Susan Haigney is lead editor of Pharmaceutical Technology and Pharmaceutical Technology Europe.

Susan Haigney

	Gene therapies are becoming a fast-growing area in the biopharmaceutical industry, creating a crowded pipeline of products in need of manufacturing. FDA expects the agency will receive more than 200 investigational new drug applications for cell and gene therapies by 2020, with the agency predicting that it will be approving 10–20 cell- and gene-therapy products each year by 2025 (1).

	Because gene therapies use the patient’s own body to manufacture the active ingredient, the treatment is specific to that patient. This tailoring can often be a more effective and longer-lasting treatment, according to Chris Murphy, general manager for viral vector services at Thermo Fisher Scientific. “Because of these developments, novel, life-changing therapies are being realized that may transform the lives of patients in need.”  

	This growth is causing contract development and manufacturing organizations (CDMOs) to take a look at their portfolios as their clients require more and more biologics-related services. Catalent has been focused on the clinical pipeline of gene therapies and anticipating the need for commercial manufacturing. “There is an abundance of gene therapy product candidates in the pipeline, and on the heels of market approvals of gene therapy products in 2017 and the influx of venture capital funding for gene therapy companies, FDA approved a second gene therapy this year. We see this as a watershed moment, where gene therapies are gaining regulatory acceptance and setting a precedent for other programs in the pipeline,” says Bernie Clark, vice-president, marketing and strategy, Catalent Biologics & Specialty Drug Delivery.

	According to Clark, outsourcing the manufacture of gene therapies requires relatively low volumes to fulfill demand, making it an attractive option. To better service its clients’ outsourcing needs in this area, Catalent acquired Paragon Bioservices, Inc., a viral vector development and manufacturing company for gene therapies with expertise in adeno-associated virus vectors, in May 2019 (2).

	Clark believes the acquisition will help Catalent accelerate its growth. “Paragon offers its partners GMP-compliant manufacturing capacity, scale-up expertise, and customized downstream processing without the added time, costs, and risks of building a new viral facility,” says Clark. “The acquisition also brings complementary capabilities that will fundamentally enhance our biologics business and our end-to-end integrated biopharmaceutical solutions for customers. We have also gained the experienced leadership and dedicated team at Paragon, who will continue to run the business going forward, bringing their expertise and capabilities to the Catalent family.”

	Thermo Fisher Scientific Inc. took a major step into the viral-vector manufacturing arena with the announced purchase of Brammer Bio, a leading viral vector CDMO, with 600 employees and locations in Massachusetts and Florida. The purchase agreement, announced in a March 24, 2019 press statement, is for approximately $1.7 billion in cash. Brammer Bio joins Patheon, acquired in 2017, and Fisher Clinical Services, which have been combined to form the Thermo Fisher’s Pharma Services business (3).

	The acquisition enhances the company’s pharmaceutical and biotechnology customer value proposition by combining cell-culture media, single-use bioprocessing capabilities, analytical instruments, and related consumables. “Brammer Bio is an exciting addition to our Pharma Services business. By sharing our combined capabilities, expanding commercial scale and broadening deep customer relationships, we will strengthen our position as a trusted partner to our pharma and biotech customers. We will accelerate advancements in gene and cell therapy, meet the increasing demand of the customers we serve and bring life-changing medicines to patients in need,” says Murphy.

	Viral vectors are crucial to gene therapy because they deliver the therapy into the patient. “Viruses are evolutionarily designed to enter mammalian cells and reproduce themselves. Gene therapy harnesses this feature to transport the genetic material-or ‘active ingredient’-to target tissue or cells. Viral vectors are engineered to be safe for humans and can target specific cells or tissues in our bodies to maximize the effect of the treatment,” says Murphy. Thermo Fisher Scientific’s acquisition of Brammer Bio’s viral vector process development and manufacturing leverages capabilities in the company’s biologics business.

	Clark also emphasizes the importance of viral vectors. “During gene therapy biomanufacturing, cells package the therapeutic genetic material into viral vesicles and secrete the vesicles into the media to be purified, then undergo formulation development to be ultimately filled into a vial or syringe,” says Clark. According to Clark, however, few innovators have the capacity, expertise, or resources to manufacture viral vectors. Catalent’s acquisition of Paragon helps the company manufacture viral vectors for their clients. “There are several types of viral vectors that can be utilized for gene therapy. Adeno-associated virus (AAV) is the vector most commonly used today in clinical trials and approved gene therapies, due to its safety and tissue-specific targeting abilities, and Paragon is one of the leading development and manufacturing providers for AAV vectors,” says Clark.

