Introduction

Vendor (or supplier) qualification (VQ) is the process of determining a vendor’s capability to fulfill the specified requirements of necessary products or services. For manufacturing of cell therapies, necessary goods and services can cover a broad range including raw material selection, aseptic filling, manufacturing, formulation and cryopreservation services, analytical assays, kitting services, and cold chain distribution. The VQ process informs all involved parties that the products and/or services meet the acceptable criteria for identity, quality, and purity and provides assurance that the product and service consistently meet the specified Good Manufacturing Practices (GMP) requirements.

The cell therapy industry is in its nascent stage, currently with minimal standardized regulatory policies or guidelines for VQ. However, most manufacturing entities (sponsors and contract development and manufacturing organizations) adhere to standards established by the FDA, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH E6 R2 and ICH Q10), and the International Organization for Standardization (ISO). Unfortunately, these agencies provide minimal details on VQ programs specifically for cell therapy manufacturers, requiring these manufacturers to establish a robust VQ program as a first step in monitoring, identifying, and mitigating vendor-associated risks.

A typical VQ process can be divided into 4 steps:

  1. Define vendor requirements and develop a vendor questionnaire
  2. Compile a list of potential vendors and evaluate capabilities to identify the top candidates
  3. Conduct a comprehensive audit and choose appropriate vendors
  4. Develop and implement vendor requalification plan

Define vendor requirements

The first step in a vendor evaluation begins with defining vendor requirements and designing a comprehensive questionnaire. Vendor requirements should address several varied attributes (see Table 1 for some topics). The questionnaire should also address other significant vendor policies such as change control management (e.g., changes in internal suppliers and production locations; change notification policy timing and exceptions). In the end, the vendor’s responses to the questions should help assign risk levels to several key areas including the vendor’s process performance and quality management system, corrective action and preventive action (CAPA) system, and change management system (CMS). (See Compile a list of potential vendors and assess their capabilities below).

Table 1. Common topics covered in a vendor selection questionnaire.

  • Vendor’s skills to deliver the materials and services
  • Vendor’s open, timely, and transparent communication, with a well-defined plan to manage emergencies
  • Vendor’s control of its policies and procedures to ensure consistent performance
  • Vendor’s commitment to maintain quality and performance
  • Vendor’s guarantee in the form of documents that prove the ability to deliver consistent product/services for timely delivery
  • Vendor’s sustainability policy
  • Cost associated with requested goods and services
  • Capacity for timely delivery of required products
  • Policies and strategies in place to anticipate and mitigate changes related to the internal supply chain, warehouse, raw materials, and manpower
  • Financial standing (cash reserves) and resources to cover any future increased commercial manufacturing demand
  • Alignment of supplier and customer corporate cultures and core values

Compile a list of potential vendors and assess their capabilities

The next steps include developing a list of relevant vendors of the raw materials and determining each vendor’s capabilities and other attributes based on their responses to the questionnaire. While the questionnaires are being completed by potential vendors, the internal team conducts a further internal assessment focusing on a literature review, the vendor’s technical capabilities, the vendor’s regulatory history (e.g., FDA 483 documents, recalls, warnings, etc.), the vendor’s annual reports, and any previous or current client references.

Upon receipt of the completed vendor questionnaire, the Quality Assurance (QA) team of the manufacturing entity reviews the questionnaire for completeness and acceptability within a specified time period from receipt. Any identified concerns arising from the internal research or the questionnaire triggers a written response to the vendor’s Quality team requesting specific clarifications needed to make a final selection. Once all questions are answered satisfactorily, the initial evaluation process is complete, resulting in a narrowed vendor list. The evaluation also highlights specific items that require close scrutiny in the audit phase.

An important step in this exercise includes evaluation of vendor’s own supply chain strategy. This relates to understanding the quality and origin of vendor’s raw materials, business continuity and contingency plans for uninterrupted supply. One of the worst scenarios facing a cell therapy manufacturer is the need to replace or substitute a raw material during clinical trials. Likewise, once a product is commercialized, the manufacturer needs to closely monitor the raw material supplies in order to avoid delays in production. The supply chains for manufacturing specific cell therapies can be quite complex and require overseeing of a large number of suppliers. A risk-based approach to this oversight can simplify that task [1].

A risk-based strategy would evaluate the individual raw materials based on their criticality to the manufacturing process, leading to a framework that allows the manufacturers to assign risk levels to the supplier’s capabilities. This approach also allows manufacturers to better allocate time and resources to monitor the materials after commercialization. Table 2 provides an example of some general factors associated with risk, although individual manufacturers would probably have additional issues to add to each level.

Table 2. Risk levels (adapted from Reference 1).

