Life Science Compliance Update

December 06, 2017

FDA Releases Guidelines for Physicians Using Investigational Drugs in Emergency Situations


In a recent Manual of Policies and Procedures (MAPP), the FDA laid out the process by which physicians can access an investigational drug for treatment in an individual patient in an emergency situation, both during and after normal business hours.

MAPP Specifics

The MAPP describes the policies and procedures established in the Center for Drug Evaluation and Research (CDER) for managing and processing applications for individual patient expanded access for emergency use (or, emergency investigational new drug applications (EINDs)) for licensed physicians seeking access to an investigational drug for treatment use in an individual patient in an emergency situation, both during and after normal business hours.

Although access to an investigational drug for an individual patient in an emergency situation may be requested and authorized through submission of a protocol for such use by an investigational new drug application (IND) holder to its existing IND, this situation is not common and is not addressed in this MAPP. Most emergency access is requested and authorized through submission of a protocol under a new IND (EIND). This scenario (emergency access requested and allowed under an EIND) is addressed in this MAPP.


On August 13, 2009, FDA published in the Federal Register the final rule “Expanded Access to Investigational Drugs for Treatment Use.” This final rule added subpart I regarding expanded access to investigational new drugs for treatment use into 21 CFR part 312.2:

“This subpart contains the requirements for the use of investigational new drugs and approved drugs where availability is limited by a risk evaluation and mitigation strategy (REMS) when the primary purpose is to diagnose, monitor, or treat a patient’s disease or condition. The aim of this subpart is to facilitate the availability of such drugs to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient’s disease or condition.”

Subpart I describes the requirements for expanded access to an investigational drug for treatment use, including access for individual patients in emergencies. Whereas 21 CFR 312.305 describes the requirements for all expanded access uses, 21 CFR 312.310 specifically describes the requirements unique to individual patient access and 21 CFR 312.310(d) describes the procedures for requesting and authorizing access to an investigational new drug for use in an individual patient in an emergency situation.

As explained in 21 CFR 312.305(c), a patient may obtain access to an investigational drug for treatment use, including in an emergency situation, through a licensed physician. A licensed physician under whose immediate direction an investigational drug is administered or dispensed for an expanded access use is considered an investigator. An individual or entity that submits an expanded access IND is considered a sponsor. A licensed physician under whose immediate direction an investigational drug is administered or dispensed and who submits an IND for expanded access is a sponsor-investigator and must comply with the regulatory requirements for sponsors and investigators.

Policy Specifics

Because of the urgency of the situation, CDER will review requests for EINDs immediately upon receipt. CDER may receive requests for EINDs by telephone, facsimile, or other means of electronic communication, although CDER generally does not monitor facsimile transmissions and electronic communications received during nonbusiness hours. During nonbusiness hours, CDER receives requests for EINDs by telephone through FDA’s Emergency Call Center, which is operational 24 hours a day/7 days a week.

The decision to authorize or deny emergency access will be communicated by telephone. Staff will obtain verbal agreement from the licensed physician who contacts FDA to request an EIND for treatment use in his or her patient to submit all necessary forms and information within 15 working days of FDA authorizing access. As described under 21 CFR 56.104(c), emergency use of an investigational drug is exempt from the requirement of a prospective institutional review board (IRB) review, provided that such emergency use is reported to the IRB within 5 working days of treatment initiation. In general, any subsequent uses of the same investigational drug at the same institution will require prior IRB review and approval.

When, however, prior IRB review and approval is not feasible for a subsequent expanded access emergency use of the same investigational drug at the same institution, FDA will not deny the subsequent request for emergency access because of a lack of prospective IRB review. FDA will advise the sponsor to report the use to his or her IRB within 5 working days of treatment initiation.

The Office of New Drugs (OND) review staff will accept single copies of original IND submissions or subsequent amendments to INDs from physicians who submit individual patient expanded access INDs, including EINDs. And an EIND will be authorized only when there is an emergency that requires the patient to be treated before a written submission to FDA can be made.

December 05, 2017

FDA Offers Draft Guidance on E-Submissions of REMS Documents


The FDA recently released draft guidance describing how FDA plans to implement the requirements for the electronic submission of Risk Evaluation and Mitigation Strategies (REMS) documents in certain submissions under new drug applications, abbreviated new drug applications and biologics license applications.

FDA Comments on Stakeholder Feedback

In the guidance, FDA describes three years of engagement and analysis of stakeholder feedback regarding REMS standardization. The agency’s findings were published as a report: “Standardizing and Evaluating Risk Evaluation and Mitigation Strategies (REMS).” As the report describes, some stakeholders expressed concern about the clarity and consistency with which information about REMS materials and requirements are communicated to stakeholders. They told FDA that REMS materials and requirements may be difficult to locate, and that specific activities and requirements of various stakeholders (e.g., prescriber, pharmacist) are not always clearly outlined.

