Qualification of Suppliers – excipients

The quality, efficacy and safety of the medicinal product depends on many factors of which we’ve already tackled a few in previous blog posts. The one we will be talking about this time is supplier qualification of excipients.

Supplier qualification is a very broad term for the qualification process used to determine whether the starting materials and packaging materials used in the final medicinal product are of the required quality. It’s not exclusively used for materials but also for the suppliers of services, being all GxP relevant processes carried out by third parties (e.g. contract laboratory, calibration, pest control).

The qualification of suppliers is about ensuring supply chain dependability. It guarantees the quality and their subsequent process steps such as storage, transport and distribution. Additionally, it ensures that the quality of materials and services is also reliably maintained. All together it can lead to positive trends as reduction of complaints and reduction of costs related to non-quality when the process is guarded to be and to remain robust.

Supplier qualification of excipients has to be risk-based. This is a key element in the organization of this process and also consistently mentioned in all the regulations with regards to supplier qualification.

But how do start? The ‘guidelines of 19 March 2015 on the formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use’ define an approach where we look at the type and the use of the excipient to subdivide them into low, medium or high risk with regards to being GMP appropriate. Therefore the risks presented to the quality, safety and function of each excipient and each source should be assessed before being used in a GMP environment.

Below a non-exhaustive list of risks is presented for which the risk management methods mentioned in ICH Q9 can be used to determine the risk. The items below are in most cases challenged via a questionnaire, also known as paper audit, sent by the manufacturing authorization holder.

1. Risk profile with regards to the source of the excipient

1. TSE (transmissible spongiform encephalopathy)
2. Potential viral contamination
3. Potential microbiological/endotoxin/pyrogen contamination
4. Potential impurities (e.g. aflatoxins or pesticides, residual solvents and catalysts)
5. Sterility assurance (if applicable)
6. Potential impurities carried over from other processes, in absence of dedicated equipment and/or facilities
7. Environmental control and storage/transportation conditions including cold chain management
8. Supply chain complexity (how many vendors/brokers are involved?)
9. Stability of excipient
10. Packaging integrity evidence

2. Risk profile of the use and function of the excipient

1. Route of administration (e.g. orally, intravenous)
2. Function of the excipient (e.g. pH regulator, conservative, solvent)
3. Percentage of excipient present in the formulation
4. Maximum allowable daily dose
5. Any known defects or fraudulent adulteration?
6. Is the excipient a composite?
7. Potential impact on the critical quality attributes of the medicinal product?
8. Other factors that can be relevant for patient safety (e.g. allergens)?

3. Risk profile of the manufacturer and/or supplier; the following items are considered to be a minimum of GMP compliance that is expected from the manufacturer and/or supplier

1. Establishment and implementation of an effective pharmaceutical quality system
2. Sufficient competent and appropriately qualified personnel
3. Defined job descriptions for managerial and supervisory staff responsible for manufacturing and quality activities
4. Training programs for all staff involved in manufacturing and quality activities
5. Training programs related to health, hygiene and clothing as identified as necessary to the intended operations
6. Provision and maintenance of premises and equipment appropriate to the intended operations
7. Documentation system(s) covering all processes and specifications for the various manufacturing and quality operations
8. Systems for coding and identifying starting materials, intermediates and excipients to allow full traceability
9. Qualification program of suppliers
10. System for quality control of the excipient and a responsible person independent from production to release the batches
11. Retention of records for incoming materials and excipients and retention of samples of excipients for the periods required by EudraLex Volume 4, Part IISystems to ensure that any activity contracted out is subject to a written contract
12. Maintenance of an effective system whereby complaints are reviewed and excipients may be recalled
13. Change management and deviation management system
14. Self-inspection program
15. Environmental control and storage conditions

4. Overall risk profile (combination of risks)

Using a RPN (risk priority number) or a combination of RPN’s, it can be defined whether the overall risk is low, medium or high and what consequences this should have in light of accepting, conditionally accepting (with mitigating actions) or rejecting the manufacturer/supplier of the concerned excipient.

Mitigating actions to reduce the risk and to eventually accept a manufacturer/supplier could be conducting an on-site audit, requesting more documentation or implementing corrective actions.

5. Monitoring

Once a manufacturer and/or supplier is approved, their GMP compliance need to be reconfirmed on a periodic basis (normally 3-5 years) to re-evaluate their risk based on monitoring parameters such as;

1. Number of defects in ratio to batches of excipient received
2. Type/severity of such defects
3. Monitoring and trend analysis of excipient quality
4. Loss of relevant quality system and/or GMP certification by excipient manufacturer
5. Observation of trends in drug product quality attributes; this will depend on the nature and role of excipient
6. Observed organizational, procedural or technical/process changes at the excipient manufacturer

This assessment can be done by performing an audit/re-audit or sending a questionnaire. Based on the outcome of this assessment, the manufacturer and/or supplier is then re-approved, rejected or subject to additional mitigating actions.

6. QA Agreement

When using a raw material from an approved manufacturer/supplier it’s important to agree on some mutual expectations/obligations between the contract giver and the contract acceptor. Aspects that are important to be included into the agreement are (non-exhaustive);

1. The roles and responsibilities of the contract giver and the contract acceptor with regards to compliance to applicable GMP standards
2. Agreement on specifications and used packaging materials
3. How deviations and out-of-specification results will be communicated, investigated, documented and resolved
4. How changes that have an impact on the manufacturing process, equipment, analytical methods or specifications are managed and communicated
5. How complaints and recalls are handled and resolved
6. What rights the company has for on-site audits and management of audit observations

Considering the regulatory challenges and the difficulty to receive all necessary information from the manufacturer and/or supplier, supplier qualification can become a very complex system of which procedural compliance is easily lost when not maintained properly. The key is – as always – to keep it simple and to maybe start with favoring manufacturers that can supply compliant and high-quality products to create a reliable portfolio and a manageable workload.