Close

Comments regarding ICH Q5E

<p>
May 19, 2004</p>
<p>
Dockets Management Branch (HFA-305)<br />
Food and Drug Administration<br />
5600 Fishers Lane, Rm. 1061<br />
Rockville, MD 20852</p>
<p>
Re: Docket No. 2004D-0118, CDER 2003190. International Conference on Harmonisation; Draft Guidance on Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process. 69 Fed. Reg. 16580 (March 30, 2004)</p>
<p>
Dear Sir or Madam:</p>
<p>
The Biotechnology Industry Organization (BIO) provides the following comments. BIO represents more than 1,000 biotechnology companies, academic institutions, state biotechnology centers and related organizations in 45 U.S. states and 32 other nations. BIO members are involved in the research and development of health-care, agricultural, industrial and environmental biotechnology products. BIO appreciates the opportunity to comment on the Food and Drug Administration&#39;s (FDA&#39;s) draft <i>Guidance for Industry: Step 2 of ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process</i> (hereinafter ICH Q5E Step 2).</p>
<p>
<b>General Comment: The integration of FDA&#39;s Guidances -- ICH and non-ICH -- on Comparability</b></p>
<p>
When FDA announced the availability of ICH Q5E Step 2 on March 30, 2004, the Agency stated that ICH Q5E Step 2 was a draft guidance that when finalized would represent FDA&#39;s current thinking on comparability assessments (see boxed statement on page one of ICH Q5E Step 2). Thus, it is important for BIO member companies to understand the relationship between ICH Q5E Step 2 and other FDA documents on comparability. We have a number of questions and concerns in this regard.</p>
<p>
First, we are concerned that FDA&#39;s process for issuing guidance on comparability is not integrating ICH and non-ICH guidance. On September 5, 2003, FDA released its draft <i>Guidance for Industry: Comparability Protocols - Protein Drug Products and Biological Products - Chemistry, Manufacturing, and Controls Information</i> (hereinafter FDA&#39;s Comparability Draft Guidance). Comments were due on December 4, 2003. ICH Q5E Step 2 became available for publication on November 13, 2003, within the comment period for FDA&#39;s Comparability Draft Guidance. However, ICH Q5E Step 2 was not published for comment until March 30, 2004, several months after the comments to FDA&#39;s Comparability Draft Guidance were due. We recognize that the FDA document and the ICH document are focused in different ways (that is, FDA&#39;s Comparability Draft Guidance is more of a tactical document, primarily providing guidance on how to assemble a comparability protocol; ICH Q5E Step 2 provides strategic principles for developing a comparability assessment). However, we believe it would have been beneficial for FDA to have published ICH Q5E Step 2 while FDA&#39;s Comparability Draft Guidance docket was still open, or to have extended the comment period for the latter docket. That way, any inconsistencies between the two documents could have been discussed while both dockets were open.</p>
<p>
We recommend that, to the extent possible, FDA revise its process so that draft guidances and proposed rules on a particular topic are released for review simultaneously, and respondents to the docket can integrate comments across all applicable documents. We also request that FDA provide an assessment of the similarities and differences between FDA&#39;s Comparability Draft Guidance and ICH Q5E Step 2 so that sponsors can be assured that they fully understand the content of both.</p>
<p>
Second, we request an explanation from FDA of how the ICH Q5E Step 2 document relates to any extant final FDA guidances or rules concerning comparability for biotechnology products, and particularly where Q5E would change established requirements. Specifically, BIO asks for clarification of whether FDA anticipates that Q5E will replace the April 1996 FDA Guidance Concerning Demonstration of Comparability of Human Biological Products Including Therapeutic Biotechnology-derived Products, and how Q5E relates to the July 1997 Guidance on Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products.</p>
<p>