	In May 2019, Thermo Fisher Scientific announced that it is investing more than $50 million into its global bioproduction capabilities. The expansion will provide additional capacity for manufacturing single-use bioprocess container (BPC) systems. In Cramlington, United Kingdom, the company will expand assembly capacity and add BPC systems manufacturing. The proximity of these capabilities to customers in Europe will shorten lead times and improve overall global efficiency, according to the company (4).

	In the United States, the company will expand cleanroom space for BPC chamber and related assembly production processes at its site in Logan, UT, and further expand capacity at its site in Millersburg, PA. Construction is expected to be completed by the end of 2020.

	“The demand for our bioproduction products and services continues to outpace the market,” said Cory Stevenson, president of Thermo Fisher Scientific’s bioproduction business, in a company press release. “These investments will expand capabilities across our existing bioproduction network while we look to extend our footprint into new regions to meet increasing customer demand for our industry-leading single-use technologies.”

	To further develop its biologics offerings, Catalent is launching OneBio Suite, a new offering for the integrated development, manufacturing, and clinical supply of biologic drugs. The Suite is designed to address challenges that arise when accelerating programs to clinic or market, while also Â­reducing Â­complexity and risks from projects. The OneBio Suite is built on Catalent’s track record in biologic drugs development, which includes more than 115 global clinical trials and 11 commercially marketed monoclonal antibodies using the company’s GPEx cell line development technology, and 20 approved products through fill/finish and commercial supply to global markets, the company reports. According to Clark, the company has multiple initiatives in the works to shorten timelines and increase efficiency (5).

	“Time is often lost for sponsors on the path to clinic from contract negotiation, site inspections, handoffs, and poor communication between multiple vendors,” commented Clark in a press statement announcing the service. “Through our new OneBio Suite, Catalent is uniquely positioned to provide an integrated offering that can accelerate biologic development potentially shaving weeks to months off standard timelines and allowing our customers to get to clinic and market faster.”

	1.  FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D. and Peter Marks, M.D., Ph.D., Director of the Center for Biologics Evaluation and Research on New Policies to Advance Development of Safe and Effective Cell and Gene Therapies,” 

	2. Catalent, “Catalent To Acquire Gene Therapy Leader Paragon Bioservices, Inc. for $1.2 Billion,” Press Release, April 15, 2019.

	3. Thermo Fisher Scientific, “Thermo Fisher Scientific to Acquire Brammer Bio, a Leader in Viral Vector Manufacturing,” Press Release, March 24, 2019.

	4. Thermo Fisher Scientific, “Thermo Fisher Scientific to Invest $50 Million to Expand Bioproduction Capabilities,” Press Release, May 20, 2019.

	5.  Catalent, “Catalent to Launch OneBio Suite For Integrated Biologics Development, Manufacturing and Supply at BIO International 2019, Press Release, May 23, 2019.


	Vol. 43, No. 7
	July 2019
	Pages: 52-53

	When referring to this article, please cite it as S. Haigney, "Gene Therapies Propel Outsourcing Investment," 

Articles

The increasing growth in the cell- and gene-therapy markets is inspiring CDMOs to expand their services in this emerging biologic drug arena. 

Gene Therapies Propel Outsourcing Investment

 spoke with Roger Croucher, senior manager, R&D projects, at Catalent Pharma Solutions; Daniel M. Bowles, senior director, chemical development, at Cambrex; and Kurt J Kiewel, director, new product development and analytical services, also at Cambrex about best practices for a successful technology transfer.

 What are the first steps that should be taken when starting the process of tech transfer?

The early transfer of information between companies is critical to a successful process transfer. At the RFP [request for proposal] stage, the receiving site should review the information provided and set up a teleconference to fully define the goals of the transfer and discuss the information provided in detail.  The discussion between the technical staff on both sides helps to fill in any gaps in the information and to eliminate any ambiguities in the RFP and assumptions in the proposal.  Early alignment between parties allows a proposal to be tailored to the precise goals of the program and reduces unnecessary back-and-forth during the proposal generation process.  When possible, representatives from the receiving site should travel to the sending site in order to witness key operations first hand.

