EDITED EXCERPTS FROM ACTUAL 483 … · Specifically, your Quality unit failed to include or...

To: Responsible Person, Director of Quality Assurance

Pharmaceutical and Related Industries 5600 Regulation Lane

United States of America and Worldwide Pharmaceutical and Medical Device

September 1, 2017

Issue #975

Editor 09/01/17

firm name street address

city, state and country type of establishment inspected

SEE REVERSEOF THIS PAGE

employee(s) signature employee(s) name and title date issued

FORM GMP VOLUME I SUPPLEMENTS PREVIOUS EDITIONS INSPECTIONAL OBSERVATIONS

during a review of inspection reports of u.s. firms (i) (we) observed:

district address date of issue

c.i. issue

name and title of individual to whom report is issued




Editor

GMP Trends LLCP.O. Box 1111Firestone, Colorado 80520

GMP Trends LLC

EDITED EXCERPTS FROM ACTUAL 483 OBSERVATION REPORTSBY FOOD AND DRUG ADMINISTRATION INVESTIGATORSMANUFACTURING CONTROLS 1. …..The separate or defined areas and control system necessary to prevent contamination or mix-ups are deficient.

Specifically, for your highly potent drug products, there are no adequate control systems in place for the sampling, manufacturing and packaging of these products in non-dedicated rooms and with non-dedicated equipment that are stationary and non-stationary.

a. Cleaning procedure ….., “Process Room Cleaning Procedure,” is a generalized facility operations procedure that does not include specific instructions for cleaning the production, processing, packaging and sampling rooms after these drug products have been manufactured, packaged or sampled.

b. The cleaning validation studies performed did not evaluate whether the cleaning procedure ….., “Process Room Cleaning Procedure,” used in the production, processing, packaging and sampling rooms of these drug products is effective in preventing cross contamination to the next drug product.

c. Standard Operating Procedure ….., “Gowning Procedure,” does not include the specific gowning procedures and requirements used for the manufacture of these drug products.

d. The cleaning procedure for the respirators of manufacturing personnel has not been written or evaluated for effectiveness in removing all drug product residues before being stored in issued personnel lockers located in an area accessible to all employees.

e. There is no documentation of the differential pressure between the hallway and processing rooms during the manufacture of these products.

f. Each night the HVAC systems for the production area and raw material sampling booth, which include the HEPA filters and exhaust fans, are turned off. Samples of drug products are left in the processing rooms overnight.

g. The material production record for ….. tablets does not include any instruction for containing the product during manufacturing and cleaning.

2. …..Written production and process control procedures are not followed in the execution of production and process control functions and documented at the time of performance.

Specifically, your production technicians failed to follow the manufacturing instructions for compression specified in the master batch record for ….., Caplets 25mg and 75mg. For example, the manufacturing instructions for compression state the press speed acceptance criteria for the start-up of the Tablet Press as ….., with a target range of ….., since the initial validation for the ….. Caplets 25mg and for the ….. Caplets 75mg were run at the target press speed of ….. However, over the last six months your production technicians have conducted the start-up of the Tablet Press at a press speed of ….. Your quality unit was unable to provide a justification or an approved change control for the shift in the press speed from the target of ….. to the current press speed of ….. In addition, during the batch record review your quality unit failed to document and investigate the downward trend in press speed.

3. …..Equipment for adequate control over micro-organisms is not provided when appropriate for the manufacture, processing, packing or holding of a drug product.

Specifically, there is no monitoring program to detect micro-organism contamination of products, production environment, or production equipment used in the manufacture of products used to treat open sores.

— GMP Trends®LLC edits and publishes this information dissemination report semi-monthly for quality-minded executives in the pharmaceutical and related industries. For subscription details visit www.gmptrends.com

©2017 GMP Trends®LLC PHONE (303) 443-8716, FAX (303) 443-3317, e-mail: [email protected]

Photocopying without permission is strictly prohibited. See page 3.




September 1, 2017

Issue #975

Editor 09/01/17








c.i. issue





Editor


GMP Trends LLC

LABORATORY CONTROLS 1. .....The responsibilities and procedures applicable to the quality control unit are not fully followed.

