######## COMMENTS TO DOCKET: 03D-0061

###### FORMAL COMMENTS ON THE FDA's DRAFT GUIDANCE,

######  "Comparability Protocols --- Chemistry, Manufacturing, and Controls Information"

by

Dr. Paul G. King

President, **Paul G. King Consulting**

######### Founder, FAME Systems

**Introduction**

These comments are being submitted with the hope that they will
encourage the FDA to require that any submission **first** be
*scientifically sound* and *appropriate*, and **second** *fully comply*
with **[all]{.underline}** of the applicable CGMP *minimum* requirements
set forth in **21 CFR 211**.

In addition, any guidance document should fully comply with all
applicable regulations because, in 1988 in Berkowitz v. US, the United
States Supreme Court held that an FDA administrator has no latitude with
respect to any clearly written statute or regulation.

To facilitate differentiation between the proposed alternative and the
FDA's Draft, the changes will be in Lydian or highlighted Lydian font
and the FDA draft will be in the Perpetua font.

With the preceding in mind, let us proceed to review the proposed draft.

**Comments**

+-----+-------------------------------------+--------------------------+
| **  | ##### Proposed Text                 | **FDA Draft Text**       |
| Lin |                                     |                          |
| e** |                                     |                          |
|     |                                     |                          |
| **R |                                     |                          |
| ang |                                     |                          |
| e** |                                     |                          |
+-----+-------------------------------------+--------------------------+
| *   | ## A.                               | ## A. What is a          |
| *95 |  What is a Comparability Protocol?  |  Comparability Protocol? |
| -10 |                                     |                          |
| 3** | A comparability protocol must be a  | A comparability protocol |
|     | *scientifically sound* and          | is a well-defined,       |
|     | *appropriate*, well-defined,        | detailed, written plan   |
|     | detailed, written plan for          | for assessing the effect |
|     | assessing the effect of specific    | of specific CMC changes  |
|     | CMC changes in the identity,        | in the identity,         |
|     | strength, quality, purity, and      | strength, quality,       |
|     | potency of a specific drug product  | purity, and potency of a |
|     | as these factors relate to the      | specific drug product as |
|     | safety and effectiveness of the     | these factors relate to  |
|     | product and compliance with the     | the safety and           |
|     | applicable CGMP regulations. A      | effectiveness of the     |
|     | comparability protocol describes    | product. A comparability |
|     | the changes that are covered under  | protocol describes the   |
|     | the protocol and specifies the      | changes that are covered |
|     | tests and studies that will be      | under the protocol and   |
|     | performed, including the analytical | specifies the tests and  |
|     | procedures that will be used, and   | studies that will be     |
|     | the CGMP‑compliant acceptance       | performed, including the |
|     | criteria that must be achieved to   | analytical procedures    |
|     | demonstrate that specified CMC      | that will be used, and   |
|     | changes do not adversely affect the | acceptance criteria that |
|     | product. Though the submission of a | will be achieved to      |
|     | comparability protocol is optional, | demonstrate that         |
|     | it is recommended that one be       | specified CMC changes do |
|     | submitted whenever a written        | not adversely affect the |
|     | submission is required prior to     | product. The submission  |
|     | effecting a change.                 | of a comparability       |
|     |                                     | protocol is optional.    |
+-----+-------------------------------------+--------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | #                                 | ## D. Where Can More       |
| 127 | # D. Where Can More Information o | Information on Postapprova |
| -13 | n Post-approval Changes and Demon | l Changes and Demonstratio |
| 5** | stration of Equivalence Be Found? | n of Equivalence Be Found? |
|     |                                   |                            |
|     | This guidance, once finalized, is | This guidance, once        |
|     | not intended to supersede other   | finalized, is not intended |
|     | FDA guidance documents nor the    | to supersede other FDA     |
|     | applicable CGMP regulations       | guidance documents, rather |
|     | governing drugs and drug          | it supplements them with   |
|     | products, rather it supplements   | information on using       |
|     | them with information on using    | comparability protocols to |
|     | comparability protocols to        | implement postapproval CMC |
|     | implement post-approval CMC       | changes. We recommend that |
|     | changes. We recommend that        | applicants consult all     |
|     | applicants consult all relevant   | relevant guidances[^2] for |
|     | guidances [^1] for information    | information relating to    |
|     | relating to post-approval         | postapproval changes. The  |
|     | changes. The following guidances  | following guidances        |
|     | provide especially relevant       | provide especially         |
|     | information on (1) demonstrating  | relevant information on    |
|     | equivalence, (2) documentation to | (1) demonstrating          |
|     | be provided to support            | equivalence, (2)           |
|     | post-approval changes, and (3)    | documentation to be        |
|     | the recommended reporting         | provided to support        |
|     | categories.                       | postapproval changes, and  |
|     |                                   | (3) the recommended        |
|     |                                   | reporting categories.      |
+-----+-----------------------------------+----------------------------+
| **  | We recommend that you have        | We recommend that you have |
| 165 | sufficient batch‑representative   | sufficient manufacturing   |
| -17 | manufacturing information (e.g.,  | information (e.g.,         |
| 0** | developmental studies,            | developmental studies,     |
|     | manufacturing experience,         | manufacturing experience,  |
|     | demonstrated process capability,  | demonstrated process       |
|     | out-of-specification (OOS)        | capability,                |
|     | investigations, stability data)   | out-of-specification (OOS) |
|     | with the particular product or    | investigations, stability  |
|     | process or similar products or    | data) with the particular  |
|     | processes so you can specify a    | product or process or      |
|     | priori the tests, studies,        | similar products or        |
|     | analytical procedures, and the    | processes so you can       |
|     | scientifically sound and          | specify a priori the       |
|     | appropriate CGMP-compliant        | tests, studies, analytical |
|     | acceptance criteria appropriate   | procedures, and acceptance |
|     | for demonstrating that the CMC    | criteria appropriate for   |
|     | change or changes will still      | demonstrating that the CMC |
|     | fully comply with all of the      | change or changes will not |
|     | applicable CGMP requirements, are | adversely affect the       |
|     | based on recognized standards and | product.                   |
|     | sound science, and will not       |                            |
|     | adversely affect the product.     |                            |
+-----+-----------------------------------+----------------------------+
| **  | We recommend you consider         | We recommend you consider  |
| 173 | product-specific and              | product-specific and       |
| -17 | process-specific characteristics  | process-specific           |
| 5** | when determining whether to       | attributes when            |
|     | develop a comparability protocol. | determining whether to     |
|     | Characteristics can include, but  | develop a comparability    |
|     | are not limited to, the           | protocol. Attributes can   |
|     | following:                        | include, but are not       |
|     |                                   | limited to, the following: |
|     | (The use of the word              |                            |
|     | "**attribute**" should be         |                            |
|     | restricted to those               |                            |
|     | "**characteristics**" that may    |                            |
|     | are **inspected** by *sampling*   |                            |
|     | and *examination or               |                            |
|     | classification* to be consistent  |                            |
|     | with the recognized American      |                            |
|     | scientific inspection standard    |                            |
|     | **ANSI Z 1.4**. Similarly,        |                            |
|     | characteristics that are sampled  |                            |
|     | and tested for a level should be  |                            |
|     | called "factors" to be consistent |                            |
|     | with **ANSI Z 1.9**, the          |                            |
|     | recognized standard governing     |                            |
|     | such inspections.)                |                            |
+-----+-----------------------------------+----------------------------+

