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Philip Lienbacher is head manager of raw material policy ownership at Shire, Vienna.
Manfred Karner is head of material lifecycle management at Shire, Vienna.
By working together and taking a QA-based approach, manufacturers and suppliers can reduce raw material testing requirements.
Testing incoming raw materials is crucial for ensuring the safety of any final drug product. However, close collaboration between the final drug manufacturer and its raw material supplier can reduce the amount of testing required during the incoming inspection of raw materials. This approach requires complete mutual trust and working with suppliers that have demonstrated commitment to quality. This approach allows some tests to be outsourced, but leaves the final drug product licenseholder fully responsible for release of the materials. Taking this approach requires moving from a traditional quality control (QC) approach, to more of a quality assurance (QA) model. This article summarizes requirements for incoming raw materials testing and supplier assessment and discusses how testing can be reduced.
Currently, regulations in the United States and the European Union allow for outsourcing of incoming raw materials testing, by using a manufacturer’s/supplier’s certificate of analysis (CoA) in lieu of performing the tests in house. This approach is described in both 21 Code of Federal Regulations §211 (1) and the EU current good manufacturing practice (cGMP) guide (2). The most relevant passages from legal requirements are excerpted below:
CFR § 211.84 d (2) and (3): (1)
EU GMP Guide Part II/International Council on Harmonization of Human Drug Products (ICH) Q7: (2)
EU GMP Guide Part I - Chapter 5 (3): (literally mentioning APIs/excipients since revision in 2015)
Even to consider this type of approach, a pharmaceutical manufacturer must have a close relationship with the manufacturer/supplier of a raw material. When selecting potential suppliers, pharmaceutical manufacturers must thoroughly assess their capabilities in terms of quality and quantity, pricing, global footprint, and willingness to support continuous improvement.
Suppliers should be categorized into different levels of risk based on the following:
Having a standardized system for supplier/manufacturer classification ensures uniform management practices and defines audit interval, scope, intensity, and duration. The manufacturing process should be inspected in addition to the quality systems during the audit.
Before placing a raw material under reduced testing, it is important to identify the whole chain of distribution. The CoA from the manufacturer might not be representative if multiple steps of manipulation (e.g., repackaging, refilling) occur throughout the supply chain. European regulators ask for this information specifically, since the Guideline on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use (5) took effect in March 2015.
Each process step in the supply chain must be evaluated and, if needed, qualified, and its quality determined during an on-site audit. Quality agreements should be put in place to define the responsibilities and expectations within the supply chain.
Any change made to the process in the supply chain must be communicated through a formalized process (“notification of change”) and undergo thorough evaluation. Examples would include changing the primary packaging of a raw material, which could have devastating effects if extractables or leachables were to alter the raw material and, subsequently, the quality of the drug product.
Ideally, raw materials should be sourced directly from the manufacturer. For one thing, the manufacturer is the best source of information about the material. Furthermore, communicating directly with the manufacturer allows for more direct information and a shorter supply chain.
In cases where the material must be sourced from a distributor, the company must first explain how the material is manipulated and stored throughout the supply chain, and the customer must verify this information. It is crucial that the distributor be able to name the manufacturer, to allow for direct communication when issues arise. If the supplier does not reveal this information, the pharmaceutical manufacturer should consider whether to work with this company.
A quality agreement should capture at least the following points:
It is important to consider the following aspects during the qualification process:
Having a system in place to rate or evaluate suppliers is a regulatory requirement, but can also be a useful tool, showing which suppliers may need closer supervision and collaboration to improve quality and/or performance. Additionally, the tool can be used for strategic purposes, aiding in such decisions as which materials require a second source and which suppliers should be considered for strategic partnerships in the future, or when buying a new material.
Purchasing and planning departments typically use criteria such as “adherence to schedules” (i.e., providing the correct amount of the correct material at the right time) to rate suppliers, it is also important to give raw material quality appropriate weight in supplier evaluations (see Figure 1).
Information is needed on such indicators as critical deviations, and on timely receipt of information about process or product changes in case of customer complaints. In fact, these data should be part of the regular evaluation for any supplier. In addition, evaluating risk and the potential impact of changes on the manufacturing process, product, and patient safety must be considered. If a supplier receives an unacceptable rating, action must be taken immediately. At the very least, the root causes for the rating must be discussed with the supplier, and followup actions determined. In some cases, an ad hoc or early inspection should be scheduled.
If the measures taken jointly fail to improve the supplier’s rating, the company should no longer be used as a supplier. This decision requires alignment with purchasing and supply-chain departments. In general, the better the supplier’s quality rating, the more acceptable the incoming raw material quality testing reduction becomes (see Figure 2).
