Assuring Process Control and Extending CSP Beyond-Use Dating by Pharmacy in Accordance with USP <797> and <71>
Does your pharmacy need to produce safe and effective Piggy-Back batches with the longest-possible expiration dating? SVP Batch compounding will assure your pharmacy the lowest possible cost for the safest, best quality CSPs, available whenever they are needed.
Concern about the quality of CSPs acquired from commercial compounding facilities by the hospital and clinical pharmacy has led to an increased interest in performing batch compounding in-house. Even when the chemical stability of the drug is sufficient to allow longer expiration dating, this practice cannot be performed efficiently and economically within the beyond-use dating (BUD) constraints of USP<797> in the absence of compendial sterility testing. Until now, such sterility testing of compounded batches has been very inconvenient, complex, and cost-prohibitive.
The ExtenDATE™ Sterility Testing system provides a convenient, simple, and inexpensive answer. The revolutionary ExtenDATE™ system allows hospital and clinical pharmacies to safely, accurately, and economically batch-compound CSPs between 40mL and 200mL in volume. This system is also an excellent method for reputable compounding pharmacy vendors to demonstrate USP<71>-compliant sterility testing of their products to their concerned customers.
The ExtenDATE™ System produces not only fast and efficient compendial sterility testing of these products, but also includes systematic, step-by-step instruction in performing both this type of compounding, and it's testing in a manner that is meaningful and valid. Properly used, ExtenDATE™ provides real confirmation of the efficacy of these products, rather than a dangerous false confidence that may lead to patient harm.
Batch Sterility Testing
For the purposes of sterility testing, a batch is not simply "a group of containers of the same solution compounded at the same time." In order to make any meaningful statement about the quality of the entire batch based upon the quality of the items sampled, all items in the batch must be prepared in an IDENTICAL way, as a continuous operation with no variation in the compounding materials, environment, equipment, methods, or techniques. There can be no variation in the factors that present a possibility of microbial contamination, or the compounding process will encompass too many uncontrolled variables, and the results of testing will not be adequately representative of batch quality.
For hand-compounded preparations, special efforts are required and quality assurance procedures must be adhered to if sterility testing is to be relied upon as the basis for extending dating. In order to assure that all items are identically prepared, there should be a compounding operative strictly following a completely defined procedure (see discussion below) and an observer/verifier to detect any items where any variation has occurred in the process. Such items must be identified and removed from the batch, and, although they may be suitable for use within the time period allowed by USP <797>, they should be excluded from the sterility-tested batch. At issue here is assuring that sterility testing of a sample of the batch is representative of every other item in the batch; not whether or not a deviation in the process was likely to lead to contamination.
For any items removed, a deviation report should be written, and an analysis performed to determine the items suitability for use within the USP <797> BUD structure, and ONLY if this analysis demonstrates that the item is not compromised should it be used. It is also possible for a deviation to be something that would decrease the likelihood of contamination (for example, performing extra glove decontamination) which poses the risk that testing would indicate higher quality than the rest of the batch actually possesses. In either case, if an item used for testing is prepared differently from all the other items of the batch, a false indication of batch quality may result.
Requirements for Batch Compounding
The facility in which compounding occurs must be designed, constructed, tested, monitored, maintained, and routinely cleaned in complete compliance with the requirements of USP <797>. Any fluctuation or variation in the compounding environment can affect the quality of the preparations. All compounding should be conducted in a properly functioning ISO-Class 5 Laminar Airflow Workstation (LAFW) that is housed within an ISO-Class 7 buffer area, with an anteroom of at least ISO-Class 8 where gowning, de-gowning, and pre-cleaning of supplies is conducted. Batch compounding should not be conducted outside a designated and validated CSP compounding facility having these attributes.
Equipment and Supplies
Any equipment used in the compounding process must be carefully evaluated for suitability, calibrated and/or tested as required, cleaned, and verified to be in good repair and operating properly. All disposable supplies should be assembled, inspected, and pre-cleaned as appropriate, to avoid interruptions of the process once it is initiated.
