| Quality clinical supplies are one of the cornerstones for a successful clinical trial. The manufacturing and the packaging of the pivotal/biobatch for a new drug product is often the most important batch in the product's life cycle. Given this importance in the product life cycle, having clinical supplies produced by contract service providers creates an additional challenge to the completion of this crucial juncture.
For some contractors, clinical supply production is a core competency. However, for many other contract manufacturing and packaging sites, clinical supply production is not. Patented new dosage forms, biotechnology products and specialized products such as continuous valve aerosols often involve contractors that have limited or no experience with the rigorous controls needed to produce blinded supplies. Extensive training prior to the initiation of clinical trials, as well as on-site monitoring by teams of quality assurance and other technical departments, are often needed to assure that clinical studies results are reflective of new drug efficacy and not some error in clinical supply production.
Standard audit checklists for manufacturers and packagers need to be amended for the additional concerns that arise in a clinical supply relationship. Contractors approved for currently marketed products should not be assumed to be acceptable for clinical manufacturing and packaging. Besides the requirements for commercial production, the audits must verify that procedures and processes are in place specifically addressing the clinical supplies process. Critical packaging controls for blinded, randomized supplies need to be addressed. Additional focus will need to be placed on the availability of specific SOPs and training relevant to clinical supplies.
For the manufacturers of new novel dosage forms and biotechnology products, the production of clinical supplies can be the first time that current Good Manufacturing Practices (cGMPs) requirements will need to be met. Besides the equipment used directly for production of the clinical supplies, the supportive operational systems will need to be addressed. When preclinical supplies are produced at the facility, the installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ) for the air handling and water systems may not have been fully addressed. The firm may also not have completed all of the needed IQ, OQ and PQ for production equipment needed to manufacture and package the clinical product. Often the contractor does not have the experience needed to perform these validation processes. Sufficient time needs to be built into the timeline to assure that all equipment and operating system qualifications are complete for clinical supply production.
The Quality Assurance department of the drug sponsor may have no choice in the production location of clinical supplies for new novel dosage forms or biotechnology products. In those cases, the audit will serve as a means to identify the systems that are missing and are a starting point for the Corrective Action/Preventative Action (CAPA) plans needed. With QA or Project Management as the lead, Resources from many disciplines will be needed to assist the contractor successfully. Formulation, analytical development, compliance and technical transfer staff are among the in-house resources that can be mobilized in the clinical supply production mode. When insufficient resources or experience exist for the challenging transition from research into the development stage at the contractor, then consultants with this type of experience can be invaluable in this growth phase for the contractor.
Specialized training in the requirements of clinical supplies must occur before the initiation of the clinical supply production. Although specific training in the SOPs pertaining to clinical supply production is needed, individuals involved with all phases of the clinical supply process need to be familiar with the general requirements for clinical studies. Basic clinical trial concepts like blinding and patient randomization must be understood by the contractor's personnel to decrease the risk of the mix-up of placebo and active drug(s). Individuals at the contractor need to understand that the normal ways to identify the contents of the bulk and packaged product are not true for clinical supplies. The use of easily removable, often color-coded labeling on the unit packages of clinical supplies prior to patient randomization needs to be explained. The importance of the identification of the storage carton or bin becomes even more important to clinical supplies than for commercial production. While commercial tablets and capsules have easily identifiable markings, the clinical supply products will generally have no markings. Even if there is some kind of marking for the product, each of the placebos and the various dose(s) of actives will look the same.
On-site monitoring by the Quality Assurance staff of the sponsor should be done routinely. When sites have limited clinical supply experience, then on-site monitoring is essential to quality assurance. Arrival at the contract site one day before the production of the clinical supplies allows the drug sponsor's QA representative to verify that all records are complete, all raw materials and components are released and the final training specific to the drug sponsor's clinical supply run has occurred with appropriate manufacturing and/or packaging personnel.
