Author: Dr. Jasvir Pannu (PhD), CCIC ID: R711711

 

This blog provides a brief summary of pros and cons of three different platforms used for vaccine development. (a) Conventional vaccine, (b) Viral Vector based vaccine (C) Nucleic acid vaccine

Conventional vaccine
Conventional vaccine use live attenuated or inactivated pathogens responsible for the disease such as monkey pox. This technology has been beneficial against several infectious diseases in the past. But carries the risk of reversion and severe adverse effects, in particulars for highly pathogenic organisms. Furthermore, commercial production of this type of vaccine is challenging because of cultivation of whole pathogen posing biosafety risks. Additionally, full characterization of new pathogen requires time so this technology may not be practical during outbreak situations because of time constraints as seen during COVID-19 pandemic.
Viral vector-based vaccine
viral vector-based vaccine, however, can compensate the risk and time disadvantages of conventional vaccines. The viral vectors are used to encode heterologous antigens that use host cells as production factories. Antigens delivered to host cells are expressed inside cells that triggers immune response. This platform appeared to be effective against variety of pathogens such as Ebola virus, Zika virus. However, the concerns for viral vectors use include being genetically modified organisms and the risk of integration into the host genome, by persistent replication in the host cells.
Nucleic acid vaccine
Nucleic acid vaccines, both DNA and RNA vaccines, presents more advanced platform with significant benefits over conventional vaccines. Nucleic acid vaccines are easy to manufacture and customize to accommodate multi antigens and to compensate mutation in the pathogen. This type of vaccine can induce both humoral and cellular immune responses. This type of vaccines also have an edge over the viral-vector-based vaccines because they are derived from recombinant plasmids of bacterial origin. Therefore, a persistent replication and host genome integration, is less likely. Furthermore, the FDA has recommended that the termination of a study is not required if plasmid DNA remains below 30,000 copies per µg of host DNA. As a matter of fact, RNA vaccine was the first one that provided relief during COVID pandemic sufferings.
In summary, conventional vaccines may be the old tested and tried method for vaccine development but with modern tools of molecular biology tools available to researchers, viral vector and nucleic acid technologies are the future vaccine arena.
Reference
Chaube, Ruchi. “Vaccine Against SARS-CoV-2: Challenges and Considerations.” Canada Communicable Disease Report 47.3 (2021)ProQuest. Web. 30 Sep. 2022.

Purpose of risk assessment is to determine appropriate control strategy to mitigate potential risk to safety, purity and efficacy of a drug product. First question to ask in any risk management strategy: What are the potential risks that can be introduced throughout the life cycle of a product? Answer to these questions depends on type of a product. For example, in biologics produced using mammalian cells there is risk of introduction of adventitious organisms at each step of subculture of the cell line. Therefore, initial master cell banks created to produce working cell banks will require extensive testing. In contrast, in the case of small molecules, utilization of compendial material and testing can be easily used to confirm the quality of ingoing raw materials and final product. However, risks in a manufacturing process are not limited to raw materials, all steps of a process need to be considered to come up with a list, and level of potential risks.

Manufacturer can use quality risk management (QRM, ICH Q9) tools to rank and select quality attributes, including material and process parameters that should be further evaluated and/or controlled within appropriate ranges to ensure the desired product quality. Critical quality attributes (CQA) are established based on the previous knowledge of the product and scientific justification. Relationship between CQA and process parameters is established using appropriate DOE and available models. Prior knowledge obtained from developmental studies and scientific literature to be considered during risk assessment, can be tabulated in a concise form. Some common examples of known risks factors include degradation, solubility, interactions with excipients, risk of presence of BSE/TSE, carcinogens, nitrosamines and microbial contamination. In addition to devising controls to mitigate highly ranked risks, the identification of potential residual risk that may remain after the implementation of the proposed control strategy should also be considered. These risks may include scaling up to commercial scale that will require a validated plan for managing the risk. Plan will entails conducting the evaluation of relationship between CPPs, CQAs, and overall quality of product. Furthermore, the effect of large-scale commercial equipment will require production of engineering batches to optimize CPPs.

Control strategies indicated by validation studies are incorporated in the batch records and all other relevant documents are revised accordingly. For example, if a mathematical expression is used for determining a process parameter or a CQA, the batch record should include the input values for variables and the calculated result. Ranges of process parameters are clearly tabulated in the batch record and control charts can be used to monitor the movement of process parameters.

Additional data gained through manufacturing campaigns are collected and trended. Any shift within the approved design as defined in the ICH Q8(R2), does not call for a regulatory filing. However, movement outside the design space, requires the use of risk assessment in determining the impact of the change on quality, safety, and efficacy. This type of change will warrant appropriate regulatory filing to the agency as prescribed by regional requirements.

