----------------- ----------------- ----------------- -----------------
  Section           Current           FDA Proposed      PDA Suggested
                    Regulation        Revision          Revision

  **Human checks on                                     
  automated systems                                     
  and equipment**                                       
  ----------------- ----------------- ----------------- -----------------

+-----------------+-----------------+-----------------+-----------------+
| 211.68(c)       | There is a new  | "Such automated | "Automated      |
|                 | sub-section     | equipment used  | equipment used  |
| Automatic,      |                 | for performance | in conformance  |
| mechanical and  |                 | of operations   | with this       |
| electronic      |                 | addressed by    | section can     |
| equipment       |                 | Sec. 211.101(c) | satisfy the     |
|                 |                 | or (d),         | requirements    |
|                 |                 | 211.103,        | for             |
|                 |                 | 211.182, or     | verification of |
|                 |                 | 211.188(b)(11)  | proper          |
|                 |                 | can satisfy the | operations      |
|                 |                 | requirements    | addressed by    |
|                 |                 | included in     | Sec. 211.101(c) |
|                 |                 | those sections  | or (d),         |
|                 |                 | relating to the | 211.103,        |
|                 |                 | performance of  | 211.182, or     |
|                 |                 | an operation by | 211.188(b)(11), |
|                 |                 | one person and  | as follows: i)  |
|                 |                 | checking by     | if such unit    |
|                 |                 | another person  | operation is    |
|                 |                 | if such         | fully           |
|                 |                 | equipment is    | automated, then |
|                 |                 | used in         | no manual       |
|                 |                 | conformity with | verification is |
|                 |                 | this section    | necessary, or   |
|                 |                 | and one person  | ii) if there is |
|                 |                 | verified that   | an operator for |
|                 |                 | the operations  | the automated   |
|                 |                 | addressed in    | equipment, then |
|                 |                 | those sections  | the verifying   |
|                 |                 | are performed   | individual may  |
|                 |                 | accurately by   | be, but is not  |
|                 |                 | such            | required to be, |
|                 |                 | equipment."     | the operator."  |
+-----------------+-----------------+-----------------+-----------------+
| **Rationale:**  |                 |                 |                 |
| The rationale   |                 |                 |                 |
| for PDA's       |                 |                 |                 |
| recommendation  |                 |                 |                 |
| is              |                 |                 |                 |
| multi-faceted;  |                 |                 |                 |
|                 |                 |                 |                 |
| 1\) Automated,  |                 |                 |                 |
| validated       |                 |                 |                 |
| systems         |                 |                 |                 |
| equipped with   |                 |                 |                 |
| real time       |                 |                 |                 |
| alarms that do  |                 |                 |                 |
| not require any |                 |                 |                 |
| human           |                 |                 |                 |
| intervention    |                 |                 |                 |
| should not      |                 |                 |                 |
| require human   |                 |                 |                 |
| verification    |                 |                 |                 |
| with each use,  |                 |                 |                 |
| as section      |                 |                 |                 |
| 211.68(a)       |                 |                 |                 |
| currently and   |                 |                 |                 |
| adequately      |                 |                 |                 |
| addresses the   |                 |                 |                 |
| maintenance and |                 |                 |                 |
| verification of |                 |                 |                 |
| automated       |                 |                 |                 |
| systems         |                 |                 |                 |
| performance.    |                 |                 |                 |
|                 |                 |                 |                 |
| 2\) The need    |                 |                 |                 |
| and type of     |                 |                 |                 |
| verification    |                 |                 |                 |
| required should |                 |                 |                 |
| be consistent   |                 |                 |                 |
| with the level  |                 |                 |                 |
| of automation   |                 |                 |                 |
| used:           |                 |                 |                 |
|                 |                 |                 |                 |
| a\. Fully       |                 |                 |                 |
| automated and   |                 |                 |                 |
| alarmed         |                 |                 |                 |
| operations      |                 |                 |                 |
| using systems   |                 |                 |                 |
| compliant with  |                 |                 |                 |
| CGMP            |                 |                 |                 |
| qualification,  |                 |                 |                 |
| maintenance,    |                 |                 |                 |
| and data trail  |                 |                 |                 |
| requirements    |                 |                 |                 |
| should require  |                 |                 |                 |
