Life Science Compliance Update

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FDA Issues Draft Guidance on Biologic License Applications


The FDA recently released draft guidance offering recommendations for holders of biologics license applications (BLAs) on the minor changes that should be documented in an annual report.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."


October 17, 2017

AmerisourceBergen Specialty Group Pleads Guilty to Distributing Misbranded Drugs


On September 27, 2017, AmerisourceBergen Specialty Group (ABSG), a wholly-owned subsidiary of AmerisourceBergen Corporation, one of the nation’s largest wholesale drug companies, pled guilty to illegally distributing misbranded drugs. ABSG agreed to pay a total of $260 million to resolve criminal liability for its distribution of oncology supportive-care drugs from a facility that was not registered with the Food and Drug Administration (FDA). The guilty plea and sentencing took place before United States District Judge Nina Gershon. 

As set forth in court records, between 2001 and 2014, two of ABSG’s Alabama-based subsidiaries, Medical Initiatives Inc. (MII) and Oncology Supply Company (OSC), prepared millions of syringes that had been pre-filled with oncology supportive care drugs: Aloxi®, Anzemet®, generic versions of granisetron injection, Kytril®, Neupogen® and Procrit®. The syringes were shipped to oncology centers, medical practices, and physicians for administration to immunocompromised cancer patients undergoing chemotherapy treatment in all 50 states.

To prepare pre-filled syringes (PFS), MII removed FDA-approved drug products from their original glass vials and repackaged them into plastic syringes through a process that allowed MII to access and sell excess drug product in the vials, known as “overfill.” As alleged in the Information, however, MII prepared PFS in an unclean, unsterile environment. Accordingly, MII’s process for creating PFS resulted in some PFS that contained particles or foreign matter, which MII employees identified and termed “floaters.” PFS were also at times not of the quality or purity that MII and OSC represented them to be to their customers. 

MII’s business model was to combine the contents of multiple vials in a process known as “pooling.” However, as set forth in the Information, many of the vials used by MII to prepare PFS were designated by the drug manufacturer as “single use” vials, meaning that the manufacturer could not guarantee the sterility of the drug product if the vials were breached. However, in the pooling process, MII’s technicians frequently breached drug vials multiple times, thereby increasing the risk of contamination.

To avoid the FDA’s regulatory oversight, ABSG did not register MII as a re-packager or manufacturer with the FDA as required by the Federal Food, Drug and Cosmetic Act.  Instead, ABSG inaccurately portrayed MII to its customers and to state agencies as a state-regulated pharmacy in the business of dispensing drugs pursuant valid prescriptions. By holding MII out as a pharmacy, ABSG unlawfully exploited an exemption to the FDA registration requirement that is reserved for legitimate pharmacies, not for manufacturers or re-packagers. 

As part of its guilty plea, ABSG has agreed to pay a $208 million criminal fine, plus $52 million in criminal forfeiture, for a total financial penalty of $260 million. In addition, ABSG has entered into an agreement with the Office and the Department of Justice’s Consumer Protection Branch to maintain a compliance and ethics program designed to increase accountability of individuals and corporate board members, to increase transparency, and to strengthen ABSG’s compliance with the FDCA. The compliance and ethics program requires corporate board members to review annually the effectiveness of the company’s compliance program and for ABSG to maintain a hotline that will receive and process complaints about any improper practices.

October 06, 2017

FDA Releases Draft Guidance for Industry: Statistical Approaches to Evaluate Analytical Similarity


The FDA announced a draft guidance for industry titled “Statistical Approaches to Evaluate Analytical Similarity”. The draft guidance offers advice to biosimilar sponsors on the evaluation of analytical similarity of a biosimilar to its reference product. FDA says this type of evaluation is performed as part of the biosimilar approval process to support a demonstration that the proposed biosimilar is highly similar to a reference product.

The draft guidance describes “the type of information a sponsor of a proposed biosimilar product should obtain about the structural/physicochemical and functional attributes of the reference product, how that information is used in the development of an analytical similarity assessment plan for the proposed biosimilar, and the statistical approaches recommended for evaluating analytical similarity.”

The draft guidance released is part of a series of guidance documents that FDA is developing related to the biosimilar approval process. Comments on the draft guidance are due to FDA within 60 days; on or around November 22, 2017. All submissions received must include the Docket No. FDA-2017-D-5525 for “Statistical Approaches to Evaluate Analytical Similarity; Draft Guidance for Industry; Availability.”

Guidance Specifics

According to the FDA, the objective of this guidance is to assist sponsors in demonstrating, through an evaluation of the analytical similarity of the proposed biosimilar and reference product, that the proposed biosimilar and reference product are highly similar to support licensure under section 351(k) of the PHS Act. In general, an analytical similarity assessment involves a comparison of structural/physicochemical and functional attributes using multiple lots of the proposed biosimilar product and the reference product.

To address the challenges of conducting appropriate statistical analyses in the evaluation of analytical similarity, FDA recommends using a risk-based approach. This approach to the evaluation of analytical similarity consists of several steps:

  • The first step is a determination of the quality attributes that characterize the reference product in terms of its structural/physicochemical and functional properties.
  • In the second step, these quality attributes are then ranked according to their risk of potential clinical impact.
  • Third, these attributes/assays are evaluated according to one of three tiers of statistical approaches based on a consideration of risk ranking as well as other factors. However, some attributes may be important but not amenable to quantitative evaluation.

FDA recommends that the analytical similarity evaluation begin with an understanding of the structural/physicochemical and functional attributes of the reference product. Based on information obtained about these attributes during development of the proposed biosimilar, the sponsor should develop an analytical similarity assessment plan. A key component of this plan is the description of lots available for similarity testing.

In general, principles for evaluating analytical similarity should be assessed by using appropriate statistic methods to evaluate the analytical data. Methods of varying statistical rigor should be applied depending on the risk ranking of the quality attributes. Sponsors should develop an analytical similarity assessment plan that includes their proposed statistical approach to evaluation and then should discuss this approach with the FDA as early in the development program as feasible.

The final analytical similarity report, which should include the analytical similarity assessment plan, should be included when a 351(k) biologics license application is submitted. The development of the analytical similarity assessment plan is the topic of the first subsection of the guidance, followed by a discussion of FDA’s current thinking on the statistical methods to be applied for evaluation.


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