Felicity Thomas is Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

Insights into underlying mechanisms of ASDs

Researchers from the University of Basel in Switzerland and The Peoples’ Friendship University of Russia (RUDN University), investigated the underlying drug absorption mechanisms of amorphous solid dispersions (ASDs), proving the effectiveness of a novel, particle-forming ASD drug-delivery system for poorly soluble compounds (1).

 employed a model ASD formulation of efavirenz, which is an antiretroviral medication that is classified on the biopharmaceutics classification system as a class II drug—one with poor solubility but high permeability. The model formulation comprised hydroxypropyl methylcellulose phthalate (HPMCP) as a polymer with sucrose palmitate and polysorbate 80 as surfactants in a hot-melt extrusion process.

Sixteen healthy male patients were included in the study and were randomized to receive efavirenz in three different ways: intervention 1 was ASD of efavirenz (50 mg) as a capsule with 500 mL buffer solution; intervention 2 was dissolved ASD of efavirenz (50 mg) in 500 mL of buffer solution, forming drug-rich particles; and intervention 3 was efavirenz (3 mg) solution in a 500 mL buffer solution. The study participants were randomly selected to receive the interventions in different orders (either 1-2-3, 2-3-1, or 3-2-1) and a washout period of 14 to 21 days was performed between interventions.

Blood samples were obtained pre-dose and at multiple time points post-dose so that the plasma concentration of efavirenz could be determined through bioanalysis techniques. The pharmacokinetic profiles of efavirenz plasma concentrations compared to time were used as the primary study endpoints, with further pharmacokinetic analysis and modeling used as secondary endpoints. Furthermore, study results were compared with existing pharmacokinetic data available for a marketed formulation of efavirenz (Stocrin).

Based on the study results, it was found that the dissolved ASD of 50 mg of efavirenz (intervention 2) pharmacokinetically behaved nearly identically to the solution of efavirenz 3 mg (intervention 3). Therefore, intervention 2, which comprised a supersaturated aqueous solution containing drug-rich particles, behaved as a solution, and assuming passive absorption, the researchers deduced that the dissolved drug concentration in the intestine of intervention 3 was higher by a factor of 16.7 than intervention 2.

As a result of the drug concentration exceeding that of the aqueous solubility of efavirenz, it was concluded that drug-rich particles from ASDs are efficient oral drug delivery systems and drug absorption was fast and complete in humans. Additionally, the findings of the study confirmed the conceptual models of how drug molecules are released from ASDs and how they are subsequently absorbed into the intestinal tract.

Non-classical nucleation theory and application on ASD design

A group of international researchers (from Northern Ireland, China, Switzerland, and the United States) have recently reviewed the potential theory behind the formation of drug-rich phases of ASDs with a focus on non-classical nucleation (2). In the study, Kaijie Qian 

 specifically assessed the associated thermodynamics and kinetics of the formation of drug-rich phases from the dissolution of an ASD, as well as the in-vitro permeability enhancement and 

 bioavailability enhancement of the ASD formulation, among other aspects associated with drug-rich phases.

Elaborating on the mechanistic understanding of ASDs solubility, dissolution, and potential phase separation process during dissolution and storage, the researchers found that if amorphous drug particles are suspended in solution, the drug concentration can temporarily reach beyond the drug crystalline solubility threshold, as a result of their higher Gibbs free energy, and achieve a higher solubility than their crystalline counterparts. The resultant high supersaturation of drug solution leads to phase separation, which the researchers noted will typically happen via a classical nucleation and growth process.

However, as a result of the imperfect miscibility of drug and excipients, there is the possibility for an amorphous-amorphous phase separation (AAPS) phenomenon to occur during manufacture or storage of ASDs. The researchers revealed that several models have been described on the drug-polymer-water interactions, in relation to moisture/solvent presence. Using the same concept, the researchers found that when dissolving the ASD in water the presence of excipients played an important role in the drug’s phase separation. Furthermore, it was found that certain excipients can kinetically stabilize the drug-rich metastable phases of ASDs for a considerable period of time, which may promote oral absorption of the drug due to high concentration levels in solution. Additionally, it was highlighted that the properties of polymeric excipients were important to drug permeability enhancement of ASDs.

Based on their work, the researchers suggested that the enhanced oral bioavailability achieved with supersaturated ASD solutions is aided by the excipient-assisted formation and stabilization of drug-rich metastable phases, which follow a non-classical nucleation pathway. ASD formulations that are designed to enable synergistic effects of a variety of different mechanisms could provide benefits for drug oral absorption and, as such, future medicine development, the researchers concluded.

