Continuous Manufacturing (CM) – Is it a feasible approach to achieve QbD?

FDA issued a draft guideline on continuous manufacturing (CM) in Feb 2019 highly recommending firms to adopt it. ICH also endorsed the concept and have established a working group. Continuous manufacturing was proposed at about the same time when the QbD principles and expectations were being discussed, as it is an excellent approach for achieving QbD objectives. 

Let us delve on why the regulators suggest it to be a better approach. Although continuous manufacturing is an emerging concept, it has many advantages over conventional manufacturing, which have been highlighted in the guidelines, such as a reduction in production cost, improvement in quality due to better controls, higher flexibility, and higher product yields. Other advantages are - less manual handling and labour cost, lesser investment due to reduction in the capital as well as operating cost, fewer utilities, shorter processing time, easier scaling up to meet increasing demand and improved efficiency. It is suggested that all these advantages would result in lesser instances of drug shortage issues.

Most firms still prefer the conservative or conventional approach and are reluctant to shift to or adopt continuous manufacturing. So why are firms having an inhibition to adopt this approach? To find out, let us understand the difference between the two approaches with a brief overview of some of the pros and cons.

1)     Conventional manufacturing is based on the principle of a batch or lot processing approach which consists of many unit operations or steps during the manufacturing of a product. Continuous manufacturing is more of an integrated approach involving a single and continuous system of manufacturing. So, a CM is more seamless operation, which would result in shorter processing time and lesser wastage.

2)     The end-point variability, which indicates that the unit operation or a process is complete to give the desired output, is comparatively higher in the conventional approach. It is considered that the variability will be much lower, as it will be controlled better in continuous manufacturing by using in-line and on-line monitoring techniques such as Process Analytical Testing (PAT) approach/tools which will ensure real-time release while the process is on.

3)     The conventional approach is highly labour intensive and is largely dependent on the efficiency of operators as against in continuous approach where automation and use of the latest technology are employed to ensure both - processing and control measures.

4)     Continuous manufacturing is a process that requires a very high technical as well as process understanding and is complex system as compared to the conventional approach. It requires extensive development studies based on quality by design principles and a detailed study of risks.

5)     Conducting process validation for achieving integration as well as to meet the quality objectives throughout the manufacturing is much more challenging in CM. The goal to achieve the finished product specification as the material is being processed and tested on-line requires an extremely well-defined control strategy involving technically advanced tools for multivariate controls. This will also involve a lot of interactions with vendors and suppliers of API, excipients for controlling material attributes. Equipment qualifications and PAT implementation will not be an easy task and there will be constant interactions with the equipment manufacturers too.

6)     Managing deviation during processing is of utmost importance and hence the sampling plan will need to be devised in a manner that the variability is continuously monitored and controlled consistently. Corrective actions for any deviations would need to happen in real-time, as and when required, to avoid failures.

7)     One of the biggest challenges perceived by the firms to adopt continuous manufacturing approach is regulatory acceptance. Many firms either have none or limited experience of handling these kinds of complex systems, while they have been comfortably managing submissions and approvals based on the conventional approach. Firms are still studying and understanding the requirements for proving equivalency between the two approaches which is a big task and time consuming as well.

8)     Another big hurdle is that firms do not want to hamper their regular supplies by shifting their already approved process to a new one which would be a significant change and will require submission of a lot of data before approval.

Apart from the challenges listed above, there are other important aspects such as addressing the risk of cross contamination, cleaning validations, managing equipment shutdowns or breaks downs.

So in case of continuous manufacturing, while the cost of capital investment is low, labour cost is low, flexibility to scale up is high, resulting into a higher quality product, there will be a lot of activities during development and integration for understanding material attributes and process, conducting risk evaluations and developing a robust control strategy by employing advanced tools like PAT. It is obvious that the cost of shifting will be considerably high involving significant investments and may only make sense for high-value products that ensure a good return on investment (ROI). However, if this approach is adopted early on during new product development itself it would be far more beneficial. Hence every firm may need to do a case by case evaluation before adopting this strategy as it should also make good business sense. Few big firms have already adopted and implemented this approach managing all the above challenges, but how widely it shall be used in the pharmaceutical industry is still a big question. 