Syringes should be sized to provide the greatest possible accuracy, yet with sufficient size to promote ease of manipulation. In the case of hazardous drugs, the syringe should not be more than 3/4 full. Twist-on needle hubs are recommended. Syringes should not be reused.
Needles should be a twist-to-lock design and no thicker than 21 gauge to minimize disintegration of the septa. If more than one puncture is required in the septa of the final container, any additional punctures should not be made through the same hole. Aseptically applying an injection port sterile seal for each finished container within the LAFW is recommended for the same reason.
USP<797> requires that personnel must be trained and their knowledge and skills verified through testing at least annually at the skill level appropriate to their compounding duties. However, because extending dating, by definition, makes a preparation high-risk, personnel who perform the batch-preparation of CSPs must receive additional training and technique verification at least semi-annually. This training and verification must be matched to the most complex and longest duration processes they will employ.
Additional training topics should include the risk of clinically-significant microbial contamination associated with extended dating, the statistical basis of sterility testing, the need for all items to be compounded identically, and the documentation requirements for each batch. Operatives must also develop skilled, robotic accuracy in the precise process for batch compounding. Their semi-annual verification procedure should exactly simulate the process, using sterile growth medium in place of the intended sterile drug additives in sufficient quantity to result in a final concentration of 3 grams of Trypticase Soy Broth (TSB) powder per 100mL of solution. This verification procedure should also be observed and graded in its entirety by a qualified observer/verifier for compliance with good aseptic technique and for consistent application of the specified process to all items prepared.
The presence of a qualified observer/verifier is a critical component of the quality assurance protocol for extended expiration dating of hand-compounded batches. The temptation to omit this verification and the routine presence of the qualified observer/verifier may be high, but without it, there is no method of demonstrating that the actual compounding and resulting sterility testing is representative and valid for the purpose of extending the BUD. Omitting this component places the institution at risk of misrepresenting the sterility of preparations with extended BUD.
The process to be used for preparation of a batch must be precisely defined in detail. This begins with the development of a Master Batch Record and always requires complete documentation. The Master Batch Record must include:
- name of the finished product
- product concentration
- product expiration date
- product lot number
- list of ingredients, including all specifications
- amount and unit of measure
- manufacturers expiry
- conditions of storage
- chemical stability in the final solution
- source of authority for chemical stability claims
- special handling requirements
A batch should be made entirely from only one manufacturers lot of each component.
The exact placement of supplies within the critical work zone should be defined, and the exact steps in the compounding process listed in a Batch Production Protocol. If necessary, diagrams and/or photographs may be included. Any special handling requirements must be described in detail. The equipment and tools to be used must also be specifically defined.
Critical pathways must be disinfected prior to compounding using sterile alcohol. If sterile alcohol pads are used, they are to be used only once. Studies have shown that the most effective decontamination procedure is to combine an alcohol pad-swipe (which will remove visible debris from the septa) and a spray (which improves contact). The observer/verifier should pay close attention to the critical pathways, and verify they are maintained in first air after decontamination.
Gowning, hygiene, and facility cleaning should be provided in a Standard Operating Procedure (SOP) and performed and maintained in accordance with USP <797>. Sterile gloves should be aseptically donned, disinfected frequently as specified in the process instructions, and changed every 20-30 minutes. The work surface should also be cleaned and disinfected and the minimum frequency should also be specified. (For example, if a group of three items is compounded together, the process might specify cleaning and disinfecting the work surface between groups, and then re-disinfecting the gloves.)
Monitoring procedures should be employed to verify the efficacy of the process or detect the need for improvements. In the example just given, the observer/verifier should periodically sample the work surface and gloves just before the process instructions call for re-cleaning and disinfecting. If either the critical work surface or the dominant-hand glove fingers are found to have greater than three colony-forming units (CFUs), the frequency is not sufficient to maintain the cleanliness specified in USP <797>. The process instructions should be adjusted until monitoring consistently yields acceptable results.