| no additional   |                 |                 |                 |
| human           |                 |                 |                 |
| verification.   |                 |                 |                 |
| (Of course, the |                 |                 |                 |
| data trail of   |                 |                 |                 |
| performance     |                 |                 |                 |
| would be        |                 |                 |                 |
| subject to the  |                 |                 |                 |
| Quality Unit's  |                 |                 |                 |
| review prior to |                 |                 |                 |
| product         |                 |                 |                 |
| release.)       |                 |                 |                 |
|                 |                 |                 |                 |
| b\. Operations  |                 |                 |                 |
| which are not   |                 |                 |                 |
| fully automated |                 |                 |                 |
| using systems   |                 |                 |                 |
| that meet CGMP  |                 |                 |                 |
| expectations    |                 |                 |                 |
| (per above) but |                 |                 |                 |
| require         |                 |                 |                 |
| operator        |                 |                 |                 |
| participation   |                 |                 |                 |
| may serve as    |                 |                 |                 |
| verification of |                 |                 |                 |
| the operator's  |                 |                 |                 |
| activities,     |                 |                 |                 |
| replacing the   |                 |                 |                 |
| current second  |                 |                 |                 |
| human           |                 |                 |                 |
| verification    |                 |                 |                 |
| requirement.    |                 |                 |                 |
|                 |                 |                 |                 |
| c\. Fully       |                 |                 |                 |
| manual          |                 |                 |                 |
| operations      |                 |                 |                 |
| would continue  |                 |                 |                 |
| to require a    |                 |                 |                 |
| second human    |                 |                 |                 |
| verification.   |                 |                 |                 |
|                 |                 |                 |                 |
| 3\) As written, |                 |                 |                 |
| the proposed    |                 |                 |                 |
| regulation may  |                 |                 |                 |
| hinder the      |                 |                 |                 |
| adoption of     |                 |                 |                 |
| PAT. For        |                 |                 |                 |
| example, in     |                 |                 |                 |
| instances when  |                 |                 |                 |
| components are  |                 |                 |                 |
| charged in a    |                 |                 |                 |
| fully automated |                 |                 |                 |
| manner per a    |                 |                 |                 |
| validated       |                 |                 |                 |
| algorithm,      |                 |                 |                 |
| there would not |                 |                 |                 |
| appear to be    |                 |                 |                 |
| any value added |                 |                 |                 |
| by a manual     |                 |                 |                 |
| verification of |                 |                 |                 |
| that component  |                 |                 |                 |
| addition.       |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| Section         | Current         | FDA Proposed    | PDA Suggested   |
|                 | Regulation      | Revision        | Revision        |
+-----------------+-----------------+-----------------+-----------------+
| 211.101(c)(3)   | No existing     | If the          | "If the         |
|                 | rule.           | weighing,       | weighing,       |
| Charge-in of    |                 | measuring, or   | measuring, or   |
| components      |                 | subdividing     | subdividing     |
|                 |                 | operations are  | operations are  |
|                 |                 | performed by    | performed by    |
|                 |                 | automated       | automated       |
|                 |                 | equipment under | equipment, then |
|                 |                 | Sec. 211.68,    | verification    |
|                 |                 | only one person | that paragraphs |
|                 |                 | is needed to    | (c)(1), (c)(2), |
|                 |                 | assure          | and (c)(3) of   |
|                 |                 | paragraphs      | this section    |
|                 |                 | (c)(1), (c)(2), | have been met   |
|                 |                 | and (c)(3) of   | shall be in     |
|                 |                 | this section    | accordance with |
|                 |                 | have been met.  | section         |
|                 |                 |                 | 211.68(c)."     |
+-----------------+-----------------+-----------------+-----------------+
| **Rationale:**  |                 |                 |                 |
| Please refer to |                 |                 |                 |
| the comments on |                 |                 |                 |
| the proposed    |                 |                 |                 |
| revision to     |                 |                 |                 |
| section         |                 |                 |                 |
| 211.68(c).      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| 211.101(d)      | "Each component | "Each component | "Each component |
|                 | shall be added  | shall either be | shall either be |
| Charge-in of    | to the batch by | added to the    | added to the    |
| components      | one person      | batch by one    | batch by one    |