References

• https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8-q9-q10-questions-and-answers-appendix-qas-training-sessions-q8-q9-q10-points-consider#VII.B_Continuous
• https://www.pharmaguideline.com/2011/07/sop-for-quality-risk-management.html

The purpose of a supplier qualification is to ensure that supplier’s product is produced under controlled condition, following all applicable guidelines to meet quality conformance. In general the head of Production, Quality Control and Quality Assurance of a drug manufacturer have a shared responsibility to approve and monitor the quality of components provided by suppliers. Quality of these components can partly be ensured by supplier qualification. A brief description of and benefits of supplier qualification is described below.

At the beginning of a supplier qualification process, the regulatory requirements regarding the type of material and specifications are identified. Then supplier audit is planned by indicating the scope of the audit to the supplier. However, according to 21 CFR 211.84 “Testing and approval or rejection of components, drug product containers, and closures” all lots of components used in drug products should be tested fully to assess compliance with predetermined specifications. Therefore from the point of view of FDA, it is not required for a drug company to do a site audit of a supplier or vendor. FDA generally encourages supplier audits, as an onsite inspection can build confidence in the supplier. Additionally, qualifying a supplier will eventually help manufacturer in cutting down the full testing requirements of drug components. If the manufacturer proves the reliability of the analytical testing results of the supplier through a proper validation then manufacture can release components by doing just one ID test on each lot. Validation of a supplier test results can be achieved through full testing and examinations of first few lots, and comparing the results with supplier’s COA.

Conducting a successful audit of the supplier however does not conclude the qualification process. The compliance of the supplier with the pre specified requirements needs to be evaluated periodically. Furthermore, any changes at the supplier´s site such as manufacturing process; packaging material etc may pose a risk to quality compliance. There should be a process in place so that any change made by the supplier should be notified and agreed upon by the client. A supplier must also notify the client immediately on occurrence of any deviation that may cause negative impact on the material quality.  All deviations and non conformities should be assessed collectively to define appropriate corrective and preventive action.

In addition to assessing the quality of the material provided by the supplier, the other important parameters such as quotation time, purchase order execution and delivery time of the material should also be tracked and compared among all the qualified vendors using an established system such as performance scorecard. In summary, the process of a supplier qualification and maintenance is a relationship created to generate a  win-win situation for both parties as long as relationship is grounded in strong compliance, transparent communications, and ’right on time’ delivery of the material.

References:

https://www.gmp-compliance.org/gmp-news/what-are-the-gmp-requirements-for-supplier-qualification

http://www.expertbriefings.com/tips/reminders-about-fda-requirements-for-qualifying-vendors/

There are just a few areas that QMS auditor or FDA focuses to find out if a firm follows a system of continuous improvement. These areas include inventory, calibrations, deviations and CAPA system. Warning letter issued by FDA usually contain abundance of examples indicating how firms fail to follow their own deviation and CAPA systems. Question is: why do manufacturers fail to carry out meaningful deviation investigations? Principles of CAPA and analysis of various sources and FDA warning letters point to the following main points.

• Product being manufactured is not grounded in quality by design (QbD), meaning R&D did not develop and optimize processes by keeping the final goal in mind. Perhaps their main focus was to beat the competitor in filing IND submission to FDA. In that scenario the critical activity of continuous improvement, falls completely in the jurisdiction of manufacturing department.
• In general deviations would occur any way regardless of problems at R&D stage of a products’ life cycle. But the issue becomes complicated when open deviations are not closed properly and on a timely basis. In many cases departments only start to pay attentions to deviations when it’s time to release a product batch. At that stage the proper information and scientific facts to close the investigation may be missing, as a result of which either release of the product will be delayed or investigation is closed without the detection of real cause of the deviation!
• To reach the bottom of the root causes a broader focus of an investigation is required that may extend to more than one batch of product. For example an investigation on the contamination of a product that utilizes open vessel mixing may not be closed by evaluation of one batch only. If a batch of such product got contamination from rust or blistering paint of mixing equipment that problem is likely to extend to multiple batches. So an investigation narrow in scope will not serve any meaningful purpose.

In summary to mitigate the problem of mishandling deviations and CAPA and to avoid warning letters and 483s, firm should keep their focus of investigations broader. Furthermore use of multiple methodologies of root cause analysis rather than single method would be beneficial. For example utilizing just 5 whys method may not be adequate strategy to strive for continuous QMS improvement. Fishbone diagram, brain storming, input from subject matter experts of differ deportments are likely to produce a better resolution and mitigation of problem, moving the firm towards continuous improvement.

References:

• http://www.expertbriefings.com/tips/top-10-reasons-deviation-investigation-systems-fail/
• https://www.ba-guru.com/cause-and-effect-fishbone-5-whys/