How the use of a pre-established Quality Agreement  between API and Drug Product Manufacturers can  solve the burden of QA negotiations

This article was written with the kind agreement of APIC

General Constraints of the Pharmaceutical Manufacturing Industry

Pharmaceutical manufacturing, complex and regulated, operates under stringent requirements, imposing strict standards at every stage of the process from raw materials for the drug substance manufacturing to the drug product distribution.

These standards are legislatively dictated to meet public health imperatives.

GMP is a must for drug manufacturers, imposing high standards in production, quality control, documentation, and supply chain. Health agencies conduct regular inspections to ensure manufacturers comply with these standards. Non-compliance can result in severe consequences, including production suspension or withdrawal.

Need for a Quality Agreement (QA) between API and Drug Product Manufacturers

This document clearly outlines the responsibilities of each party, ensuring transparent collaboration in line with stringent regulatory standards. It commits the parties to maintain high standards, thus ensuring the quality and safety of the final product.

This QA template can be used for both generic APIs and exclusive APIs also called custom synthesis.

If the API is sold to a distributor by the original manufacturer and further sold by the distributor to one or multiple end-customers (MAHs) guidance is given with the QA template which may also be used for three-way agreements by adding a third column in the compliance section.

Today, authorities do not consider the establishment of Quality Agreements as the sole responsibility of the drug product manufacturer anymore, but there are expectations at many national authorities also towards the API manufacturer to have Quality Agreements in place with its customers (MAHs)

Description of APIC and its Role in Europe

The Active Pharmaceutical Ingredients Committee (APIC), a Sector Group under the European Chemical Industry Council (CEFIC), was established in 1992 in response to the escalating regulatory demands in Europe affecting the production of APIs. APIC serves as the representative body for API and API intermediates manufacturers in Europe, benefiting diverse membership of over 70 companies across the continent, alongside several national industry associations.

For approximately two-thirds of its members, the primary focus is on the sale of APIs and intermediates, while the remaining third predominantly markets final medicinal products. APIC has evolved into a prominent industry association emphasizing worldwide Quality, Good Manufacturing Practice (GMP), and Regulatory considerations related to APIs and intermediates.

Over the years, APIC has actively contributed to the pharmaceutical landscape by developing a series of guidance documents and position papers accessible at https://apic.cefi c.org/.

Notably, these resources provide best industry practices and guidance for establishing QA between API manufacturers and their customers. The guidelines underscore key factors to consider when negotiating and finalizing such agreements between both parties.

History of the APIC QA Template

Since its initial release in 2009, the APIC QA template has undergone significant evolution through the current version (V2, published in 2017), continuously adapting to the needs of the pharmaceutical industry. The revision in progress (V3, publication expected in March 2024 on the APIC website), a product of continuous improvement, integrates best practices and overall, the cumulative members' experience over the years.

Detailed Content Example of the APIC QA Template

The APIC QA template provides a detailed structure to frame quality agreements between API suppliers and drug product manufacturers. Let’s dive into key sections of this document:

General Provisions

The introduction and general provisions sections address the scope and terms and conditions of the agreement. The “Quality Responsibilities” section – in some cases also called “division (or: delimitation) of responsibilities” – includes the main quality and regulatory points and corresponding responsibilities that should typically be found in a QA. The quality responsibilities may be assigned to one or both parties, as appropriate. To allow a convenient and quick overview a tabular format has been chosen for that section.

A glossary, which includes useful definitions of terms that are not defined in ICH Q7, may be part of the QA and has been suggested in the guideline. For instance, the definitions of timelines such as “immediately”, “promptly”, or “with undue delay” allows covering all specific cases.

1. Quality Management: The template demands compliance with the applicable GMPs, and it is not necessary to repeat guideline text in the template. It should rather include some additional clarification on responsibilities, timelines, and documents/information to be provided.

§1.01: “Manufacturing PRODUCT in compliance with the applicable Current Good Manufacturing Practices (CGMPs).

For this agreement, CGMP shall mean the principles (i) described in the ICH Q7 Guide (incl. the Q&As published in 2015) as well as the ICH Q9 and Q10 Guidelines, (ii) promulgated by any governmental or regulatory authority having jurisdiction over the manufacture of the PRODUCT.”

2. Change Control: A major strength of the APIC QA template lies in its proactive change management to notify the customer within a reasonable time, before implementation, and provide him with the necessary change documentation. This will allow – for the customer - to assess the potential impact of the change on the supply or its use at the customer.

§2.01: “SUPPLIER shall have a documented and effective change control system in place. SUPPLIER shall inform CUSTOMER of any intended changes to the manufacture of PRODUCT, which are expected to have

» a significant impact on the quality or safety of supplied PRODUCT, and/or

» an impact on any regulatory applications of CUSTOMER related to PRODUCT.”

3. Data Integrity: Another aspect of the QA template is its particular attention to data integrity. In an environment where data accuracy and reliability are crucial, the template stipulates clear requirements to ensure integrity throughout the manufacturing and documentation process.

