How have advances in raw materials functionality, supply and quality affected the pharm/biopharma industry?
Ashish A. Joshi, PhD, Pharma Technical Manager, BASF Pharma Solutions: A small variation in the impurity profile, viscosity, particle size, dissolution characteristics, molecular weight etc. of an excipient could have drastic impact on the end performance of a pharmaceutical formulation or process. The variation may well be within the allowable pharmacopoeial limits or sometimes the parameter(s) may not be even listed in the monograph. BASF recently launched a high purity cellculture shear protectant, KOLLIPHOR® P188 BIO. It is devoid of specific hydrophobic impurities, (not listed in the compendial monograph) which allows significantly higher cell-culture yield in biopharmaceutical upstream processing. Biopharma companies worked in close partnership with BASF during the development and evaluation phase of this advanced processing aid, thus ensuring its quick acceptance by the industry in a relatively short time. Many promising new excipients are not embraced by the pharma industry due to regulatory, toxicological or functionality constraints. Moving forward, this model of developing newer high-functionality excipients in close co-operation with pharma industry is the key to address issues with bioavailability, continuous manufacturing, and Quality-by-Design (QbD), thus enabling quicker launch of future life-saving blockbuster pharmaceuticals.
Steven Ruhl, VP of Manufacturing, CURE Pharmaceutical: Regulatory and quality expectations of excipients will continue to increase, which has put more pressure on excipient and raw material companies to invest in characterizing functionality and building robust processes to consistently address company needs. This has led to a greater focus on understanding critical material attributes and ranges by both suppliers and customers earlier in the development process. Examples of controlling excipient variability and understanding impact to product quality has enhanced manufacturing controls and increased speed to market.
Jasmine Musakhanian, Scientific and Marketing Director – Pharmaceutical Division, GATTEFOSSÉ USA: The need for high quality, functional excipients is driven by an ever-increasing number of drug molecules with poor solubility, burgeoning molecular sizes, and poor oral absorption properties. To address these challenges, every avenue, including novel uses for existing excipients, new formulation and/or processing technologies, and/ or alternative routes of administration, needs to be explored. In the interest of public safety, the regulatory pathways for new excipients are as narrow as those for new drugs. Therefore, excipient providers are driven to innovate with the existing (currently approved) raw materials. In parallel, there is the collective affirmation that excipients are not always inert or inactive. Combined, these developments force the pharma industry to excel in defining, characterizing, and better understanding the role of each excipient; exploring new combinations of excipients; and using new processing technologies for the development of appropriate drug delivery systems. In-vitro models to predict the performance of the drug delivery system in vivo are emerging, and Quality by Design (QbD) initiatives demand closer collaboration between drug makers and excipient suppliers to identify and control the critical material parameters.
Karin Schrooten, Senior Director, Global Quality Operations, Lonza Pharma & Biotech: While excipients have no pharmacological effect, suggesting they are inactive or inert is an out of date perspective. QbD principles and the ICH Quality Guideline Q9 on Pharmaceutical Development require robust formulations where excipients are selected with an understanding of their characteristics that can influence the drug product manufacturing and performance.
Today, excipient manufacturers are expected to understand the intended use of their products and have systems in place to capture these application-dependent quality requirements - exceeding mere compendial compliance.
This has led to an increase in customization within the excipient business; the model where ‘one size fits all’ doesn’t apply anymore and the excipient manufacturers need to invest in process improvements to guarantee high-process capabilities covering the range of customization they offer.
As a next step beyond customization, suppliers are developing more innovative products which target specific applications. As an example, Lonza Pharma & Biotech has launched two unique capsulebased platforms, Vcaps®Enteric and enTRinsic®, which provide gastro-protective and enteric characteristics. The introduction of these specific platforms at an early stage of drug development can lead to oral dosage formulations where, in the past, other dosage forms where required.
