Sterile GMP UpdateAugust 2017

Moshe Ben Yitzhak, MSc., MBA

CGMP Solutions, Ltd.

Objective

• This presentation provides a high-level review of some recent (2016-2017) inspections of manufacturers of sterile drugs produced by aseptic processing.

• It covers seven firms inspected – some of them multiple times – over this period.

• Results are presented in a tabular form; the recent Consent Decree agreed to by Isomeric is covered separately.

What is a FDA 483?• An FDA 483 is a standardized form that inspectors use to

report violations of cGMPs.

• It is typically the first step that the FDA takes when a firm is found to be in violation.

• The Agency may issue a Warning Letter (which is more severe) if the violations were:– Observed on previous inspections, or

– Too numerous (there is no hard rule as to how many observations are too many), or

– The company that was inspected was non-cooperative during the inspection.

• FDA 483s may be found at:

https://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htm

Disclaimer• FDA 483s always start with a disclaimer that reads as

follows:

– This document lists observations made by the FDA representatives duringthe inspection of your facility. They are inspectional observations; and donot represent a final Agency determination regarding your compliance. Ifyou have an objection regarding an observations, or have implemented orplan to implement corrective action in response to an observation, youmay discuss the objection or action with FDA representative(s) during theinspection or submit this information to FDA at the address above. If youhave any questions, please contact FDA at the phone number and addressabove.

• In other words, the results of the inspection are going to bereviewed by higher levels in the FDA, and the FDA 483 is notnecessarily the last word on the subject.

General Format of the FDA 483

• Header section with contact information

• Disclaimer

• Inspectional observations

– Quality System element (note: some inspectors do not identify this)

• Observation– Supporting evidence.

– Inspectors usually provide multiple examples of violations.

– If a particular violation was noted in the previous inspection, they may provide just one example.

Example

Production System

Observation 1: Deviations from written production and process control procedures are not recorded and justified. Specifically:

Investigation 14-14-01453 was initiated 26NOV2014 for a Media Fill failure. The most probable root causes of contamination were attributed to the following:

Slower than routine production) leading to issues in stoppering; a larger than usual media fill, leading to operator fatigue where commercial fills are limited to a maximum of [vials – exact number redacted].

A broken bolt on the table and frame required personnel to lift and secure the vial mechanism.

This led to operators leaning over filled, partially-stoppered vials to clear jams, which would have led to the full clearance and reject of units during a commercial production run.

Inspectors then quoted from the company’s SOPs relevant to this activity.

Example

• Based on the contents of the FDA 483:– There was a failure; and

– The company investigated; and

– It came to conclusions regarding the root causes.

• However:– According to the firm’s own SOPs, media fills are supposed to be

treated exactly like commercial batches, including the decision when to abort a batch.

– According to interviews with management, batches are aborted before filling and stoppering, so this media batch should not have been filled.

– Management also stated that the inoperability of downstream equipment should have triggered the aborting of the batch – that did not happen either.

– Finally, operators failed to complete logbook entries regarding this media fill, as required by SOP.

Example

From this one observation we can draw several conclusions about

how the FDA conducted this inspection:

1. Although the inspection was conducted in June 2016, the

inspectors reviewed records of media line failures at least as

far back as November 2014.

2. This indicates that the inspectors asked for and received:

a) A list of media batches produced, and/or

b) A list of media batch failures, and/or

c) A list of deviation investigations.

3. The inspectors thoroughly review records.

4. The inspectors thoroughly review a company’s procedures.

Recent Inspections

• The inspectional observations in this presentation aresummarized from:– Akorn Pharmaceuticals

– Cantrell Drug Company

– Delta Pharma

– Fusion IV Pharmaceuticals

– KRS Global Biotechnology

– RAM Pharma

• All of these are relatively small companies. The havetheir own products (mostly generic), provide contractmanufacturing for larger firms, and also manufactureclinical supplies on contract.

Inspectional Observations

• The following series of tables identify the inspectional observations.

Observation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

Aseptic processing areas are

deficient regarding the system for

cleaning and disinfecting the room

and equipment to produce aseptic

conditions.

5-Delta

4-RAM

§211.42(a)

§211.42(c)X X

Inspectional Observation

Obs. No. in FDA 483

GMP Reference

Companies

Summary of Observations – Equipment & Facilities

Observation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

Aseptic processing areas are

deficient regarding the system for

cleaning and disinfecting the room

and equipment to produce aseptic

conditions.