A few additional points must be considered, however, before moving to testing reduction (see Figure 3). The following are some of the most important caveats:
Analytical aspects as well as the materials attributes have to be considered during the regular verification. Having a list in place that clearly states which degree of divergence between in-house testing results versus CoA results is acceptable is the ideal way to manage the verification but is hard to create and to keep up to date.
As far as efficiency is concerned, it makes sense to discuss outsourcing of raw material testing for the following scenarios, when:
Any contract testing laboratory that is used to perform testing for the purpose of releasing material or any other testing that is feeding into a regulated activity must be qualified as a service provider by the pharmaceutical manufacturer’s supplier quality management department, and a quality agreement must be put in place with that testing company. However, having verification testing done in an external contract laboratory may complicate assessments of deviations during testing. In some cases, the pharmaceutical manufacturer may not have a deep understanding of the testing method, but will still be responsible for assessing the quality of the material batch and releasing it for manufacturing. It will be up to the manufacturer to address these issues thoroughly before outsourcing any testing.
The incoming inspection of processing aids (i.e., materials, apart from solvents, that are used to manufacture the active substance or bulk product that are not part of a chemical or biological reaction) should include a visual verification of the shipment (including the suppliers’ product labeling) and verification of the supplier’s CoA.
This concept can also be used for dangerous, hazardous, or “specific” substances (see 7.32 of EU GMP Guide Part II (2). The incoming inspection approach for such items should be justified, documented, and approved by respective management representatives (in the EU, this must be done by the “head of quality control” and/or “qualified person”).
Analytical inspection of a delivery may be omitted as long as a batch of material is transferred within the area of control of a company (e.g., from one facility to another). Verifying the release documentation of the facility that initially received the material batch from an external supplier, checking the identity of each container, and ensuring that the integrity of the containers is unharmed is sufficient. It can help to use seals to ensure that containers were not opened, and that product was not tampered with, during transport).
Taking this approach eliminates redundant data collection and documentation, because only one site in the company will be required to write and own material specifications (including acknowledgement by the supplier), as well as to test and release the material batch. Internal supply chains must be documented and approved in quality agreements to ensure clear definition of responsibilities for each site and distribution of change notifications from the supplier. Reducing or eliminating the in-house identity testing of externally purchased starting materials for the manufacturing of a medicinal drug product is not allowed (see EU GMP Guide Annex 8  and WHO Technical Report Series 929-Annex 2 ).
The general requirement is to take a unique sample from each container. Identity testing described in pharmacopeias can often be considered as pass/fail testing (e.g., a qualitative rather than quantitative approach in which results will be reflected in a color change caused by the presence of a specific ion or functional group) and, thus, blending of samples is not allowed. A single incorrectly labeled container with a different substance would not be detectable when samples for identity testing are blended.
Once a proper validation has been conducted, a sampling plan can be used for identity testing. However, Annex 8 (4) is specific in stating that a successful validation is unlikely if the source of material is unknown, if the manufacturer has not been audited, or when dealing with starting materials used in parenteral drug products.
During the validation, type, status, quality systems, and manufacturing conditions must be considered, as well as labeling processes, with additional attention paid to repackaging within the supply chain.
Regulations in the United States and European Union allow incoming inspection of raw materials to be reduced if certain conditions are met and if a supplier quality management system is in place. However, the drug product license holder remains, at all times, responsible for release and use of these raw materials. Materials that do not fulfill the expectations put the manufacturing process and, subsequently, the quality of the drug product at risk. More importantly, they can harm patients who depend on the drug. This specific responsibility must be considered. In some cases, it can lead to a rigid and intense inspection program to ensure the quality of the drug product and patient safety. Materials that have undergone thorough testing by the supplier needn’t be tested twice (except for identity testing). This approach allows oversight to move from a QC- to a more QA-focused approach, assuming that results are verified regularly.
1. FDA, Code of Federal Regulations, 21 CFR § 211.84, Testing and approval or rejection of components, drug product containers and closures. FDA.gov.
2. European Commission, Eudralex, ec.eu, EU Guideline to GMP Part II, Basic Requirements for Active Substances used as Starting Materials (also published as ICH Guidance for Industry Q7A, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients).
3. European Commission, Eudralex, ec.eu, EU Guideline to GMP Part I, Basic Requirements for Medicinal Products, Chapter 5 - Production.
4. European Commission, Eudralelx.ec.eu, EU GMP Guide Annex 8 Sampling of Starting and Packaging Materials.
5. Eudralex, Eudralelx.ec.eu, Guideline of 19 March 2015 on the formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use.
6. World Health Organization (WHO), WHO.org, WHO Technical Report Series, No. 929, WHO Expert Committee on specifications for pharmaceutical preparations, Annex 2.
Vol. 41, No. 2
When referring to this article, please cite it as P. Lienbacher and M. Karner, “Collaborating for Efficiency and Safety in Raw Material Inspection," Supplement to Pharmaceutical Technology 41 (2) February 2017.