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October 30, 2019

When we think about cell and gene therapies (CGTs) what most often comes to mind is the early stage scientific innovation responsible for finding new ways to treat diseases. A lot of complex research and testing is performed to confirm Proof of Concept and that the therapy performs as desired. 

Congratulations! That is a huge accomplishment.

The next step is to prepare the product for in-human testing. Clinical protocols are developed in consultation with the regulatory authorities, a target patient population is identified, clinical investigators and an appropriate contract research organization are selected, and funds are obtained to begin the studies. What is sometimes overlooked, or left to the last minute, is the less-than-glamorous, but still critical, manufacturing steps that ensure a new, potentially life-saving treatment reaches patients in a safe and reliable form.HVC13 - Download now button - new design

In this post we will map the five critical steps that require thoughtful measured consideration for a CGT product to be produced in a good manufacturing practices (GMP) facility.

The five steps for ensuring products are GMP compliant are:

  1. Entry of Raw Materials into the Manufacturing Supply Chain:

    Raw materials are all the ingredients needed to make a given product and can include patient samples arriving from hospitals/clinics, cell lines supplied by commercial vendors, reagents (e. cell culture media), and consumables (e.g. plastics). When any of these items arrive at the GMP facility, a receiving document is created, and the rigorous documentation pathway required for any GMP product begins.

  2. Quality Control and/or Quality Assurance Release of Raw Materials:

    Typically, raw materials arrive with a certificate of analysis (CoA) and/or certificate of conformance (CoC) provided by the vendor/supplier. The supply chain group ensures that ordering and receiving of materials happens in an organized manner. Using a master specification sheet as a guide, the Quality Unit – made up of the quality assurance (QA) and quality control (QC) teams – ensure that the raw material meets the specifications set out in the CoA and CoC and can be used for GMP manufacturing a guide, the Quality Unit – made up of the quality assurance (QA) and quality control (QC) teams – ensure that the raw material meets the specifications set out in the CoA and CoC and can be used for GMP manufacturing purposes.

    This can potentially be a bottleneck step should the raw material fail to meet specifications, resulting in rejection or quarantine of the material, and can significantly delay the start of manufacturing if replacement materials need to be qualified and sourced. Delays can also be a result of problems with the documentation accompanying raw materials. For example, if documents arrive in a different language they will need to be translated. Another common issue is documents that conform with local regulatory requirements for the supplier, but not the receiving facility. It is important to note that everything that comes into the GMP facility, from cells to pipette tips, will go through this process, and that some raw materials will be easier to release than others so it is essential that the materials be qualified in advance and that they arrive with the appropriate documentation to support release into GMP production.
  3. Manufacturing:

    A GMP manufacturing process is usually accompanied by a detailed protocol and Master Batch Record that is reviewed and approved by both the client and quality assurance team in the GMP facility. As the operators in the GMP facility work through the manufacturing protocol, they will document each step in an approved copy of the Master Batch Record that is traceable by a distinct lot number. The purpose of the completed batch record is to demonstrate that a specific batch of product was generated in accordance with the manufacturing protocol and to document any The batch record is key to maintaining traceability of raw materials and manufacturing practices. During manufacturing, routine environmental monitoring is carried out to ensure sterility is maintained during production and compliance to regulatory guidelines are adhered to.
  4. Quality Control Release Testing:

    Once the product is manufactured in accordance with the approved batch record and meets the requirements outlined in an approved protocol and Master Batch Record, it is ready for Quality Control Testing. This step is critical in ensuring the final product meets basic safety requirements and adheres to the release specification set out in the protocol and approved by both manufacturer QA and client. See a previous post to learn about the standard quality control tests performed during this step.
  5. Final Product Release:

    At the end of manufacturing, before a product is released to the end user, manufacturing documents are meticulously checked against the batch record by the QA team. For this step to proceed without delay, good documentation practices, as outlined in a Standard Operating Procedure (SOP), must be followed. The SOP covers everything about how to properly document manufacturing. For example, it will describe exactly how an operator should record a cancellation or change in the batch record. Since most batch records are documented manually by the manufacturing operators, making a change is not as simple as scratching something out and writing over it. Human error is always a factor in this process, and the QA verification step is designed to identify and correct any instances where mistakes were made in product documentation. Once a client’s quality unit confirms that manufacturing was performed and documented properly and released for clinical use, the product makes its way to patients. When working with CGTs that have a very short shelf life or that are destined for patients who are already critically ill, time is of the essence.

Understanding the life cycle of a GMP product and where delays can occur will help therapy developers and manufacturers work efficiently towards generating a safe and reliable final product.

Do you require a consultation for your GMP manufacturing needs? Contact us now.

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