How are Potency Specifications Established?

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Drug products that are designated compendial grade (USP; BP; JP etc), must meet specific requirements for quality.  These requirements are specified in the corresponding compendia and monograph for the product.  This article will clarify how to go about establishing quality requirements for potency.  Requirement, acceptance criteria, specification and specification range will be used interchangeably throughout this article.

Some companies rely on their contract laboratory to advise them on the potency specification for a drug product.  However, the ultimate responsibility for establishing the specification for a drug product, rests solely with the organization that produces the drug.  This is a critical detail to understand when a regulatory investigator or client auditor asks what went into establishing the specification.  There needs to be an official reference, and/or documented justification for established acceptance criteria.  Simply stating that the laboratory set the specification is typically not an acceptable answer.

The easiest place to start when establishing a specification, is to determine if there is a monograph for the drug product.  If there is, use the acceptance criteria specified in the monograph.  For example, Acetaminophen Tablets need to be “not less than (NLT) 90.0% and not more than (NMT) 110.0% of the labeled amount”.  The most common specification range for potency is 90.0% to 110.0%.  However, there are products that have narrower ranges (e.g. Hydromorphone Hydrochloride Injection = 95.0% to 105.0%), and products that have wider ranges (e.g. Gentamycin Injection = 90.0% to 125.0%).  For drug products that do not have a monograph, the USP states that 90.0% to 110.0% is acceptable to use as a potency specification.  If the potency specification from the monograph is used, it needs to be referenced as the source for the acceptance criteria.

A majority of potency specifications can be established using the approach mentioned in the previous paragraph.  However, there are situations where the specification will need to be wider than what is specified in the monograph, or the default range of 90.0% to 110.0% when there isn’t a monograph.  It is in situations such as these, that there needs to be a well-documented justification based on scientific reasoning, and when necessary, empirically generated data.

An example when this might be relevant is if a drug product is being compounded from commercially available product, rather than a pure raw material.  For example, if a Hydromorphone Hydrochloride Injection is compounded from a commercially available drug, the potency range might need to be wider (i.e. 90.0% to 110.0%) than the 95.0% to 105.0% range specified in the monograph.  The justification behind assigning this wider specification might go something like this.  The commercially available product has an acceptable range of 95.0% to 105.0%, which means the actual potency of the product can be ±5% of the label value.  If the actual value for a specific lot of the commercially available product was 95.1%, which is within the acceptable range, and that lot was used to compound a second product, it is highly likely (i.e. ~50%) that the compounded product would be less than the 95.0% lower limit specified in the monograph. Due to the additional complexity of compounding process combined with the fact that a potentially less accurate product (i.e. the commercial drug product vs raw material) is being used as the starting material, a wider specification range of 90.0% to 110.0% could be justified.

Additional situations may justify a wider specification than what is found in the monograph.  For example, when a multi-active drug is compounded from a number of single active drugs, the specification for one or more of the actives may need to be wider than the monograph specification due to the additional complexity of the compounding process.  Additionally, if there isn’t a monograph for the drug product, and the drug product is inherently difficult to compound there may be a need to have a specification that is wider than the default 90.0% to 110.0%.  There are also situations where tighter specifications are required.  For example, Piperacillin for Injection, has a specification of 90.0% to NMT 120%. However, when Piperacillin and Tazobactam are together in a medication, the acceptable range for Piperacillin narrows to 90.0%-110.0%.

The most important thing to remember when establishing specifications, is to document the reference and/or justification for the specification, and if necessary generate data to further justify your decisions.  At times, the data might justify narrowing or widening specifications that were initially wider or narrower than the compendial monograph or default specification.

A cautionary note.  At no time should specifications be widened due to poor process or quality controls.  Not only is this practice a huge risk to patient safety, broadening specifications to “make it pass” is frowned on by regulatory agencies and customers alike.  When discovered, this practice can result in lost business, FDA 483 observations or warning letters, product recalls, and ultimately shuttered businesses.