Third, a general goal of the ICH process is to harmonize and simplify the regulatory requirements of the United States, European Union, and Japan; this is a goal that BIO members support. Therefore, BIO remains concerned that FDA not treat ICH guidelines as a &quot;floor&quot; upon which further FDA regulatory requirements build. In the comparability area, as in others, BIO urges FDA to coordinate its guidance with that of ICH, perhaps issuing separate FDA guidance only in those cases where U.S. requirements are necessarily different from those established by ICH. BIO requests that in order to streamline the drug approval process, differences between ICH and FDA standards be foregone unless they have a clearly articulated and important impact on critical product safety, effectiveness, and quality parameters.</p>
<p>
<b>Specific Comments</b></p>
<p>
<u>Definition of the word &quot;product&quot;:</u></p>
<p>
In FDA&#39;s Comparability Draft Guidance, the word &quot;product&quot; is defined to mean &quot;drug substance, drug product, and intermediate, or in-process material, as appropriate&quot; (FDA&#39;s Comparability Draft Guidance, p. 1, fn 2).</p>
<p>
In ICH Q5E Step 2, the word &quot;product&quot; is defined slightly differently, as &quot;intermediates, drug substance, and drug product&quot; (ICH Q5E, p. 1, fn. 3). We request that the Agency clarify whether there is a substantive difference between these definitions.</p>
<p>
<u>Section 1.3: Scope, Lines 37- 48</u></p>
<dl>
</dl>
<p>
Comment: We believe the ICH Q5E Step 2 guidance should apply only to changes made by the manufacturer to its own process/product, not to an assessment of two products made by two different manufacturers. In Section 1.3, the second and third bullets include only changes made by a manufacturer to its own product. However the first bullet could be read to include comparability assessments between two different products made by two different manufacturers. We suggest that a note be added to clarify explicitly that the document applies to situations in which all three bullets apply.</p>
<p>
As BIO noted in our response to the FDA&#39;s Comparability Protocol Draft Guidance (submitted December 4, 2003 to Docket 2003D-0385), we believe the term &quot;comparability&quot; should not be applied to a comparison of an innovator&#39;s biologic product to another manufacturer&#39;s generic or follow-on biologic product because the second manufacturer will not have access to the innovator&#39;s historical data nor to in-process and bulk product materials from the innovator, so a comparison of before and after is not possible nor relevant. Therefore, we recommend that ICH Q5E Step 2 be revised to incorporate a declarative statement excluding generic or follow-on biologics from the scope of the guideline.</p>
<p>
BIO also requests that FDA clarify the ways, if any, in which the scope of ICH Q5E differs from the scope of FDA&#39;s Comparability Draft Guidance.</p>
<p>
<u>Section 1.3: Scope, Lines 49-52</u></p>
<p>
<i>The principles outlined in this document might also apply to other product types such as proteins and polypeptides isolated from tissues and other body fluids. Manufacturers are advised to consult with the appropriate regional Regulatory Authority to determine applicability.</i></p>
<p>
Comment: As part of the finalization of ICH Q5E, we suggest that FDA produce a companion document that explains whether the principles outlined in Q5E will apply to other product types such as proteins and polypeptides isolated from tissues and other body fluids, so that each manufacturer does not need to ask FDA individually.</p>
<p>
<u>Section 1.4: General Principles, Lines 58-61<br />
and<br />
Section 4.0: Glossary, Lines 427-431</u></p>
<p>
Comment: BIO follows general industry practice in using the word &quot;comparable&quot; to refer to a particular product pre-and post-manufacturing change, and the word &quot;similar&quot; to refer (under certain circumstances) to two products made by two different manufacturers. The EU uses the word &quot;similars&quot; to refer to generic drugs, and it uses the term &quot;biosimilar&quot; as an official term in the pharmaceutical legislation for a &quot;follow on&quot; or &quot;generic&quot; biological medicinal product. Because the comparability exercise is supposed to assess whether there is any adverse effect on quality, safety, and efficacy of a particular product made by an individual manufacturer, we recommend that the phrase &quot;highly similar,&quot; which is used throughout the document, be either (A) dropped when used to assess a product pre- and post- manufacturing change and replaced with a phrase such as &quot;a product with a similar profile,&quot; or (B) defined in the glossary in a manner that reflects the exclusion of generic or follow-on biologics from the scope of the guideline.</p>
<p>
