Guidance 129 – Labeling of APIs and API Intermediates

In the absence of a comprehensive labelling guideline for API and API intermediates from any single regulatory agency, the site labelling requirements should be distilled from a combination of regulatory guidance and from the requirements defined by various pharmacopoeia. The World Health Organization (WHO) has published the guide “Good trade and distribution practices for pharmaceutical starting materials.” Within this GMP guidance sections 6.7 and 6.8 define expectations for API label content as follows:

“Labels should be clear, unambiguous, permanently affixed and the printing should be indelible. Each container should bear a label that gives: a) the name of the material, including grade and reference to pharmacopoeias, where relevant, b) if applicable, the International Nonproprietary Names (INNs), c) the amount (weight or volume), d) the batch number assigned by the original manufacturer or the batch number assigned by the repacker, if the material has been repacked or relabeled, e) the retest date or expiry date (where applicable), f) any special storage conditions, g) handling precautions, where necessary, h) identification number of the original manufacturing site, and i) name and contact details of the supplier.”

The WHO guidance encompasses and expands API GMP guidance for labelling recommendations presented in Q7A:

“Labels used on containers of intermediates or APIs should indicate the name or identifying code, batch number, and storage conditions when such information is critical to ensure the quality of intermediate or API.” 

“If the intermediate or API is intended to be transferred outside the control of the manufacturer’s material management system, the name and address of the manufacturer, quantity of contents, special transport conditions, and any special legal requirements should also be on the label. For intermediates or APIs with an expiry date, the expiry date should be indicated on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.”

If an API or intermediate is claimed to meet the requirements of one or more pharmacopoeia, it is expected that this will be stated on the container label or on accompanying documentation. Most pharmacopoeias, including the USP, defer to the specific labelling requirements of the national or supranational health authorities. The USP also states that:

“A shipping container containing a single article, unless such container is also essentially the immediate container or the outside of the consumer package, is labelled with a minimum of product identification (except for controlled articles), lot number, expiration date and conditions for storage and distribution.”

Occasionally, a pharmacopoeia monograph will include a labelling requirement. This will be described under the monograph subheading “Labelling” and is required to appear either on the container label or accompanying information, e.g. Certificate of Analysis. Both FDA guidance (e.g. reference 5) and EMEA guidance (e.g. references 6 and 7) for label storage conditions indicate that any storage conditions or related information (i.e. expiry or retest date) be based on the results of formal stability studies. Storage conditions listed on the label (temperature, light, humidity) should be consistent with the language provided in these guidance documents. The use of terms such as “ambient conditions” or “room temperature” is unacceptable.

The EMEA guidance also state “for substances to be stored/transported refrigerated or frozen, the temperature range should be included in the labelling.” Material safety or hazard information is important to the handling of APIs and intermediates.

Often an abstract of this information has been included as text on the primary label. This is still acceptable practice but the API site should develop a separate labelling system for material safety and hazard information that at some point will supersede current practices. Hence, it is also considered acceptable to provide safety information on a label separate from the primary label used for GMP and/or regulatory purposes.

APIs or intermediates that are classified as controlled substances must bear labels indicating the appropriate designations or codes for such materials in the countries or regions in which they are produced and/or shipped.

APIs and intermediates may also be subject to other country-specific or customer-specific labelling requirements. It is not the intent of this document to attempt to define or make recommendations to all such requirements. However, the United States has certain import/export regulatory requirements and the requirement that certain APIs and intermediates be “drug listed” with FDA. In order to avoid a noncompliance situation and/or the potential for a shipment of an API or intermediate to be detained at the port-of-entry to the US, company API plants and third party manufacturers shipping materials to company plants in the US need to understand and address the requirements of these provisions of the US Code of Federal Regulations (CFR).