Bikash Chatterjee, President and Chief Scientific Officer, Pharmatech Associates: Functional excipients are having a great impact on the Chemistry, Manufacturing, and Controls (CMC) component of the drug development process. Partially driven by novel dosage form development such as Antibody Drug Conjugates and CAR-T drug therapy concepts, and by innovative drug delivery frameworks, like abuse-tolerant product designs, and the escalation of pre-filled syringe biologic drug therapies, the importance of fully characterizing these excipients has never been greater. Overall, the issuance of the 2011 Process Validation guidance in the U.S. and Annex 15 in the E.U. illustrates the need to demonstrate a clear understanding of the control strategy for all identified critical raw materials, and their impact on the final drug process and product performance. This is translating into a larger, more intimate role for the raw material supplier in providing foundational characterization information that can be used by the drug sponsor to complement the necessary studies required to support its regulatory submission. It also elevates the supplier qualification program, especially for virtual organizations, as raw material suppliers become central partners in demonstrating process- and product understanding.
Renata Bouabci:Americas Area Marketing Manager, Pharmaceutical; Elham Blouet, Global Market Manager, Injectables, Dialysis & Specialty APIs, Roquette: The pharma companies in general are looking for safe and reproducible quality of their raw materials, active substances and excipients. In addition, the impact of the physicochemical and biological properties of these raw materials, including the intended functionality of each excipient are assessed during the pharmaceutical development in order to determine the critical quality attributes that should ensure the desired quality target product profile of the drug product as it relates to quality, safety and efficacy considering the route of administration, dosage form, bioavailability, strength and stability.
The biopharma industry involves sensitive, costly and sophisticated processes that in turn require high level quality of raw materials with a continuity of supply.
Roquette strives to respond to pharma and biopharma companies needs by offering a wide range of high quality pharmaceutical actives substances, functional and multifunctional excipients compatible to pharma process technology and required for different oral dosage forms. Moreover compliance with the latest in force regulation and compendia monographs, as well as guaranteed traceability is part Roquette’s commitment to pharma and biopharma industries.
When evaluating suppliers of raw materials/excipient suppliers what processes or steps should a company take? What are some important questions to ask?
Joshi: To maintain economy of production-scale, excipient companies may manufacture ingredients on a large scale, which could be supplied to various industries with different regulatory requirements. BASF ensures that all its pharma grade excipients, not only meet or exceed strict pharmacopoeial requirements but also with the highest standards of pharma GMP, quality, audit, supply-chain, warehousing and associated documentation. In addition, the pharma industry greatly values the ability of BASF to rapidly provide expert technical, regulatory and applications support to enable the best use of its excipients. Assuring global supply of the same grade high quality excipients is very important in this day and age where pharmaceuticals may be developed in one geographical area but manufactured in a very different location halfway across the world. The multiple manufacturing sites of BASF all over the world greatly help in assuring a steady supply of excipients globally and mitigating supply risk for pharmaceutical manufacturers. Last but not the least, being in business for over 150 years provides an assurance that BASF is a highly stable and dependable partner whom the pharma industry can fully trust to support their future product launches.
Ruhl: As a precursor, it is important that material and process requirements be understood by the company prior to sourcing raw materials from a supplier.
Vendor selection criteria should then start upon a review of potential vendors with a proven history of supplying products to the pharmaceutical industry. Mutually agreeing to a set of specifications should be a key first step, since the company is ultimately responsible for developing processes to ensure the control of outsourced activities and quality of purchased materials. For critical vendors, consider defining the responsibilities and communication processes in a written quality agreement as part of vendor qualification.
Invest time in understanding supplier’s processes and controls upfront, utilizing quality risk tools to avoid preventable and costly delays based on quality of the material or supply interruptions. Onsite visits to see the process and meet with the key management will accelerate the process.
Lastly, review and analyze vendor performance to identify areas of improvement.
Musakhanian: Successful excipient providers have a well-established rapport with their clients, anticipate their needs, and take steps to address them. An important question is whether the excipient manufacturer is fully vested and engaged with the pharmaceutical development. Can the excipient provider be a reliable business partner for the long run? Beyond providing evidence for excipient functionality, safety, quality, or regulatory acceptance, does the excipient manufacturer have dedicated support staff to guide and support customers throughout the development cycle? Can they offer support in analytical, preclinical, and stability? Are they able to assist with regulatory filings in other countries? Is there support for quality by design initiatives? What about flexibility in supply quantity or packaging? Are there any back up manufacturing sites?