 The first step in allowing for a successful tech transfer is to evaluate the overall organizational impact in terms of operations, analytical, and quality. Then, the customer should provide a robust technical transfer information packet to the contract development and manufacturing organization (CDMO) to ensure all pertinent information is shared. Where a robust information packet is not available, a risk management approach and governance reviews become even more important. This information packet will include GMP [good manufacturing practice] batch records, special processing items (i.e., there are important processing steps that can be gained by talking to the actual operators, scientists, and engineers that played a role in the initial work performed, then these items are critical pieces of information that can make the difference in having a successful tech transfers), development reports (ranging from small lab-scale), and specific methods, such as in-process moisture, excipient release, and finished process testing. Equipment variability is also important (like-for-like equipment may or may not be available); working with a CDMO that has the experience in accounting for such variability, ensuring that the right size of equipment is available, and that the operating procedures for the specific project are confirmed as suitable and/or revised is a key element to a successful tech transfer.

 Should both entities be involved in developing the tech transfer process?

Yes. Subject matter experts (SMEs) from the transferring site and the recipient site should be a part of the handover teams. In my experience, most successful transfers involve an intermediary from the transferring site to ensure the successful transfer of documentation, etc. The technical team from the customer’s company have the knowledge of the product and processes involved, while the CDMO’s technical team understands the available site infrastructure capacity, technologies, and equipment. Marrying these two groups, and their areas of expertise, is critical to a smooth transfer and a shared understanding of the product.

	Sponsor companies will often have to consider many factors before they decide whether to produce a product in-house or to outsource. This decision may include factors such as how their global assets are being utilized, how efficiently they can produce now and in the future, and whether their own manufacturing network or that of an external contract manufacturing organization (CMO) or CDMO offers the better scalability to meet the sponsor’s aspirations for the product. The period before work commences, sometimes referred to as the planning horizon, therefore may be much greater for internal transfers than it is for the CMO or CDMO and can even be considered strategically by the sponsor company. If the decision is to use an external vendor, then an assessment or selection process is required to choose the correct partner, and that will often include an evaluation of what efficiencies or other benefits can be expected by outsourcing. This, in turn, requires some degree of disclosure to potential partners, and careful assessment by the sponsor company. Commercial terms need to be reached and, of course, an agreement to be made on how the tech transfer process teams will work together, including detailed comparisons of how policies and procedures compare. This naturally takes time and careful planning and may lead to the program starting later than it may have for an internal transfer.

 The receiving site should drive the transfer process, as it will ultimately be responsible for adherence to internal SOPs [standard operating procedures] and the final outcome of the transfer. The manner of transferring a specific technology or process from site to site should not be developed in an ad-hoc manner, but instead by following a clear, well-defined, SOP-driven method, regardless of whether the transfer is within a company or between a sponsor and CDMO.

	Inter-company transfers should start at the early development stage with an understanding that the process is being developed for transfer to a known inter-company site, and unit operations should be developed with the full knowledge of both sites’ capabilities. Additionally, analytical methods should be developed for instrumentation which has been harmonized between sites in order to streamline method transfer. 

 What are some best practices and challenges in technology transfer, and how are these addressed? Are there specific considerations when it comes to large-molecule products/processes versus small-molecule?

 One of the key challenges facing technology transfer for manufacturing is the difference between equipment and specific reactors at different facilities. For internal transfers within a company, standard practice should be that the development work done at the developing/sending site is carried out with careful consideration for the equipment capabilities of the receiving site-a true one-company approach.

 Time-to-market constraints can be challenging, as can insufficient documentation of processes, and key equipment capabilities. The main way to overcome these challenges and ensure a successful tech transfer is by establishing open communication streams between the sponsor and the CDMO, along with regular project reviews and updates. Having strong project management and technical teams will help move the project along to completion efficiently too, because the collective wisdom and experience of the team can overcome most problems given enough notice. While timelines are a key driver to product development, small investments in process improvement or early formulation development to improve product performance can lead to substantial savings later, as well as reveal opportunities for improved market positioning. Given the number of products a CDMO works on every year, innovators should expect their CDMOs to provide thoughtful input into development throughout the life of the product.