, 13 (3) 401 (2021).
2. K. Qian, et al., 

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Articles

Recent research has highlighted the underlying mechanisms of amorphous solid dispersions and theory behind the formation of drug-rich phases.

Recent Research on Amorphous Solid Dispersions

Outsourcing time-consuming and costly services is becoming increasingly popular within the bio/pharma industry. The right contract development and manufacturing organization (CDMO) can not only provide the best equipment for certain tasks but can also provide a wealth of expertise to provide the best possible chance of success.

To learn more about best practices for selecting an outsourcing partner and the questions that should be posed to a sponsor company when approaching a method development project, 

 spoke with a panel of experts. The panel included Emma Leishman, manager, Advanced Analytics, Avomeen; Alex Wheeler, senior technician, and Louise Rigden, technical documentation officer, both from Wickham Laboratories; Rebecca Coutts, general manager, and Amanda Curson, head of Analytical Development, both at PCI Pharma Services; Vincent Thibon, technical development lead, RSSL; Jerry Mizell, senior director, Analytical Services, Metrics Contract Services; and Anders Mörtberg, analytical chemist, Recipharm.

 Could you provide some best practices for selecting the optimal outsourcing partner for method development?

 Finding an outsourcing partner can be tough—nobody wants to be left hanging on a critical project due to outsourcing delays. A good outsourcing partner will understand this and will do their best to meet your needs. Communication is key. You should be able to talk directly to the scientists and technical directors who will be overseeing the project. That way, the project can get started correctly with everyone on the same page.

When selecting an outsourcing partner, the experience, expertise, and equipment capabilities of the outsourcing lab should be assessed. If the method is for filing with a regulatory authority, then quality systems should be part of the initial assessment. It is especially promising when a partner has prior experience with similar methodology or even recommendations from previous clients.

 Before contacting a contract research organization (CRO), the company should establish exactly what aspects of the method development can be done in-house and what needs outsourcing. Once it has been established what testing is required, the relevant stakeholders internally should familiarize themselves with the regulatory guidelines of these tests to provide at least a basic understanding of the testing requirements. By having this knowledge, it will make communicating the company’s needs easier and ensure the chosen CRO can offer the best-suited and most robust testing.

When first reaching out to potential partners, important questions to ask are what they can offer you, which tests they have validated and have experience with conducting regularly, and what regulatory certificates they have. For a good manufacturing practice (GMP) product to successfully go to market, it is imperative to ensure that the testing is performed by a GMP accredited CRO.

Also, and possibly most importantly, expectations around timelines should always be discussed before engaging in testing as just because a company can offer the testing does not always mean their availability will match the required timeframes for any given project. A good recommendation is to establish expectations early, communicate clearly, and ensure there is contingency built into your project timeline to deal with any issues that may arise.

 Moreover, the experts in a CRO can advise on regulatory requirements and therefore assist in advising on the testing required as it can sometimes be difficult to interpret the guidelines. Consultancy services can be invaluable to a smaller drug development organization, or to clients such as student researchers who may not have experience of the industry.

 Best practices for selecting the best outsourcing partner for method development include picking a partner who has the following: previous practical experience in developing methods for particular dosage forms; a number of successful validations as a result of initial method development over the past five years; available equipment with multiple models, capacity, and resources that will be allocated; the ability to deliver within required timelines; the ability to provide summary development reports or copies of data required to support regulatory submissions; a good history with the regulatory authorities; and lastly, the ability to safely handle certain compounds, for example, potent molecules.

 In addition to the outsourcing partner complying with regulatory standards (e.g., company standards, GMP approvals, quality compliance procedures, and auditing systems), we think that the correct outsourcing partner would ensure that there is good, clear communication and collaboration, and good planning to meet agreed timelines. With these practices, a strong relationship can be built as trust is key.

Key questions to consider when selecting a potential outsourcing partner include: Are the labs approved by the relevant regulatory body (e.g., FDA or Medicines and Healthcare products Regulatory Agency)? What technical knowledge and instrument capabilities are available at the CRO? Can they assist developing all the methods that are required? Can they develop the methods within the required deadlines?

 A company should ask for examples of previous development projects and what led to success. Detail should be given regarding the types of samples in which methodology was developed. For example, asking whether a company specializes in method development for inhalation, ointments, creams, liquids, or solid oral dosage formulations is an essential first question. Detail should also be given describing development experience with challenging molecules or formulations and how those challenges were overcome. For the initial meeting with the prospective CDMO, sponsors should interview chemists and ask for the strategies that would be employed when developing methodologies. This could include asking what strategy they use to develop a tablet dissolution procedure where the API is practically water insoluble.