+------+----------------------------------+----------------------------+
| **Li | ##### Proposed Text              | **FDA Draft Text**         |
| ne** |                                  |                            |
|      |                                  |                            |
| *    |                                  |                            |
| *Ran |                                  |                            |
| ge** |                                  |                            |
+------+----------------------------------+----------------------------+
| **1  | In general, ~~we recommend       | In general, we recommend   |
| 90-1 | that~~ a comparability protocol  | that a comparability       |
| 94** | should be considered only if the | protocol be considered     |
|      | product resulting from the       | only if the product        |
|      | changes is expected to meet all  | resulting from the changes |
|      | the requisite CGMP‑compliant,    | is expected to meet the    |
|      | approved drug substance,         | approved drug substance    |
|      | in-process, and/or drug product  | and/or drug product        |
|      | specifications for each batch    | specifications and         |
|      | and appropriate and sensitive    | appropriate and sensitive  |
|      | analytical procedures have been  | analytical procedures have |
|      | established and validated or     | been established and       |
|      | qualified (i.e., for non-routine | validated or qualified     |
|      | tests such as characterization   | (i.e., for nonroutine      |
|      | studies) to detect and assess    | tests such as              |
|      | the effect, if any, of the       | characterization studies)  |
|      | change on the approved product.  | to detect the effect of    |
|      |                                  | the change on the approved |
|      |                                  | product.                   |
+------+----------------------------------+----------------------------+
| *    | ## D. When Is a Co               |                            |
| *Bet | mparability Protocol Proscribed? |                            |
| ween |                                  |                            |
| l    | A comparability protocol is      |                            |
| ines | proscribed whenever the proposed |                            |
| 232  | CMC changes do **not** meet the  |                            |
| and  | requirements established in the  |                            |
| 2    | applicable CGMP regulations      |                            |
| 33** | governing the process or product |                            |
|      | for which a firm is considering  |                            |
|      | such CMC changes. Thus, before   |                            |
|      | considering any CMC changes, the |                            |
|      | firm should ensure that said CMC |                            |
|      | changes collectively, and        |                            |
|      | individually, do not conflict    |                            |
|      | with any applicable CGMP         |                            |
|      | requirement.                     |                            |
+------+----------------------------------+----------------------------+
| **2  | Furthermore, an applicant who is | Furthermore, an applicant  |
| 55-2 | using an approved comparability  | who is using an approved   |
| 59** | protocol to implement            | comparability protocol to  |
|      | post-approval CMC changes must   | implement postapproval CMC |
|      | assess the effect of the changes | changes must assess the    |
|      | on the identity, strength,       | effect of the changes on   |
|      | quality **(**including, but not  | the identity, strength,    |
|      | limited to, the batch uniformity | quality, purity, and       |
|      | of the active or actives in the  | potency of the product as  |
|      | dosage units and their release   | these factors relate to    |
|      | from the dosage units**)**,      | the safety or efficacy of  |
|      | purity, and potency of the       | the product prior to       |
|      | product as these factors relate  | distributing product made  |
|      | to the safety or efficacy of the | with the change. (Section  |
|      | product prior to distributing    | 506A(b) of the act)).      |
|      | product made with the change.    |                            |
|      | (Section 506A(b) of the          |                            |
|      | act**.)**)**.**                  |                            |
+------+----------------------------------+----------------------------+
| **2  | If you decide to pursue the      | If you decide to pursue    |
| 78-2 | change, you should submit a      | the change, you should     |
| 81** | prior approval supplement that   | submit a prior approval    |
|      | provides supporting data from a  | supplement that provides   |
|      | statistically sufficient number  | the supporting data to     |
|      | of batch-representative units to | justify why the change     |
|      | justify why the change will not  | will not adversely affect  |
|      | adversely affect the identity,   | the identity, strength,    |
|      | strength, quality                | quality, purity, and       |
|      | **(**including, but not limited  | potency of the specific    |
|      | to, the batch uniformity of the  | drug product as these      |
|      | active or actives in the dosage  | factors relate to the      |
|      | units and their release from the | safety and effectiveness   |
|      | dosage units**)**, purity, and   | of the product.            |
|      | potency of the specific drug     |                            |
|      | product as these factors relate  |                            |
|      | to the safety and effectiveness  |                            |
|      | of the product.                  |                            |
+------+----------------------------------+----------------------------+
| **2  | We recommend you review the      | We recommend you review    |
| 88-2 | tests, studies, analytical       | the tests, studies,        |
| 90** | procedures, and acceptance       | analytical procedures, and |
|      | criteria in your approved        | acceptance criteria in     |
|      | comparability protocol to ensure | your approved              |
|      | they remain current and          | comparability protocol to  |
|      | consistent with the applicable   | ensure they remain current |
|      | CGMP requirements, approved      | and consistent with the    |
|      | application**,** and current FDA | approved application and   |
|      | policy.                          | current FDA policy.        |
+------+----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | The comparability protocol can    | The comparability protocol |
| 325 | describe a single CMC change or   | can describe a single CMC  |
| -32 | multiple changes. Each change     | change or multiple         |
| 8** | should be specified and the       | changes. Each change       |
|     | CGMP-compliant                    | should be specified and    |
|     | batch-representative inspection   | the acceptance criteria    |
|     | plans and batch acceptance        | for evaluating the effect  |
|     | criteria for evaluating the       | of the changes should be   |
|     | effect of the changes should be   | well defined. If multiple  |
|     | well defined. If multiple changes | changes are included in a  |
|     | are included in a protocol, we    | protocol, we recommend     |
|     | recommend that the multiple       | that the multiple changes  |
|     | changes be interrelated (i.e.,    | be interrelated (i.e., one |
|     | one change cannot be made without | change cannot be made with |
|     | the others).                      | out the others).           |
+-----+-----------------------------------+----------------------------+
| **  | ### 2. Specific Sampling Plans,   | ### 2. Specific Tests a    |
| 343 | Tests and Studies to Be Performed | nd Studies to Be Performed |
| -35 |                                   |                            |
| 2** | A list should be included of the  | A list should be included  |
|     | specific batch‑representative     | of the specific tests      |