§6.01: “SUPPLIER agrees to have procedures in place to ensure quality-relevant data and metadata (electronic or paper) relevant to PRODUCT complies with the ALCOA+ criteria, and that it can be traced to its source and is readily available during regulatory inspections.”

The evolution from Version 2 to Version 3 of the Data Integrity section reflects strong improvements, strategically aligned with the review and recommendations of the dedicated “Data Integrity” task force of the APIC.

4. Certificates, Statements, and Declarations: These specify the certificates and statements suppliers must provide, covering aspects like GMP, BSE/TSE, residual solvents, elemental impurities, nitrosamines, and importation into the EU. Additionally, it allows customers to request further certificates or statements as justified, fostering a collaborative approach to Quality Assurance.

5. Material Control: Raw material control is fundamental to ensuring the quality of finished products. The template establishes clear procedures for setting specifications, supplier qualification, and incoming material control.

§15.03: “ Sampling and inspecting or testing of incoming materials, as appropriate. Materials supplied by qualified vendors can be subject to reduced testing but a minimum ID testing (or visual examination of containers, labels, and documentation in case of hazardous or highly toxic raw materials) needs to be performed for each delivery and each lot.”

6. Process Validation: The “Validation” section is pivotal for ensuring pharmaceutical manufacturing quality. It outlines procedures for equipment, process, and analytical method validation, emphasizing compliance with industry standards and ICH Q7.

§16.01 + 16.02: “Qualifying of equipment, utilities, and facilities.

Validating the manufacturing process, cleaning procedures, analytical methods, and computerized systems.”

7. Sub-contracting: With the outsourcing of certain activities, effective management of subcontractors is essential. The QA template demands rigorous assessment and qualification of subcontractors, ensuring compliance with all regulations.

§19.01: “ SUPPLIER will use its established GMP systems for evaluation, qualification, approval, and maintenance/ monitoring of all sub-contracted services with a GMP impact on PRODUCT manufactured.”

8. Complaints: This section outlines the responsibilities of both CUSTOMER and SUPPLIER in handling complaints, emphasizing transparency, timely communication, and effective corrective actions.

§24.02: “All complaints related to the PRODUCT, regardless of source (e.g., consumers, doctors, pharmacists, sales representatives) will be communicated to SUPPLIER in writing.”

§24.03: “SUPPLIER will respond to complaints by the CUSTOMER promptly and according to formally agreed procedures”

These excerpts highlight the rigor and clarity of the APIC QA template, establishing a comprehensive framework for collaboration between API suppliers and finished product manufacturers. Compliance with these guidelines enhances the quality, traceability, and security of pharmaceutical products, ensuring optimal compliance throughout the supply chain.

Advantages of the APIC QA Template

The drafting, review, and negotiation of QA can often represent a significant burden for API manufacturers and their customers. Questions arising during activities on these agreements are numerous: How long does it take to obtain final approval? How many QA land on your desk each month? Are you still managing all the diverse and specific requirements or commitments expressed by your customers?

The APIC QA task force addresses these issues thanks to this template:

1. Significant Workload Reduction: Drafting, reviewing, and discussing Quality Agreements can be time-consuming. The standardized APIC template offers a pre-established structure, reducing the time required for these processes. This results in a significant reduction in workload, allowing stakeholders to focus on other crucial aspects of their operations.
2. Accelerated Implementation: By standardizing the format of Quality Agreements, the APIC template reduces review and approval times. With pre-established clauses, discussions can focus on specific adjustments, if needed/requested, thus accelerating the overall implementation of agreements.
3. Reduced Complexity: The diversity of requirements and commitments in Quality Agreements can complicate management and compliance. Opting for a standardized template reduces complexity, aligning parties on common terms and facilitating mutual understanding.
4. Resolution of Controversial Topics: The template explicitly addresses topics often subject to debate, such as product-related changes, service continuity beyond the end of supply, and the definition of specific legal terms. This avoids prolonged negotiations on these sensitive points.
5. Standardization of Commitments: By presenting concrete examples of different requirements and commitments, the template promotes a standardized approach. It serves as a guide to align expectations and avoid unnecessary divergences, leading to improved collaboration.

Conclusion: Persuasive Reasons to Use this Template!

In conclusion, the APIC QA template emerges as a precious tool for drug manufacturers. In response to pervasive challenges related to quality agreements, this model offers a key solution. By adopting this standardized approach, players in the pharmaceutical industry can achieve significant gains in terms of time, complexity, and consistency in managing their agreements.

The utility of this template goes beyond a pure pre-established structure. It represents a crucial milestone toward optimized industrial practices. By aligning expectations and providing pre-established clauses, the template strengthens regulatory compliance, enhances product quality, and fosters increased trust among stakeholders.

Author Details 

Samuel Perret, Technical Customer Service Manager -SEQENS; Member of the APIC, communicationseqens@seqens.com

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