It’s All About the Small Things

Independent of the type of medicine or dosage form, whether it be a solid-dose pill for treating headaches or a pre-filled biologic to treat autoimmune disorders, the materials that create drugs are the building blocks for treatment. These materials must meet certain qualifications in order to be used in a medicine. Manufacturers and providers of these ingredients, be they APIs or excipients, also must meet qualifications to ensure a safe and effective final drug product.

Contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs), especially those offering end-to-end services to sponsors, play a role in the sourcing, testing, and qualifying of drug materials and the companies that manufacture them.

Qualifying suppliers of raw materials is an important step in the supply chain and assures regulators that the materials used in drug products are safe and effective for patients.

“CDMOs use APIs, intermediates, excipients, and other inputs to manufacture and supply the finished product to sponsors. Their quality performance is determined by the quality of these input materials,” says Sundar Narsimhan, chief procurement officer at Neuland Labs. “CDMOs may set up robust quality systems that address the quality and regulatory requirements of the end markets. These include audits and inspections of their material suppliers, incoming testing, and release.”

“It is an old but true saying that quality cannot be tested into a product because by the time a sample is in the QC [quality control] laboratory, the quality is already determined! But the good news is that CMOs and CDMOs can do a lot to help ensure the quality of APIs and excipients,” says Iain McGhee, vice-president of Quality at Ascend Advanced Therapies. “Externally, this will require clear oversight of any suppliers and the supply chain. Internally, this includes maintaining control of the manufacturing process and keeping good records.”

Contract organizations can assist sponsors to select and qualify material suppliers by understanding what the materials are being used for, understanding regulations and markets, and performing robust onboarding and qualification, according to Kim Arsenault, Quality Compliance manager, BIOVECTRA. “Both the CDMO and the client need to clearly understand and document the intended use and processes involving the material, including the end product’s phase and timeline,” says Arsenault. “[Both parties should know] the regulatory requirements of the target market ensure all material attributes and sampling needs are defined and met, while avoiding any compliance issues that could arise during or after product launch.”

“To ensure the quality of pharmaceuticals in the final product it is important to have an up-front understanding and alignment of critical quality attributes (CQAs)/specifications from customers,” says Josh Hoerner, general manager and executive vice president, Purisys (part of the Noramco Group). “Many factors may play into a customer’s quality requirements, including information only the customer may have, such as that derived from toxicological studies, feedback from regulatory authorities, dosing strategy and other information that is important to patient safety. Incorporating this information into the API or excipient process design requirements is critical to developing products that are safe for patients. As a CDMO, we also need to consider and provide input on CMC [chemistry, manufacturing, and controls] aspects of the API or excipient such as chemical manufacturing process capability, analytical method capability and limits, compendial quality standards, control of impurities (such as genotoxic impurities and nitrosoamines), etc.”

CMOs/CDMOs also assist in ensuring the quality of materials in other ways, including storage and handling, quarantine processes, and testing, according to Mayank Nagar, vice-president and head of Tech Services & New Product Launches, North Americas, and Himanshu Joshi, director, New Product Launches, North Americas, at Dr. Reddy’s Laboratories. “Analyst training is equally an integral part of ensuring consistent quality,” says Nagar. “As the adage goes, ‘The quality of the input material dictates the quality of the final product’.”

It begins with selection

When selecting a supplier of raw materials, quality compliance is ensured through an audit and qualification process, says David Shell, head of Quality, Andelyn. CDMOs and CMOs offer sponsors assistance in this endeavor. And a phase-based approach may be the best way to select such a supplier, according to Adelyn, depending on what the CDMO/CMO’s client requires and the phase of the program. “A balanced approach may be considered based on the specific regulatory requirements for each program, for current needs and having flexibility to be forward-looking if additional quality standards are needed, if cost or timing considerations are a key factor. Having a clear and concise definition for critical versus non-critical materials and classification is also important. It can be important to categorize suppliers based on risk: how critical the component or service is to the process and final product,” says Shell.

“When selecting materials suppliers, it is critical to ensure that ingredients are fit for purpose for pharmaceutical use (e.g., GMP [good manufacturing practice] grade),” says McGhee. “Normally, the grade will increase as a product gets closer to commercialization (research grades during process development and pharmacopeial grades for GMP manufacture). With gene therapies, this approach is not always the best. And while GMP compliant suppliers will be more costly, sourcing from non-GMP suppliers or using low grade materials for less cost can be catastrophic.”

Often, says McGhee, contract organizations already have relationships in place with suppliers. McGhee also states CMO/CDMOs can also ensure contract negotiations include all quality levels and chemistry, manufacturing, and controls (CMC) information needed for regulatory filings.

Arsenault agrees, stating, “leveraging existing relationships and industry expertise can support sponsors, especially those new to the industry, in navigating material sourcing. A sponsor who is new to the industry may not have an extensive supplier network to draw from. Alternatively, a small/mid-size CDMO may need to leverage existing supplier relationships between a larger/more established sponsor and their supplier network in some instances.”

According to Arsenault, a strong, systematic onboarding process should be in place, as well as processes for qualifying, approving, and documenting the use of raw materials. “It must be capable of accurately identifying how/where materials are used and the lifecycle stage of these processes to manage material requirements effectively as they evolve,” Arsenault stresses. Onboarding and qualification processes should ensure that suppliers have solid quality systems, and performance should be monitored by quality audits and notification/approval processes. Supporting material statements should also be in place, says Arsenault, to verify quality, traceability, and safety.