|     | sampling plans (e.g., ANSI Z 1.4, | (e.g., release,            |
|     | ANSI Z 1.9 or ISO 3951,           | in-process) and studies    |
|     | in-house), analytical procedures  | (e.g., characterization,   |
|     | (e.g., content, release,          | stability, removal of      |
|     | impurity, appearance), control    | impurities,                |
|     | points (e.g., incoming,           | laboratory-scale           |
|     | in-process release, post release) | adventitious agent removal |
|     | and studies (e.g.,                | or inactivation) you will  |
|     | characterization, stability,      | perform to assess the      |
|     | removal of impurities,            | effect of the change on    |
|     | laboratory-scale adventitious     | the drug substance, drug   |
|     | agent removal or inactivation)    | product, and/or, if        |
|     | you will perform to assess the    | appropriate, the           |
|     | effect of the change on the drug  | intermediate, in-process   |
|     | substance, drug product, and/or,  | material, or component     |
|     | if appropriate, the intermediate, | (e.g., container closure   |
|     | in-process material, or component | system) directly affected  |
|     | (e.g., container closure system)  | by the change. Include the |
|     | directly affected by the change.  | rationale for selecting    |
|     | Include the *scientifically       | the particular battery of  |
|     | sound* rationale for selecting    | tests and studies. For     |
|     | the particular battery of tests   | example, the use of        |
|     | and studies. For example, the use | nonroutine studies (e.g.,  |
|     | of non-routine studies (e.g.,     | characterization) can be   |
|     | characterization) can be          | warranted in cases where   |
|     | warranted in cases where          | in-process or release      |
|     | in-process or release             | specifications are not     |
|     | specifications are not            | sufficiently               |
|     | sufficiently discriminatory to    | discriminatory to evaluate |
|     | evaluate the change.              | the change.                |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | The protocol should specify the   | The protocol should        |
| 356 | number and type (e.g., pilot,     | specify the number and     |
| -36 | production) of population         | type (e.g., pilot,         |
| 5** | **representative** pre- and post- | production) of pre- and    |
|     | change batches and/or batch       | postchange batches and/or  |
|     | **representative** samples that   | samples that will be       |
|     | will be compared. The number and  | compared. The number and   |
|     | type of batches and/or samples to | type of batches and/or     |
|     | be compared can vary depending on | samples to be compared can |
|     | the extent of the proposed        | vary depending on the      |
|     | change, type of product or        | extent of the proposed     |
|     | process, and available            | change, type of product or |
|     | manufacturing information.        | process, and available     |
|     |                                   | manufacturing information. |
|     | However, the numbers chosen must  | Retained samples of        |
|     | be scientifically sound and       | prechange material can be  |
|     | representative, and statistically | used for comparison,       |
|     | justified. Retained samples of    | provided there is no       |
|     | pre-change material can be used   | significant change in      |
|     | for comparison, provided **said   | material on storage (e.g., |
|     | samples are batch                 | level of degradants        |
|     | representative** and there is no  | increasing over time). A   |
|     | significant change in material on | plan would specify whether |
|     | storage (e.g., level of           | retained samples are going |
|     | degradants increasing over time). | to be used and the maximum |
|     | A plan would specify whether      | age of the retained        |
|     | retained samples are going to be  | samples, and include       |
|     | used, and the maximum age of the  | information to support the |
|     | retained samples, and include     | appropriateness of the use |
|     | information to establish that the | of retained samples. In    |
|     | samples are **batch               | general, the results from  |
|     | representative** and otherwise    | postchange material should |
|     | support the appropriateness of    | fall within the normal     |
|     | the use of retained samples. In   | batch-to-batch variation   |
|     | general, the results from the     | observed for prechange     |
|     | evaluation of a population        | material.                  |
|     | representative number of          |                            |
|     | post‑change material samples      |                            |
|     | should fall within the normal     |                            |
|     | batch‑to-batch variation observed |                            |
|     | for a population representative   |                            |
|     | number of pre-change material     |                            |
|     | samples.                          |                            |
+-----+-----------------------------------+----------------------------+
| **  | A comparability protocol should   | A comparability protocol   |
| 367 | include an inspection plan for    | should include a plan for  |
| -37 | the stability studies that will   | the stability studies that |
| 6** | be performed on population        | will be performed to       |
|     | representative samples to         | demonstrate the            |
|     | demonstrate the equivalence of    | equivalence of pre- and    |
|     | pre- and post-change product. The | postchange product. The    |
|     | comparability protocol would      | comparability protocol     |
|     | provide (1) information that      | would provide (1)          |
|     | should be typically provided in a | information that is        |
|     | stability protocol, such as the   | typically provided in a    |
|     | number and type of batches that   | stability protocol, such   |
|     | will be studied, test conditions, | as the number and type of  |
|     | and test time points or (2) a     | batches that will be       |
|     | reference to the currently        | studied, test conditions,  |
|     | approved stability protocol. The  | and test time points or    |
|     | amount of stability data that     | (2) a reference to the     |
|     | will be generated before the      | currently approved         |
|     | product made with the change is   | stability protocol. The    |
|     | distributed would be specified.   | amount of stability data   |
|     | The plan for evaluating stability | that will be generated     |
|     | could vary depending on the       | before the product made    |
|     | extent of the proposed change,    | with the change is         |
|     | type of product, and available    | distributed would be       |
|     | manufacturing information.        | specified. The plan for    |
|     | However, the number of            | evaluating stability could |
|     | representative samples tested     | vary depending on the      |
|     | must be a scientifically sound,   | extent of the proposed     |
|     | statistically justifiable number. | change, type of product,   |
|     | In some cases, no stability       | and available              |
|     | studies may be warranted or a     | manufacturing information. |
|     | commitment to report results from | In some cases, no          |
|     | stability studies in an AR can be | stability studies may be   |
|     | sufficient. If no stability       | warranted or a commitment  |
|     | studies are planned, we recommend | to report results from     |
|     | that this be stated clearly and   | stability studies in an AR |
|     | justified.                        | can be sufficient. If no   |
|     |                                   | stability studies are      |
|     |                                   | planned, we recommend that |
|     |                                   | this be stated clearly.    |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | The differences, if any, in the   | The differences, if any,   |
