Audit hot Topics and

Regulatory Requirements

Julie Roberts

Overview

Hot Topics

Examples in warning letters

Tips to detecting data integrity

Recent changes in regulatory requirements

Hot Topics

Microbial Control Strategy

EM programme

Risk Assessments

Investigations

Insufficient investigation

RC not determined

Data Integrity

Recording of data

Second person verification

Chain of custody

Maintaining compliance with Regulatory changes

Hot Topics - Microbial Control Strategy

Overall philosophy for how you control microbial

contamination for your processes.

May need one per type of process e.g. aseptic fill vs terminal

sterilisation vs non-sterile products

Microbial control strategy demonstrates you understand

your process,

the limitations e.g. external materials/internal processes,

what needs to be controlled,

what can be measured,

what cannot be measured

Hot Topics – EM Programmes

EM Programmes

Written rationalisation for sample location i.e. risk

assessment of activities

Linkage to smoke studies

Linkage to operational activities (not just at rest

assessments)

Periodic review of the applicability/relevance of the

sampling programme

Appropriate and useful review of data

Hot Topics - Investigations

Insufficient investigation

Not timely – hard to resolve as time passes

Assumptions made preventing a full investigation

Investigation report does not document all investigation

activities

people so close they miss to document assumptions

& thought processes

Hot Topics – Common Audit Observations

Trending of EM- insufficient, too narrow, % recovery

rates not used

Biological indicators – D-value audits or on-site

determination

Cleaning validation maps indicating location of

swabs/samples

Counting of plates – second person verification/ review

of data/ accuracy of result

Hot Topics – Common Audit Observations

Trending of EM- insufficient, too narrow, % recovery

rates not used

Biological indicators – D-value audits or on-site

determination

Cleaning validation maps indicating location of

swabs/samples

Counting of plates – second person verification/ review

of data/ accuracy of result

Hot topics within Microbiology pertaining to

Data Integrity

Canada

An FDA investigator observed your microbiologist reading an

environmental monitoring (personnel) plate. The microbiologist

reported the result for that plate as zero; however, our FDA

investigator observed one (1) colony forming unit (CFU) on the

plate. Your microbiologist corrected this observation on the form XX

after the FDA investigator pointed it out to him. Your firm did not

take further action to investigate and determine the impact of

inaccurate reporting of your microbiological plate readings on the

release of your batches.

Your firm failed to record the incubation dates of the

microbiological plates in the validation study of the (x) of (x) for (x)

Solution (x) and (x) Spray.

China

On March 2, 2015, we observed that all 14 culture media plates in

incubator #6 were dried out and cracked, which compromised

microbial growth promotion and accurate enumeration. These plates

were used to test multiple API batches of (b)(4).

You stated that tests for microbial limits were not routine for (b)(4).

The microbiologist documented test methods and results

“when she had time,” and “there was a possibility that our QC

microbiologist documents results by memory instead of

document (sic) at time of operation.”

India

EM results sheets show X, Y and Z samples were taken on dates [x,

y, z] however review of video recording for these periods do not

show such samples being taken

Your active air sampler samples 1000L of air taking 5.5mins,

however video recording collection of this sample shows a

sample time of <3mins.

Since 2005, you have been using an un-validated and

unqualified Agilent data acquisition unit (DAU) to monitor the

temperature of the microbiological incubation rooms for media

filled vials.

India

Finished drug product (b)(4) Tablets (b)(4)mg batches (b)(4) and (b)(4)

microbial sample plates/tubes were placed in the incubators on June

19-20, 2014, as documented in your LIMS computer system. The plates

should have been incubated for (b)(4) days, per your procedures. On June

23, 2014, no plates/tubes for this batch were observed in any of the

incubation chambers.