For facilities with limited or no clinical supply production and packaging experience, the drug sponsor's representative must be present at the start-up of the clinical run and between the placebo and the active ingredient product(s) batches. Assurance of the removal of all of the placebo dosage units prior to active dosage unit production is essential. The need for the blinded placebo and active to look exactly the same result in an inability of the contractor's personnel to identify a foreign tablet in the production area. If a placebo were to replace an active dosage unit in the clinical trial, there is an increased possibility for reduced efficacy results for the active drug product. Of greater significance is the potential for the discovery of placebo and active mix-up after the clinical study has been initiated. If this clinical supply mix-up is verified, the entire clinical study is at risk and the cost to the drug sponsor in approval time and cost is monumental.
Clinical Supply Manufacturing
The cleaning validation program for the contractor needs to be extremely well understood. Residual product from previous manufacturing in the same equipment train as the clinical supply not only has compliance implications but could also result in unnecessary adverse event reports for the clinical study. Thorough review of the cleaning validation program is needed and the contractor must provide adequate assurances that proper cleaning has occurred before the production of the clinical supply lot. The contractor should be questioned as to whether there are other products in the research or development phase being produced in the equipment train. If so, verification should be obtained from the contractor that their cleaning validation program has included these products.
Product yield requirements for clinical supply production are not assumed to be the same as accountability requirements for commercial products. If a similar product is manufactured in the same equipment train, then the use of that yield could be appropriate. Since the product yield needs to be based on the production history and no sufficient history exists at the time of clinical supply production, some discretion must be used in deciding appropriate yield specifications for various steps and the final product. When there is concern about the contractor's experience in clinical production, a higher yield can be required and appropriate investigation performed when the limit is not met. Prior to setting the higher yield requirements it is important to review those parts of the equipment train where product cannot be recovered as waste, e.g. liquid product in lines that must be flushed to remove the product. Higher yields serve as a strong reminder to the contractor's manufacturing staff that all efforts must be made to account for finished and waste product in the manufacturing process.
Shipment of Bulk Clinical Supplies
If the clinical supply contract manufacturer will not be the clinical supply packager, additional precautions need to be taken to assure that the placebo and the active(s) are not mixed during shipment of the bulk. Each individual unit should be marked in some manner to be sure that the placebo and each strength of the active product could be identified. Besides the required labeling on the external shipping unit, it is also helpful to put product and lot identification tags on the inside of the shipping unit. Furthermore it is helpful if shipment of each lot of the placebo and active is made separately. Receipt of the bulk material on different days at the packaging site provides an additional control for the separation of each of the blinded supplies for the complete clinical package.
Blinding of Packaged Product
Experienced contractors for blistered clinical supplies are readily available and accessible. For drug sponsors with limited clinical study experience, contractors often provide the clinical supply package design, which results in improved patient compliance during the study. Large contract packagers often provide clinical supply services as a means of introducing new clients to their packaging capabilities. By successfully assisting firms to complete the FDA pre-approval inspections, the contractors have established their facility as approved for commercial production.
Drug sponsors are often concerned with the "intellectual property" implications of active ingredient and dissolution test methods/specifications for a new drug product. Although the drug sponsor may be using the clinical supply contractor for production and packaging of previously approved new drugs, there is often some hesitancy on the part of the sponsor to have the contractor perform key analytical testing for clinical supplies. When possible, the drug sponsor's own analytical development department can provide the needed release testing of the bulk and finished packaged product. In the case where supplies are for a clinical study aimed at gaining approval of a new indication for an existing dosage form, analytical test methods would already be included in the United States Pharmacopeia (USP) and can be tested by the approved contractor.
For virtual companies, using an analytical development contract firm and contract laboratories can mitigate the risk of the loss of intellectual property. Companies with internal analytical development have the ability to use their own laboratories to provide the maximum assurance of IP protection.