| 378 | tests and studies from those      | in the tests and studies   |
| -38 | previously reported in the        | from those previously      |
| 0** | approved application or           | reported in the approved   |
|     | subsequent updates (i.e.,         | application or subsequent  |
|     | supplements, annual reports)      | updates (i.e.,             |
|     | should be described.              | supplements, annual        |
|     |                                   | reports) would be          |
|     |                                   | described.                 |
+-----+-----------------------------------+----------------------------+
| **  | A protocol should specify the     | A protocol should specify  |
| 384 | validated analytical procedures   | the analytical procedures  |
| -40 | that you intend to use to assess  | that you intend to use to  |
| 0** | the effect of the CMC changes on  | assess the effect of the   |
|     | the product or intermediate       | CMC changes on the product |
|     | material. Analytical procedures   | or intermediate material.  |
|     | with a demonstrated capability to | Analytical procedures      |
|     | detect new impurities or other    | would be chosen capable of |
|     | changes in a product that can     | detecting new impurities   |
|     | result from the change should be  | or other changes in a      |
|     | chosen.                           | product that can result    |
|     |                                   | from the change.           |
|     | Since the current approved        |                            |
|     | analytical procedures are         | Since the current approved |
|     | optimized for the approved        | analytical procedures are  |
|     | product and process, modified or  | optimized for the approved |
|     | new procedures may be warranted.  | product and process,       |
|     | For example, revised or new       | modified or new procedures |
|     | validated analytical procedures   | may be warranted. For      |
|     | can be called for to monitor the  | example, revised or new    |
|     | removal of a new process impurity | analytical procedures can  |
|     | generated by a new manufacturing  | be called for to monitor   |
|     | process. In this situation,       | the removal of a new       |
|     | submission of population          | process impurity generated |
|     | representative results for pre-   | by a new manufacturing     |
|     | and post- change products using   | process. In this           |
|     | both the old and new analytical   | situation, submission of   |
|     | procedures may be warranted.      | results for pre- and       |
|     | Studies performed to assess the   | postchange products using  |
|     | feasibility of the proposed       | both the old and new       |
|     | change can often be helpful in    | analytical procedures may  |
|     | determining whether the current   | be warranted. Studies      |
|     | approved analytical procedures    | performed to assess the    |
|     | will be appropriate for assessing | feasibility of the         |
|     | the effect of the change on the   | proposed change can often  |
|     | product (see V.A.5). Validation   | be helpful in determining  |
|     | of new modified analytical        | whether the current        |
|     | procedures or revalidation of     | approved analytical        |
|     | existing analytical procedures    | procedures will be         |
|     | should be performed, as           | appropriate for assessing  |
|     | appropriate. The protocol should  | the effect of the change   |
|     | specify that any new or revised   | on the product (see        |
|     | analytical procedures and their   | V.A.5). Validation of new  |
|     | appropriate validation or         | modified analytical        |
|     | revalidation information will be  | procedures or revalidation |
|     | provided whenever a post-approval | of existing analytical     |
|     | CMC change**,** implemented using | procedures should be       |
|     | the approved comparability        | performed, as appropriate. |
|     | protocol**,** is reported to FDA. | The protocol would specify |
|     |                                   | that any new or revised    |
|     |                                   | analytical procedures and  |
|     |                                   | the appropriate validation |
|     |                                   | or revalidation            |
|     |                                   | information would be       |
|     |                                   | provided when a            |
|     |                                   | postapproval CMC change    |
|     |                                   | implemented using the      |
|     |                                   | approved comparability     |
|     |                                   | protocol is reported to    |
|     |                                   | FDA.                       |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | However, if these analytical      | However, if these          |
| 406 | procedures are specified in and   | analytical procedures are  |
| -41 | provided as part of a             | specified in and provided  |
| 4** | comparability protocol, any new   | as part of a comparability |
|     | or revised analytical procedures  | protocol, any new or       |
|     | and, as appropriate, results from | revised analytical         |
|     | validation or qualification       | procedures and, as         |
|     | studies for any modified          | appropriate, results from  |
|     | procedure should be provided      | validation or              |
|     | whenever a post‑approval CMC      | qualification studies for  |
|     | change implemented using the      | any modified procedure     |
|     | approved comparability protocol   | would be provided when a   |
|     | is reported to FDA.               | postapproval CMC change    |
|     |                                   | implemented using the      |
|     | In cases where changes in         | approved comparability     |
|     | analytical procedures are         | protocol is reported to    |
|     | intended to be implemented        | FDA.                       |
|     | independent of other CMC changes, |                            |
|     | we recommend that a comparability | In cases where changes in  |
|     | protocol specific for analytical  | analytical procedures are  |
|     | procedure changes should be       | intended to be implemented |
|     | submitted (see V.C)               | independent of other CMC   |
|     |                                   | changes, we recommend that |
|     |                                   | a comparability protocol   |
|     |                                   | specific for analytical    |
|     |                                   | procedure changes be       |
|     |                                   | submitted (see V.C)        |
+-----+-----------------------------------+----------------------------+
| **  | ### 4. Acceptance Criteria        | #                          |
| 418 |                                   | ## 4. Acceptance Criteria  |
| -42 | You should include the            |                            |
| 3** | *scientifically sound and         | You should include the     |
|     | appropriate*, statistics based    | acceptance criteria        |
|     | acceptance criteria (numerical    | (numerical limits, ranges  |
|     | limits, ranges or other criteria) | or other criteria) for     |
|     | and their scientific              | each specified test and    |
|     | justification for each specified  | study that will be used to |
|     | test and study that will be used  | assess the effect of the   |
|     | to assess the effect of the CMC   | CMC changes on the product |
|     | changes on the product or other   | or other material and/or   |
|     | material and/or demonstrate       | demonstrate equivalence    |
|     | equivalence between pre- and      | between pre- and           |
|     | post- change material. In         | postchange material. In    |
|     | general, the drug substance and   | general, the drug          |
|     | drug product specification should | substance and drug product |
|     | be **CGMP-compliant** and         | specification would be     |
