FDA warning | CP PharmaceuticalsMold, ceiling holes cited in CP Pharma warning

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FDA warning | CP PharmaceuticalsMold, ceiling holes cited in CP Pharma warning

November 18, 2010 — 8:52am ET | By

http://www.fiercepharmamanufacturing.com/story/mold-ceiling-holes-cited-cp-pharm\

a-warning/2010-11-18

Mold in a class 100 production room and holes in a ceiling at a CP

Pharmaceuticals plant in Wrexham, U.K., are part of a list of violations

identified by FDA inspectors in Warning Letter 320-11-002. The letter follows a

July inspection. Because CP took more than 15 days to reply to the Form 483

report issued after the inspection, the regulator doesn't acknowledge them in

the warning.

The mold and the holes are some of the building-related inspection details the

FDA documents. Inspectors note the holes in the ceiling of a freeze dryer room

and say they saw outside light entering in the vicinity of the ventilation

system. The letter says the room is subject to regular maintenance, yet the

holes remain despite an incident report from late last year that describes them.

Another item from the incident report: bubbling vinyl and disintegration of the

wall beneath it.

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Inspectors found more mold in a class 10,000 area, almost a year after it was

first seen there. The warning cites CP for lack of a schedule for cleaning with

a spore killer.

- here's the warning letter

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm233036.htm

- Inspections, Compliance, Enforcement, and Criminal Investigations

CP Pharmaceuticals, Ltd. 10/29/10

Department of Health and Human Services Public Health Service

Food and Drug Administration

Silver Spring MD 20993

Warning Letter

WL: 320-11-002

October 29, 2010

Mr. Sirjiwan Singh

Managing Director

CP Pharmaceuticals, Ltd.

Ash Road North

Wrexham Industrial Estate

Wrexham, LL13 9UF, United Kingdom

Dear Mr. Singh:

During our July 22-29, 2010 inspection of your pharmaceutical manufacturing

facility, CP Pharmaceuticals, Ltd., located at Ash Road North, Wrexham

Industrial Estate, Wrexham, LL13 9UF, United Kingdom, investigators from the

Food and Drug Administration (FDA) identified significant violations of Current

Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals,

Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause

your drug products to be adulterated within the meaning of section 501(a)(2)(

of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(]

in that the methods used in, or the facilities or controls used for, their

manufacture, processing, packing, or holding do not conform to, or are not

operated or administered in conformity with, CGMP.

We acknowledge your written responses, dated September 3, 2010, and September

24, 2010, to the Form FDA 483. However, because these responses were received

more then 15 business days after the Form FDA 483 was issued, the responses have

not been considered. We plan to evaluate your responses to the Form FDA 483,

along with any other written material provided, as a direct response to this

Warning Letter.

Specific violations observed during the inspection include, but are not limited,

to the following:

1. Your firm has not established separate or defined areas or such other control

systems to prevent contamination during aseptic processing [21 C.F.R. §

211.42©]. For example,

a. There is no documentary evidence of in-situ air pattern analysis (e.g., smoke

studies) conducted at critical areas to demonstrate unidirectional airflow and

sweeping action over and away from the product under dynamic conditions. Your

firm failed to demonstrate that the appropriate design and controls are in place

to prevent turbulence and stagnant air in the critical area. It is essential

that you evaluate airflow patterns for turbulence that can act as a channel for

air contamination. The studies should be well documented with written

conclusions, and should include an evaluation of the impact of aseptic

manipulations (e.g., interventions) and the equipment design.

b. Your aseptic processing control systems and operations do not provide

assurance that the production rooms and equipment maintain aseptic conditions.

Additionally, your environmental monitoring practices do not include adequate

routine examination of the facilities and equipment to ensure that possible

contaminants can be detected.

The inspection documented mold contamination in the class 100 production room

and poor conditions of a wall in the freeze dryer room, even though maintenance

is conducted on the freeze dryer every ((4) months. An incident report,

initiated in November 2009, identifies holes in the ceiling and visible light

coming from the roof near the ventilation system, bubbling of the vinyl and

disintegration of the wall under vinyl in the freeze dryer room, visible black

mold on the wall, a poor drain system for the freeze dryer steam venting system,

and a soft (spongy) wall.

c. Operators involved in the filling operations for the sterile drug products

manufactured at your facility do not practice adequate aseptic techniques to

prevent product contamination. The environmental monitoring performed at the end

of the production run consist of sampling the chest and the hand most frequently

used (right or left) of the employee's gown. Also, this procedure is performed

by the gowned operator and is not monitored by a second qualified person (e.g.,

supervisor; quality unit personnel) to ensure the proper techniques are being

applied. This practice is unacceptable. We expect that all operators who conduct

operations within aseptic processing areas be properly trained and monitored to

ensure that proper techniques are utilized during all operations, including

aseptic filling operations and personnel sampling.