 There are a few key questions that a drug developer should ask of a potential partner before entering a working relationship with them. These questions include do you have experience in similar projects to mine? Do you know what to do, and will your solutions work effectively? What is your track record in successful method development in my particular field or category, such as small molecules, or biopharma? What are your team’s qualifications? How many members of your team have in-depth expertise in my field? Do you have the necessary instrumentation and infrastructure to support me and my project? Do you have a GMP-certified laboratory? When can the work be finished? It is often the case that developers ask when the work can be started, but delivery is the key issue to consider. Are you a reliable and well-established partner that will still be around to be able to deliver the project? How will the method development work be documented? It is important to understand how and why specific method parameter choices were made by a partner. When the new International Council for Harmonisation guideline Q14 on method development will become effective, it is important the outsourcing partner is well versed with its implications for method development practices.

 August 2021 print issue: “F. Thomas, “Picking the Perfect Method Development Partner,” 

 Are there specific questions the outsourcing partner should ask too, before undertaking a potential method development project?

 Before undertaking a potential method development project, outsourcing partners may want to ask what data [are] available for review on the physical and chemical properties of the drug substance, also whether there is information on potential dosage form, strength, formulation information, and the phase of drug development. Additionally, they may want to ask if there is any previous analytical information or methodology available. For example, a client may require a method developed for the drug product and may already have developed drug substance methods that can be shared to help inform the drug product method development approach.

 First, the potential partner should ask is there a technical package for the API or drug product that describes the chemical and physical properties of both? Properties such as morphology, solubility (organic, aqueous, and pH range solvents), stability, and any forced degradation data should be requested along with methodology, and any associated validation reports. Having a solid technical package available when beginning development typically accelerates the development process.

 Questions we try to ask before undertaking potential method development projects include: What are the purposes of the method? How many formulations and are there any plans to extend formulations? When the method is used routinely, will it be used for quality control testing or investigation only? When is the method needed by and have other alternative techniques been considered? Is the method development project to improve an existing method or develop something from scratch?

 There are several questions that a drug developer can expect to hear from a potential partner. Answering these questions as comprehensively as possible is key to help the partner provide a realistic timeframe for delivery and deliver the best possible service. The key questions a drug developer should answer include what is the ‘pre-history’ of the project? Could you provide any background information and context to help understanding of the project’s needs? How do you intend to use the method once it is developed? Any method development project needs to address the actual use of the method to be successful. When does the project need to be delivered in full? Answering ‘as soon as possible’ should be avoided as it will necessarily lead to higher costs. What deliverables do you want to specify? What protocols, reports, or method descriptions do you want to receive on completion of the project?

 Potential partners should establish the intended use of the product. Knowing this can not only help the potential partner establish testing but could also help deliver valuable insight regarding how the product should be tested, specific quantities to test, and any regulatory specifications. If the CRO has tested similar products before, they may also be aware of additional requirements which had not already been considered, and capturing these issues early on could save time later.

The CRO should be asking questions specifically relating to the product. For instance, if the testing required is microbial limits testing, then it should be established if the product contains properties or constituents which might inhibit microbial growth during the product’s validation.

A timeframe should also be established early on, with the CRO confirming they have the capacity to perform exactly what the client has requested. If those targets cannot be met, it should be considered whether there is room to compromise on the timeline or alternatively, whether new methods or systems could be considered for validation to facilitate the project.

It is also critical that confidentiality and technical agreements are in place to provide guidelines for the relationship between the parties before any testing commences as this protects the customer and the CRO by establishing responsibilities and ensuring they are meeting regulatory and legal requirements.

 The purpose of the method must be established to guide the work. A method development scientist will ask questions to figure out the purpose. For example, who will be using this method? What sort of conclusions will be made based on data obtained from the method? Where is the method going to be used? At a single lab or transferred between sites? When will this method need to be implemented? Why is this method required? How has this testing been performed in the past? Does the method need updating to keep up with current standards?

The regulatory requirements and the timeline should be established to scope the work. Timelines to reach the end goal of the method need to be realistic—it is not possible to develop a method from scratch and validate it within a week. Obtaining detailed information on the analyte, the matrix, and the final purpose of the method assists with devising a customized and purpose-driven scope of work.


Supplement: Outsourcing Resources 2021
August 2021
Pages: 26–29

When referring to this article, please cite it as F. Thomas, “Picking the Perfect Method Development Partner,” Outsourcing Resources 2021 (August 2021).

There are some key questions that should be asked by both the sponsor company and the outsourcing partner before undertaking a method development project.