	The key to any successful tech transfer is the understanding that each molecule is unique and will have its own set of challenges. How a CDMO prepares for any foreseen and/or unforeseen challenges can determine the molecule’s success. Utilizing a risk management approach throughout each stage of the project will assist in airing, addressing, and overcoming challenges as the program moves through each phase of its introduction and throughout life.

	When referring to this article, please cite it as S. Haigney, "Successful Technology Transfer," 

Pharmaceutical Technology spoke with Roger Croucher, senior manager, R&D projects, at Catalent Pharma Solutions; Daniel M. Bowles, senior director, chemical development, at Cambrex; and Kurt J Kiewel, director, new product development and analytical services, also at Cambrex about best practices for a successful technology transfer. 

Successful Technology Transfer

Innovation in the bio/pharmaceutical industry brings success to pharma companies and new options for patients. New treatments and therapies, however, often come with new and/or additional analytical testing requirements. Many bio/pharmaceutical companies don’t have the knowledge, experience, instruments, or personnel to perform such testing; therefore, many analytical processes are outsourced to contract research, contract development, or contract manufacturing organizations (CROs, CDMOs, CMOs). And outsourcing of these and other services is expected to grow in the coming years (1).

	So how can contract laboratories serve the pharma industry? 

 spoke with Kimberly McClintock, executive vice-president at Metrics Contract Services, which offers method development and validation for small-molecule drug substances and drug product stability and release testing including on-site microbial testing; and Patrick A. Tishmack, PhD, analytical services general manager at AMRI West Lafayette, which offers both small- and large-molecule analysis, about the benefits of outsourcing analytical processes and testing. 

Why should pharmaceutical companies outsource their analytical processes?

One of the main reasons to outsource laboratory testing is to access expertise and instrumentation. It may not be feasible for pharmaceutical companies to purchase and operate specialized equipment themselves for a limited number of programs. Contract labs support hundreds of programs, making significant investments worthwhile and enabling them to hire and retain qualified, experienced staff for specialized testing. Examples of this include inductively coupled plasma-mass spectrometry (ICP–MS) and inductively coupled plasma-optical emission spectrometry (ICP–OES), which are used to detect elemental impurities.

	Working on a wide variety of programs gives contract labs an advantage for problem solving and regulatory compliance. Frequent inputs from global regulatory agencies and client quality departments give contract labs a strong sense of industry expectations and numerous examples of how to plan, execute, and report method development and testing that is acceptable for submission.

 Certain analytical techniques are more conveniently outsourced because they may be tedious or require significant overhead or training that could distract from a company’s focus.  This might include potent compounds, controlled substances, or other special handling requirements such as inert atmosphere.

	Virtual companies that do not have any internal analytical capabilities usually call on one or more contract research organizations to do all of their analytical testing.

	Larger pharmaceutical companies may want to outsource certain types of analytical testing to be done in parallel to internal studies for validation or troubleshooting.  Outsourcing is also a good way for a pharmaceutical company to expedite development timelines or to move lower priority development out of their laboratory so that there will be some progress when it eventually becomes a higher priority.

 Which small-molecule analytical services should pharma companies consider outsourcing?

 Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry are commonly outsourced because these capabilities are typically quite expensive to acquire and maintain. Both techniques usually require experts to properly maintain the instruments and to implement advanced applications that will obtain maximum value from the techniques.

	Elemental analysis and metals analysis are very commonly outsourced, particularly if GMP compliance is needed.  Carbon, hydrogen, nitrogen, and sulfur analyses are relatively simple to perform, which means that high volume is the only economical way to use the instrument.  Metals analysis by ICP–MS or ICP–OES may be more conveniently outsourced due to the acid hydrolysis procedure needed for sample preparation and the instrument maintenance requirements.

 Which large-molecule analytical services should biopharma companies consider outsourcing?

 Mass spectrometry is typically used for peptide mapping and protein sequencing, which requires a high-performance instrument and an experienced scientist. 

	NMR spectroscopy of large molecules is still a very specialized technique that requires a highly skilled scientist with specialized training to collect good quality data and to properly interpret the complex NMR spectra.  Therefore, relatively few CROs have this capability.

	Capillary electrophoresis, particularly combined with mass spectrometry, is a high-value analytical technique for most biologics and larger molecules.  This technique is very useful for difficult separation and characterization procedures.

	Cell-based assays can be quite difficult to develop and validate, so an experienced CRO will expedite biologics development and preclude the need to invest in the specialized infrastructure required for maintaining cell lines.