The general labelling requirement to import an API is that the API must have labelling that lists adequate directions for its use [as defined in section 502(f)(1) of the Food and Drug Act] unless it meets the labelling exemption criteria defined in 21CFR201.122. Because API labels generally don’t meet the requirements of section 502(f)(1), it must be demonstrated that the APIs are exempt under 21CFR201.122. Under the exemption, APIs for import must bear a label statement such as “Caution: For manufacturing, processing, or repacking.”

Also, their use must be covered by an approved NDA, ANDA, NADA, or ANADA. If no application is approved, the label statement should read “Caution: For manufacturing, processing, repacking in the preparation of a new drug or new animal drug limited by Federal law to investigational use,” i.e. the API is covered by an IND or INAD. The section 502(f) (1) requirements do not apply to APIs used exclusively in human OTC drugs or human prescription drugs that don’t require a new drug application.

Clear labelling and adequate documentation is key to avoid API and intermediate shipments being detained at the US port of entry. This has become more important because of 9/11 and because of increased efforts to prevent the importation of unapproved or counterfeit drugs. FDA (CDER & CVM) have issued import alerts #6666 (see reference 9) and #6809 (see reference 11) regarding potential misbranding under section 502(f)(1). In these alerts, FDA has also provided guidance to industry on how to release detained articles.

In addition to these import requirements, certain APIs and intermediates must be “drug listed” with FDA. Before a foreign plant (affiliate or third party) can ship to the US for the first time an API or drug product for human or animal health use, the manufacturer must list the API or drug product with the FDA Drug Registration and Listing Office. This is a separate activity from the FDA Review Division’s assessment and approval of a new manufacturing site.

Third Party Manufacturers (TPMs) must identify a non-affiliated US agent to act as the contact with FDA on their behalf.

FDA drug listing is required for all API’s manufactured in a foreign facility and used in human pharmaceutical products (Rx or OTC) marketed in the US. FDA drug listing is required for all materials (i.e. APIs and intermediates) regulated as controlled substances EXCEPT when the material is transferred between affiliate plants within the US/Puerto Rico. FDA drug listing is NOT required for an API manufactured in the US/Puerto Rico if the API is used exclusively in the manufacture of a drug product by the same registered establishment. FDA drug listing is NOT required for drugs shipped from one affiliate entity in the US/Puerto Rico to another affiliate entity in the US/Puerto Rico (i.e. interplant transfer) if listing is performed at the time the API is used in a product marketed in the US. FDA drug listing is NOT required for intermediates, drugs used in clinical investigations, or for non-clinical research purposes EXCEPT if they are considered to be controlled substances. FDA drug listing is NOT required for APIs used exclusively in animal health products EXCEPT if they are imported to the US, exported from the US or are controlled substances.

The drug listing process requires the submission of FDA Forms 2656 (Drug Establishment Registration) and 2657(Drug Listing) to the FDA Drug Registration and Listing Office. The 2656 form is filed for a new establishment registration, or a revision to an existing registration. The information required to complete this form is: 1) site name/address/telephone number, 2) labeller code (for revisions only), 3) registration number (for revisions only), 4) reason for submission, 5) type of ownership, 6) labeler code/firm name of other firms doing business at this site.

The 2657 form is filed for new foreign-source bulk drug substances introduced for commercial distribution into the U.S. that have not been previously drug listed, for drug substances previously listed which have been discontinued, for previously discontinued drug substances which are being re-entered into commercial distribution, or for any change in the information previously submitted.

The information required to complete the 2657 form and the submission is: 1) site of manufacture of the API including site registration number and labeller code, 2) site labeller, product and package code, 3) label title, 4) package types (bag, drum, canister) and package quantities, 5) confirmation that the API meets the aforementioned criteria for drug listing, and 6) two original samples of the

API drum label that includes wording consistent with the requirements of 21CFR201.122. It should be noted that changes to the label for an API or intermediate that is drug listed requires updating the Form FDA 2657 drug listing information filed with FDA. Such changes should be communicated to Regulatory Affairs for human health products or animal health products.