|     | identical to, or within, the      | identical to that in the   |
|     | specification limit, range or     | approved application. Any  |
|     | other criteria contained in the   | statistical analyses that  |
|     | approved application. Any         | will be performed and the  |
|     | statistical analyses, *including  | associated evaluation      |
|     | those required by* **21 CFR       | criteria would be          |
|     | 211.165(d)** *for the drug        | identified.                |
|     | product*, that will be performed  |                            |
|     | and the associated evaluation     |                            |
|     | criteria should be identified.    |                            |
|     | \[**Note:** If a firm's current   |                            |
|     | approved drug‑product application |                            |
|     | does not comply with the          |                            |
|     | requirements set forth in **21    |                            |
|     | CFR 211**, then that deficiency   |                            |
|     | should be corrected before any    |                            |
|     | other comparability protocol is   |                            |
|     | submitted.\]                      |                            |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | If implementing a change using a  | If implementing a change   |
| 425 | comparability protocol calls for  | using a comparability      |
| -43 | a revision of the drug product or | protocol calls for a       |
| 5** | drug substance specification, we  | revision of the drug       |
|     | recommend you consider the        | product or drug substance  |
|     | designated reporting category[^3] | specification, we          |
|     | for the type of specification     | recommend you consider the |
|     | change as well as the designated  | recommended reporting      |
|     | reporting category for reporting  | category[^4] for the type  |
|     | a change using your comparability | of specification change as |
|     | protocol.                         | well as the designated     |
|     |                                   | reporting category for     |
|     | When the recommended reporting    | reporting a change using   |
|     | category for the specification    | your comparability         |
|     | change is higher (e.g., PAS) than | protocol. When the         |
|     | the reporting category for        | recommended reporting      |
|     | changes made under the            | category for the           |
|     | comparability protocol (e.g.,     | specification change is    |
|     | CBE-30), the change should be     | higher (e.g., PAS) than    |
|     | reported as recommended for the   | the reporting category for |
|     | specification change.             | changes made under the     |
|     |                                   | comparability protocol     |
|     | If the recommended reporting      | (e.g., CBE-30), the change |
|     | category for the specification    | would be reported as       |
|     | change is the same as, or lower   | recommended for the        |
|     | than**,** the designated          | specification change. If   |
|     | reporting category for changes    | the recommended reporting  |
|     | made under the comparability      | category for the           |
|     | protocol, the specification can   | specification change is    |
|     | be updated and provided to the    | the same or lower than the |
|     | FDA when the post-approval CMC    | designated reporting       |
|     | change, using the approved        | category for changes made  |
|     | comparability protocol, is        | under the comparability    |
|     | implemented and reported to FDA.  | protocol, the              |
|     |                                   | specification can be       |
|     |                                   | updated and provided when  |
|     |                                   | a postapproval CMC change  |
|     |                                   | implemented using the      |
|     |                                   | approved comparability     |
|     |                                   | protocol is reported to    |
|     |                                   | FDA.                       |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | ### 5. Dat                        | ### 5. Data to             |
| 437 | a to Be Reported Under or Include |  Be Reported Under or Incl |
| -45 | d With the Comparability Protocol | uded With the ... Protocol |
| 0** |                                   |                            |
|     | You should identify the type      | You should identify the    |
|     | (e.g., in-coming material,        | type (e.g., release,       |
|     | in-process material, drug-product | long-term or accelerated   |
|     | acceptance in compliance with 21  | stability data) and amount |
|     | CFR 211.165 and, where            | of data (e.g., 3-months    |
|     | applicable, 21 CFR 211.167,       | accelerated stability      |
|     | long-term or accelerated          | data) that will be         |
|     | stability data) and the amount of | submitted at the time a    |
|     | data (e.g., "n~i~"                | postapproval CMC change    |
|     | lot‑representative samples of     | implemented using the      |
|     | "m~i~" incoming lots for "li"     | approved comparability     |
|     | characteristics, "n~p~"           | protocol is reported to    |
|     | representative sample sets from   | FDA and, when appropriate, |
|     | "m~p~" process representative     | generated prior to your    |
|     | evaluations of "k~pa~" attribute  | distributing the product   |
|     | factors and "l~pv~" variable      | made with the change       |
|     | factors, "n~dp~"                  | (e.g., when proposed       |
|     | batch‑representative sample sets  | reporting category is a    |
|     | from "m~dp~" batch evaluations of | CBE-30, CBE-0, or AR).     |
|     | "k~dpa~" attribute factors and    |                            |
|     | "l~dpv~" variable factors of the  | If available, you can      |
|     | drug product for acceptance,      | include any data from      |
|     | 3-months accelerated stability    | studies performed to       |
|     | data) that will be submitted at   | assess the feasibility of  |
|     | the time a post-approval CMC      | the proposed change with   |
|     | change implemented using an       | the proposed comparability |
|     | approved comparability protocol   | protocol. Data obtained    |
|     | is reported to FDA and, when      | from a small-scale process |
|     | appropriate, generated prior to   | or other studies           |
|     | your distributing the product     | incorporating the proposed |
|     | made with the change (e.g., when  | change can provide         |
|     | proposed reporting category is a  | preliminary evidence that  |
|     | CBE-30, CBE-0, or AR).            | the change is feasible, as |
|     |                                   | well as preliminary        |
|     | If available, you may include any | information on the effect  |
|     | **population representative**     | of the change on the       |
|     | data from studies performed to    | product. Development or    |
|     | assess the feasibility of the     | feasibility studies can    |
|     | proposed change with the proposed | provide insight into the   |
|     | comparability protocol. Data      | relevance and adequacy of  |
|     | obtained from a *scientifically   | the choice of the battery  |
|     | sound and appropriate*            | of tests you have          |
|     | small-scale process or other      | identified to assess the   |
|     | *scientifically sound and         | product.                   |
|     | appropriate* studies**,**         |                            |
|     | incorporating the proposed        |                            |
|     | change**,** can be used as        |                            |
|     | preliminary evidence that the     |                            |
|     | change is feasible, as well as    |                            |
|     | provide preliminary information   |                            |
|     | on the effect of the change on    |                            |
|     | the product. *Scientifically      |                            |
