied on virtual meetings to communicate with international partners since the pandemic started and has organized several online conferences. “These have included training on the new 

 approach to the Management of Extraneous Agents in IVMPs and special information sessions for new chairs of groups of experts of the 

EDQM is working closely with the European Medicines Agency (EMA) to provide COVID-19 vaccine developers access to guidelines, resources, and applicable pharmacopeial texts, says Keitel. “The EDQM, for its part, has made available 

 texts that are relevant for developers in the context of Marketing Authorisation Applications for candidate vaccines,” she says. Some academic institutions and small- and medium-sized enterprises involved in COVID-19 vaccine development, according to Keitel, may not be aware of all the applicable regulatory requirements.

“More than 40 quality standards relevant for vaccines have been published on our website. Developers can take them into account to help build appropriate analytical control strategies for their COVID-19 candidate vaccines and ensure the quality and safety of the final product,” says Keitel. “Furthermore, a document compiling selected training materials related to vaccines was also published to help accelerate users’ understanding of the 

and how to apply relevant texts. To bridge a gap, the EDQM has also drafted and published a non-binding guidance document on viral vectored vaccines, one of the new technology platforms of special interest for COVID-19 candidate vaccines.”

EDQM is also coordinating the European Network of Official Medicines Control Laboratories (OMCLs) for official control authority batch release (OCABR) to prepare for the additional release test for COVID-19 vaccines independent from the manufacturer, in line with European Union legislation. “This work includes a guidance document on the transfer of relevant tests, which, in order to save time, will not depend on the final validation of the analytical methods; and an information table on the testing capabilities of the different OMCLs, so that manufacturers can easily select the most appropriate OMCL for their products,” says Keitel.

“And of course, we have also continued to meet regularly with various stakeholders. We met with National Pharmacopoeia Authorities (NPAs) on a weekly basis during the first half of the year, and we now meet on a monthly basis in addition to the traditional annual meeting. We also have frequent meetings with industry associations and representatives of the OMCL system. Last but not least, we have liaised regularly with other international pharmacopoeias to help co-ordinate the public health response in Europe with that of the other world pharmacopoeias,” she says.

. in 2020, according to Keitel, including a new general chapter (2.6.32. Test for bacterial endotoxins using recombinant factor C) in Supplement 10.3 that offers an alternative to limulus amoebocyte lysate (LAL)-based testing methods. Supplement 10.3, which was published in July 2020, also included a revision to general chapter 2.9.19. Particulate contamination: sub-visible particles. This allows for alternative procedures for small-volume biologics. “The new general chapter, 5.17.2. Recommendations on testing of particulate contamination: visible particles, provides clarity on how to interpret the requirement to be ‘practically free from particles’ in production and quality control, including during stability studies,” says Keitel.

“A revised dosage form monograph on Nasal preparations (0676) was aligned with EMA guidelines for uniformity requirements for nasal sprays, number of deliveries and leak rate. Similarly, for oromucosal preparations, dental preparations were added and the sections on sprays and drops were separated. Chapter 2.2.2. Degree of coloration of liquids, revised by the Pharmacopoeial Discussion Group (PDG) with the addition of a harmonized instrumental method, also came into force in 2020,” says Keitel.

In 2021, EDQM plans to continue to implement the International Council for Harmonisation (ICH) Q3D guideline on individual monographs. There are also plans for a revision of the general notices for the dissolution test, a new technical guide on finished product monographs, and a general chapter on the analysis of N-nitrosamine impurities in active substances and finished products, according to Keitel.

“Depending on our harmonization work conducted with the US Pharmacopeia and the Japanese Pharmacopoeia in the Pharmacopoeial Discussion Group, we expect to finalize the revision of chromatographic separation techniques, the 

 chapter 2.2.46,” says Keitel. “Other updates will concern requirements for parenteral preparations on visible and sub-visible particulate and bacterial endotoxin text/endotoxin testing. In addition, medicated plasters will be covered by a dosage form monograph and the disintegration method
for large tablets in general chapter 2.9.1. Disintegration of tablets and capsules will be adapted to allow stepwise testing.”

Vol. 32, No. 12
December 2020
Pages: 28–29

When referring to this article, please cite it as S. Haigney, "EDQM Combats COVID-19 and Makes Plans for Future," 

The European Pharmacopoeia is preparing for 2021 while also supporting the industry to develop vaccines and treatments for COVID-19.