Picking the Perfect Method Development Partner

The oral administration of drugs has persistently been the preferred route of drug delivery for many years, mainly due to patient convenience and manufacturability of the dosage form. “Tablets are the most stable and used oral sold dosage (OSD) form on the market that allows for drug price reductions while also guaranteeing good production yields combined with patient compliance,” asserts Federica Giatti, compression technologist at IMA Group.

However, conventional immediate-release tablets are designed to release an active ingredient shortly after oral administration, which generally means a rapid absorption of drug occurs without any specific targeting of therapeutic action. Various methods have been employed to be able to manipulate the release of APIs in the body, in order to control the therapeutic efficacy of treatments, improve patient compliance, and reduce dose frequency.

Bi-layer tablets have been employed as a means of administering more than one API in a single dosage form to achieve controlled drug delivery. Although these dosage forms can offer key advantages, there are also specific complications and challenges that must be overcome to ensure success.

In the modern era, continuous scientific research into disease areas and multi-targeted approaches is opening a wide range of possibilities in pharmaceutical development and manufacturing, Giatti confirms. “The possibility to use bi-layer tablets offers some advantages that must be taken into consideration when developing a combination of two or more APIs in a single pharmaceutical form,” she says.

Some advantages of bi-layer tablets include the option of fine-tuning the availability of each API with the possibility of differentiating their release-times, being able to separate incompatible APIs, prolonging the medicine effect after administration, and reducing the dose frequency, Giatti highlights. For example, she continues, in elderly patients, the high number of tablets or medicines that may be required each day can impact quality of life or can lead to medication errors, so bi-layer tablets can be particularly beneficial for this patient population.

“Bi-layer or multi-layer can provide the delivery of more than one drug in one dose thereby adding convenience,” concurs Anthony Carpanzano, director of R&D at JRS Pharma. “Delivery in separate layers can avoid incompatibilities between the compounds that otherwise could not be prevented in a single monolithic structure. Multiple layers also allow for delivery of the components at different rates and visually, multi-layer tablets provide brand recognition.”

Formulating a bi-layer tablet is more complex than for a conventional monolayer tablet as two (or more) suitable granulations must be developed. “Generally, to have a blend suitable for compression, the powder should be free-flowing and uniform in terms of particle size distribution; it should be characterized by particles cohesive enough to lock and hold together but not too much so they can adhere to metal surfaces,” notes Giatti.

“Blend characteristics, such as compactability, flow, homogeneity, and low dustiness—to minimize ‘cross-contamination’ between layers—are important,” agrees Carpanzano. “Flow is especially important for layers two and beyond.”

By guaranteeing the blend characteristics, the final tablet should be uniform and defect-free, Giatti continues. “Compatibility is another crucial characteristic to be considered. If the APIs inserted in the formulation are incompatible, they must be separated in different layers and formulated with dedicated release,” she says. “Last but not least, the sufficient bonding between the two layers must be guaranteed even immediately after tableting and during storage, packaging, and shipping.”

To ensure a stable tablet process, when developing and manufacturing a bi-layer tablet, manufacturers must choose the correct tamping and pre- and main-compression forces, and formulation scientists need to select an excipient that is suitable for direct compression, which will allow for easy flowability, compression, and tableting of the blend, Giatti explains. “The tableting should be performed without any contamination between the two layers,” she adds. “[Formulators can improve the chances of being contamination-free] by choosing powder with a coarser particle size that can reduce blend volatility around the machine, and manufacturers assist with dedicated aspiration.”

Most of the challenges to overcome when developing a bi-layer tablet pertain to process or equipment issues, emphasizes Carpanzano, but other significant considerations include layer adhesion and layer thickness versus tooling shape—in particular, cut depth.

A greater amount of attention should be focused on the bonding between the two layers, asserts Giatti. “From a manufacturer point of view, this [bonding issue] can be solved by applying a slight tamping force in the first layer, whereas for formulators the inner features of all the excipient and APIs present (crystalline habitus, real density, particle size distribution) should be taken into consideration from the beginning,” she says.

But, for Giatti, the most significant challenge to overcome is in relation to incompatibilities of the ingredients. “Different release profiles and physical separation of the APIs should be ensured by choosing the relevant type and percentage of excipient(s) or manufacturing technology to use,” she states.

Additionally, the development of technologies designed for the compression of multilayer tablets has matured with systems now at the point of simply needing ‘fine-tuning’, reveals Carpanzano. “More development of compression coating or ‘tablet-in-tablet’ is ongoing,” he adds.