|                 | verified by a   | person and      | person and      |
|                 | second person." | verified by a   | verified by a   |
|                 |                 | second person   | second person   |
|                 |                 | or, if the      | or, if added by |
|                 |                 | components are  | automated       |
|                 |                 | added by        | equipment,      |
|                 |                 | automated       | verified in     |
|                 |                 | equipment under | accordance with |
|                 |                 | Sec. 211.68,    | section         |
|                 |                 | only verified   | 211.68(c)."     |
|                 |                 | by one person.  |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Rationale:**  |                 |                 |                 |
| Please refer to |                 |                 |                 |
| the comments on |                 |                 |                 |
| the proposed    |                 |                 |                 |
| revision to     |                 |                 |                 |
| section         |                 |                 |                 |
| 211.68(c).      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| Section         | Current         | FDA Proposed    | PDA Suggested   |
|                 | Regulation      | Revision        | Revision        |
+-----------------+-----------------+-----------------+-----------------+
| 211.103         | "Actual yields  | "Actual yields  | "Actual yields  |
|                 | and percentages | and percentages | and percentages |
| Calculation of  | of theoretical  | of theoretical  | of theoretical  |
| yield           | yield shall be  | yield shall be  | yield shall be  |
|                 | determined at   | determined at   | determined at   |
|                 | the conclusion  | the conclusion  | the conclusion  |
|                 | of each         | of each         | of each         |
|                 | appropriate     | appropriate     | appropriate     |
|                 | phase of        | phase of        | phase of        |
|                 | manufacturing,  | manufacturing,  | manufacturing,  |
|                 | processing,     | processing,     | processing,     |
|                 | packaging, or   | packaging, or   | packaging, or   |
|                 | holding of the  | holding of the  | holding of the  |
|                 | drug product.   | drug product.   | drug product.   |
|                 | Such            | Such            | Such            |
|                 | calculations    | calculations    | calculations    |
|                 | shall be        | shall either be | shall either be |
|                 | performed by    | performed by    | performed by    |
|                 | one person and  | one person and  | one person and  |
|                 | independently   | independently   | independently   |
|                 | verified by a   | verified by a   | verified by a   |
|                 | second person." | second person   | second person   |
|                 |                 | or, if the      | or, if          |
|                 |                 | yield is        | calculated by   |
|                 |                 | calculated by   | automated       |
|                 |                 | automated       | equipment,      |
|                 |                 | equipment under | verified in     |
|                 |                 | Section 211.68, | accordance with |
|                 |                 | be              | section         |
|                 |                 | independently   | 211.68(c)."     |
|                 |                 | verified by one |                 |
|                 |                 | person."        |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Rationale:**  |                 |                 |                 |
| Please refer to |                 |                 |                 |
| the comments on |                 |                 |                 |
| the proposed    |                 |                 |                 |
| revision to     |                 |                 |                 |
| section         |                 |                 |                 |
| 211.68(c).      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| 211.188(b)(11)  | "Identification | "Identification | "Identification |
|                 | of the persons  | of the persons  | of the          |
| Batch           | performing and  | performing and  | person(s)       |
| production and  | directly        | directly        | and/or          |
| control records | supervising or  | supervising or  | automated       |
|                 | checking each   | checking each   | systems         |
|                 | significant     | significant     | performing or   |
|                 | step in the     | step in the     | checking each   |
|                 | operation."     | operation, or   | significant     |
|                 |                 | if a            | step in the     |
|                 |                 | significant     | operation."     |
|                 |                 | step in the     |                 |
|                 |                 | operation is    | The proposed    |
|                 |                 | performed by    | PDA revision is |
|                 |                 | automated       | predicated upon |
|                 |                 | equipment under | FDA accepting   |
|                 |                 | Sec. 211.68,    | the             |
|                 |                 | the             | PDA-proposed    |
|                 |                 | identification  | revision to     |
|                 |                 | of the person   | 211.68.         |
|                 |                 | checking the    |                 |
|                 |                 | significant     |                 |
|                 |                 | step performed  |                 |
|                 |                 | by the          |                 |
|                 |                 | automated       |                 |
|                 |                 | equipment."     |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Rationale:**  |                 |                 |                 |
| Please refer to |                 |                 |                 |
| the comments on |                 |                 |                 |
| the proposed    |                 |                 |                 |
| revision to     |                 |                 |                 |
| section         |                 |                 |                 |
| 211.68(c).      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| Section         | Current         | FDA Proposed    | PDA Suggested   |