 What are the downsides to outsourcing analytical services?

 Analytical methods and results are a critical part of product development, so outsourcing this work could create a gap for the pharmaceutical company.  A strong contract lab partner will make sure the sponsor understands more than just the values reported. For example, the contract lab will convey observations made during dissolution since these can be critical to assessing whether the formulation and process are robust.

	Best practices for outsourcing analytics

 What are some best practices for data integrity and tech transfer when it comes to outsourcing analytical services?

 It is a tech transfer best practice to completely evaluate method(s) being transferred for method competency and successful transfer.

A highly competent quality unit is a key indicator that the CRO knows what it takes for appropriate regulatory compliance.  A good indicator that a CRO has adequate control over their processes is the existence of a laboratory information management system (LIMS), particularly if nearly all laboratory processes, data integrity, and quality assurance procedures are integrated into it.  A critical consideration is determining if the CRO has electronic records that are created and maintained by software with rigorous user access control, extensive audit trailing, and secure archiving of data files.  It is also very important to determine whether the CRO has experienced scientists with extensive training who can provide expert analytical method development and validation under GMP compliance.

 Which outsourced analytical services are in high demand?

 We are seeing high client demand for residual solvents, elemental impurities, API solubility and dissolution method development, and API characterization.

 Unknown particle identification, NMR spectroscopy of solids and liquids, chromatography, and mass spectrometry have all been growth areas, especially non-routine testing to solve unusual problems.

 Are there analytical processes not currently being outsourced that you anticipate will be in the future?

 Pharmaceutical companies typically adopt new analytical techniques rather quickly, but they tend to rely on them for release testing of drug substances and drug products only after significant assurance of reliability.  Although nearly every common analytical technique can be outsourced if desired, many pharmaceutical companies are selective in the types of analyses outsourced to a CRO depending on their own experience and internal capabilities. 

	Selective outsourcing of biologics testing is quite common because pharmaceutical companies are reluctant to rely on potentially less experienced CROs to transfer or develop analytical methods for biologics that are difficult and expensive to make and test.  Atypical analytical techniques that are still in the development stage may eventually be outsourced once they have been better established as suitable tests for pharmaceutical development.

	            1.         R. Rader and E. Langer, “The Outlook for CMO Outsourcing in 2019, 

	When referring to this article, please cite it as S. Haigney, “Utilizing Analytical Services for Success in Innovation," 

Outsourcing of analytical testing and processes can help bio/pharmaceutical companies expand their product profiles. 

Utilizing Analytical Services for Success in Innovation

spoke with John Pirro, senior director of large molecule bioanalysis at WuXi AppTec, which provides anti-drug antibody (ADA) and neutralizing antibody (Nab) assay development, validation, and sample analysis services, about best practices to ensure that biologics are safe and effective.

 Immunogenicity refers to the ability of an antigen to induce an immune response. Biological products with an increased potential for eliciting ADAs include therapeutic antibodies, enzyme therapies, peptides, and combination products. ADA can reduce the ability of the drug to reach the intended target, alter the PK [pharmacokinetics] profile, and potentially mediate serious adverse effects. A subgroup of ADAs, which are called neutralizing antibodies, can also cause potentially serious adverse effects.  

 Which immunogenicity testing methods are used to determine immunogenicity profile of a biologic? How do these methods differ, if at all, for biosimilars?

 In practice, immunogenicity is assessed by the detection of antidrug antibodies using a positive control antibody, representing a potential polyclonal antibody in a biological system. There are many different types of assays ranging from classic ‘bridging’ assays to more complex ‘bead acid dissociation’ assays.

	Which assay to use depends on the reagent you use as a positive control and the baseline immunogenicity of the drug in question. The methods can differ depending on the type of biosimilar (modified to stay in plasma longer) to other types of biologics (bi-specific antibodies) depending on the makeup of the biologic and the method of action. You must have experience in all forms of assays for immunogenicity to modify the design to fit each case.  

 How does immunogenicity testing differ when dealing with antibodies compared to other biologics?

 For non-antibody biologics, test development needs to emphasize the fact that non-human amino acid sequences are often used to modify the protein, and these sequences are typically immunogenic. It’s important to use polyclonal antibodies as positive control. For antibodies, testing differs depending on the site of modification (Fb region for bi-specific), attachment sites for antibody drug conjugates, and whether it is a fusion type of antibody design. Special considerations have to be taken with these types of biotherapeutics, specifically around the reagents used to capture and detect the biologic. It is in this case that the use of monoclonal antibodies and IgY antibodies come into use. 