Specifically, your Quality unit failed to include or document the analyst signature as part of the OOS investigation report or QC laboratory incident report form. The analyst involved in the analytical testing and generating the OOS, OOT (i.e. Out of Trend) or incident reports does not sign the report. In addition, there is no assurance of when the preliminary investigation is conducted because neither the analyst nor reviewer sign/date it. Furthermore, the analyst’s signature is not required by the following SOPs, SOP ….., “Investigation Out of Specification (OOS) and Out of Trend (OOT) Test Results” and SOP ….., “Quality Control Laboratory Incidents.”

2. …..Laboratory records do not include complete records of the periodic calibration of laboratory instruments.

Specifically, your firm failed to qualify the laboratory analytical instruments used for the testing of in- process, finished product and stability samples for all products. For example: The Operation Qualification (OQ) for the analytical and micro-analytical balances are inadequate in that the reproducibility test is not included as part of the quarterly operation qualification. In addition, the current OQ balances tests (i.e. precision and accuracy) are qualified but not under the instruments intended use ranges. The analytical balance is qualified at a weight mass range of ….., and the micro-analytical balance is qualified under a weight mass range of ….. However, the analytical balance is usually used under a weight mass of ….. and the micro-analytical balance is usually used under ….. Furthermore, the Performance Qualification (PQ) is also checked but not in the intended use range.

3. .....Each batch of drug product required to be free of objectionable microorganisms is not tested through appropriate laboratory testing.

Specifically, the firm generated Certificate of Analyses for their drug products indicating microbiology testing was conducted with passing test results, however, the firm did not conduct these tests either in-house, because they do not have a microbiology laboratory, or through a third-party laboratory. The firm used pre-populated template values on their Certificate of Analyses for “Microbiology.” The firm indicated that the source data for the microbiology test results was from supplier raw materials Certificate of Analyses.

4. …..Laboratory controls do not include the establishment of scientifically sound and appropriate standards and test procedures designed to assure that components, in-process materials and drug products conform to appropriate standards of identity, strength, quality and purity.

Specifically, the identification test by Infrared Spectroscopy, performed as part of the release testing of Active Pharmaceutical Ingredients (API) is not appropriately performed. As part of the test, the sample spectrum is compared against a printed infrared standard spectrum. The reference standard spectrum are not generated concurrently and under the same conditions as the tested samples. In addition, there are no procedures for limiting the number of samples tested concurrently resulting in several spectra printed on the same graph making it difficult to determine differences in the spectral profile.

5. …..Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel.

Specifically, the ….. titrator was not qualified to ensure data accuracy, reliability, consistent intended performance and the ability to discern invalid or altered records. The firm has no control mechanism to prevent unauthorized testing or discarding of data generated by this instrument. The titrator is used for testing ….. of ….. API used in the production of ….. capsules.

— Information contained in this report has been edited and reproduced from actual FD 483 inspection observations and related reports. This information is made available twice monthly to quality minded executives by GMP Trends®LLC No analytical evaluation or interpretation of the contents of this report and its significance to GMP regulations is intended.




September 1, 2017

Issue #975

Editor 09/01/17








c.i. issue





Editor


GMP Trends LLC

MANUFACTURING-ACTIVE PHARMACEUTICAL INGREDIENTS (API)

1. …..The responsibilities and procedures applicable to the quality control unit are not fully followed.

Specifically, your firm’ s Quality Unit failed to adequately track the progress of your firm’s action plan to perform cleaning validation studies through CAPA ….. and has failed to ensure cleaning activities for commercial products assessed as a high priority were prioritized commensurate with the risk they were assessed. CAPA ….. was initiated to track the progress of the cleaning validation studies. A review of CAPA ….. during the inspection found the status to be 77 days overdue. No progress or updates were reported on the CAPA to document the work performed on this project. No justification was provided or documented for the 77 days over the CAPA was overdue.

2. …..The responsibilities and procedures applicable to the quality control unit are not fully followed.

Specifically, Change Control ….. was initiated by Quality to capture the upgrade of ….. software to …... software in the Analytical Lab. Although your Quality Unit was aware of the on-going update to ….., your Quality Unit had no oversight or control over this change of a validated GMP system. The system upgrade was released for use without Quality’s approval or awareness and has been used to perform testing although qualification is not complete. Analysis for ….., Lots ….., were performed using the unqualified software and this product was released to the client.