|                 | Regulation      | Revision        | Revision        |
+-----------------+-----------------+-----------------+-----------------+
| 211.94(c)       | "Drug product   | "Drug product   | "Drug product   |
|                 | containers and  | containers and  | containers and  |
| Drug product    | closures shall  | closures shall  | closures shall  |
| containers and  | be clean and,   | be clean and,   | be clean and,   |
| closures        | where indicated | where indicated | where indicated |
|                 | by the nature   | by the nature   | by the nature   |
|                 | of the drug,    | of the drug,    | of the drug and |
|                 | sterilized and  | sterilized and  | its             |
|                 | processed to    | processed to    | manufacturing   |
|                 | remove          | remove          | process,        |
|                 | pyrogenic       | pyrogenic       | sterile and     |
|                 | properties to   | properties to   | non-pyrogenic   |
|                 | assure that     | assure that     | to assure they  |
|                 | they are        | they are        | are suitable    |
|                 | suitable for    | suitable for    | for their       |
|                 | their intended  | their intended  | intended use.   |
|                 | use."           | use. Such       | Where           |
|                 |                 | depyrogenation  | containers and  |
|                 |                 | processes shall | closures are    |
|                 |                 | be validated.   | actively        |
|                 |                 |                 | rendered        |
|                 |                 |                 | non-pyrogenic   |
|                 |                 |                 | by a designated |
|                 |                 |                 | depyrogenation  |
|                 |                 |                 | process, the    |
|                 |                 |                 | depyrogenation  |
|                 |                 |                 | process shall   |
|                 |                 |                 | be validated."  |
+-----------------+-----------------+-----------------+-----------------+
| **Rationale:**  |                 |                 |                 |
| It is important |                 |                 |                 |
| to note that    |                 |                 |                 |
| currently not   |                 |                 |                 |
| all containers  |                 |                 |                 |
| and closures    |                 |                 |                 |
| for sterile     |                 |                 |                 |
| drug products   |                 |                 |                 |
| are actively    |                 |                 |                 |
| tr              |                 |                 |                 |
| eated/processed |                 |                 |                 |
| to              |                 |                 |                 |
| reduce/remove   |                 |                 |                 |
| pyrogens. The   |                 |                 |                 |
| supplementary   |                 |                 |                 |
| information for |                 |                 |                 |
| this proposed   |                 |                 |                 |
| rule (Part      |                 |                 |                 |
| II.B. *Aseptic  |                 |                 |                 |
| Processing*,    |                 |                 |                 |
| Section         |                 |                 |                 |
| 211.94(c))      |                 |                 |                 |
| appears to      |                 |                 |                 |
| presume that    |                 |                 |                 |
| all containers  |                 |                 |                 |
| and closures    |                 |                 |                 |
| are actively    |                 |                 |                 |
| depyrogenated:  |                 |                 |                 |
| "To assure that |                 |                 |                 |
| certain         |                 |                 |                 |
| products are    |                 |                 |                 |
| suitable for    |                 |                 |                 |
| their intended  |                 |                 |                 |
| use, drug       |                 |                 |                 |
| product         |                 |                 |                 |
| containers and  |                 |                 |                 |
| closures are    |                 |                 |                 |
| required to be  |                 |                 |                 |
| sterilized and  |                 |                 |                 |
| depyrogenated   |                 |                 |                 |
| to remove       |                 |                 |                 |
| microbial       |                 |                 |                 |
| contamination   |                 |                 |                 |
| and pyrogens or |                 |                 |                 |
| endotoxin."     |                 |                 |                 |
|                 |                 |                 |                 |
| Some containers |                 |                 |                 |
| and closures    |                 |                 |                 |
| are             |                 |                 |                 |
| non-pyrogenic   |                 |                 |                 |
| by nature       |                 |                 |                 |
| and/or design   |                 |                 |                 |
| of their        |                 |                 |                 |
| manufacturing   |                 |                 |                 |
| process(es) or  |                 |                 |                 |
| have been       |                 |                 |                 |
| qualified not   |                 |                 |                 |
| to require      |                 |                 |                 |
| active          |                 |                 |                 |
| depyrogenation. |                 |                 |                 |
| Handling        |                 |                 |                 |
| procedures are  |                 |                 |                 |
| also designed   |                 |                 |                 |