Software is available that can help developers in choosing the correct formulation, such as IMAGO (IMA Group), highlights Giatti. “This software consists of an instrument that acquires the data of the cells mounted in the machine, such as pre-main compression and ejection force, as well as tablet characteristics (weight, thickness, diameter, and tablet strength) to consider powder behavior,” she explains.

Other software exists that guide the choice of ratio and type of excipient, such as ZoomLab by BASF, Giatti continues. “The combination between these aids and the experience of the supplier and manufacturer, can improve and facilitate the choices of the formulators,” she says.

“Excipient selection for bi-layer tablets is as important as it is for single-component tablets, and there are instances when it is most important,” Gernot Warnke, global head of R&D at JRS Pharma stresses. “For example, when running a high-speed tablet press, the filling of the die with the blend to be compressed occurs when the die passes below the feed frame and the lower punch is drawn downward. This downward motion happens quickly and creates a degree of suction which aids in filling the die. This suction helps to compensate for materials with less than optimal flow in achieving uniform die filling and ultimately consistent tablet weight uniformity.”

However, Warnke warns, for multi-layer tablets, the benefits of the downward motion of the punch are only achieved for the first or lower layer of the tablet. “Any subsequent layers must rely solely on blend flow to fill the die cavity. It is therefore imperative to select excipients that impart the best flow characteristics to provide adequate flow characteristics to subsequent layers,” he says.

Selecting the optimal excipient for the first layer is also important to ensure the surface, after tamping, has a rough enough porosity to allow for adequate adhesion of the second layer, continues Warnke. “It has been shown that if the first layer is too smooth (due to makeup or excessive tamping) the second or subsequent layer will not adhere well and layers may separate with minimal agitation (i.e., during ejection, discharge, packaging, or over the shelf-life of the product),” he says.

“Due to the fact that the first layer [in a multi-layer tablet] is generally subjected to low compression forces, the formulation should be able to cope with further compression in the second phases of tableting without leading to a fragile tablet,” adds Giatti. Furthermore, selecting an excipient with good compressibility can improve the overall tableting output and help to overcome the potential problem of later separation and delamination and capping, she notes.

“To conclude,” continues Giatti, “the flowability of the formulation of the first and second layer should be good enough to not generate any issues during the feeding of the tablet press that could cause a reduction of output or [overall equipment effectiveness] of the manufacturing equipment.”

Widely encompassing regulatory factors are to be considered when approaching bi-layer tablets: following the correct good manufacturing practice approach to ensure a high-quality tablet is produced that complies with the standard customer specifications and pharmacopeial requirements, specifies Giatti. “At the same time, tablets must be defect-free, capping and separation of the two individual layers should be prevented, and the final tablet hardness has to be sufficient to cope with downstream processes or handling,” she adds.

A deep analysis of any incompatibility between the API and excipient is critical, and the cross-contamination among the layers should be avoided, asserts Giatti. “Finally, the two layers should be clearly separated to ensure the correct API release, to avoid undesired contamination, and for aesthetic reasons,” she says.

“Bi-layer (and multi-layer) products fall into the category of combination products, and thus must have a therapeutic ‘reason for being’,” states Carpanzano. “Clinical studies to support the combination must therefore be established and approved.” The analysis, method development, validation, and quality control of bi-layer tablets is more complex than for monolayer products and, as a result, can be a more time-consuming process, he notes.

Ongoing research into various disease areas that demand a multi-targeted approach is broadening the potential utility of bi-layer tablets for developers, asserts Giatti. “[Bi-layer tablets offer developers] a real chance to reduce the number of medicines being taken by a patient, increasing medication compliance on one hand, and reducing the potential for administration error on the other, which in turn increases the therapeutic effect of medicines being prescribed,” she says.

“In my opinion, multi-layer tablets are still under-utilized and can offer cost-effective alternatives to much more complex drug delivery options, both in immediate-release as well as in modified-release formats,” summarizes Warnke. “Even with the advent of 3D printing of tablets, multi-layer tableting remains a much cheaper option, especially in the case of high production volumes.”


Vol. 45, No. 7
July 2021
Pages: 32–34, 46

When referring to this article, please cite it as F. Thomas, “Formulating Tablets Layer by Layer,” 

Bi-layer tablets are an under-utilized option that can be employed to help reduce treatment burden, but their formulation is more complex than for conventional monolayer products.

Formulating Tablets Layer by Layer

The European Union’s good manufacturing practice (GMP) guide for sterile products, Annex 1, has been under review for some time, with the revisions being considered more along the lines of a rewrite due to the extensive and comprehensive nature of the changes. In a webinar, hosted by the Parenteral Drug Association (PDA) Ireland Chapter, experts outlined key changes, considerations, interpretations, and ways of implementing the revised guidelines (1). In this article, some of the fundamental insights from that meeting are summarized.