|     | sound and appropriate*            |                            |
|     | development or feasibility        |                            |
|     | studies can provide insight into  |                            |
|     | the relevance and adequacy of the |                            |
|     | choice of the battery of tests    |                            |
|     | you have identified to assess the |                            |
|     | product.                          |                            |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | ### 7. Equi                       | ### 7. Equivalence Not De  |
| 462 | valence Not Demonstrated Using th | monstrated Using the Appro |
| -46 | e Approved Comparability Protocol | ved Comparability Protocol |
| 8** |                                   |                            |
|     | It is anticipated that some       | It is anticipated that     |
|     | changes in the manufacturing      | some changes in the        |
|     | process will result in a          | manufacturing process will |
|     | post-change drug product that:    | result in a postchange     |
|     | **a)** cannot be demonstrated to  | product that cannot be     |
|     | be equivalent to the pre-change   | demonstrated to be         |
|     | drug product without more         | equivalent to the          |
|     | extensive physicochemical,        | prechange product without  |
|     | biological, pharmacology, PK/PD,  | more extensive             |
|     | efficacy, or safety testing or    | physicochemical,           |
|     | **b)** does not meet the          | biological, pharmacology,  |
|     | pre‑specified acceptance criteria | PK/PD, efficacy, or safety |
|     | in the protocol. You should       | testing or in a product    |
|     | include in the protocol the       | that does not meet the     |
|     | explicit steps you will take      | prespecified acceptance    |
|     | should either circumstance occur. | criteria in the protocol.  |
|     |                                   | You should identify in the |
|     |                                   | protocol the steps you     |
|     |                                   | will take in such          |
|     |                                   | circumstances.             |
+-----+-----------------------------------+----------------------------+
| **  | ### 1. Compa                      | ### 1. Comparison o        |
| 481 | rison of Physical Characteristics | f Physical Characteristics |
| -48 |                                   |                            |
| 5** | A comparability protocol should   | A comparability protocol   |
|     | normally include incoming         | would normally include a   |
|     | material and/or in-process        | plan to compare the        |
|     | material inspection plans that    | physical characteristics   |
|     | compare the physical              | (e.g., polymorph forms,    |
|     | characteristics (e.g., polymorph  | particle size              |
|     | forms, particle size              | distribution) of the       |
|     | distribution, density, flow,      | product produced using the |
|     | affinity) of materials that make  | old and new processes when |
|     | up the product produced using the | these characteristics are  |
|     | old and new processes when these  | relevant to the safety     |
|     | characteristics are relevant to   | and/or efficacy of the     |
|     | the safety and the **uniformity** | product.                   |
|     | of: **a)** the active or actives, |                            |
|     | **b)** the release of the active  |                            |
|     | or actives, or **c)** any other   |                            |
|     | key quality factors in the        |                            |
|     | product that can affect its       |                            |
|     | efficacy of the product when      |                            |
|     | taken by the consumer.            |                            |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | ### 2.                            | ### 2. Compar              |
| 489 |  Comparison of Impurity Profiles  | ison of Impurity Profiles  |
| -50 |                                   |                            |
| 2** | A comparability protocol would    | A comparability protocol   |
|     | include a scientifically sound    | would include a plan to    |
|     | and appropriate inspection plan   | determine the impurity     |
|     | to determine the impurity profile | profile of the product     |
|     | of the product produced using the | produced using the new     |
|     | new process. The studies would    | process. The studies would |
|     | assess product-related impurities | assess product-related     |
|     | and process-related impurities,   | impurities and             |
|     | including, if applicable          | process-related            |
|     | in-process reagents and           | impurities, including, if  |
|     | catalysts. We recommend that      | applicable in-process      |
|     | attention be given to             | reagents and catalysts. We |
|     | demonstrating the absence of any  | recommend that attention   |
|     | new impurities or contaminants,   | be given to demonstrating  |
|     | or that they are removed or       | the absence of any new     |
|     | inactivated by downstream         | impurities or              |
|     | processing. Any changes in the    | contaminants, or that they |
|     | impurity profile would meet the   | are removed or inactivated |
|     | predefined criteria (see section  | by downstream processing.  |
|     | V.A.4). The predefined criteria   | Any changes in the         |
|     | should indicate when              | impurity profile would     |
|     | qualification studies will be     | meet the predefined        |
|     | warranted to evaluate an          | criteria (see section      |
|     | increased level of an existing    | V.A.4). The predefined     |
|     | impurity or a new impurity (or an | criteria would indicate    |
|     | applicant could reference a       | when qualification studies |
|     | relevant FDA guidance that        | will be warranted to       |
|     | recommends qualification levels). | evaluate an increased      |
|     | Unless: **a)** the structure of   | level of an existing       |
|     | any new impurity is unequivocally | impurity or a new impurity |
|     | established, **b)** an authentic  | (or an applicant could     |
|     | standard for the impurity is      | reference a relevant FDA   |
|     | available, **c)** its acute and   | guidance that recommends   |
|     | chronic toxicity and mechanism of | qualification levels).     |
|     | action in mammalian species       |                            |
|     | including man is well defined,    | If during implementation   |
|     | and **d)** the interaction with   | of a change under an       |
|     | the active and other impurities   | approved comparability     |
|     | is known to be non-synergistic,   | protocol, the data         |
|     | the appropriate safety studies    | indicate that nonclinical  |
|     | should be conducted,              | or clinical qualification  |
|     |                                   | studies for impurities are |
|     | If during implementation of a     | warranted, the change      |
|     | change under an approved          | would not be appropriate   |
|     | comparability protocol, the valid | for implementation under   |
|     | data from the testing of the      | the approved comparability |
|     | appropriate population            | protocol (see III.C and    |
|     | representative samples indicate   | V.A.7)                     |
|     | that non-clinical or clinical     |                            |
|     | qualification studies for         |                            |
|     | impurities are warranted, the     |                            |
|     | change would not be appropriate   |                            |
|     | for implementation under the      |                            |
|     | approved comparability protocol   |                            |
|     | (see III.C and V.A.7)             |                            |
+-----+-----------------------------------+----------------------------+
| **  | ### 4. Effect on Process          | ### 4. Effect              |
