In order to facilitate a seamless transition from clinical to full-scale manufacture and to ensure continuity of supply, it may be possible to introduce some flexibilities into manufacturing processes provided there is sufficient attention given to the risks associated with applying these flexibilities. Manufacturers wishing to provide support to development companies will have a responsibility to manage the risk associated with rapid pivot into new processes to manufacture previously unmanufactured products as quickly as possible without compromising user safety.
As far back as 2011, FDA gave consideration to ensuring supply of necessary medicines. The FDA guidance document titled, “Planning For The Effects Of High Absenteeism To Ensure Availability Of Medically Necessary Drug Products,”2 outlines measures such as production equipment routine maintenance and utility system performance checks and maintenance which may be reduced in frequency, delayed, or substituted by a suitable alternative when there is a requirement for continued supply of medically necessary products.
As part of Operation Warp Speed, the U.S. government has committed to ensuring continuity of supply as scale up manufacture of critical vaccines occur by funding investment in manufacturing facilities and by indicating that accelerated manufacture can be facilitated while products are still in development, rather than being subject to scale-up after approval or authorization, as is traditionally the case.3
In Europe, the European Medicines Agency (EMA) has published a Notice to Stakeholders entitled, “Question and Answers on Regulatory Expectations for Medicinal Products for Human Use During the Covid-19 Pandemic.”4
Consideration has been given to both temporary changes that can be built into existing quality systems, such as periodic review of quality documents; periodic re-trainings and deferral of stability testing of non-essential medicines, as well as bandwidth enhancements where there is a requirement for re-purposing of facilities and personnel in order to meet demand and ensure continuous availability such as the introduction of premises and equipment following limited prospective qualification and the performance of concurrent validation of a new manufacturing process. In all instances, specific criteria are laid out in order to ensure that the necessary guard rails are in place to prevent any impact on product quality, safety and efficacy arising out of the introduced changes.
Where there is a requirement to introduce premises and equipment following limited qualification, a number of factors are required to be considered such as application of Quality Risk Management to ensure that the appropriate level of qualification is carried out before proceeding, additional mitigation measures are introduced to verify the process and a commitment to resume regular qualification tasks at a time when there is no longer a need for flexibility to ensure rapid delivery of products.
Where concurrent validation approaches are considered, data-based evidence is required to show that acceptance criteria are being met. Additionally, equipment and test methods must be qualified and validated before proceeding with a concurrent validation strategy. Where the product is a sterile product, sterility assurance processes are required to be validated prior to commencing concurrent process validation.4
Both FDA and EU have documented guidance on concurrent validation. The FDA guidance, “Process Validation: General Principles and Practices,”5 provides clear recommendations to manufacturers regarding concurrent validation strategies, focusing on robust systems for oversight of distributed product, rapid assessment of complaints and inclusion of batches in the stability program undertaken. Additionally, FDA recommends that stability data associated with the batches manufactured via the concurrent validation strategy are immediately reviewed to ensure that any problems are identified as early as possible.
Challenges for manufacturers
The key driver in allowing the introduction of GMP flexibilities into manufacturing processes and associated GMP activities is to ensure rapid delivery of essential medicine. However, these flexibilities do not absolve manufacturers of their regulatory and product quality responsibilities and it is crucial that Quality Risk Management principles are employed in order to assess manufacturing capability of the candidate product, underpinned by robust, mature quality systems to defend against non-conformance.
Manufacturers seeking approval to provide extra capability will be obliged to prove that existing quality systems can cope with new product and process introduction, however temporary, and display a history of compliance with other products manufactured at the proposed site. Close collaboration with the development site is critical to ensure that the requirements for manufacture of the new product can be met by the proposed manufacturing site and that current systems, capabilities and controls in place are suitable to ensure that product quality can be guaranteed when the new product is introduced.