What mistakes do companies make when performing immunogenicity testing?

 The usual mistake is in the design of the ADA assay (lack of Domain ADA assays for fusion proteins, etc.) or in the reagent they are using to detect or capture the biotherapeutic. For example, using a monoclonal antibody when you should use polyclonal antibodies or not considering the use of IgYs to develop positive controls, which do not bind to rheumatoid Factors; the determination of the positive control for ADA or Nab assay; and not understanding that you will have to re-determine the cut point with disease state serum from the study.

	When referring to this article, please cite it as S. Haigney, “Xxxxxxx," 

Pharmaceutical Technology spoke with John Pirro, senior director of large molecule bioanalysis at WuXi AppTec, which provides anti-drug antibody (ADA) and neutralizing antibody (Nab) assay development, validation, and sample analysis services, about best practices to ensure that biologics are safe and effective.

Best Practices for Immunogenicity Testing of Biologics

spoke with Lisa Crandall, MS, associate director CMC Project Management, and Peter Angus, PhD, director of Pharmaceutical Sciences, at Velesco Pharma, which provides a full range of stability testing of API and drug products, about best practices in stability testing.

 Which methods are used to determine stability of a drug in early development? In later-stage development? Do these methods differ?

 In early development, typical API and drug product stability analysis include appearance, assay, related substances, and water. Additionally, depending upon type of drug product formulation being assessed, tests such as assay of preservatives and/or antioxidants, pH, viscosity, osmolality, particulates, antimicrobial effectiveness, and microbiological bioburden may be necessary. Specific methods such as high-performance liquid chromatography (HPLC) for assay/impurities are phase appropriate.  In later development, the stability indicating techniques haven’t changed, but the specific methods have evolved with the product.  Quantitation of known impurities is now possible.

What steps should be taken to ensure stability of a drug?

 To increase the chances that your drug is stable, it is vital to pay attention to all early data pertaining to the effects of temperature, humidity, light, polymorph, salt form, etc., as well as excipient compatibility and packaging. Discovering limitations and interactions early in development provides a better chance of success, especially in situations in which one polymorph is significantly more stable than others.

 What mistakes do companies make in early development that could lead to instability?

 Common mistakes early in development are ignoring the importance of risk assessment using the philosophies in International Council for Harmonization (ICH) Q8 and Q9, and not allowing enough time for designing a quality product. With appropriate foreknowledge, many drug instability challenges can be overcome by designing the synthetic route, formulation, packaging, storage, etc., with the future in mind.

What are some best practices for ensuring product stability in both early and later-stage development?

 To ensure the best chance for a successful and stable product, it is important to design early phase experiments to provide as much understanding about the API and product as possible. As the product progresses, it is important to use and build upon the data in hand to make necessary adjustments to synthetic routes, formulations, manufacturing processes, packaging, and analytical methods.

	When referring to this article, please cite it as S. Haigney, “Determining Drug Stability," 

Pharmaceutical Technology spoke with Lisa Crandall, MS, associate director CMC Project Management, and Peter Angus, PhD, director of Pharmaceutical Sciences, at Velesco Pharma, which provides a full range of stability testing of API and drug products, about best practices in stability testing.

Determining Drug Stability

Editor's Note: An abbreviated version of this article was published in 

Drug shortages are one of the most talked about topics in bio/pharma in recent years. External factors such as natural disasters and regulatory pressures, over which pharmaceutical companies might have little control, can contribute to drug shortages. Internal factors, such as failure in process controls, can and should be addressed by the pharmaceutical industry. Robust process development can help ensure that life-saving medicines reach patients.

	Chris Moreton of FinnBrit Consulting and Susan J. Schniepp, executive vice-president of Post-Approval Pharma and Distinguished Fellow at Regulatory Compliance Associates, discuss how poor process design can affect the supply chain and the pitfalls some pharma companies fall into.

 What are some common pitfalls pharmaceutical manufacturers face when developing manufacturing processes for the manufacture of small- or large-molecule drugs?