Qualifying the materials supplier

Ensuring the quality of materials used in developing and manufacturing drug products is a crucial step for sponsors. CMOs and CDMOs can provide supplier qualifications as part of the sponsor/client quality agreement, says Cyrill Kellerhals, COO at Andelyn. Qualification requirements, according to Kellerhals, include manufacturing/production capabilities, quality standards and certifications, quality regulatory and compliance requirements, technology, customer service standards, delivery and cycle times, and lifecycle management.

Supplier qualification should align with current good manufacturing practice (CGMP), say Nagar and Joshi, with quality agreements that define roles and responsibilities. “Additionally, based on the historical usage of materials and prior experience with suppliers, a risk-based approach can be matured, considering the criticality of the API and excipients,” says Nagar.

A supplier qualification typically involves seven steps, according to Narsimhan. These include ascertaining the criticality of the material, developing a procurement strategy, using due diligence to identify suppliers, floating RFP [request for proposal] to the shortlist [of potential suppliers], performing a pre-qualification audit, conducting a techno-commercial environmental, social, and governance (ESG) evaluation, and then awarding the contract. “In addition, CDMOs can assist their sponsors by performing their gap analysis and critical evaluation of sources and recommending risk mitigation pathways,” says Narsimhan.

Hoerner suggests having a pre-filled standard questionnaire that details supplier qualifications regarding quality systems and inspection history. “As a CMO/CDMO, it is also important to be open to a customer audit before business is contracted to build confidence between a sponsor’s quality unit and a supplier’s quality unit,” says Hoerner. “Before and during any CMO/CDMO audit, it will also be important to align and ensure the scope and extent of qualification of facilities, buildings, and production equipment and/or laboratory instruments to be used in manufacturing the customer/sponsor’s materials.”

Managing risk

When developing a quality risk management (QRM) plan for qualifying materials suppliers, Narsimhan recommends the following elements:

Determine the quality objectives, criticality factors, end-use, and specifications.

Assess the material’s quality vulnerabilities and variability by looking at the manufacturing process, quality culture and track record of the supplier, and traceability.

Compare the supplier’s performance and capability against established criteria during site visits, audits, checking of documentation and quality control infrastructure, and reviewing supplier feedback.

Continually assess the supplier’s performance through tracking, corrective and preventive actions/process improvements, and tracking quality indicators.

Arsenault stresses that both quality and business risks should be considered with managing risk in suppliers. “We categorize suppliers based on the type of materials supplied, their criticality to the overall process, and the process/phase where they are used. Additionally, we evaluate business risks such as single vs. multi-source availability, geographical location, political climate, industry reputation, and EHS [environment, health, and safety]/safety/ethics practices,” says Arsenault.

Documentation provided by the supplier should be reviewed, according to Arsenault, as well as change control and notification policies, previous adverse events or regulatory notices, and the type of supply (single source vs. alternative source).

“For critical suppliers, we include a detailed assessment of the associated processes, validation status, quality audits, and any out-of-specification events. For software providers, we evaluate the software validation status and associated risk score,” says Arsenault.

Supplier and vendor audits may be performed based on risk assessment has stated in the International Council for Harmonisation’s (ICH) Q9 document, according to Betsy Torres, QA compliance manager at Andelyn. Assigning a risk score will allow the determination of the frequency needed for requalification and future audits, according to Torres.

“Having a transparent process with proper documentation and compliant quality systems is critical in order to provide proper visibility into the manufacturing and quality processes, so the client is assured that supplier risk is mitigate[d] [to] the best extent possible,” Torres says.

“You have to have a [QRM] approach that is (ideally) stepwise and follows the principles outlined in ICH Q9 for risk identification, analysis, evaluation, reduction, acceptance and review,” Hoerner concurs. “During discussions with a supplier, you need to establish compliance with ICH Q9 and what tools a supplier uses to manage risk (e.g., FMEA [failure modes and effects analysis], FTA [fault tree analysis], PHA [process hazard analysis], etc.). To ensure alignment of roles and responsibilities between a supplier and customer in terms of communication, a quality agreement can serve the purpose of defining a supplier’s responsibility to report and communicate risks and issues.”

Monitoring a supplier for potential future problems is crucial, according to McGhee. This includes manufacturing and delivery status. “If any delivery timelines are shifting, could there be an underlying issue at the manufacturing site?” McGhee asks. Restructuring, mergers, or any changes in leadership at the supplier should be identified. These changes would impact experience at the supplier, says McGhee. Suppliers should have strict cyber security. “This is particularly important for organizations that have electronic quality systems or are using any type of AI [artificial intelligence] or VR [virtual reality] technology,” says McGhee. Finaly, McGhee suggests having secondary sources validated.

“Continuous monitoring through regular audits, performance reviews, and material testing is essential, alongside maintaining open communication channels for prompt issue resolution,” Nagar and Joshi agree.

“Comprehensive documentation of all evaluations, audits, and quality assessments is crucial to ensure traceability and compliance, ultimately ensuring consistent material quality and regulatory adherence,” they conclude.

About the author

Susan Haigney is lead editor for Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 48, No. 9
September 2024
Pages: 31–33

Citation

When referring to this article, please cite it as Haigney, S. It’s All About the Small Things. Pharmaceutical Technology. 2024 48 (9).