2. Your firm has not thoroughly investigated the failure of a batch or any of

its components to meet its specifications whether or not the batch has already

been distributed [21 C.F.R. § 211.192].

For example, your firm's microbiology laboratory does not perform species

identification on a routine basis of the yeast and molds detected in your

production area. There was no identification raw data available for the media

fill that failed in November 2009. Additionally, your firm does not perform

challenge testing to the sterility media with environmental isolates from the

environmental monitoring program.

3. Your firm has not established scientifically sound and appropriate

specifications, standards, sampling plans, and test procedures designed to

assure that components, in-process materials, and drug products conform to

appropriate standards of identity, strength, quality, and purity [21 C.F.R. §

211.160(].

For example, at the time of the inspection the validation data for several

laboratory methods was incomplete or unavailable (i.e. total viable aerobic

count for the API, total viable aerobic plate count of raw materials, and

bacterial endotoxin testing for (((4)). However, you approved the validation

for these methods without the complete data in place.

In addition to the items listed above, the inspection uncovered deficiencies

that increase our concerns regarding the quality of the sterile drug products

manufactured at your facility. These issues include, but are not limited, to:

& #56256; & #56451; Your firm failed to adequately address the increased adverse

trends observed in the environmental monitoring trends for the period of August

2009 to May 2010; and, therefore, did not recognize that the environment did not

appear to be under control.

& #56256; & #56451; Your firm did not establish a schedule for the cleaning with an

agent designed to kill spores, although mold continued to be found in the class

10,000 area. Our investigators observed that the mold contamination had not been

eliminated at the time of the inspection in July 2010, almost a year after the

initial discovery.

We are concerned that your firm has not properly evaluated the risk these

deviations pose to the products that have been released and distributed. Your

firm has not provided a scientific justification to ensure the product available

in the United States (U.S.) market is in compliance with CGMP standards. Please

provide a list of all the products and lots shipped to the U.S. that remain

within expiration, and any additional corrective actions you plan to initiate.

It is important that you take appropriate actions to address these deficiencies

and notify us if any actions are planned for lots of sterile drug products

manufactured by your Wrexham facility, and include your rationale.

The violations cited in this letter are not intended to be an all-inclusive

statement of violations that exist at your facility. You are responsible for

investigating and determining the causes of the violations identified above and

for preventing their recurrence and the occurrence of other violations. If you

wish to continue to ship your products to the United States, it is the

responsibility of your firm to ensure compliance with all U.S. standards for

CGMP and all applicable U.S. laws and regulations.

Until all corrections have been completed and FDA has confirmed corrections of

the violations and your firm's compliance with CGMP, FDA may withhold approval

of any new applications or supplements listing your firm as a drug product

manufacturer. In addition, failure to correct these violations may result in FDA

refusing admission of articles manufactured at CP Pharmaceuticals, Ltd., Ash

Road North, Wrexham Industrial Estate, Wrexham, LL13 9UF, United Kingdom, into

the United States. The articles are subject to refusal of admission pursuant to

section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)], in that, the methods and

controls used in their manufacture do not appear to conform to Current Good

Manufacturing Practice within the meaning of section 501(a)(2)( of the Act [21

U.S.C. § 351(a)(2)(].

Within fifteen working days of receipt of this letter, please notify this office

in writing of the specific steps that you have taken to correct violations.

Include an explanation of each step being taken to prevent the recurrence of

violations and copies of supporting documentation. If you cannot complete

corrective action within fifteen working days, state the reason for the delay

and the date by which you will have completed the correction. Please identify

your response with FEI # 3003369660.

If you have questions or concerns regarding this letter, contact Hidee Molina,

Compliance Officer, at the below address and telephone number.

U.S. Food and Drug Administration

Center for Drug Evaluation and Research

Division of Manufacturing and Product Quality

International Compliance Branch

White Oak, Building 51, Room 4224

10903 New Hampshire Ave

Silver Spring, MD 20993

Tel: (301) 796-3201

Fax: (301) 847-8741

Sincerely,

/ L. Friedman/

L. Friedman

Director

Division of Manufacturing and Product Quality

Office of Compliance

Center for Drug Evaluation and Research

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