Pre-use, post-sterilization integrity testing (PUPSIT) is not a new requirement, explained Andrew Hopkins, director operation quality, Quality Assurance Audit and Compliance, AbbVie, ex-Medicines and Healthcare products Regulatory Agency (MHRA) regulator, and previous member of the Annex 1 working group. As there was no clear push from regulators or industry on the matter of PUPSIT previously, there is the misconception that it is a new addition brought in with the latest revisions; however, it has been included in the Annex 1 guidance since 1997, he revealed in the webinar.

PUPSIT specifically pertains to the integrity testing of the sterilizing filter and assembly. The reasoning behind why it is necessary is because filters can become “blind” and can mask flaws during post-use integrity testing, which would have an impact on the quality of a product. Work on the mechanisms and risks of filter flaw masking is being performed by PDA and the Biophorum Operations Group (BPOG); the results are not yet completed or published at the time of writing (2), but there has been some evidence of masking, which means it is an issue to be wary of, warned Hopkins.

In the latest revisions of Annex 1, however, the wording for PUPSIT is much more driven by quality risk management (QRM), which means that satellite navigation risk assessments cannot be used when risk assessments are performed. It is important to be completely honest about them and base them on scientific justification, emphasized Hopkins.

The contamination control strategy (CCS) is also based on QRM principles, with an emphasis on good design for equipment, facility, and processes in the first instance, then on well thought out procedures, and finally on

the monitoring system, Hopkins stated. The last sentence in the revised document, which says, “exclusively monitoring or testing does not assure sterility,” was highlighted as being of particular import by Hopkins (3).

Another aspect of the draft Annex 1 revision, that caught the attention of Hopkins, is the fact that there is discussion around how a CCS is a number of aspects that are put together rather than individual items, which would not achieve the required item in isolation. “So, it’s how all of those individual items work together to give you the overall CCS,” Hopkins added.

Furthermore, the revised guidance emphasizes the need for the correct people to develop the CCS (i.e., those people with the necessary technical and process knowledge). “I think that [aspect] is really important,” added Hopkins. “[The CCS] is not something that is developed by either the quality assurance (QA) manager, sat in his office, or the production manager, or one person, it is about making sure that all of the right people are involved.”

“The other key thing to realize,” Hopkins continued, “is that [the CCS] is supposed to be a dynamic process, and [the revised draft] talks to periodic reviews.” Based on his experience as a regulator, Hopkins’ opinion is that a periodic review tends to indicate an annual occurrence, at least.

Currently, the Annex 1 that is in place is “silent on the CCS” revealed Hopkins. However, this does not necessarily indicate that it is a new requirement, and, in fact, there was some talk of contamination control in the Chapter 3 GMP requirements that were brought into operation in 2015 (4), he added.

QRM principles, which are also discussed in the International Council for Harmonisation Q9 guideline (5), are important to bear in mind when approaching a CCS, asserted Hopkins. These principles are focused on scientific knowledge and protecting the patient, but also, are steering the industry to the fact that the level of effort put into the evaluation of risk to quality should be commensurate with the risk. “So, with steriles, we’re going to be tending toward that higher end of the risk element, but there may be bits that aren’t quite as important as other bits, so make sure you put the right work in at the right stage,” Hopkins confirmed.

The CCS needs to be a living document that is reviewed periodically, taking into consideration various feedback on processes, information on monitoring, or technological improvements that need to be included, and so on, to ensure that the strategy continues to work, Hopkins stressed. Importantly, the document should be written in a way that it is understandable to an inspector, and widening that out, it should be simple enough for everyone to understand, he summarized.

Despite there not being much change in terms of the Annex 1 revision and the requirements of aseptic process simulations (APS) for manufacturers, there is certainly now a lot more detail included in the guidance, revealed Greg McGurk, executive director Industrial Operations and Product Supply, Regeneron Pharmaceuticals, ex-Health Products Regulatory Agency (HPRA) regulator, and previous member of Annex 1 working group.

An aspect of the thought processes behind APS in the revised guidance is whether or not they are a true aseptic validation strategy or if they are an evaluation of the process and ongoing process controls, which led to the topic being moved in the guidance to the section where process monitoring is discussed, McGurk explained in the webinar. “When you consider [APS], they do form part of the overall CCS, so to speak, in that they are used to monitor those controls and minimize the risks associated with aseptic processes,” he said.