On the other hand, regulators like FDA are supporting this approach in a big way and are suggesting and urging the industry to discuss it with them before final implementation as they will be able to help and support by providing clarity in terms of regulatory expectations and approvals. On their part, the FDA has developed programs to help the industry in adopting the latest technologies to achieve modernization in pharmaceutical manufacturing. In the draft guidance, they have covered critical aspects such as quality considerations, batch definitions and its applicability, process validations, scaling up, stability and quality system requirements. They have also covered the data requirements for new ANDA, NDA submissions or handling it as a post-approval change for an approved product. The guidance provides a list of sections of eCTD where these data can be provided.

Industry commented on the draft guidance of the FDA and till the time this blog was published, there were in all 24 comments posted by firms and associations. They have raised questions on critical aspects such as non-conforming materials, risk-based equipment qualifications, lack of clarity in terms of differentiation between regulatory and GMP requirements, bioequivalence study requirements to establish equivalency, alignment of this guidance and its applicability when ICH issues their final guidelines and many more. They have urged FDA to make changes to the draft guidelines to provide more clarity. Industry comments are available under the public docket of website regulations.gov. I would recommend everyone to read the guidance and all these comments to get an insight on this topic. 

So, to summarise it has been a widely accepted fact that the advantages offered by continuous manufacturing make it an important approach to adopt. Feasibility of adopting this will depend on many factors, but despite all the challenges it still has lot of benefits. Deeper involvement and continuous interactions with the FDA and other health authorities will clarify things further and implementing this for global developments will happen only if more and more firms see the merits and gears up for the challenge. Making this choice will ensure long term benefits, cost savings and hence there is a need to invest upfront in a better technology that will ensure a higher quality product developed on QbD principles. In the current scenario, it is a wait and watch situation for many firms and only time will tell whether this will become the future of pharmaceutical manufacturing!!

In my next blog I will touch upon the quality metrics initiative by FDA. See you soon!!

Data Integrity – Topmost Priority for the Pharmaceutical Industry

Data integrity has become a hot topic in the pharmaceutical industry and rightly so. Our industry needs to adhere to ethics of the highest order, and we deal with a lot of data being generated every day.

Data integrity is a concept which has been prevalent right from the time when the requirements of Good Manufacturing Practices (GMP) and the pharmaceutical quality system came into existence. So, it is not a new concept or a new requirement. In fact, GMP compliance cannot happen unless data integrity is ensured at all levels in an organization. In the last few years, it has become more relevant than ever before due to the findings during audit and inspections conducted by the FDA and EU. The latest trend indicates that data integrity is one of the major concerns of GMP violations in many firms in different geographies.

Why is data integrity so important? Simply because all these data are the basis of maintaining the quality, safety and, efficacy of a product, as many critical decisions are taken based on the data generated in real-time.

Let me share some situations for better understanding:

1)    A person has the authority to review and then approve a document electronically and the person is on leave. Someone else has access to his account and logs in through his account to approve the document.

2)    A duplicate copy of a signed certificate of analysis of an API is found as scrap in a dust bin of a quality control lab.

3)    Date, time and signature of the person recording the endpoint of a unit operation, while manufacturing of a batch is missing in the BMR and there has been overwriting of date and time at many places.

4)    There is a mismatch between the data recorded in the logbook and results reported in the computer system.

All the above examples will lead to cGMP violations concerning data integrity. The data integrity violations may occur due to systemic, cultural or operational issues. Hence it is paramount for any firm to first introspectively identify the risk within an organisation and then design a robust system to mitigate it. In my view, data integrity primarily demands cultural alignment to two of the most important requirements – 1) being truthful and transparent 2) tracking and capturing details in real time, as and when it happened. 