Schrooten: The current regulatory framework on medicinal products requires excipient suppliers to be carefully selected – from start-up throughout the product’s lifecycle.
Therefore, pharmaceutical formulators should embark on a dialogue with raw material suppliers to build a genuine understanding of the excipient characteristics and variables based on its starting materials, their origin and manufacturing processes. This ensures a science- and risk-based selection for a robust formulation by taking into account the use and function of the excipient in the finished drug product.
Additionally, supplier qualification processes should include an evaluation of the manufacturer’s adherence to quality standards and, more specifically, to excipient GMPs. This will ensure – beyond mere product purity and safety – a commitment to change management and notification procedures. This safeguards product performance throughout its lifecycle and ongoing regulatory compliance with product registrations.
Sandra Wassink, Principal Process Engineer, Pharmatech Associates: The importance of raw materials/excipients in the drug product functionality continues to grow. When selecting a supplier, a company needs to assess the supplier’s commitment to quality management. As part of this evaluation, the company should evaluate multiple lots of material to determine consistency and impact on manufacturing process and drug product critical attributes. Also, a company and supplier should collaborate on identifying and sharing the critical attributes of the raw material and test methods used to evaluate these attributes. You need to determine their willingness to collaborate. A quality agreement with the supplier should contain the attributes that need to meet specifications and are important to maintain drug product performance. Ask about batch rejections or rejection rate and cause for rejection. A review of their Out of Specification procedures and CAPA system is imperative. Request to review their validation work. Is the supplier maintaining their Drug Master File and are they in good standing with regulatory authorities? Another consideration is the supplier’s business viability to maintain supply. Have they had any issues maintaining supply and providing on time? A supply agreement should contain language to ensure supply and proper notification of any supply issues. A company needs to do a thorough due diligence of the suppliers QMS, on their standing with regulatory authorities, and business viability before selecting and putting in place quality and supplier agreements.
Bouabci and Blouet: Once the intended functionality of an excipient has been determined in a specific formulation, the users will look first into the list of their approved suppliers otherwise they will search for suppliers providing this particular functionality.
The first step would be to get samples of these excipients in order to evaluate their performance in the formulation. Then the users will ask for the excipient information package that will include any information related to the composition of such excipient, regulatory information (specifications and compliance to compendial or multicompendial), description of the manufacturing process and facility, the site and supply chain measures. The technical information supporting the functional performance of the excipient can be also requested along with any data showing the performance of such excipient in achieving the desired functionality.
Stability data can also be requested in the commercial packaging and defined storage conditions that are intended to protect the excipient from degradation throughout the supply chain.
Finally any raw material (active substance, excipients) used in the pharmaceutical drug product will be required to be manufactured under appropriate Good Manufacturing Practices (GMP) and supplied under Good Distribution Practices (GDP). The exact definition of GMP or GDP will depend on the material in question (e.g. excipient, active pharmaceutical ingredient, packaging etc.) and legislation where the excipient is supplied or sold.
The final step of qualifying a raw material supplier is when the drug product manufacturer will conduct an audit to make sure the quality systems that are in place are suitable and all process and methods are validated. Before the commercial supply, a quality agreement will be established between both parties.
In addition to supplying raw materials/ excipients/ingredients what are some other value-added services suppliers of the products can offer their customers?
Joshi: Successful excipient companies not only manufacture and supply high quality excipients but also generate scientific data to support the best use of their excipients. BASF global centers of excellence provide such value-added services for excipients used in various pharmaceutical formulations. For example the BASF skin delivery center of excellence conducts extensive research on understanding the microstructure of dermal creams, gels, lotions etc. and its effect on the performance, stability and excipient selection in dermal formulations. The BASF solubilization center of excellence offers automated robotic high-throughput screening ability to understand interaction of actives with a variety of solubilizing excipients. The data from these studies greatly helps in providing guidance on recommending the best bioavailability-enhancing excipient for active ingredients used in oral, dermal or parenteral formulations. BASF solid dosage laboratories routinely conduct research on developing the best parameters for applying enteric or modified release coatings on hard to coat surfaces like those of soft-gel capsules. Finally, BASF has a very active innovation R&D division where the pharmaceutical excipients of tomorrow are envisioned and designed to exacting standards.