| 513 | Controls and Controls of Intermed |  on Process Controls and C |
| -51 | iates and/or In-process Materials | ontrols of Intermediates a |
| 9** |                                   | nd/or In-process Materials |
|     | We recommend you identify and     |                            |
|     | justify the implementation of any | We recommend you identify  |
|     | and all: **a)** new controls or   | and justify implementation |
|     | **b)** **deviations** from        | of new controls or         |
|     | approved controls. We recommend a | variations from approved   |
|     | statement be included that all of | controls. We recommend a   |
|     | the controls, including those     | statement be included that |
|     | that have been validated to       | controls, including those  |
|     | inactivate and remove impurities  | that have been validated   |
|     | or contaminants, will be          | to inactivate and remove   |
|     | revalidated for the new           | impurities or              |
|     | production process,               | contaminants, will be      |
|     | [unless]{.underline} an           | revalidated for the new    |
|     | appropriate body of sound         | production process, if     |
|     | scientific evidence clearly       | appropriate.               |
|     | establishes that each of said     |                            |
|     | controls are currently operating  |                            |
|     | in the "is valid" state.          |                            |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | ## C. Does FDA Have Specific Co   | ## C. Does                 |
| 521 | ncerns About Changes in Analytica |  FDA Have Specific Concern |
| -54 | l Procedures That Should Be Addre | s About Changes in Analyti |
| 7** | ssed in a Comparability Protocol? | cal Procedures That ... in |
|     |                                   |  a Comparability Protocol? |
|     | A comparability protocol for      |                            |
|     | changing an analytical procedure  | A comparability protocol   |
|     | would provide the plan for        | for changing an analytical |
|     | validation of the changed         | procedure would provide    |
|     | analytical procedure and indicate | the plan for validation of |
|     | whether the protocol will be      | the changed analytical     |
|     | used**: a)** to modify the        | procedure and indicate     |
|     | existing analytical procedure     | whether the protocol will  |
|     | (i.e., retaining the same         | be used to modify the      |
|     | principle), or **b)** to change   | existing analytical        |
|     | from one analytical procedure to  | procedure (i.e., retaining |
|     | another (e.g., normal to reverse  | the same principle), or to |
|     | phase HPLC/UV or from HPLC/UV to  | change from one analytical |
|     | GC/FID, or from HPLC to           | procedure to another       |
|     | rapid-scan UV/Visible             | (e.g., normal to reverse   |
|     | spectroscopy, or from titration   | phase HPLC). The           |
|     | to HPLC/UV). The comparability    | comparability protocol     |
|     | protocol would be designed to     | would be designed to       |
|     | demonstrate that the proposed     | demonstrate that the       |
|     | changes in the analytical         | proposed changes in the    |
|     | procedures**: a)** improve or     | analytical procedures      |
|     | **b)** do not significantly       | improve or do not          |
|     | affect the critical               | significantly change       |
|     | characteristics (e.g., accuracy,  | characteristics used in    |
|     | precision, specificity, detection | methods validation that    |
|     | limit, quantitation limit,        | are relevant to the type   |
|     | linearity, and/or **linear**      | of analytical procedure    |
|     | range) [^5] used in the           | (e.g., accuracy,           |
|     | validation of methods that are    | precision, specificity,    |
|     | relevant to the type of           | detection limit,           |
|     | analytical procedure (e.g.,       | quantitation limit,        |
|     | active content evaluation, active | linearity, range).[^6]     |
|     | release or rate of release,       |                            |
|     | impurity, identity).              | Methods validation         |
|     |                                   | includes an assessment of  |
|     | Method validation should include  | the suitability of the     |
|     | an assessment of the suitability  | analytical procedure. A    |
|     | of the analytical procedure. A    | validation plan would have |
|     | validation plan should have       | prespecified acceptance    |
|     | *scientifically sound and         | criteria for relevant      |
|     | appropriate* pre-specified        | validation parameters such |
|     | acceptance criteria for relevant  | as precision, range,       |
|     | validation parameters such as     | accuracy, specificity,     |
|     | precision, range, accuracy,       | detection limit, and       |
|     | specificity, detection limit, and | quantitation limit. The    |
|     | quantitation limit. The proposed  | proposed acceptance        |
|     | acceptance criteria for these     | criteria for these         |
|     | parameters should ensure that the | parameters would ensure    |
|     | analytical procedure is           | that the analytical        |
|     | scientifically sound and          | procedure is appropriate   |
|     | appropriate for its intended use. | for its intended use. The  |
|     | The validation plan should assess | validation plan would      |
|     | whether a revised procedure is    | assess whether a revised   |
|     | more susceptible than the         | procedure is more          |
|     | original procedure to matrix      | susceptible than the       |
|     | effects by process buffers/media, | original procedure to      |
|     | product-related contaminants, or  | matrix effects by process  |
|     | other components present in the   | buffers/media,             |
|     | material being tested. A plan     | product-related            |
|     | should identify any statistical   | contaminants, or other     |
|     | analyses that will be performed   | components present in the  |
|     | and whether the plan intends to   | dosage form. A plan would  |
|     | use CGMP-compliant product        | identify any statistical   |
|     | testing to compare the two        | analyses that will be      |
|     | procedures. The need**,** and     | performed and whether      |
|     | plan**,** for using population    | product testing to compare |
|     | representative product testing to | the two procedures is      |
|     | compare the two procedures could  | intended. The need and     |
|     | vary depending on the extent of   | plan for providing product |
|     | the proposed change, type of      | testing to compare the two |
|     | product, and type of test (e.g.,  | procedures could vary      |
|     | chemical, biological).            | depending on the extent of |
|     |                                   | the proposed change, type  |
|     | ##                                | of product, and type of    |
|     |                                   | test (e.g., chemical,      |
|     | When used for release or process  | biological).               |
|     | control, use of the new revised   |                            |
|     | analytical procedure should not   | ##                         |
|     | result in deletion of a test or   |                            |
|     | relaxation of acceptance criteria | When used for release or   |
|     | that are described in the         | process control, use of    |
|     | approved application. \[**Note:** | the new revised analytical |
|     | The acceptance criteria in the    | procedure should not       |
|     | approved application must meet    | result in deletion of a    |
|     | the minimums established in the   | test or relaxation of      |
|     | applicable CGMP regulations.\]    | acceptance criteria that   |
|     |                                   | are described in the       |
|     |                                   | approved application.      |
+-----+-----------------------------------+----------------------------+