There are many guidelines concerning data integrity issued by different health authorities. Most of these guidelines requires firms to develop a robust quality system that ensures that any breach or deliberate attempt to manipulate data is recorded and reported. The guidelines state that all data should be legible, attributable, complete, consistent, contemporaneously recorded, accurate and, original (ALCOA+). Huge emphasis is on security and reliability of data. Another important aspect is that it must be stored properly for the desired period so that it is easily retrieved during audits or inspections. 

Data can be in the form of hard copy such as paper-based or electronic form. Sometimes a hybrid system exists where data is managed in both paper-based and electronic form.  Various guidelines are in place to ensure the data integrity of both the above forms. For example, an audit trail for managing all electronic data is a must as per the US rules outlined in the Code of Federal Register (21 CFR part 11). Electronic signatures and record-keeping requirements have also been highlighted in the rule. So, a defined system for entry, access, retrieval and storage of data is of utmost importance. 

Some suggested measures to design a quality system to achieve the required goals and objectives are listed below. It is not an all-inclusive list but captures critical aspects.

1)    Developing an open and transparent culture that is driven by quality with the direct involvement of top management executives. Quality should be everyone’s business. The culture of any firm should encourage the reporting of deviations rather than hiding it. For any reported deviations, corrective and preventive actions should be documented transparently.

2)    Writing the SOPs or manuals effectively to ensure correct understanding by the end-user.

3)    Training is extremely essential and periodic evaluations are must to check the validity that the imparted training is purposeful and useful. Similarly, conducting appropriate validation of process or electronic systems, wherever applicable, is mandate.

4)    Ensuring good security measures such that different levels of authorization are well-defined for handling electronic or paper-based data. For example, having a system of an access control to an authorized person for entry and review of data, including authorization of changes to data. Regular reviews of IT systems and transaction logs by authorized person is required.

5)    Having a defined system for retention of data during life cycle management till the specified retention time and then the disposition of data at the end of the retention period. A good archival or back up system without any duplication of data and protection of data from accidental damage are important aspects to be considered while designing a system.

6)    Having a self-inspection team with a clear understanding of data integrity requirements to conduct internal audits is essentially required.

In current times, when a firm has many partners like contract clinical site, contract manufacturers or contract laboratories, it is the outsourcing firm’s responsibility to design the quality system in a manner that will ensure the controls for ensuring data integrity. Quality agreements or service level agreements should capture relevant aspects with defined responsibility of all partners involved. Thorough due diligence and constant monitoring of partner site activities will ensure that the data generated are valid and reliable.

To the best of my knowledge, many firms have taken data integrity issues seriously and have already sprung into action. Specialized internal investigation teams, who are primarily responsible for a detailed review of data concerning research, analytical, manufacturing, root cause analysis, deviations, CAPAs, logbooks, raw data, system SOPs, computer data and other such critical data generated throughout the lifecycle of a product, have been formed. Many opt for inviting external auditors (third-party) to get unbiased feedback since this is highly recommended and appreciated by regulators and health authorities. Many large firms are working towards having electronic quality management system (EQMS) to ensure control at enterprise level to maintain quality compliance as per requirements of FDA, EMEA and other health authorities.

The pharmaceutical industry has realized that compliance to data integrity not only ensures a good reputation but at the same time also makes good business sense since it saves on the extensive cost of remediation for being compliant.

I would conclude my blog by suggesting a simple work ethic - “Do as you say and say as you do”.

That’s the least we can do as pharma professionals working in an industry that demands a high adherence to ethical principles. See you soon with my next blog on continuous manufacturing!!

Elemental Impurities Compliance - Good Example of Quality by Design (QbD)

The implementation of requirements concerning elemental impurities in a drug product is a good example to understand how quality is built into the product to ensure the safety of the product. 

At the outset, I would like to share some basic aspects of elemental impurities. These are most often added during synthesis and manufacturing of an API or excipients as a catalyst, but it may also be present at the source in the raw material. Sometimes an element may leach out, during processing/manufacturing from the equipment used during manufacturing. It may also leach out during stability testing from the packaging component. These impurities have no therapeutic benefit but have a potential toxic effect and, hence is required to be removed to the extent possible. If it cannot be completely removed, then it must be controlled within a permissible or acceptable limit. There are different classes of elemental impurities defined in ICH, USP, EP and other Pharmacopeias. The classes and limits are defined according to the inherent risk associated with it based on their chemical structure while also additionally considering the dosage form and route of administration. Guidelines and general chapters in USP and EP, on elemental impurity came into existence as the previous method of heavy metals testing was a qualitative method that was not very specific and that was not designed to eliminate the risk associated with many elemental impurities. Another objective was achieving harmonization between ICH and official book of standards like USP and EP.

As per the new requirement, the drug product manufacturer must ensure that the elements are monitored in their product after an appropriate risk assessment and the limits are based on an approach of establishing permitted daily exposures (PDEs) for these impurities in a drug product. This led to gathering information from the API and excipient manufacturers and even requesting them to identify and quantify these using validated methods if they cannot be completely removed. API and excipient manufacturers were expected to report the levels to the drug product/finished formulation manufacturer for appropriate risk assessment. 

When these requirements were introduced by ICH, USP, EP, and other pharmacopoeias, there were a lot of challenges faced by Industry. These tests were not routinely done and were not part of the specification for many API and almost all the excipients. The certification from the suppliers only claimed that these were not present in their product as it was not added in the manufacturing process. Other sources of contamination were never considered or evaluated. Most excipients were not tested and hence finding the actual metal concentration was not possible. The risk assessment for the product was not easy due to the lack of data. The finished product manufacturers would need to conduct extensive testing on the finished formulations/ drug product to ensure compliance. There were technical challenges too. The method to test the elemental impurities (like ICP-MS) was not commonly employed and the instruments were also expensive. Not many contract laboratories were equipped to conduct this test. Training was required to use and for qualification of the new equipment and methodology and all these were time-consuming.

IPEC America developed a template for exchange of information between the vendors or suppliers of API and excipients and the manufacturers of the finished product. This template acted as a guiding tool to all stakeholders involved as it resulted into a better understanding of the metal impurity level that led to a meaningful risk assessment. 

It was clear that for implementation the industry had to develop an action plan. It became extremely critical for the pharmaceutical industry to communicate extensively with the API and excipients manufacturers. A collective approach of implementation was highly desired. Suppliers had to gear up and ensure that this did not lead to any disruption of the supply of materials. Drug product manufacturers had to get equipped for conducting a risk assessment of each metal which could potentially be present, setting a specification based on permitted daily exposure limit and testing by a validated method (Pharmacopeia or alternate developed new method). 

The good news is that the industry was able to manage all these challenges and ensure compliance to requirements of elemental impurities by the time it was mandated for registration of new drugs or new generics by various countries and health authorities. Compliance for products which were already registered and in the market was also achieved in a phase-wise manner and updated information was provided from time to time, product by product, to health authorities by most firms.

The elements which make it a good case study for QbD is listed below:

1)      Implementation of this required the industry to work with a holistic approach, to identify the sources of contamination through which an element would be introduced into the product - such as from APIs, excipients, packaging components, water source, equipment’s or interactions between the dosage form and packaging component.

2)      It emphasized heavily on risk-based evaluations and establishing control strategies only after thorough risk assessment.

3)      It required working with a data-driven approach in terms of evaluating both the generated information and any published data available on the elements and its toxic potential.

Regulatory professionals may have experienced the challenges and would agree with me on the point that ensuring compliance for elemental impurities was a long process that necessitated working on the principles of QbD to achieve desired outcome. For complete information about the elemental impurities test and methodology please refer to ICH Q3D, USP general chapter <232> and <233>.

My next blogs will be on data integrity and continuous manufacturing. See you soon!!