Investigations During Clinical Trials
The contractor needs to be actively involved in the investigation of clinical supplies should complaints occur during the clinical trial. The sponsor's Quality Assurance unit should work closely with the contractor to determine the cause of any supply-related complaints in the study. Failure of the packaging system can be a critical error when the package failure makes the drug fail specifications or causes the product to become unblinded. Assessments of these kinds of defects are essential in determining whether there is a specific study site problem, a warehousing problem or a broader issue.
When clinical supplies are returned as a complaint to the Quality Assurance department of the drug sponsor, there should be an immediate assessment as to whether the returned unit(s) needs to be assessed at the contractor. For example when the product is a continuous valve aerosol can, assessment cannot be completed without a breakdown of the can to determine whether there has been a failure in the valve assembly or crimp seal for the product. The expertise of the contractor may need to be augmented by the experience of the packaging component supplier.
Preparation for Pre-Approval Inspection
The Quality Assurance department of the drug sponsor can provide an independent evaluation of the readiness of the contractor for an inspection. During preparation, the drug sponsor can verify that all of the CAPA items have been addressed successfully and that active remediation is occurring for items not yet completed. Additionally the availability of all biobatch records should be checked. Any records that might have been archived off-site should be retrieved and completeness verified.
The sponsor may prefer to be present during the pre-approval inspection at the contractor. The sponsor's presence can assist in assuring that the FDA gets all needed records and requested information in a timely manner. The sponsor's presence at a non-U.S. clinical supply contractor normally facilitates the inspection. Knowledge of the entire clinical production records and often greater familiarity with FDA requirements lets the sponsor facilitate successful completion of the pre-approval inspection. Even if no one from the sponsor can be at the contractor's site during the pre-approval inspection, a designated individual from the sponsor must be available at all hours when the FDA inspectional team is at the contractor. The contractor's Quality Assurance staff, which will assist with the inspection, should all know the sponsor's contact.
Record Retention and Retains
Extra precautions are needed at the contractor to be sure that the clinical supply production records are not archived in the same manner as commercial production. The records should continue to be readily retrievable throughout the clinical trials and easily available to an FDA investigator when a pre-approval inspection is performed. Furthermore, the clinical batches (particularly the pivotal/biobatch records) are also extremely critical should a failure occur after product approval. Not only should the batch records be maintained but also all supportive documentation. For example, a common excipient may be pulled from commercial inventory for the clinical supply. The testing results for the lot(s) of excipients need to be maintained beyond normal commercial requirements. The raw material testing results can be invaluable when an investigation needs to be performed or product optimization efforts are being evaluated.
The drug's sponsor should also maintain a complete set of these records, especially when the sponsor is the New Drug Application (NDA) holder. If the contractor does not focus on clinical supplies it is very easy for the records to be destroyed using standard commercial record retention periods.
Besides the biobatch samples required to be maintained at the clinical sites for FDA, the quality assurance department of the drug sponsor needs to maintain additional retains of the biobatch lots. The drug sponsor's QA samples should be in addition to any samples that the analytical and formulation departments might require. When the drug substance is not prohibitively expensive, quality assurance should be sure that the quantity of samples of the bulk and packaged clinical supplies will be sufficient for all of the department's needs.
Additional retains of the active ingredient lots used in all clinical supplies but particularly the biobatch need to be retained by the drug sponsor. When the drug sponsor is a virtual firm, then an established contract laboratory can be used to store the active ingredient in the required temperature and humidity conditions.
Through a process of auditing, planning and monitoring, clinical supplies can be manufactured and packaged to the same level of quality as in-house clinical departments. New dosage forms and biotechnology products can make a successful transition from research into the development mode with the active participation of the Quality Assurance unit of the drug sponsor. Clinical supply contractors with extensive experience can assure that a company meets or exceeds the current industry standards that pertain to clinical supply production.
A Quality Assurance perspective
By Edith Lewis-Rogers
Published August 23, 2005
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