Finished drug product (b)(4) Tablets (b)(4) mg Exhibit Batch (b)(4) sample for

microbial testing was prepared on June 13, 2014. Your firm failed to

provide the FDA investigator with the worksheet to document the

incubation times and media used for the analysis. Your analyst described

that the entire microbial test for this batch had already been completed the

previous week but that the analyst had "forgotten" to document the details on

the worksheet.

The FDA investigator noted other instances of missing samples/plates for

in-process drug products, potable water, and growth promotion, even

though records indicated that they were in the incubator.

Hot topics relating to Data Integrity & Data

Compliance

Chain of Custody

Demonstration of chain of custody of EM plates

WL in India/China showing fabrication of data

Documented evidence for number of plates released

to production, exposed, returned to lab, incubated,

counted, destroyed

Barcoding samples gives timing (exposure) also

Logbooks can track

Independence of personnel logging each stage

Hot topics relating to Data Integrity & Data

Compliance

Chain of custody (cont’d)

Ability to link each identification back to original plates

Traceability of all activities

Second person verification of counts

What to verify? What to review?

Looking for Data Issues

Notebooks, diaries, laboratory notebooks

Drawers, cupboards, lockers – amnesty review & clear out

Review of data

Are personnel trained to detect electronic edits (not just

hand written edits)?

Will your current reviews detect DI issues?

What constitutes raw data? API strips?

Looking for Data Issues

Equipment

Controls around password/ number of licences

available

User access levels – are they appropriate? Are they

being shared? Who has more than one level of user

access?

Run a report of Admin log-on’s – check frequency

Explore the Admin screen- what can be changed/

switched on/off? How many audit trails are available?

Audit trails – have a plan of what is reviewed, why its

being reviewed, and how often you will review it.

Looking for Data issues

Air samplers

Can the sampling time be alerted/shortened?

What data is the sampling machine retaining

electronically (albeit transient) beyond your printout?

EM programme

Is your programme realistic for the number of staff?

How long should it take someone to conduct all the

EM required by your SOP? Are personnel completing

it too quickly (same with Water Sampling)

Looking for Data issues

Review electronic folders

Do you have a policy or SOP for set up of electronic

folders

Check each system for atypical folder names/trial

folders/project folders etc

Check the waste basket on the pc –when was it last

emptied. What is in there??

Get IT to run activity reports from your various equipment

for erroneous log-on’s/ specific activity/ activity out of hours

Looking for Data issues

Conduct random recounts of plates – different days/

different personnel

Review camera footage from production

Operator behaviour

EM & water sampler behaviour

Cleaners

Hot topics – Regulatory Updates and

Changes

Regulatory Updates and Changes

Demonstration of how you review updates to

legislation

Demonstration of review of applicability to your

operations

Implementation of the new guidance/requirements

Sop to manage this process

Evidence of change control to document the review,

risk impact, and any changes required

Recent Regulatory Updates (courtesy Dr T Sandle)

Production of WFI - Ph.Eur. Monograph 169

revised to include ‘by a purification process that

is equivalent to distillation. RO (single or double

pass), coupled with other techniques such as

EDI, UF or Nanofiltration is suitable’

http://www.ema.europa.eu/docs/en_GB/docum

ent_library/Scientific_guideline/2016/08/WC500

211657.pdf

EMA Q&A provides clarification and guidance

in the use of RO for manufacture of WFI, and to

provide detailed guidance on the control of

Biofilms

Regulatory Updates

WHO draft guidance, “Supplementary guidelines on

Good Manufacturing Practices for Heating, Ventilation

and Air-Conditioning Systems for Non-Sterile

Pharmaceutical Dosage Forms.”

Scope of the document is:

Solid dosage forms

Covers other dosage forms (such as liquids, cream,

ointments) and other classes of products including biological

products, herbal medicines, complementary medicines and

finishing process steps for APIs.”

Working document QAS/15.639/Rev.1, May 2016

http://www.who.int/medicines/areas/quality_safety/quality_assurance

/HVAC_QAS15-639_31082015.pdf

Regulatory Updates

EMA introduced a new draft guideline April 2016

"Guideline on the sterilisation of the medicinal

product, active substance, excipient and primary

container.”

