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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Sanquin Plasma Products - Untitled Letter


Express Mail

Robert Tiebout, MD
Managing Director Plasma Products Division
Sanquin Plasma Products
Plesmanlaan 125
1006 CX Amsterdam, Netherlands
Dear Dr. Tiebout:
The Food and Drug Administration (FDA) conducted an inspection of Sanquin Plasma Products, located at Plesmanlaan 125, 1006 CX Amsterdam, Netherlands, from September 19 - 28, 2011.  During the inspection, FDA investigators documented deviations from current good manufacturing practice (CGMP) requirements in the manufacture of your licensed biological product Cinryze. Deviations from CGMP include the applicable requirements of Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (FD&C Act), Section 351(a) of the Public Health Service Act (PHS Act), and Title 21, Code of Federal Regulations (21 CFR) Parts 210 and 211. 
At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations that described a number of significant objectionable conditions relating to your facility’s compliance with CGMP.  Significant deviations observed during the inspection include, but were not limited to, the following:
  1. You failed to establish appropriate written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Specifically, since 2009, multiple interventions have been conducted to remove fallen, both fully and partially stoppered vials, and to wipe the spilled contents from the vial transport belt in the Class --b(4)-- filling room to prevent product contamination. No corrective and preventive action has been instituted regarding these issues. The only response has been to add the process of removing the vials and wiping the belt into SOP PV086/5.0 titled “Intervention during Aseptic Filling and Freeze-drying” [21 CFR 211.100(a)].
  2. You failed to establish scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. For example:
    1. The volume of -----b(4)---- tested for bioburden is not representative of the volume manufactured. Specifically, the maximum volume of Cinryze filled into vials is approximately --b(4)-- yet only a --b(4)-- sample is taken per test. In your response to observation 18b on the 2009 FDA Form 483 you committed to –b(4)----- the sample size to --b(4)--  but to date no such change has taken place. 
    2. There are no qualification studies for the locations of non-viable particle counters for the vial filling needles and stopper bunker in the Class --b(4)-- Filling Room --b(4)--.
Additionally, significant deviations in the manufacture of Cinryze product intermediate were observed during the inspection.  These deviations violate Section 501(a)(2)(B) of the FD&C Act and Section 351(a) of the PHS Act.  Specific areas of concern include, but are not limited to:
Control of Components
  1. There is no procedure in place to test incoming containers of --b(4)-- for bioburden. Your firm relies on a Certificate of Analysis from supplier --b(4)-- to indicate the quality of the incoming product, however, since December 21, 2009, there have been four containers of      --b(4)-- received at your firm that were not properly sealed.   These containers with broken seals were not tested for bioburden before being pooled and used in manufacturing.
  2. There is no procedure in place to ensure that --b(4)----- intermediates produced at your facility, whose containers are improperly sealed, are tested for bioburden. Since December 21, 2009, there have been ----b(4)------ intermediates produced at your facility which were found to have improperly sealed containers. These containers were not tested for bioburden before being used for further manufacture. 
Production and Process Control

  1. There is no validation study to support the use of only --b(4)------ for both the ----b(4)------------------- procedure performed in the class --b(4)-- area and the addition of ---------b(4)-------- in the class --b(4)--  area during formulation. Your process allows the --b(4)--  of up to --b(4)-------------------------------------in order to achieve maximum yield. The ------b(4)------------------------------------------------------------ in a class --b(4)-- area. The --b(4)-- is then transferred to a class --b(4)--  area where it is used for the ---------b(4)-------------------------------------------
  2. There is no documentation that you have approval to --b(4)--  nanofiltrate through the            --b(4)-------------------. Deviation #8437 noted that Cinryze planova filtrate using the –b(4)-------------- was over concentrated to a -----------------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------- In addition, this batch was not placed on stability, nor was the –b(4)------------- noted on the batch record.
Failure Investigations
  1. Your investigation into the blocking of the Planova filters did not take into account the          -----b(4)-------------------------------------------------------------------------------------------------- is not listed in the manufacturing procedure under “used equipment” as an approved –b(4)--------------- that can be used for this step was not validated for its ability to adequately -----b(4)---------------
  2. Your investigation conducted into the black particles observed in the containers of                 -b(4)------ during the –b(4)---- of Cinryze batch –b(4)------- for –b(4)-------- per deviation report #008251 is incomplete. For example:
    1. There is no documentation that the black particles were identified to confirm the source or solubility of these particles in the product solvents.
    2. There is no documentation that a literature search was performed to determine the toxicity or human sensitivity to the particles if dissolved in the product for the user population.
We acknowledge receipt of your written response dated October 18, 2011, which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection.  We also acknowledge your commitments made in your response to address the items listed on the Form FDA 483.
We have reviewed your responses and have the following specific comments.  The items are numbered to correspond to the observations listed on the Form FDA 483.
Observation 1 – In your response you state “with respect to vial cleaning: at present, vials are cleaned using --b(4)-- as the cleaning agent. Cleaning has always been performed on the -----b(4)----------------------------- is not used.” However, deviation reports 9050 and 8701 clearly indicate that the vials were cleaned using --b(4)--. Please explain this discrepancy.
Observation 1 – Your response indicates that you plan to submit an update in January 2012, detailing the actions necessary and plans for implementing adjustments to the ----b(4)------------------------ filling machine. Please include in this update summaries of the related Corrective and Preventive Actions (CAPAs) you reference in your response (11141 and 11142) including dates the CAPAs were opened, progress to date, and interim plans for fallen and tipping vials between now and 2013, when you anticipate your CAPA relating to -----b(4)--------------------- for production will be closed.
Observation 3a - Please provide an update on your progress in revalidating your method to test    ----b(4)------------------------ for bioburden as described in change control 11182 and CAPA 11169. 
Observation 4 – Your response indicates you plan to request that the Subject Matter Expert (SME) perform an additional review of the Water for Injection (WFI) system to confirm all potential dead legs have been removed. Please provide evidence that a comprehensive evaluation of your WFI system has been completed and was shown to contain no dead legs.
Observation 4 - You indicate in your response that since investigations into bioburden excursions for WFI/Highly Purified Water (HPW) and bioburden Out of Specification (OOS) results for product intermediates are currently performed under separate SOPs, it may result in difficulty linking bioburden failures in the water system with bioburden failures in intermediate product. Please provide details as to what changes are being made to assure that a link between water system OOS results/excursions and bioburden failures in intermediate products, is made in the future.
Observation 12 – We acknowledge your submission of reports 036-217R3 and 036-217R4, which provide data to support your claim of column use ----b(4)---------------------. Please be advised, however, that retrospective studies of this type are based on limited data and do not adequately validate your process. Please contact Nancy Kirschbaum in the Office of Blood Research and Review (OBRR) at 301-827-3893 in order to clarify what steps need to be taken to adequately validate your chromatography process.
Observations 14-16-17-18 – Please provide an update on the progress made under CAPAs 2011-011 and 2011-010 as they pertain to observations 14, 16, 17, and 18.
Neither the above deviations, nor the observations listed on the Form FDA 483 presented to your firm at the conclusion of the inspection, are intended to be an all-inclusive list of deviations at your establishment.  It is your responsibility to ensure compliance with all requirements of the laws and regulations administered by FDA.
Your reply should be sent to me at the following address: U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20852-1448. 
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
cc:        Kelvin K Lee, RPM
US Agent for Sanquin
Global Regulatory Affairs – CMC
Viropharma Incorporated