5-Delta

4-RAM

§211.42(a)

§211.42(c)X X

Aseptic processing areas are

deficient in that walls are not

smooth and/or hard surfaces that

are easily cleanable.

6-Delta

3-RAM

§211.42(a)

§211.42(c)X X

Routine calibration of equipment is

not performed according to a

written program designed to assure

proper performance.

8-Delta

11-RAM§211.67(a),(b) X X

Control procedures are not

established which validate the

performance of those

manufacturing processes that may

be responsible for causing variability

in the characteristics of in-process

material and the drug product.

6-Akorn §211.100(a) X

Summary of Observations – Equipment & Facilities

Observation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

PharmaAseptic processing areas are deficient

regarding the system for cleaning and

disinfecting the room and equipment to

produce aseptic conditions.

1-Cantrell §211.113(b) X

Aseptic processing areas are deficient

regarding air supply that is filtered

through HEPA filters under positive

pressure.

8-Cantrell

3-KRS

Global

§211.46(b) X X

The building lacks adequate space for

the orderly placement of equipment

and materials to prevent mix-ups

between different components, drug

product containers, labeling, in-process

materials and drug products to prevent

contamination.

9-Cantrell §211.42(a),(b) X

Separate or defined areas to prevent

contamination or mix-ups are deficient

regarding operations related to aseptic

processing of drug products.

3-Cantrell §211.113(b) X

Summary of Observations – QC LabObservation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

Laboratory controls do

not include the

establishment of

scientifically sound and

appropriate sampling

plans designed to assure

that in-process materials

and drug products

conform to appropriate

standards of identity,

strength, quality and

purity. The suitability of

all testing methods is

not verified under actual

conditions of use.

5-Akorn §211.160(a) X

Test procedures relative

to appropriate

laboratory testing for

sterility and pyrogens

are not written and

followed.

4-Cantrell §211.160(a) X

Summary of Observations – QC LabObservation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

There is no written testing

program designed to

assess the stability

characteristics of drug

products.

5-Cantrell

10-Delta

8-RAM

§211.166(a) X X X

Testing and release of drug

product for distribution do

not include appropriate

laboratory determination

of satisfactory

conformance to the

identity and strength of

each active ingredient

prior to release.

6-Cantrell

5-Fusion IV

7-RAM

§211.165(a) X X X

Testing and release of drug

product for distribution do

not include appropriate

laboratory determination

of satisfactory

conformance to the final

specifications prior to use.

9-Delta

6-RAM§211.165(d) X X

Summary of Observations – Packaging & Labeling

Observation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

The labeling of your

outsourcing facility's drug

products are deficient.

11-Cantrell

12-Delta

6-Fusion IV

6-KRS Global

12-RAM

FDCA,

§503B(b)X X X X X

Strict control is not exercised

over labeling issued for use

in drug product labeling

operations.

7-Fusion IV§211.137(a),

(b)X

Your outsourcing facility did

not submit an initial report

to FDA identifying products

compounded during the

previous six months as

required by section

503B(b)(2)(A).

8-Fusion IV

13-RAM

FDCA,

§503B(b)X X

Summary of Observations - ProductionObservation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

Deviations from written

production and process

control procedures are not

recorded and justified.

1-Akorn §211.101(a) X X

Aseptic areas are deficient

regarding the system for

monitoring environmental

conditions.

7-Cantrell

4-KRS Global

2-RAM

§211.110(a)(6) X X X

Procedures designed to

prevent microbiological

contamination of sterile

drug products are not

established.

2-Cantrell

1-Fusion IV

1-KRS Global

1-RAM

§211.110(a) X X X X

Procedures designed to

prevent microbiological

contamination of sterile

drug product do not

include validation of

sterilization process.

1-Delta

2-Fusion IV

2-KRS Global

5-RAM

§211.113(b) X X X X

Summary of Observations - ProductionObservation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

Drug product containers are

clean, sterilize and processed to

remove pyrogenic properties to

assure that they are suitable for

their intended use.

2-Delta

3-Fusion IV

§211.94(c)

§211.94(d)X X

Clothing of personnel engaged

in the processing of injectable

drug products is not

appropriate for the duties they

perform.