| and controlled  |                 |                 |                 |
| (e.g., bulk     |                 |                 |                 |
| packaging,      |                 |                 |                 |
| incoming parts  |                 |                 |                 |
| control,        |                 |                 |                 |
| storage,        |                 |                 |                 |
| personnel       |                 |                 |                 |
| control, etc.)  |                 |                 |                 |
| to minimize the |                 |                 |                 |
| risk of pyrogen |                 |                 |                 |
| contamination   |                 |                 |                 |
| during finished |                 |                 |                 |
| product         |                 |                 |                 |
| manufacturing.  |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| Section         | Current         | FDA Proposed    | PDA Suggested   |
|                 | Regulation      | Revision        | Revision        |
+-----------------+-----------------+-----------------+-----------------+
| **Control of    |                 |                 |                 |
| Aseptic         |                 |                 |                 |
| Processing**    |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| 211.113(b)      | "Appropriate    | "Appropriate    | PDA proposes    |
|                 | written         | written         | that this       |
| Control of      | procedures,     | procedures,     | section not be  |
| microbiological | designed to     | designed to     | revised from    |
| contamination   | prevent         | prevent         | the current     |
|                 | microbiological | microbiological | regulation.     |
|                 | contamination   | contamination   |                 |
|                 | of drug         | of drug         |                 |
|                 | products        | products        |                 |
|                 | purporting to   | purporting to   |                 |
|                 | be sterile,     | be sterile,     |                 |
|                 | shall be        | shall be        |                 |
|                 | established and | established and |                 |
|                 | followed. Such  | followed. Such  |                 |
|                 | procedures      | procedures      |                 |
|                 | shall include   | shall include   |                 |
|                 | validation of   | validation of   |                 |
|                 | all             | all aseptic and |                 |
|                 | sterilization   | sterilization   |                 |
|                 | processes."     | processes."     |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Rationale:**  |                 |                 |                 |
| We feel that    |                 |                 |                 |
| the statements  |                 |                 |                 |
| in the preamble |                 |                 |                 |
| accompanying    |                 |                 |                 |
| the proposed    |                 |                 |                 |
| GMP changes     |                 |                 |                 |
| \["Even before  |                 |                 |                 |
| 1987, when the  |                 |                 |                 |
| Guideline for   |                 |                 |                 |
| Sterile Drug    |                 |                 |                 |
| Products        |                 |                 |                 |
| Produced by     |                 |                 |                 |
| Aseptic         |                 |                 |                 |
| Processing was  |                 |                 |                 |
| issued,         |                 |                 |                 |
| industry        |                 |                 |                 |
| routinely       |                 |                 |                 |
| conducted       |                 |                 |                 |
| validation      |                 |                 |                 |
| studies that    |                 |                 |                 |
| substituted     |                 |                 |                 |
| microbiological |                 |                 |                 |
| media for the   |                 |                 |                 |
| actual product  |                 |                 |                 |
| to demonstrate  |                 |                 |                 |
| that its        |                 |                 |                 |
| aseptic         |                 |                 |                 |
| processes were  |                 |                 |                 |
| validated.      |                 |                 |                 |
| These parts of  |                 |                 |                 |
| validation      |                 |                 |                 |
| studies are     |                 |                 |                 |
| often referred  |                 |                 |                 |
| to as media     |                 |                 |                 |
| fills. (Federal |                 |                 |                 |
| Register/Volume |                 |                 |                 |
| 72, No. 232,    |                 |                 |                 |
| page 68066)\]   |                 |                 |                 |
| could lead the  |                 |                 |                 |
| reader to       |                 |                 |                 |
| incorrectly     |                 |                 |                 |
| conclude that   |                 |                 |                 |
| only media      |                 |                 |                 |
| fills are       |                 |                 |                 |
| required to     |                 |                 |                 |
| validate an     |                 |                 |                 |
| aseptic         |                 |                 |                 |
| process.        |                 |                 |                 |
|                 |                 |                 |                 |
| PDA believes    |                 |                 |                 |
| that a well     |                 |                 |                 |
| controlled,     |                 |                 |                 |
| robust process  |                 |                 |                 |
| is required for |                 |                 |                 |
| aseptic         |                 |                 |                 |
| processes. A    |                 |                 |                 |
| highly defined  |                 |                 |                 |
| system of risk  |                 |                 |                 |
| evaluation and  |                 |                 |                 |
| management,     |                 |                 |                 |
| engineering and |                 |                 |                 |
| manufacturing   |                 |                 |                 |
| controls,       |                 |                 |                 |
| maintenance,    |                 |                 |                 |
| quality         |                 |                 |                 |
| systems,        |                 |                 |                 |
| employee        |                 |                 |                 |
| training,       |                 |                 |                 |
| written         |                 |                 |                 |
| procedures,     |                 |                 |                 |
| environmental   |                 |                 |                 |
| monitoring,     |                 |                 |                 |
| strict          |                 |                 |                 |
| adherence to    |                 |                 |                 |
| aseptic         |                 |                 |                 |
| technique, and  |                 |                 |                 |
| minimal         |                 |                 |                 |
| personnel       |                 |                 |                 |
| intervention,   |                 |                 |                 |
| can establish a |                 |                 |                 |
| state of        |                 |                 |                 |
| control,        |                 |                 |                 |
| ensuring that   |                 |                 |                 |
| the aseptically |                 |                 |                 |
| produced        |                 |                 |                 |
| product         |                 |                 |                 |
| consistently    |                 |                 |                 |
| meets its       |                 |                 |                 |
| pre-determined  |                 |                 |                 |
| specifications  |                 |                 |                 |
| and quality     |                 |                 |                 |
| attributes.     |                 |                 |                 |
| Once the state  |                 |                 |                 |
| of control has  |                 |                 |                 |
| been            |                 |                 |                 |
| established,    |                 |                 |                 |
| process         |                 |                 |                 |
| simulations     |                 |                 |                 |
| (media fills)   |                 |                 |                 |
| can be useful   |                 |                 |                 |
| in confirming   |                 |                 |                 |
| the state of    |                 |                 |                 |
| control.        |                 |                 |                 |
|                 |                 |                 |                 |
| So, unless the  |                 |                 |                 |
| new preamble    |                 |                 |                 |
| can be          |                 |                 |                 |
| modified, we    |                 |                 |                 |
| recommend this  |                 |                 |                 |
| section not be  |                 |                 |                 |
| revised from    |                 |                 |                 |
| the current     |                 |                 |                 |
| regulation. The |                 |                 |                 |
| current         |                 |                 |                 |
| regulation, and |                 |                 |                 |
| the             |                 |                 |                 |
| accompanying    |                 |                 |                 |
| preamble, which |                 |                 |                 |
| states, "The    |                 |                 |                 |
| Commissioner    |                 |                 |                 |
| believes this   |                 |                 |                 |
| paragraph, as   |                 |                 |                 |
| written, can    |                 |                 |                 |
| apply to both   |                 |                 |                 |
| sterile fill    |                 |                 |                 |
| process and     |                 |                 |                 |
| terminal        |                 |                 |                 |
| sterilization   |                 |                 |                 |
| process. In     |                 |                 |                 |
| both instances  |                 |                 |                 |
| there must be   |                 |                 |                 |
| validation of   |                 |                 |                 |
| the process     |                 |                 |                 |
| used to show    |                 |                 |                 |
| that it         |                 |                 |                 |
| produces a      |                 |                 |                 |
| sterile         |                 |                 |                 |
| product"        |                 |                 |                 |
| provide         |                 |                 |                 |
| sufficient      |                 |                 |                 |
| regulatory      |                 |                 |                 |
| authority for   |                 |                 |                 |
| the agency to   |                 |                 |                 |
| assure that     |                 |                 |                 |
| firms           |                 |                 |                 |
| demonstrate a   |                 |                 |                 |
| state of        |                 |                 |                 |
| control for     |                 |                 |                 |