Ruhl: Suppliers that invest time into understanding customer and market needs, combined with openness of information with their process controls and material attributes, offer a key service to their customers. Building a partnership with the customer and demonstrating a willingness to engage with improving raw material quality and functionality differentiates premium suppliers from those who should be avoided. Ultimately a supplier should be trusted to provide guidance and recommend the appropriate fit for purpose of an excipient/raw material as well as provide a service to support the most expeditious acceptance by a health agency.
Schrooten: Drug product manufacturers and ingredient suppliers work together today as partners to develop, manufacture and maintain life cycle support. This partnership is focused on achieving quality compliance and resource efficiency.
Beyond valuable knowledge about their products, suppliers with extensive experience in formulation provide the expertise needed to address formulation challenges. As every compound and development program is different, involving suppliers in product design helps Lonza to provide a tailored approach to optimally meet each customer’s specific target product profile and commercial objectives.
Ingredient suppliers offering products under independent excipient GMP certification (such as EXCiPACT™) provide evidence of compliance with expected GMPs and facilitate regulatory compliance. This EXCiPACT™ certification may replace the on-site auditing, saving time and resources.
Operating in a highly regulated environment requires suppliers of excipients to invest in ongoing regulatory expertise and to have deep experience and understanding of changing excipient requirements. This expertise should be continuously shared through information about regulatory compliance on evolving or emerging topics and the organization of exchange platforms with experts or dedicated notifications.
Chatterjee: Today’s regulatory philosophies require that raw material suppliers be educated in the regulatory expectations of their drug sponsor customers. Most critical suppliers manage confidentiality via a well-constructed Drug Master File (DMF). These DMF can include critical information regarding the manufacture of the material, including critical process parameters, catalysts etc., that the supplier may not want to disclose, even under a confidential disclosure agreement (CDA) but that will be required for the drug sponsor’s regulatory submission. For international customers who operate in the EU, a keen understanding of both Good Distribution Practices (GDP) and qualified persons (QP) requirements will have significant impact on the drug sponsor’s ability to utilize their products with confidence. For today’s complex drug therapy concepts, the raw material vendor is likely to get involved in method development and transfer, and providing process validation documentation in support of the Regulatory Starting Material and Final Intermediates. The greater the understanding the supplier has of these requirements the more effective they become as a key supplier to the drug sponsor.
Bouabci and Blouet: The activities of manufacturing raw materials/ excipients or ingredients can be achieved by several manufacturers claiming the compliance with quality standards. However drug product manufacturers are looking for more than a manufacturer of such pharmaceutical substances. They are looking for a partner that can accompany them from the development of their drug products to the commercial launch as well as ensuring all the quality in general and continuity of supply. Roquette being committed to pharma, is offering to their pharma customers a wide range of services that bring added-value:
- Complementary offers ranging from starches , polyols to cellulosic products
- Technical assistance during the pharmaceutical development as well as trouble shooting after industrial scale thanks to their laboratory applications located in different regions; Europe, North and Latin Americas, China and Singapore
- Analytical assistance for methods application and validation
- Regulatory assistance for filing DMF and marketing authorization dossier etc.
How has the globalization of the pharmaceutical industry affected the quality/supply/cost of pharmaceutical raw materials?
Joshi: With multi-national big pharma leading the development of new pharmaceuticals and a multitude of medium to small local pharma companies, it is no surprise that the pharma industry must “think globally and act locally”. Excipient companies developing specialized multi-compendial excipients need to make them available in the exact same grade in all parts of the world. On the other hand, well-established, routinely used excipients face cost pressures, especially for local use in developing countries. Irrespective of the end use, it is imperative that the quality, supply-chain, and regulatory compliance is not compromised especially for low-cost excipients. The continuous transfer of technology and manufacturing across the world creates challenges since many regulatory requirements are not harmonized globally. A close dialog between the excipient and pharma manufacturers is imperative to understand these specific local requirements ahead of time to ensure successful launch of pharma products in various global markets. BASF excipients have been successfully used for many years in numerous approved formulations, both globally and locally, due to compliance with a wide range of regulatory and quality requirements.
Ruhl: Globalization has generally improved the quality of the excipients due to the demands of regional quality requirements driving increased consistency and standards. Cost increases are to be expected and the supplier’s challenge is to manage improvements as efficiently as possible using lean manufacturing concepts. This investment also will help a supplier to compete in a global market as more customer choices become available. Ultimately, vendors that demonstrate reliable and high-quality materials will be seen as an asset to any company valuing speed to market and the need for lotto-lot excipient quality.
Musakhanian: To offer excipients with global regulatory acceptance, manufacturers of the raw materials are obligated to maintain dialog with their clients as well as the regulatory bodies in every region of the world. This often means incurring costs for additional safety studies; allocating resources to ensure the excipient meets several compendia (US, European, Chinese, and Japanese; and being prepared for new filings in order to pave the way for the excipient’s use in a new territory. Although costly, these are worthy investments toward improved and harmonized quality of supply around the globe.
Schrooten: In recent years, several highly publicized contamination incidents have underscored the challenges associated with the increasing complexity of global supply chains and outsourcing. Good Distribution Practices (GDPs) provide guidance on best practices related to transportation, distribution and warehousing to ensure product integrity and quality. The ultimate aim is to provide door-todoor reliability throughout the value chain around the world.
The globalization of the industry also introduces the challenge of meeting the requirements of all target markets in an environment which is highly regulated but not harmonized. It is critical that excipient producers engage with customers to clarify where the finished product will be marketed or intended to be marketed in the future. This will not only mitigate the risk for regulatory barriers, but also open the opportunity to design products that maximize the specific future market potential.
Changes in global supply requirements, triggered by the pharmaceutical companies, might require a change in excipient manufacturing sites. Communication between the pharmaceutical company and the different excipient manufacturing sites is key in order to guarantee a high-quality product that complies with the specific product requirements. The exchange of technology transfer protocols between the excipient sites guarantees the quality of the excipient across the production network.
Chatterjee: No question that the maturation of the emerging markets has resulted in major competitive pressure in the rest of the world as it relates to API and raw materials. The challenge over the last decade was synchronizing product quality with the ever-evolving regional regulatory framework. Today the emerging markets are much more mature and the regulatory expectations are harmonizing. PIC/S has been the greatest catalyst to this elevation in quality expectation. Also, after several high-profile catastrophes in China, drug sponsors have developed an effective framework for evaluating both the product quality and the effectiveness of the supplier. Other emerging markets are still struggling to make the leap to a higher definition of quality held by western regulatory authorities as drug sponsors grapple with the difference between demonstrating compliance and ensuring product quality.
Bouabci and Blouet: The globalization of the pharmaceutical industry has evolved significantly in the last decades, with a trend in mergers and acquisitions as well as outsourcing in emerging countries. Roquette has continuously adapted its pharma offers to respond to this evolution. The production of the primary most used excipients or active substances can be manufactured in different manufacturing sites worldwide and a non-negotiable prerequisite is that these solutions/raw materials will respond to one quality standard regardless of their manufacturing site. This in turn will guarantee the pharmaceutical companies that they can be continuously supplied with the same product in any of their manufacturing sites located worldwide.
In addition, the production of raw materials in different regions close to the pharmaceutical companies will help cost reduction in the supply chain.
The globalization also allows the unification of regulations for suppliers that can support different markets with the same level of quality.
What do you see as the future for raw materials/ functional excipients/ingredients? Will suppliers continue to provide more advanced products? Will products have broader applications? Will product applications become more specific?