Some stakeholders expressed the need to have better ways to integrate REMS materials and procedures into their existing health information systems and health care delivery processes. Stakeholders also expressed the desire to avoid spending excessive time trying to locate, understand, and comply with different REMS requirements while ensuring safe use of drugs with REMS.

To help address these concerns, FDA intends to require applicants of NDAs, ANDAs, and BLAs to submit the content of their REMS documents in Structured Product Labeling (SPL) format. SPL can be used to capture and present REMS information in a format that is easily shared with stakeholders and readily incorporated into health information technology.

Structured Product Labeling

REMS documents will be required to be submitted in electronic format using Structured Product Labeling (SPL). SPL is a Health Level Seven (HL7) standard based on Clinical Document Architecture and HL7 Reference Information Model (RIM) accredited by the American National Standards Institute (ANSI) for the exchange of product information. Structured Product Labeling documents include a header and body. The header includes information about the document such as the type of product, author and versioning. The body of the document includes product information in both structured text and data element formats. The FDA uses SPL documents to exchange information covering a growing number of product related topics.

Requirements That Must Be Followed for Electronic Submission of the Content of REMS Documents

Under section 745A(a) of the FD&C Act, electronic submissions “shall be submitted in such electronic format as specified by [FDA].” This guidance addresses electronic submission requirements for certain documents that are part of a REMS. A REMS document, which is part of the REMS that is approved by FDA, concisely describes the goals and requirements of the REMS.

FDA has determined that the content of a REMS document must be submitted electronically in SPL format, using specifications outlined in the FDA Data Standards Catalog. REMS materials are all materials that are included as part of the REMS (e.g., communication and educational materials, enrollment forms, prescriber and patient agreements) that are also approved and enforceable, and are appended to the REMS document. REMS materials must be referenced in the SPL file. REMS supporting documents should not be submitted in SPL format.

October 19, 2017

FDA Issues Draft Guidance on Biologic License Applications


The FDA recently released draft guidance offering recommendations for holders of biologics license applications (BLAs) on the minor changes that should be documented in an annual report. As the number of chemistry, manufacturing and controls (CMC) postapproval manufacture supplements continue to increase, the FDA decided to publish this guidance.


This guidance provides recommendations to holders of biologics license applications (BLAs) for specified products regarding the types of changes to an approved BLA to be documented in an annual report under 21 CFR 601.12. Specifically, the guidance describes chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that FDA generally consider to have a minimal potential to have an adverse effect on product quality.

Under FDA regulations, postapproval changes in the product, production process, quality controls, equipment, facilities, or responsible personnel that have a minimal potential to have an adverse effect on product quality must be documented by applicants in an annual report.

Recommendations for Reporting Certain Changes in an Annual Report

FDA recommends that the changes listed in the Appendix generally should be submitted in an annual report. However, if a BLA holder is planning to make a change that is listed in the Appendix, the BLA holder should evaluate the change in the context of the holder’s particular circumstances to determine whether the proposed change would present a minimal potential to have an adverse effect on product quality and therefore would be appropriately documented in an annual report. BLA holders may, based on their specific circumstances, determine that a change described in the Appendix would appropriately be submitted as a supplement rather than in an annual report. If FDA disagrees with the categorization, FDA may notify the applicant of the correct category and request additional information.

To the extent that a recommendation in this guidance to document a single change in an annual report is found to be inconsistent with a previously published FDA guidance, the recommendations in this guidance would apply. For changes not listed in the Appendix, or if multiple related changes being implemented simultaneously increases the potential to have an adverse effect on product quality, applicants should refer to other CDER and CBER guidances to determine the appropriate reporting category for notifying the Agency of the changes.

Contents of Annual Report Notification

To document changes in an annual report, the applicant must include the following information for each change:

  • A full description of CMC changes, including:
    • The manufacturing sites or areas involved.
    • The date the change was made.
    • A cross-reference to relevant validation protocols and/or standard operating procedures.
    • Relevant data from studies and tests performance to assess the effect of the change on product quality.
  • A list of all products involved.
  • A statement that the effects of the change have been assessed.

The applicant should describe each change in an annual report in enough detail to allow the Agency to evaluate the change and determine whether the appropriate reporting category has been used. If the submitted change is inappropriate for documentation in an annual report, FDA may notify the applicant of the correct category and may request additional information.

However, inappropriate documentation should be uncommon because applicants should only use this mechanism of reporting a change when they are confident that documentation in an annual report is appropriate.


Illustrating the guidance, FDA issued the following examples under five categories:

  1. 1. Components and Composition

1.1. Elimination or reduction of an overage from the drug product manufacturing batch formula that was previously used to compensate for manufacturing losses. Note that this does not apply to loss of potency during storage.