3. …..Process changes were made to the manufacture of API without assessing the implications of the API stability.

Specifically, your firm’s VP of Quality Assurance and Quality Control stated that a ….. retest period for ….. was supported by “Pivotal Stability Batches” manufactured prior to process validation. In addition to the retest period being supported by API generated for a non-validated process, a number of processing steps have changed since the manufacture of the “Pivotal Stability Batches” without reassessing the assigned retest date.

4. …..Building, equipment and supply lines are not maintained in an adequate condition to ensure the API’s identity, strength, quality and purity.

Specifically, I observed ….. pieces of manufacturing equipment to contain insects when in the “clean” status and have a rust-like appearance and/or residue in the interior of equipment. For example:

a. ….., used in the manufacture of ….., had a screw and shaft covered with a rust like appearance. The rust like appearance came in direct contact with the APIs being produced.

b. ….., used in the manufacture of intermediates for API ….., had a visibly damaged gasket. Your firm’s VP of QA and RA stated that the gasket had “slipped out.” This gasket was in the interior of the equipment, potentially contacting drug product.

c. ….., used in the manufacture of ….., appeared to have rust completely around the shaft. Additionally, the screws connecting the shaft were discolored to rust like appearance. This shaft is within the equipment and is a product contact surface.

d. ….., used to manufacture intermediates for API ….., was soiled with ….. residue and had the appearance of rust. This debris was in the interior of the equipment, potentially contacting drug product. Your firm’s equipment status board designated this equipment as “cleaned” …..

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September 1, 2017

Issue #975

Editor 09/01/17








c.i. issue





Editor


GMP Trends LLC

MEDICAL DEVICE-MANUFACTURING CONTROLS

1. …..Corrective and preventive action activities and/or results have not been documented.

Specifically, the firm currently has an open CAPA where the problem investigated was in relation to the compound remaining on the underside of the ….. post during in-process cleaning step of the polish operation. For example:

a. During the review of complaints records, complaint ….. noted a conclusion summary where a visual examination confirmed the presence of what appears to be buff compound from the polishing operation on the proximal surface of the component.

b. During the review of complaints records, complaint ….. noted a conclusion summary where photographic evidence indicates that the contaminant is likely composed of manufacturing materials from the polishing operation.

Complaints ….. were reported as MDR’s but were not documented as CAPA’s.

2. …..Written MDR procedures have not been implemented.

Specifically a review of SOP ….., “Medical Device Reporting FDA & International Competent Authorities,” documented reportable events occurring inside or outside of the United States, shall be documented, and the report shall be forwarded according to the nation regulatory requirements. A review of complaints from the rest of the world documenting product problems including the reports of holes in the ….. catheters were similar to US based complaints which has been determine to be MDR reportable. These events, which included Incident Report ….., had not been assessed for MDR reportability to the FDA.

3. …..A Device Master Record has not been adequately maintained.

Specifically, your firm has no device master record for the ….. medical device to include device specifications, production process specifications, and acceptance criteria. I additionally observed that your firm does not have a Device Master Record, which includes labeling specifications, regarding the website used to access the software, and the internal data system within the ….. includes a dashboard and multiple screens, housing information necessary for the monitoring of ….. In addition, you did not have the installation, maintenance and servicing procedures and methods.

4. …..Risk analysis is incomplete.

Specifically, your firm uses its Product Life Cycle Risk Management Process, SOP ….., to control its risk analysis process. It is stated in the SOP to identify harm and associated harm codes and severity risk utilizing Standard Harm List. The SOP does not include the method by which the severity ratings are placed on the Standard Harms List or who is responsible for making these decisions.

5. …..Procedures for acceptance activities have not been established.

Specifically, your firm does not have incoming acceptance procedures that describe the specifications and the tests performed on incoming finished devices, such as the visual examination; Volume Retention Study; Intra-Device Variability of the Applicator Heads; and Patient Pain Assessment Study.

— Published by GMP Trends®LLC P.O. Box 1111, Firestone, Colorado 80520, PHONE (303) 443-8716, FAX (303) 443-3317 e-mail: [email protected], www.gmptrends.com ©2017 GMP Trends®LLC

Photocopying without permission is strictly prohibited. See page 3.

EDITED EXCERPTS FROM ACTUAL 483 … · Specifically, your Quality unit failed to include or...

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