General aspects of the requirements laid out in the draft revision document are that manufacturers must represent the worst-case operating parameters in APS, which is nothing new, but the revision incorporates an element allowing for the use of surrogate materials, McGurk specified. “Typically, we haven’t seen the allowance of surrogate materials over the years,” he noted. “APS is a science-based approach, however, and so whatever material you are using should not inhibit growth and should not impact the capabilities to recover growth or contamination. So, if a surrogate material is used, it has to be based in good science.”

Processes should be imitated as closely as possible, with a requirement for all aseptic operations, manipulations, and interventions that routinely—and, in some cases, non-routinely—would occur, to be evaluated, McGurk stressed. “One aspect that has been incorporated into the revision is a section on more complex unit operations,” he said. The intent of the section was in relation to an attempt to achieve a continuous evaluation of processes from one unit to another. The guidance in the draft states that this should be avoided where possible, but under certain circumstances it can be justifiable, McGurk added.

Lyophilization evaluation expectations are more detailed in the revised guidance, McGurk highlighted. The loading, unloading, and chamber dwell time information are required, and manufacturers are required to replicate the maximum time between sterilization and lyophilization, as well as the maximum hold times post‑sterilization and lyophilization, he explained. All those aspects need to be incorporated into the overarching strategy, in addition to the largest number of trays that will need to be lowered into the lyophilizer, the longest duration of loading, the length of time the chamber may be open, and so on. “I think it is good that the draft does provide an additional degree of clarity around those expectations,” McGurk stated.

Additionally, the draft Annex 1 provides some definition around inherent and corrective interventions, McGurk continued. It is important to incorporate these interventions into the APS so they can be evaluated and addressed appropriately, but when designing or selecting the types of interventions to include, it is critical that the choice is not justified based on the facility design or process design, McGurk emphasized. “[Justification via facility/process design] is just not based on good science, it is not based on minimizing risk necessarily,” he said.

The draft Annex 1 provides some additional guidance on how to develop the APS strategy overall and includes the expectations of elements that must be considered in the strategy. “So, obviously it is necessary to identify and assess the worst-case container size, line speed, container closer, or all of those, and you have to look at all the variables,” McGurk specified. “If a bracket or matrix approach is being taken, then you should justify the choice of variables that are being incorporated into the overarching APS strategy.”

Volume and agitation are other considerations in the APS strategy. It is therefore important to ensure whatever volume is being used can contact all the equipment in component surface, and if agitation and/or inversion may be required to ensure full exposure to surfaces is achieved, McGurk explained. A consideration has also been incorporated into the revised draft of Annex 1 for anaerobic simulation, he added.

The revised guidance thus provides more clarity on APS, and it is dependent upon the application of QRM to evaluate what is necessary to ensure a robust assessment of the process is being performed, McGurk confirmed. Furthermore, there is mention of manual filling, which is high risk and should be avoided where possible, McGurk added. Again, the revised draft provides guidance and clarity on the expectations for such processes that are high risk.

Moreover, it should be noted that the target for APS is to have zero growth, so any contaminated unit will result in a failed process simulation, McGurk stressed. “There were some caveats in the Annex 1 previously, which allowed for a degree of failure,” he said. “However, when dealing with APS, it is imperative to understand what the failures are and to investigate the root causes of the failures.”

In determining the root cause of a failure, if a corrective and preventive action that impacts the APS is identified, then this will call into question every batch since the last successful simulation, and it may be necessary to perform the three consecutive runs again until success is achieved, McGurk stated. “So, there are multiple elements to incorporate within such investigations, and QRM is very much one of the key fundamental elements incorporated into the draft,” he summarized.

1. PDA Ireland Chapter, “Annex 1: Interpretation and Implementation of the Latest Revision,” Webinar, 11 March 2021.
2. T. Morris, et al., “PUPSIT and the Annex 1 Revision,” 

, 29 Aug. 2019.
3. EC, “Annex 1: Manufacture of Sterile Products,” Draft Guideline under Consultation, 

 [Accessed 23 June 2021].
4. EC, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Part 1. Chapter 3: Premises and Equipment (Brussels, 13 Aug. 2014).
5. ICH, Q9 Quality Risk Management, Step 4 version (2005).

When referring to this article, please cite it as F. Thomas, “Considering Annex 1 Revisions: Expert Insights” 

The draft revisions of Annex 1 are driven by a quality risk management approach and will provide more clarity and detail for manufacturers.

Considering Annex 1 Revisions: Expert Insights

In May 2021, the European Commission (EC) proposed a strategy on COVID-19 therapeutics for the European Union (1), which complements the already working EU Vaccines Strategy (2). This therapeutics strategy was aimed at supporting the development and availability of treatments for COVID-19, including ‘long COVID’, and just over a month after it was announced, the EC has already confirmed delivery of its first outcome (3).