  1. 2. Manufacturing Sites

2.1. Site change for testing. This includes sites for testing of lower-risk process-related impurities (e.g., host cell proteins, host cell DNA, residual solvents) when the method was successfully validated at the new site and the new site, where applicable, meets relevant CGMP requirements for the type of operation involved (e.g., no outstanding FDA warning letters or "official action indicated" compliance status). This does not include sites for testing for conformance to quality control specifications, including potency, impurities (except those that are lower risk), and safety testing (e.g., sterility and virus testing).

2.2. Site change for labeling or secondary packaging when the new site has a satisfactory CGMP status.

2.3. Change in the location of manufacturing steps within a manufacturing area that is already listed in an approved BLA where those steps are part of a nonsterile drug substance production process and the new location will have no impact or will lower the risk of contamination or cross-contamination (e.g., improved air classification, better process flow, enhanced segregation of pre- and post-viral inactivation steps).

2.4. Modification of a manufacturing facility listed in an approved BLA that does not increase the risk of contamination (e.g., affect sterility assurance) or otherwise present a meaningful risk of affecting product quality.

2.5. Manufacture of an additional drug product (already licensed or an investigational product), in a multiple-product area listed in an approved BLA that is producing other products, if:

2.5.1. Specific identity tests exist to differentiate between all products manufactured at the facility; and

2.5.2. Change-over procedure between manufacturing processes does not require new changes in cleaning procedures; and

2.5.3. The products do not represent an additional level of risk. Additional levels of risk might include, but are not limited to, the manufacture of highly toxic or potent products (e.g., botulinum toxin), highly immunogenic or allergenic products (e.g., penicillin), products that can accelerate degradation of another product (e.g., proteases), products that represent a new or added risk for adventitious agents, or a product for adults added to a line manufacturing pediatric products.

  1. 3. Manufacturing Process, Batch Size and Equipment

3.1. Changes in mixing times for solution dosage forms.

3.2. Small changes in the size of pooled or separated batches to perform the next step in the manufacturing process if all batches meet the approved in-process control limits and the critical process parameter ranges for the next step remain unaffected.

3.3. Changes to batch sizes that do not involve use of different equipment (e.g., increase in roller bottle number, minor increases in fermenter volume or minor increases in load volumes for chromatography columns).

3.4. Addition of an identical duplicate process chain or unit process in the drug substance and drug product manufacturing process with no change to equipment, process methodology, in-process control limits, process parameter ranges, or product specifications, with the exception of addition of major equipment used in aseptic processing (e.g., new filling line, new lyophilizer).

3.5. Reduction of open-handling steps if there is a reduction in product exposure that represents improvement in the assurance of product protection (e.g., implementation of sterilize-in-place connections to replace aseptic connections, automated weight checks, installation of a barrier to protect product, replacement of a manual stopper recharging step with an automated recharging step).

3.6. For sterile drug products, change from a qualified sterilization chamber (ethylene oxide, autoclave) to another of the same design and operating principle for containers/closures preparation when the new chamber and load configurations are validated to operate within the previously validated parameters. This does not include situations that change the validation parameters.

  1. 4. Specifications

4.1. Addition of tests and acceptance criteria to specification for approved excipients.

4.2. Change to a drug substance or drug product to comply with an official compendial test, except for changes to assays, impurities, product-related substances, or biological activities or changes described in 21 CFR 601.12(c)(2)(iv).

4.3. Change in the regulatory analytical procedure if the acceptance criteria remain unchanged and the revised method maintains basic test methodology (e.g., change in the flow rate or sample preparation for an HPLC12 method) and provides equivalent or increased assurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it claims to have or is represented to possess.

4.4. Replacement of a nonspecific identity test with a discriminating identity test that includes a change in acceptance criteria (e.g., replacing SDS-PAGE13 with peptide mapping).

4.5. Addition of an in-process test.

4.6 Addition of a test for packaging material to provide increased quality assurance.

4.7 Tightening of an existing acceptance criterion.

  1. Container Closure System

5.1. Change in the container closure system for the storage of a nonsterile drug substance when the proposed container closure system has no increased risk of leachable substances (based on the extractables and/or leachables profile and whether stability data are consistent with historical trends), and the new container offers equivalent or greater protection properties from air and moisture.

5.2. Use of a contract manufacturing organization for the washing of a drug product stopper, provided the applicant certifies that the organization’s washing process has been validated and its site has been audited by the applicant (or by another party sponsored by the applicant) and found CGMP compliant.

5.3 Changes to a crimp cap (ferrule and cap/overseal), provided that there are no changes to the labeling or the color and that container closure integrity has been demonstrated using a validated test method."



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