Schniepp (Regulatory Compliance Associates):

 I think one of the major pitfalls that affects the development of a robust manufacturing process is consideration regarding the equipment used, not only in the development of the process, but also in the transfer of the process to various manufacturing sites. I think this pitfall applies to both large- and small-molecule development. The new products are developed with consideration to the use of modern equipment. When these products get transferred from the development arena to the manufacturing arena, the equipment might not be comparable. The manufacturing facility may have older versions of the necessary equipment for producing the product, which could result in problems during transfer of the process. In some cases, the older equipment may require more human interaction, which could compromise the ability to meet the operating requirements specified in the original process. This would prompt changes to the original process that might significantly impact the efficiency of the manufacturing process and create deviations that need to be investigated to assure the product is safe to be released. Some process changes could also result in regulatory changes requiring prior approval before they can be implemented.

 I cannot comment on big pharma, but for small pharma/start-ups working with small molecules, common pitfalls include insufficient understanding of the limitations of the API, excipients, and processing. The questions that should be asked for any pharmaceutical formulation and process development project are:

		What do we have to do to get this drug substance into a form that will provide acceptable bioavailability via the intended route of administration?

 How can poor process development affect the supply chain?

Poor process development will most likely lead to stoppages, failed batches, and possibly reduced shelf-life. If the drug product cannot be made on a routine basis, there will likely be supply chain interruptions and patients will suffer. This can apply to both clinical supply and commercial manufacture.

 Poor processes generate deviations, which need to be investigated before product can be released. The more deviations there are associated with the product, the more chance the supply chain will be interrupted. If the original deviations are not investigated thoroughly, [there is the] chance that repeat deviations will occur. The more deviations associated with the process indicates deficiencies in the process. Until these deficiencies are successfully resolved, there is a good chance that the supply chain will be disrupted.

 How can poor process development affect a company’s bottom line?

 Poor process development leads to inefficiencies in manufacturing. These inefficiencies lead to delays in product release as well as product rejection. Unless the inefficiencies are effectively resolved and remediated, the company will continue to experience delays in product release and lost revenue from product rejection.

 Problems with supply of the drug product, for whatever reason, will mean that patients may to transferred to alternative products, possibly permanently. This will result in lost sales and thus lost revenue.

	During clinical trials, interruptions to the supply of an investigational drug can compromise study results, cause delays in completion of clinical trials, and possibly delay the filing of the marketing application, and thus loss of future revenue.

 How often should process development be reassessed? How often does a process change within the lifecycle of a drug product?

 There really is no hard and fast rule to how often process development information should be reassessed. Process deviations, manufacturing equipment changes and investigation results can prompt process changes. The process development information should be used to assure these changes are acceptable to make and do not compromise the quality of the product. Process development information should not stand alone but should be used to support the continuous manufacturing of the product over the product lifecycle.

 Typically, for small-molecule drugs, manufacturing processes for APIs may change, usually to improve yields or reduce the use of toxic solvents, etc. However, this is not so common because the impact on the final drug product performance must be assessed before the change can be implemented.

	In my experience, it is very unusual to make changes to a drug product manufacturing process. If they are made, the SUPAC guidance documents (Scale-Up and Post-Approval Changes) would apply in the United States (1–3). Similar criteria would be applied in the European Union.

	Looking forward, as quality by design becomes more prevalent, with the move to continuous verification, and with the current emphasis on quality metrics, more reasons for change may be identified as there will be increased scrutiny of data.

 Are there new trends in process development? Are companies moving to continuous manufacturing? 

 For small-molecule drugs, there is interest in continuous processing. However, it will not be for every product. Smaller-volume products will continue to be batch processed because of the changeover times. It can take up to a week to clean everything associated with a continuous processing line and be ready to run the next product. Thus, continuous processing is really better suited to larger volume products.

 I think the application of quality risk management as part of development activities is one of the major trends for process development. While the concept is not new, it is being applied more routinely in the process development phase to establish appropriate specifications, identify critical process parameters, and establish manufacturing controls. Using information from pharmaceutical development studies potentially helps identify control variations that may arise during processing.

Guidance for Industry: Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, 

Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; 

Guidance for Industry: Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and 


	Volume 31, No. 1
	January 2019
	Page: 42

	When referring to this article, please cite it as S. Haigney, "Proper Process Development and Drug Shortages," 

Shortages of life-saving drugs are a regulatory and industry concern. Proper process development may help to ensure drug supply.