+-----+-----------------------------------+----------------------------+
| **  | ##### Proposed Text               | **FDA Draft Text**         |
| Lin |                                   |                            |
| e** |                                   |                            |
|     |                                   |                            |
| **R |                                   |                            |
| ang |                                   |                            |
| e** |                                   |                            |
+-----+-----------------------------------+----------------------------+
| **  | ## G. Can Implementa              | ## G. Can Imple            |
| 587 | tion of or Changes in Process Ana | mentation of or Changes in |
| -59 | lytical Technology (PAT) Be Addre |  Process Analytical Techno |
| 2** | ssed in a Comparability Protocol? | logy (PAT) Be Addressed in |
|     |                                   |  a Comparability Protocol? |
|     | FDA anticipates that              |                            |
|     | implementation of or changes in   | FDA anticipates that       |
|     | PAT could be addressed in a       | implementation of or       |
|     | comparability protocol. Early     | changes in PAT could be    |
|     | dialogue with FDA is encouraged.  | addressed in a             |
|     | The FDA intends to publish        | comparability protocol.    |
|     | **~~a~~** guidance on PAT in the  | Early dialogue with FDA is |
|     | future. However, if the PAT       | encouraged. The FDA        |
|     | intends to change from the        | intends to publish a       |
|     | quantitative testing of an        | guidance on PAT in the     |
|     | appropriate                       | future.                    |
|     | population-representative sample  |                            |
|     | set to an approach that uses      |                            |
|     | training sets and the             |                            |
|     | classification of an appropriate  |                            |
|     | set of samples, then:             |                            |
|     |                                   |                            |
|     | 1.  Appropriately rigorous        |                            |
|     |     controls will be required for |                            |
|     |     all of the components should  |                            |
|     |     be implemented for all        |                            |
|     |     components used in the        |                            |
|     |     manufacture of the product.   |                            |
|     |                                   |                            |
|     | 2.  The training sets used to     |                            |
|     |     train the classifier will     |                            |
|     |     need to appropriately span    |                            |
|     |     all of the possible component |                            |
|     |     combinations in sets that are |                            |
|     |     deliberately prepared to      |                            |
|     |     address all of the factors    |                            |
|     |     (e.g., assay, release, rate   |                            |
|     |     of release, impurity) that    |                            |
|     |     the classifier is designed to |                            |
|     |     assess. \[**Note:** The       |                            |
|     |     number of training samples in |                            |
|     |     each training required set    |                            |
|     |     should be several times the   |                            |
|     |     number of                     |                            |
|     |     population-representative     |                            |
|     |     samples required for the      |                            |
|     |     evaluation of the product.\]  |                            |
|     |                                   |                            |
|     | 3.  The typical appropriate       |                            |
|     |     number of representative      |                            |
|     |     samples that need to be       |                            |
|     |     classified from a typical     |                            |
|     |     batch of product should be    |                            |
|     |     based on the attribute number |                            |
|     |     requirements established in   |                            |
|     |     ANSI Z 1.4 because            |                            |
|     |     classification is an          |                            |
|     |     attribute assessment**.**     |                            |
+-----+-----------------------------------+----------------------------+
| **  | ## Can a DMF or                   | ##                         |
| 594 |  VMF Be Cross-Referenced in an Ap | Can a DMF or VMF Be Cross- |
| -60 | plicant's Comparability Protocol? | Referenced in an Applicant |
| 5** |                                   | 's Comparability Protocol? |
|     | A master file can be              |                            |
|     | cross-referenced in a             | A master file can be       |
|     | comparability protocol that       | cross-referenced in a      |
|     | provides for CMC changes (e.g.,   | comparability protocol     |
|     | new manufacturer of drug          | that provides for CMC      |
|     | substance, container resin). The  | changes (e.g., new         |
|     | protocol should include a         | manufacturer of drug       |
|     | commitment to provide a letter    | substance, container       |
|     | authorizing the FDA to review the | resin). The protocol would |
|     | master file when a post‑approval  | include a commitment to    |
|     | CMC change implemented using the  | provide a letter           |
|     | approved comparability protocol   | authorizing the FDA to     |
|     | is reported to FDA. The           | review the master file     |
|     | comparability protocol should     | when a postapproval CMC    |
|     | also indicate the type of         | change implemented using   |
|     | information (e.g., manufacturing  | the approved comparability |
|     | and formulation information for a | protocol is reported to    |
|     | plastic resin) that will be       | FDA. The comparability     |
|     | referenced in the master file and | protocol would also        |
|     | the information that you will     | indicate the type of       |
|     | provide including the studies you | information (e.g.,         |
|     | will perform to demonstrate the   | manufacturing and          |
|     | suitability of the new material   | formulation information    |
|     | (e.g., conformance to approved    | for a plastic resin) that  |
|     | specification, compatibility      | will be referenced in the  |
|     | studies, stability studies).      | master file and the        |
|     |                                   | information that you will  |
|     |                                   | provide such as the        |
|     |                                   | studies you will perform   |
|     |                                   | to demonstrate the         |
|     |                                   | suitability of the new     |
|     |                                   | material (e.g.,            |
|     |                                   | conformance to approved    |
|     |                                   | specification,             |
|     |                                   | compatibility studies,     |
|     |                                   | stability studies).        |
+-----+-----------------------------------+----------------------------+

**Concluding Remarks**

Hopefully, those who review the preceding comments will do so with an
open mind and a copy of the CGMP regulations for drugs (**21 CFR 210**)
and finished pharmaceuticals (**21 CFR 211**).

Hopefully, all will accept that the minimum requirements set forth in
**21 CFR 211** are truly the minimum that any firm can do and have their
FDA-regulated finished products be CGMP-compliant.

Hopefully, all will remember that products covered by **21 CFR 211**
that are not manufactured in full compliance with **21 CFR 211** are
adulterated and should not be distributed.

With the preceding in mind and remembering that the FDA has no authority
to issue guidance that differs from any of the clear requirements set
forth in **21 CFR 211**, hopefully, the FDA will appropriately revise
their draft and issue guidance that fully complies with the clear, but
seemingly overlooked, requirements of **21 CFR 211**.

[^1]:

[^2]:

[^3]:

[^4]:

[^5]:

[^6]: