From: maryfaye.s.whisler@gsk.com
Sent: Monday, November 03, 2003 1:43 PM
To: fdadockets@oc.fda.gov
Subject: Comments for Draft Guidance for Industry: Process Analytical Technology - A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance

Dear Sir or Madam: 

Herein is a copy of the letter with comments sent to the FDA for this draft guidance from GlaxoSmithKline.  The comments were also sent as hardcopy by USPS. 

November 3, 2003 

Management Dockets 
Dockets Management Branch 
Food and Drug Administration 
HFA-305 
5630 Fishers Lane, Rm 1061 
Rockville, MD 20852 
      Re:  Docket Number 2003D-0380 
      Draft Guidance for Industry:  Process Analytical Technology - A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance 

Dear Madam or Sir:: 

Enclosed please find comments from GlaxoSmithKline, including an overall viewpoint and then general and specific conmments for the Draft Guidance for Industry on Process Analytical Technology (PAT) - A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance.  These comments are presented for consideration by the FDA.  The general comments are presented first, with the specific comments presented in order by section in the draft guidance. 

GlaxoSmithKline appreciates the opportunity to provide feedback and suggestions for this draft guidance.  I am submitting this guidance both electronically, (Dockets Management, Electronic Comment Submission Form) and by hardcopy.  Therefore, you will receive a paper copy of this letter with two copies of the comments through the USPS. 

If you have any questions about these provided comments, please do not hesitate to contact me at (919) 483-5857.  Thank you for your consideration. 

Sincerely, 

Mary Faye S. Whisler, Ph.D. 
Assistant Director 
New Submissions, North America 

Review of the Draft Guidance for Industry on Process Analytical Technology (PAT) - A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance

Overall Comments 

GSK welcomes this guideline and supports the agency in the need to have clarity in this area.  GSK would like to see the guideline evolve into a guideline with more definition on the logistics of the regulatory process for handling the Process Analytical Technology (PAT) proposals.  This would include a better definition of the framework for the regulatory submission, a defined mechanism for making the submission, and more definition on the level of regulatory content.  Along with the definition of the detail, it is understood that the PAT proposals will be handled in the same defined way within different divisions of the Agency.  Additionally, we support the flexibility of this guidance in facilitating PAT proposals to be science-based, risk-based, and non-prescriptive of the technologies to be used.  However, a description of the framework that needs to be included to support the technological proposal would be! helpful.  For example, additional guidance regarding the validation of process analytical methods or the qualification of equipment used in PAT applications would be useful. 

General Comments 

The usefulness of PAT to establish process understanding is now recognized.  In addition, a PAT approach is important for formulation design work.  By facilitating and optimizing formulation design, PAT is likely to allow simplified process development.  Please clarify the intent and location of PAT in future submissions. 

Please clarify future Agency practice with respect to handling NCE's that have some aspect of PAT incorporated into them.  Define the criteria for determination if this information will trigger a PAT review process. 

We recognize that it is difficult to totally anticipate the needs of the pharmaceutical industry.  In the effort to implement the flexibility, there are area of concern as it leaves much to the interpretation of those reviewing documents or inspecting an installation.   We would welcome a regular public forum that would provide the opportunity clarify PAT issues for the industry without the preparations normally associated with formal meetings between companies and the agency.  Webcasts on PAT similar to those that have been done in the past could meet this need. 

Specific Comments 

I. Introduction 
(line 36)  The FDA intends to promote PAT and reduce fear that PAT introduction will result in a regulatory impasse.  A useful program to aid this intention would be to open PAT training of agency inspectors and auditors to include industry regulators that would encourage joint problem solving in the sessions.   This could promote better understanding and trust between the agency and the industry. 

II.  Guidance Development Process and Scope (lines 76-79) 
III. Background (lines 96-97) 
The text states that the PAT is voluntary and that it is for one product and not needed on another.  Yet later, mention of the industry's hesitancy seems to contradict this thought because the industry worries that if we do it for one product will the agency make it mandatory for all (company) products.  Please clarify. 

IV.  PAT Framework 
(lines 457-466)  Clarification is needed for handling 'Out Of Specification' results.  (With much greater numbers of data points being generated, this situation is unavoidable.) 
(lines 468-474)  The validation of PAT methods needs to be clarified as does further guidance for qualification of equipment used in PAT applications. 
(line 483)  There is reference to many existing documents (in the text and the bibliography) on validation (GAMP), software validation (General Principles of Software Validation, ASTM documents governing technology used in other unregulated industries),  and others.  Clarify how these will be applied to PAT. 
(line 520)  Burden of documentation is not addressed in the draft guidance. Please clarify the statement "An emphasis on process knowledge can provide a less burdensome approaches for validating new technologies for their intended use."   Explain how the Agency intends to address a reduction in documentation because, without it, PAT will not flourish. 

IV. B. Regulatory Strategies 
(lines 596-615 )  Clarify the allocation of PAT-based submissions to the review team.   
(line 638-640)  The safe haven or safe harbor concept has been put forward by FDA and is a welcome feature.  However more explicit definition of this concept would be useful.  For instance, the document states that PAT research data for an application to an existing product would not be inspectable, but we would expect that PAT research data for an NCE in development would likewise not be inspectable.  Some clarification is requested. 

V. PAT Regulatory Strategy 
(lines 657-659)  The document mentions "flexible regulatory assessment involving multiple Agency offices with varied responsibilities".  Industry would like to be assured that inconsistencies in review, as are currently sometimes seen between different FDA Divisions, will be avoided.  This will hopefully be possible based on the establishment of the PAT Review ad Inspection teams which will assess each PAT application; confirmation of this is requested. 
(line 682)  There are various discussions regarding the benefits of PAT in terms of providing data to support post-approval changes.  However, the only changes envisaged within the document are those intended to improve the process.  No mention is made of how PAT might affect post approval changes required for operational reasons, in particular, site changes.  To consider a change in manufacturing site when the process and equipment remain the same, there is concern that the data required to support this change might be considerably more in a case where a PAT framework had been implemented than under present non-PAT conditions.   For instance, if some form of statistical comparison was required, there are concerns that site changes could become prohibitively expensive and time consuming to complete, i.e., the number of batches that would be required to be produced at the new site to allow a meaningful comparison.!  Also, unless the new site had exactly the same plant set-up and analyzers at exactly the same points in the process as the original site, the comparison might not be easily made.  Please clarify. 

Thanks for your consideration.
Mary Faye S. Whisler, Ph. D.
Assistant Director
New Submissions North America
Global CMC Regulatory Affairs
919-483-5857