So far, the commission has identified five promising candidates as COVID-19 therapeutics that are all already in advanced stages of development. “We are taking the first step towards a broad portfolio of therapeutics to treat COVID-19. Whilst vaccination is progressing at increasing speed, the virus will not disappear, and patients will need safe and effective treatments to reduce the burden of COVID-19,” said Stella Kyriakides, commissioner for Health and Food Safety in a press release (3). “Our goal is clear, we aim to identify more front-runner candidates under development and authorize at least three new therapeutics by the end of the year. This is the European Health Union in action.”

The five candidates identified by the EC will be prioritized for review, and it is hoped that three of the therapies will gain authorization by October 2021, permitting the final data demonstrate safety, efficacy, and quality. Four of the products identified are monoclonal antibodies, which are already under rolling review by the European Medicines Agency (EMA), and the fifth product is an immunosuppressant that is already authorized for use but would require an extension of use to incorporate COVID-19 treatment.

Eli Lilly’s baricitinib—already approved as Olumiant as a treatment for rheumatoid arthritis and atopic dermatitis—is the immunosuppressant being considered for an extension of marketing authorization for COVID-19 indication. The monoclonal antibodies under rolling review are the combination of bamlanivimab and etesevimab (Eli Lilly), the combination of casirivimab and imdevimab (Regeneron Pharmaceuticals and F. Hoffman-La Roche), regdanvimab (Celltrion), and sotrovimab (GlaxoSmithKline and Vir Biotechnology).

Next steps for the commission are to broaden out the pool of potential candidates to 10 therapeutics by October. These therapies will be selected with the help of an expert group on COVID-19 variants—a high-level group on the health emergency preparedness and response authority (HERA) and HERA incubator—that was formed earlier in 2021 (4).

The selection criteria for the broader portfolio of therapies will be defined by the HERA expert group and will be agreed with the EU member states. Product categories will be identified by the working group and then the most promising candidates from each category will be selected so that it will be possible to map out the continuous development of a diverse range of therapies in a dynamic fashion. It is also hoped that the broader portfolio will provide treatment options for different patient populations and different stages and severity of disease.

Depending on research and development outcomes, EMA should start further rolling reviews of other promising therapeutics by the end of 2021, the commission revealed (3). Furthermore, to ensure supply can meet demand in the cases of potential approvals, the commission is holding a virtual matchmaking event in July (5). The event will bring together stakeholders across the whole EU COVID-19 therapeutics value chain with the aim of accelerating the development and upscaling of COVID-19 therapeutics.

1. EC, “Coronavirus: Commission Proposes EU Strategy for the Development and Availability of Therapeutics,” 

, Press Release, 6 May 2021.
2. EC, “Coronavirus: Commission Unveils EU Vaccines Strategy,” 

, Press Release, 17 June 2020.
3. EC, “COVID-19 Therapeutics Strategy: Commission Identifies Five Promising Candidate Therapeutics,” 

, Press Release, 29 June 2021.
4. EC, “Register of Commission Expert Groups and Other Similar Entities: High-Level Group on the Health Emergency Preparedness and Response Authority (HERA) and HERA Incubator (E03770),” 

 [Accessed 5 July 2021].
5. EC, “Development and Production of COVID-19 Therapeutics,” Virtual Event Notification [Accessed 5 July 2021].

When referring to this article, please cite it as F. Thomas, “Identifying Promise” 

Five therapeutic candidates for the treatment of COVID-19 are identified as promising by the European Commission.

Identifying Promising COVID-19 Therapies

Counterfeit pharmaceutical products are a global issue that impacts all stakeholders in the pharma industry and poses a potentially lethal threat to patients. Globally, measures have been put in place to help tackle the problems posed by counterfeit medicines; however, as the United Kingdom is now no longer a part of the European Union, concerns have been raised that the country could be left exposed to an increased prevalence of counterfeit medicines infiltrating the market.

Anti-counterfeiting measures are expected to become stricter in the future to ensure patients are protected and with the rising levels of data that will be required to be managed and processed, blockchain could offer a suitable solution to industry. To learn more about the issue of counterfeit medicines and the potential benefits that can be gained from using blockchain as an infrastructure technology, 

 spoke with Raja Sharif, CEO and founder of FarmaTrust—a provider of blockchain and artificial intelligence (AI) provenance systems for the pharmaceutical and healthcare sectors.

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Pharmaceutical Technology discussed the potential increased risk of counterfeit medicines in the UK post-Brexit and how blockchain could be a useful tool to tackle the issue.