Risk levelAssociated factors
High
  • Custom product with no alternatives or alternatives that would be hard to qualify
  • Product used in critical steps (e.g., direct and/or patient contact)
  • Specified source in license where alternative would require additional testing (e.g., stability testing)
Medium
  • Product alternatives available
  • Product used upstream in process; general usage; used in well-established steps
  • Alternative product available with agency preapproval or only moderate testing
Low
  • Multiple qualified product alternatives available; safety stock possible
  • Product used in well-established steps that are common practice in the industry
  • Alternative product available with minor regulatory concerns requiring only notification or minimal assessment

Conduct audits and choose final vendor(s)

This narrowed group of vendors moves to the next evaluation step. This process known as an audit, is ideally conducted by a cross-functional team that includes members from QA, process development, manufacturing, and analytical development as well as other technical experts. It is best practice for the manufacturing entity to have a standard operating procedure (SOP) to assess vendor capabilities and attributes under a variety of audit levels.

The type of audit conducted is based on many criteria including past relationships with the vendor, the longevity of the approval status, whether the vendor supplies critical or non-critical products/services, and risk assessment strategies of the manufacturing entity. Several types of auditing processes exist that are categorized by levels of stringency:

  1. No audit or check list–minimal impact materials
  2. Retrospective audit–qualification based on past performance
  3. Paper audit–qualification by an audit check list
  4. On-site audit

The types of audits and the frequency of audits required must be defined in the specific VQSOP. It is also common practice to define ongoing audit frequencies in a requalification plan (see Develop a vendor requalification plan below).

Once the audit is complete, the audit team generates an assessment covering the suitability of supplier’s facility and its quality management systems, the supplier’s staff and departmental organization (both staff levels and skill sets), a review of the supplier’s documentation procedures (e.g., relevant SOPs), and a review of the supplier’s supply chain. In some instances, it might be appropriate to ask the supplier to manufacture a test lot of the raw material prior to final selection.

Once the assessment is complete, the QA team along with designated personnel makes the final vendor selection(s). When a vendor is “Approved”, QA updates the Approved Vendor/Supplier List and issues a letter of approval to the vendor. If the vendor is deemed “Not Approved”, QA team will collaborate with relevant departments to determine what additional information and/or steps are required to qualify the vendor. Non-approved vendors can be reconsidered if they provide additional information and/or put a Corrective Action and Preventative Action (CAPA) in place. If such vendor responses are satisfactory, the vendor may be “Approved”. If the responses are not satisfactory or the vendor is not willing to make appropriate changes, they will remain “Not Approved”.

In certain exceptions (e.g., additional information is not available and/or there is no immediate alternative), a risk assessment plan is put in place to determine if the vendor can be used until further required actions are taken to avoid a shutdown of the manufacturing activities. A Quality Agreement is then put in place for all approved vendors.

Develop a vendor requalification plan

After the VQ process and final vendor selection, a plan and SOP is developed for vendor requalification using defined and preestablished intervals. While the initial VQ process involves a detailed evaluation of a vendor’s attributes and capabilities, a clinical and commercial manufacturing program’s success relies on VQ as an ongoing process, with regular supplier meetings and audits to maintain the highest quality of products and services. The requalification plan defines the types and frequency of audits and is shared with the vendor. The requalification plan also identifies instances that would trigger additional audits, such as a change in manufacturing location, addition of new plants or warehouses, moving operations to another country and change in raw materials due to global shortage of existing raw materials.

Costs associated with VQ process

The financial impact of vendor qualification is high, potentially adding to the cost of new commercial cell therapies. An estimated $130–150 million (USD) is spent annually for on-site and remote new vendor qualification assessments [2]. Table 3 shares some typical costs for various entities. These costs do not include the cost of periodically requalifying existing vendors or the indirect costs of distributing and evaluating requests for information.

Table 3. Typical costs (in USD) associated with VQ audits (VQA) [2].

 Average cost per VQAAverage yearly VQA cost
Overall$13,259$270,033
Sponsors$12,432$197,940
CROs$18,704$666,883
Small companies$12,607$150,570
Medium companies$17,072$475,445
Large companies$21,839$1,886,308

Summary

The high-level regulatory requirements established by the FDA, ICH, and ISO are useful, but lack standardization and specificity for implementing a VQ program for cell therapy manufacturing. This results in highly variable and labor-intensive VQ programs and processes, which can lead to delays and increased cost burdens to cell therapy products. Until the cell therapy industry establishes standards to streamline the VQ process, a current best practice requires a collaborative relationship based on open and timely conversations, clearly defined expectations during the qualification process, and a plan to manage risk and achieve success for both parties.

— Author: Rupa Pike, PhD, Thermo Fisher Scientific.

References

  1. Shimoni, Y et al. (2015). A Risk-Based Approach to Supplier and Raw Materials Management. BioProc Intl 13(10): 10–15.
  2. Jay A. Turpen, Senior Consultant, The Avoca Group 03.04.20 as seen in Contract Pharma.
  3. BioProcess Systems Alliance (2019) The Role of Single-Use Polymeric Solutions in Enabling Cell and Gene Therapy Production Part 3: Best Practices for Supplier Selection, Qualification, and Validation to Ensure Supply Chain Security Bio-Process Systems Alliance Cell and Gene Therapy Committee. BioProc Intl 17(6).
  4. ASTM E3051–16: Standard Guide for Specification, Design, Verification, and Application of Single-Use Systems in Pharmaceutical and Biopharmaceutical Manufacturing. ASTM International: West Conshohocken, PA, 2016; doi:10.1520/E3051-16.