The Master Batch Record should also specify final storage conditions, locations and storage monitoring procedures. No matter how carefully the batch is made and testing is conducted, improper handling and storage can compromise the quality of the preparation. Relevant storage condition parameters include temperature range, relative humidity range, and light intensity for some medications. Transport methods may also have an impact, and should be designed, controlled, and monitored to prevent deterioration, thermal degradation, or transport damage to the preparation.
All personnel engaged in batch preparation for the purpose of extending BUD must, twice-annually, simulate the process using sterile growth medium in place of drug product to demonstrate their ability to correctly and aseptically conduct the process. This exercise should also be used to verify the efficacy of the process itself. Monitoring should be conducted throughout the process to assure that required organization and cleanliness conditions are maintained throughout the process.
Prior to compounding any batch for release to patients, with the compounding facility in operation as it would be during actual compounding, all operative personnel should be observed and documented by the observer/verifier to competently perform an initial process simulation. This simulation should include completion and sign-off of an Assessment of Aseptic Technique (AAT-20) for each operative, including:
- Proper scrubbing and gowning
- Critical compounding site sanitizing and preparation
- The prescribed glove-donning validation
- Proper process setup
- Manipulative techniques using an appropriate amount of growth medium in place of the drug product
- Proper preparation of all compounded materials for storage/delivery
- Proper clean-up and disposal of all process waste materials
Process validation will be found to be effectively accomplished when all preparation, compounding, storage (incubation) and delivery techniques, and clean-up and waste disposal have been properly carried out and documented. Recurrent batching process validation and verification should be carried out and documented at least annually for all operatives.
The most important component of the Batch compounding exercise is its documentation. A proper non-destructive file and binders for all sequential documentation adequate to factually and historically validate the batch and its conduct in the form of a complete Batch Record are necessary for all batches compounded. The batch is not considered properly and completely prepared unless ALL documentation is complete and accurate. This record should include verification of the required compounding environmental conditions, qualification and re-qualification of all compounding personnel, testing and operational certification of all process equipment and environment, component lot traceability and expiry, basis for beyond-use dating, results of sterility testing, final storage conditions, storage location and monitoring procedures, results of any other testing performed (i.e., identity, stability, and/or pyrogenicity), and comments defining all concerns or exceptions. This record should be retained and made available for at least two years beyond the expiration of the batch products.
End-Product Sterility Sampling Plan
Sterility sampling should comply with USP <71> requirements in terms of the number of items required for the batch size, and the volume of the CSP solution to be tested in each growth medium (See enclosed chart: "Protocol for sterility testing based upon volume"). In accord with USP<71>, the minimum number of samples for a batch of 100 or less, is 4. (More than the minimum number may be taken.) It is recommended that one sample be taken randomly from the first third of the batch, one sample from the second, and the remaining two samples from the final third. This is because contaminants are more likely to become introduced into the compounding stream as time goes on, and the operator is more likely to make errors with fatigue and repetition. Samples should be taken randomly within those parameters (i.e., stratified-random sampling).
If the process involves grouping two or three bags (no more than three should be grouped) and dividing a single drawn-up aliquot of drug between them, or in any other way processing two or three within the same compounding segment (for example, if three are made, then the work surface and gloves are disinfected before the next three), samples for sterility testing must be taken from the last of the three, again, because it is this product that is most likely to be contaminated. Only in this way can you reasonably assume that the initial two samples are sterile.
In the absence of testing to demonstrate end-product sterility, USP <797> specifies maximum BUD for CSPs based upon demonstrated chemical stability, the presence or absence of preservatives, microbial contamination risk-level, and storage temperature. This is done to minimize the potential for clinically-significant contamination by limiting the time for any organisms which might be present to multiply. There is an allowance for the extension beyond these limits if USP <71>-compliant sterility testing demonstrates the sterility of a batch, provided the manufacturer's chemical stability can also be documented.
It is imperative that pharmacies that engage in lower-cost batch compounding have a complete understanding of all the procedures required to extend dating safely and effectively. Simply running the correct number of sterility tests for a batch of preparations does not in any way assure the sterility of that batch unless all the procedures discussed below are rigidly followed. All aspects of the pharmacy must be 100% compliant with all provisions of USP <797>, as well.