Joshi: During the minimum period of 10-15 years it takes to approve the use of a new excipient, the excipient company must continue its manufacturing, prove its safety, provide technical support, comply with regulatory audits etc. all without any return on investment. This model is not sustainable and discourages the development of totally new excipients with significantly enhanced functionalities. The easier way is to develop new excipients that are a combination of two or more already approved excipients. However, such co-processed excipients may not be able to address complex issues in the development of specialized formulations with newer actives. Developing newer and safe excipient molecules with broad and significantly enhanced application functionality is the need of the future. This feat can only be successful when the pharma and excipient manufacturers as well as the regulatory authorities collaborate early on during the development of such new excipient molecules. Along these lines, BASF has recently developed the next generation ionic polymer for bioavailability enhancement and is actively seeking collaborative support from the pharma industry.
Ruhl: Excipient and raw material suppliers will become more specialized with advances with new modalities and patient specific therapies. There will be a need for suppliers to partner more closely with companies earlier in the development process to assure materials are suitable for intended use and developed to support commercial manufacturing. Regulatory and quality expectations of excipients will continue to increase, which will put more pressure on excipient companies to invest in the areas to improve quality, purity and predictive functionality. Suppliers will continue to play an important role to enable companies to market faster and more efficiently. Suppliers that build upon that model will differentiate themselves from competitors.
Musakhanian: Unlike drugs, excipients are not pure entities. They are often heterogeneous in composition, with minor components (not to be confused with impurities) that may provide key functionality to the excipient. Excipient functionality, however, may be altered by changing the drug or the delivery system. With increasing specificity of drug molecules and disease targets, it is likely that excipient compositions will be more narrowly defined over time.
Schrooten: As demonstrated in several scientific studies over the past decade, excipients are not inert substances. In fact, they may play a role, for example, in mitigating multidrug resistance (reversibly inhibiting protein receptors such as the P-glycoprotein or Breast Cancer Resistance Protein) and mediating metabolism (sub-enzyme families such as the CYPs). While there has been an initial reluctance to acknowledge and describe such an active role, the scientific community will continue to articulate and expand such evidence and bring it to the regulatory authorities’ attention. This will lead to a more open and robust dialogue and the development of comprehensive guidelines on the use of such materials.
Formulators work with compounds that are increasingly complex. Access to powerful tools will only benefit pharmaceutical development as a whole.
Suppliers will continue to investigate, develop and innovate through more advanced products that, for example, target specific applications such as targeted delivery of drug product to the small intestine. This is evidenced by the recent launch of Vcaps® Enteric and enTRinsic®, two unique capsule based platforms that bring a high level of complexity through inherently enteric and gastro-protective functions.
Chatterjee: I have no doubt that the novel drug therapy concepts we are seeing today will evolve into platform concepts. This means we can expect that suppliers will be asked to maintain an elevated level of participation with drug sponsors for the foreseeable future. As synergies emerge between diagnostic and target disease treatment, the ability of functional excipient suppliers to provide consistent performance will be essential. Also, when our industry starts moving toward Pharma 4.0 you can expect cyber supply chain management to rise in importance for most drug sponsors. For suppliers this means a greater level of transparency and integration with multiple drug sponsors. The sophistication of raw materials will change from specialized requests to platform offerings that meet these new demands. A supplier’s ability to design, construct, and process custom compounds is likely to increase as drug sponsors gain greater insight into disease treatment and mechanism of action (MOA). Drug therapies are likely to become more specific as target drug strategies harness the insight and information harvested from diagnostic tools such as Next-Generation Gene Sequencing (NGS) and CRISPR-Cas9 to diagnose the disease state at the chromosomal level.
Bouabci and Blouet: The pharmaceutical industry has continuously evolved and will continue to do so with targeting enhancement of solubility and bioavailability of new APIs mostly lipophilic and also to improve efficacy and bioavailability of active substances through advanced drug delivery systems (sustained release, SEDDS) and technologies (nanotechnologies, solid dispersions)
Roquette, being a leader in natural-based excipients has continuously responded to the market applications by innovating in functional and multifunctional excipients adapted to different process technologies (from granulation to melt-extrusions...), in co-processed excipients for direct compression and in cutting-edge solubilizers/stabilizers and taste-masking excipients such as modified betaclycodextrin that are suitable for use in pharma and biopharma companies.
Roquette’s main concern is to understand and to address the pharma/ biopharma needs which are constantly evolving requiring more sophisticated and specific applications.