One approach which can address these needs is the completion of risk assessments in key areas in order to ascertain the suitability of the site to manufacture with the appropriate flexibilities employed to ensure rapid delivery of medicine.
Key focus areas for risk assessment include:
• Facility Assessment
Assurance that the facilities and utilities in place can meet the manufacturing requirements of the product from both process and capacity perspectives.
• Technical Assessment
Sufficient understanding of the proposed product-specific manufacturing process and analytical methodologies to assure that full scale manufacture and testing can be implemented without delay.
• Operational Assessment
Assessment of current operational procedures, controls, and resources to ensure compatibility and capability.
• Contamination Assessment
Determination of the contamination risk associated with the introduction of the new product into the facility and equipment.
• Cleaning Assessment (Chemical and Microbiological)
Review of currently employed methodologies to confirm compatibility with the new product into the facility and equipment along with analytical capabilities to test samples.
• Quality Assessment
Assure the robustness of current quality system to determine that the facility will continue to operate in an overall state of control upon introduction of the new product. Strong, mature quality systems such as change control, deviation management and complaints management are key risk mitigating factors when considering the introduction of a new product and a significant guard rail where steps are being taken to accelerate manufacture of essential medicines.
Successful completion of assessments such as these provide, in their totality, an overall picture of the compliance landscape of the proposed manufacturing site to the regulator and, in turn, a level of confidence that appropriate measures are in place to mitigate the risk associated with the introduction of a new product in a short period of time, abridged technical transfer protocols and the implementation of flexibilities in traditional activities such as process validation in order to ensure supply of medicine as quickly as possible.
The coronavirus pandemic has placed huge focus on the pharmaceutical industry in its entirety, from product development, through clinical trials, to manufacture and distribution of a safe and effective vaccine. Regulatory bodies and the industry have come together for the common good to implement structures to make a vaccine available as soon as is feasible. This involves some flexibility in order to accelerate the many processes which bring a product to the patient and it is incumbent on manufacturers to ensure that the introduction of these flexibilities does not impact product quality, safety and efficacy and thereby put vaccine recipients at risk. Application of Quality Risk Management tools is crucial to ensuring that manufactured product consistently meets these criteria and that products which are ultimately made available make it possible for healthcare systems around the world to treat Covid-19 and minimize its devastating effects.
- World Health Organization, “Draft landscape of COVID-19 candidate vaccines”, August 20, 2020, https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines.
- U.S. Food and Drug Administration, “Guidance for Industry - Planning For The Effects Of High Absenteeism To Ensure Availability Of Medically Necessary Drug Products”, March 2011, https://www.fda.gov/media/120092/download.
- U.S. Department of Health and Human Services, “Trump Administration Announces Framework and Leadership for ‘Operation Warp Speed’”, May 15, 2020 https://www.hhs.gov/about/news/2020/05/15/trump-administration-announces-framework-and-leadership-for-operation-warp-speed.html.
- European Commission, Heads of Medicines Agency, and European Medicines Agency, “Notice to Stakeholders - Questions and Answers on Regulatory Expectations for Medicinal Products for Human Use During the Covid-19 Pandemic”, Rev. 3 July 1, 2020, https://ec.europa.eu/health/sites/health/files/human-use/docs/guidance_regulatory_covid19_en.pdf.
- U.S. Food and Drug Administration, “Guidance for Industry - Process Validation: General Principles and Practices”, January 2011, https://www.fda.gov/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf.
John Darby, M.Sc., Senior Director
Lachman Consultant Services, Inc.
John Darby, M.Sc. is a Senior Director in the Compliance Practice at Lachman Consultants. Mr. Darby is a goal directed, results-focused executive professional with a strong, global background in quality assurance, compliance, audits, training, and remediation. With over 18 years of experience, Mr. Darby has been responsible for the management, organization, and strategic guidance of global, quality and operations-based training functions. He is proficient in sterile pharmaceutical manufacture, oral solid dose manufacture and API manufacture.