Steam sterilisation

Dry heat sterilisation

Ionisation radiation sterilisation

Gas sterilisation

Sterile filtration

Aseptic processing

http://www.ema.europa.eu/docs/en_GB/document_library/Sc

ientific_guideline/2016/04/WC500204724.pdf

Regulatory Updates

ISO14644 Part 1 updated

The standard is for classification and continued testing

only.

It does not replace EU GMP requirements and ≥0.5 and

≥5.0 µm need to be assessed.

There is a new statistical approach for the selection of

the number of particle locations and the evaluation of

data collected. (number of locations generally increased)

With particle counter locations, to align with GMP, the

location should be orientated to the point of greatest risk

e.g. close to fixed equipment.

Regulatory Updates

USP <1116> December 2013

In the most critical areas within an aseptic

processing operation, it is expected that less

than 1% of the samples will yield any

recoverable contamination. In the most

advanced of modern aseptic operations that

use separative technologies such as isolators

or closed RABS, the recovery rate will

approach zero at all times.

USP<1116> Table 3. Suggested Initial Contamination

Recovery Rates in Aseptic Environments a.

Room Classification Active Air Sample

(%)

Settle Plate

(9 cm) 4 h Exposure

(%)

Contact Plate or

Swab (%)

Glove or Garment

(%)

Isolator/Closed RABS

(ISO 5 or

better)

<0.1 <0.1 <0.1 <0.1

ISO 5 <1 <1 <1 <1 ISO 6 <3 <3 <3 <3 ISO 7 <5 <5 <5 <5 ISO 8 <10 <10 <10 <10 A All operators are aseptically gowned in these environments (with the exception of background environments for isolators).

These recommendations do not apply to production areas for nonsterile products or other classified environments in which

fully aseptic gowns are not donned.

Detection frequency should be based on actual monitoring data and should be re-tabulated

monthly. Action levels should be based on empirical process capability. If detection

frequencies exceed the recommendations in Table 3 or are greater than established process

capability, then corrective actions should be taken.

FDA Quality Metrics Initiative

Jan 13 – FDA Quality Metrics programme announced in Federal

Register Notice (FRN)

Jun 13 – IPSE started Quality Metrics Initiative

Dec 13 – IPSE White paper delivered to FDA

Jun-Nov 14 – ISPE Wave 1

Jun 15 – ISPE Wave 1 report issued

Jul 15 – FDA Request for Quality Metrics (Draft)

Lot Acceptance Rate

Product Quality Complaint Rate

Invalidated Out-of-Specification (OOS) Rate

Annual Product Review (APR) or Product Quality Review (PQR) on

Time Rate

CAPA effectiveness & Process Capability & APR sign off

Regulatory Updates

EU Annex 15 – updated Oct 2015

GMP for Excipients - March 2016

EU GMP chapters 3 & 5 updated and effective March 2016

Guidance in Draft

EU Annex 1 – draft in discussion

GMP for IMPs

Final version to be published in April 2017

Date for coming into force likely October 2018 (with CTR)

GMP for AT(I)MPs

Public consultation recently closed; responses under

assessment through October and November 2016

Preparing for the audit

Preparing for the audit

Be honest with yourselves

Where are the issues?

Where are your weaknesses/

gaps in knowledge

Any recurring issues from

internal audits?

Preparing for the audit

What is your timeline?

You can’t fix everything

Determine what is important to

you and prioritize

If serious gaps cannot be

addressed, look to capture them

in your CAPA plan. Proof of

intent is better than just intent

In Summary

Be aware of current hot topics

Be aware they can be inspector specific, agency specific!

Ensure you are aware of recent changes to regulations

and how they can impact you

Don’t let silly things catch you out-

cupboards/drawers/notebooks/passwords/poor

compilation of validation folders

Be confident - revise and know your own data & systems

Questions?