3-Delta

5-KRS Global

9-RAM

§211.28(a) X X X

Aseptic processing areas are

deficient regarding the system

for monitoring environmental

conditions.

4-Delta

4-Fusion IV§211.110(a)(6) X X

Time limits are not established

when appropriate for the

completion of each production

phase to assure the quality of

the drug product.

11-Delta §211.111 X

Summary of Observations - Quality

Observation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

There is no quality

control unit with the

responsibility and

authority to approve or

reject all components,

drug product containers,

closures, in-process

materials, packaging

materials, labeling and

drug products.

10-RAM §211.22(a) X

The responsibilities and

procedures applicable to

the quality control unit

are not fully followed.

2-Akorn §211.22(a) X

Summary of Observations - Quality

Observation FDA 483

Obs. No.GMP Akorn Cantrell Delta

Fusion

IV

KRS

Global

RAM

Pharma

There is a failure to review

thoroughly any unexplained

discrepancy, whether or not

the batch has already been

distributed.

10-Cantrell

7-Delta

§211.101(a)

§211.192X X

Investigations of a failure of a

batch or any of its

components to meet any of its

specifications did not extend

to other drug products that

may have been associated

with the specific failure or

discrepancy.

12-Cantrell

3-Akorn§211.192 X X

Quality controls do not include

a determination of

conformance to written

descriptions of sampling

procedures for drug products.

4-Akorn§211.22(d)

§211.84(a)X

Isomeric Pharmacy Solutions, LLC• This is the worst-case scenario!

• Isomeric was inspected in 2015 and received a FDA 483 that had five multi-part observations.

• Isomeric was inspected in 2016 and received a FDA 483 that had eleven multi-part observations.

– FDA was not satisfied with Isomeric’s response at the time, and a Warning Letter was issued in December 2016.

• Isomeric was inspected again 22/02/17 through 24/03/17 and the inspectors recorded fourteen multi-part observations.

• The same inspectors performed all three inspections.

• FDA turned to the U.S. Department of Justice to obtain relief.

Isomeric Pharmacy Solutions, LLC• U.S. District Judge Robert J. Shelby entered a consent decree of

permanent injunction yesterday against Isomeric Pharmacy Solutions on 4 August 2017.

– In it’s complaint, FDA alleged that Isomeric manufactured and distributed purportedly sterile drug products that were adulterated because the drugs were made under insanitary conditions and in violation of current good manufacturing practice requirements under the FD&C Act.

– The consent decree prohibits Isomeric from manufacturing, processing, packing, holding, or distributing drugs until they comply with the Federal Food, Drug, and Cosmetic Act (FD&C Act) and its regulations.

– FDA’s complaint also alleged that Isomeric manufactured and distributed unapproved drugs and drugs that were misbranded because their labeling did not bear adequate directions for use.

• Isomeric agreed to a voluntary nationwide recall of all lots of unexpired drug products produced for sterile use and distributed to patients, providers, hospitals, or clinics nationwide between Oct. 4, 2016 and Feb. 7, 2017.

Conclusions

• In aseptic processes, the drug product, container, and closure are subjected to sterilization methods separately, as appropriate, and then combined.

• Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment.

• Aseptic processing involves more variables than terminal sterilization, and as such, presents a higher risk to the patient.

• Thus, inspections will focus on:

– Systems and processes with the highest risk factors.

– Systems and processes that have been proved inadequate in past inspections.

Conclusions

• FDA, as explained in Guidance - Sterile Drug Products Produced by Aseptic Processing (2004), places emphasis on (this is the order in which they appear in the guidance):

– Facilities and Equipment

– Personnel training and Monitoring

– Components and Containers/Closures

– Endotoxin Control

– Validation of Aseptic Processing and Sterilization

– Laboratory Controls

– Sterility Testing

– Batch Record Review

• Quality Assurance cuts across all these systems and processes, and therefore should be evident in all of them.

Conclusions• Management – regardless of specific departmental

responsibility – needs to ask itself the following questions:

– Do I understand the concept of the Quality System approach?

– Do I understand the processes that are part of the specific Quality System for which I am responsible?

– Do I understand the documentation requirements (batch records, change control, SOPs, logbooks)?

– Do I understand the records that should be generated as a result of each process?

– Do I understand the results, and long-term trends these data indicate?

– Am I taking the appropriate actions based on the CGMP requirements?