<u>Section 2.2.1: Analytical Techniques, Lines 186-189</u></p>
<p>
<i>The measurement of quality attributes does not necessarily entail the use of validated assays but the assays should be scientifically sound and provide results that are reliable. Those methods used for batch release should be validated in accordance with ICH guidelines (ICH Q2A, Q2B, Q5C, Q6B), as appropriate.</i></p>
<p>
Comment: It is unclear what evidence would be required to demonstrate a &quot;scientifically sound&quot; assay. We recommend adding text to this section for clarification, including an explanation of under what circumstances ICH (FDA) could envision use of non-validated assays to support comparability. It is also unclear whether &quot;batch release&quot; only applies here to commercially distributed product or also to clinical materials.</p>
<p>
<u>Section 2.2.2: Characterization, Lines 241-243</u></p>
<p>
<i>When immunochemical properties are part of the characterization (e.g., for antibodies or antibody-based products), the manufacturer should confirm that post-change product is comparable in terms of the specific properties.</i></p>
<p>
Comment: The examples given suggest that this section only applies to immunochemical compounds. Is it the intention of the guidance to restrict evaluation of immunochemical properties to immunochemical compounds? We suggest adding text to this section for clarification.</p>
<p>
<u>Section 2.2.4: Stability, Lines 278-284</u></p>
<p>
<i>For many manufacturing process changes even slight modifications of the production procedures, including those made early in the manufacturing process for the drug substance, might cause changes in the stability of the post-change product. Any change with the potential to alter protein structure or purity and impurity profiles should be evaluated for its impact on stability, since proteins are frequently sensitive to changes, such as those to buffer composition, processing and holding conditions, and use of organic solvents.</i></p>
<p>
Comment: A strict interpretation of this section might suggest that a stability study should be conducted for every process change independently of when the change occurs during development. Please clarify if ICH Q5E Step 2 recommends conducting stability studies for process changes during all stages of development (i.e., pre-IND, phase I/II clinical trials, and post-pivotal trials).</p>
<p>
We suggest adding a statement to this section to recommend that stability studies should be initiated if significant changes to the characterization profile post-change are detected during any phase of development. We also suggest adding a statement recommending that stability studies be conducted for any significant process change made post-pivotal trial.</p>
<p>
<u>Section 2.2.4: Stability, Lines 289-291</u></p>
<p>
<i>Generally, therefore, real-time concurrent stability studies on the product potentially affected by the change should be conducted, as appropriate.</i></p>
<p>
Comment: It is not clear what is meant by &quot;concurrent stability studies.&quot; Is the guidance recommending that stability studies be conducted with pre-change and post-change product concurrently? Or is the guidance recommending that the stability of the post-change product be studied at the same time as the company files for such changes with regulatory agencies? We suggest adding text to this section for clarification.</p>
<p>
<u>Section 2.3: Manufacturing Process Considerations, Lines 358-359</u></p>
<p>
<i>For approved products, an appropriate number of post-change batches should be analysed to demonstrate consistent performance of the process.</i></p>
<p>
Comment: It is not clear what &quot;an appropriate number of post-change batches&quot; would be for the purposes of comparability. Existing ICH guidance (specifically, Q1A(R2) - Stability Testing of New Drug Substances and Products) recommends testing at least three batches of a drug substance or drug product to demonstrate stability. Including reference to Q1A(R2) would help clarify the meaning of &quot;an appropriate number of post-change batches.&quot;</p>
<p>
<b>Conclusion</b></p>
<p>
BIO appreciates this opportunity to comment on the ICH Q5E draft guidance: <i>Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process, Step 2</i>. We look forward to seeing the final guidance, and would be glad to work with the Agency to provide further input or clarification of our comments, as needed.</p>
<p>
Sincerely,</p>
<p>
Sara Radcliffe<br />
Director<br />
Science Policy and Bioethics</p>