| aseptic         |                 |                 |                 |
| processing.     |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

+-----------------+-----------------+-----------------+-----------------+
| Section         | Current         | FDA Proposed    | PDA Suggested   |
|                 | Regulation      | Revision        | Revision        |
+-----------------+-----------------+-----------------+-----------------+
| 211.48          | "Potable water  | "Water supplied | "Potable water  |
|                 | shall be        | by the plumbing | supplied by the |
| Plumbing        | supplied under  | system of the   | plumbing system |
|                 | continuous      | facility must   | of the facility |
|                 | positive        | be safe for     | must be safe    |
|                 | pressure in a   | human           | for human       |
|                 | plumbing system | consumption.    | consumption per |
|                 | free of defects | This water      | applicable      |
|                 | that could      | shall be        | public health   |
|                 | contribute      | supplied under  | standards. This |
|                 | contamination   | continuous      | water shall be  |
|                 | to any drug     | positive        | supplied under  |
|                 | product.        | pressure in a   | continuous      |
|                 | Potable water   | plumbing system | positive        |
|                 | shall meet the  | free of defects | pressure in a   |
|                 | standards       | that could      | plumbing system |
|                 | prescribed in   | contribute      | free of defects |
|                 | the             | contamination   | that could      |
|                 | Environmental   | to any drug     | contribute      |
|                 | Protection      | product."       | contamination   |
|                 | Agency\'s       |                 | to any drug     |
|                 | Primary         |                 | product."       |
|                 | Drinking Water  |                 |                 |
|                 | Regulations set |                 |                 |
|                 | forth in 40 CFR |                 |                 |
|                 | part 141. Water |                 |                 |
|                 | not meeting     |                 |                 |
|                 | such standards  |                 |                 |
|                 | shall not be    |                 |                 |
|                 | permitted in    |                 |                 |
|                 | the potable     |                 |                 |
|                 | water system."  |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Rationale:**  |                 |                 |                 |
| By removing the |                 |                 |                 |
| reference to    |                 |                 |                 |
| "Potable," the  |                 |                 |                 |
| language        |                 |                 |                 |
| proposed by FDA |                 |                 |                 |
| is not specific |                 |                 |                 |
| regarding the   |                 |                 |                 |
| water systems   |                 |                 |                 |
| affected by     |                 |                 |                 |
| this regulation |                 |                 |                 |
| and could be    |                 |                 |                 |
| misinterpreted  |                 |                 |                 |
| to include all  |                 |                 |                 |
| water           |                 |                 |                 |
| distribution    |                 |                 |                 |
| systems in the  |                 |                 |                 |
| facility. In    |                 |                 |                 |
| addition, PDA   |                 |                 |                 |
| believes the    |                 |                 |                 |
| term "safe for  |                 |                 |                 |
| human           |                 |                 |                 |
| consumption" is |                 |                 |                 |
| not             |                 |                 |                 |
| sufficiently    |                 |                 |                 |
| prescriptive    |                 |                 |                 |
| and not         |                 |                 |                 |
| consistent with |                 |                 |                 |
| the agency's    |                 |                 |                 |
| initiative to   |                 |                 |                 |
| be more         |                 |                 |                 |
| s               |                 |                 |                 |
| tandards-based. |                 |                 |                 |
| In order to     |                 |                 |                 |
| clarify the     |                 |                 |                 |
| expectation to  |                 |                 |                 |
| meet an         |                 |                 |                 |
| appropriate     |                 |                 |                 |
| standard, we    |                 |                 |                 |
| have suggested  |                 |                 |                 |
| terminology     |                 |                 |                 |
| that            |                 |                 |                 |
| incorporates    |                 |                 |                 |
| the following   |                 |                 |                 |
| CDC definition  |                 |                 |                 |
| for potable     |                 |                 |                 |
| water:          |                 |                 |                 |
|                 |                 |                 |                 |
| > "Potable      |                 |                 |                 |
| > (drinking)    |                 |                 |                 |
| > Water: water  |                 |                 |                 |
| > suitable for  |                 |                 |                 |
| > drinking per  |                 |                 |                 |
| > applicable    |                 |                 |                 |
| > public health |                 |                 |                 |
| > standards."   |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

PDA Comments -- FDA GMP Revisions -- Ver.9; 2-14-08