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Prequalification Team Inspection services

WHO PUBLIC INSPECTION REPORT

of the Vaccine manufacturer

Part 1 General information

Manufacturers

details Company

information

Name of

manufacturer

Hualan Biological Bacterin Co., Ltd

Corporate address of

manufacturer

No. 1-1, Hualan Avenue, Xinxiang 453003, Henan People's Republic of China.

Contact person Dr Ruowen Pan

E-mail: [email protected]

Inspected site

Address of inspected

manufacturing site if

different from that

given above

Global positioning system (GPS) coordinates in World Geodetic System (WGS)

84: North latitude 35.2825, east longitude 113.902778.

Data universal numbering system (D-U-N-S) number: 421166107

Inspection details

Dates of inspection 15-19 May 2017

Type of inspection Routine for Seasonal Influenza Vaccine,

Representative from

the National

Regulatory Authority

The Evaluation and Monitoring Center (IEMC) of Sichuan food and drug

administration (FDA) was informed and took part to the inspection:

Introduction

Brief summary of

the manufacturing

activities

The manufacturing activities comprises the establishment of seed lots, the drug

substances manufacturing, formulation, filling, visual inspection, labelling,

packaging, Quality Control and distribution of Seasonal Influenza Vaccine (Split

virion, inactivated).

General information

about the company

and site

Hualan Biological Bacterin Co., Ltd was founded in 2005 and located in Xin

xiang, Henan province. Hualan Biological Bacterin Co., Ltd is a subsidiary

company of Hualan Biological Engineering Inc. It is mainly specialized in

research, development and manufacturing of vaccines.

Currently, Influenza vaccine, ACYW135 meningococcal vaccine, Hepatitis B

vaccine are approved by CFDA and Influenza vaccine is listed in WHO list of

prequalified vaccines.




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History The previous inspections of the regulatory agency inspections are presented in

the table below.

Brief report of




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inspection

activities

undertaken

Scope and

limitations

Areas inspected The inspection focused on the production including the formulation, the filling,

the visual inspection, the labelling, the packaging, the storage, the dispatching

and the quality control of Influenza vaccine and related activities.

The inspection covered Building II (Influenza (split virion) bulk workshop I,

medium preparation center).

Building III (Filling and packaging center, testing laboratory, water preparation)

workshop II (Influenza vaccine (split virion), inactivated bulk workshop II,

bacterial and virus strain storage).

Building IV (Material warehouse area, packing area II).

Building VI (Finished product warehouse center).

Building VII (Incubation center).

Restrictions There was neither formulation activity nor visual inspection and packaging

activities for Influenza vaccine during the inspection week.

Out of scope Only Influenza vaccine and related activities were covered during this inspection.

WHO vaccines

covered by the

inspection

Seasonal Influenza Vaccine,

Abbreviations AHU air handling unit

ALCOA attributable, legible, contemporaneous, original and accurate

ADS active drug substance

APQR annual product quality review

BMR batch manufacturing record

BPR batch packaging record

CAPA corrective actions and preventive actions

CC change control

CFU colony-forming unit

CoA certificate of analysis

DQ design qualification

EM environmental monitoring

FAT factory acceptance test

FMEA failure modes and effects analysis

FTA fault tree analysis

FTIR Fourier transform infrared spectrometer

GMP good manufacturing practice

HACCP hazard analysis and critical control points




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HPLC high-performance liquid chromatograph

HVAC heating, ventilation and air conditioning

IR infrared spectrophotometer

IQ installation qualification

KF Karl Fisher

LAF laminar air flow

LIMS laboratory information management system

LoD limit of detection

LOD loss on drying

MB microbiology

MBL microbiology laboratory

MF master formulae

MR management review

NRA national regulatory agency

OQ operational qualification

PHA process hazard analysis

PM preventive maintenance

PQ performance qualification

PQR product quality review

PQS pharmaceutical quality system

QA quality assurance

QC quality control

QCL quality control laboratory

QRM quality risk management

RA risk assessment

RCA root cause analysis

SOP standard operating procedure

URS user requirements specifications

UV ultraviolet-visible spectrophotometer




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Part 2: Brief summary of the findings and comments

1. Pharmaceutical quality system

Broadly the elements of the pharmaceutical quality system were of an acceptable level of maturity however

some aspects varied in their maturity and need further attention and improvement. The company has

provided an acceptable CAPA plan to address the raised issues regarding the quality system.

Product Quality Review (PQR) Provisions for PQR were in place according to the procedure “Review Regulation Management”.

The PQR of Influenza Vaccine (split, virion, inactivated) was spot checked. The review covered the

manufacturing period from December 2015 to November 2016. 47 batches of influenza vaccine bulks and

21 batches of final product were manufactured. 20 batches of final product were released and one was

pending the official batch release certificate. The remaining stock of influenza vaccine bulk not used for this

campaign was destroyed. There was no product OOS result during the review period. The H3N2 and type B

virus strains were changed during the review period. Regarding the deviations, 13 deviations were recorded

during the period and 8 deviations were related to equipment or mechanical failures.

Quality risk management Provisions for QRM were in place as per the procedures in place. The following tools were considered for the

QRM flow diagram, fishbone diagram, failure mode and effects analysis (FMEA), failure mode effects and

criticality analysis (FMECA), hazard analysis and critical control point (HACCP).

Although the procedures for QRM were in place, this aspect of the QMS was fairly basic and this element of the

QMS requires further utilisation for fuller maturity and to make best use of resources. Although the QRM should

be systematic, the company performed only few assessments.

Change control management The change controls were managed as per the procedures in place. Change control management included

equipment and facility, production, test method, specification, process, material, key personnel and others.

Changes were categorized as major, medium and minor according to the impact to the quality, safety and

efficacy of the product.

Major changes since previous inspection:

- For the flu vaccine inactivation step, a mixing tank was added in 2014. The virus fluid was added in the

mixing tank with formaldehyde and then the mixture was transferred to the inactivation tank for holding

during the inactivation period (> 240 hours). The inactivation of each batch is carried out in a single

inactivation tank (total of 10 tanks available).

Planned future changes:

- Until now, microorganisms growth during environmental monitoring in clean rooms were not precisely

identified and in-house isolates during environmental monitoring have not yet been collected. Vitek 2

equipment was purchased and will be received within 2 months.

The list of the change control from 2015 to 2017 was spot checked.

Deviation management Provision for deviations management was in place as per the procedure in place. Deviations were

categorized as major, medium and minor according to the impact to the product quality, safety and efficacy.




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The categorisation is assigned at the time of closing the deviation by quality assurance. Timeline for

handling deviations was in place.

The list of the deviation in 2015, 2016 and 2017 was presented and spot checked.

Management review There was no periodic management reviews in place to identify opportunities for continual improvement of

products, processes and systems of the company. For more details refer to Part 3 “List of deficiencies” of

this report.

Batch release process

The QA representatives review the batch production records, batch packaging records, batch test records and

verify the lot release certificate (issued by the SFDA). The qualified person (QP) reviews, sign and release

the final products. The batch release of Influenza vaccine was spot checked. The company submitted

samples and a summary manufacturing protocol to CFDA for the official control authority batch release.

The “certificate for the release of biological products” was provided by the CFDA, based on examination of

summary manufacturing protocol and laboratory tests (hemagglutinin content, identity, content of

ovalbumin, abnormal toxicity, and sterility). The company released the batch after receipt of the “certificate

for the release of biological products”.

2. Good manufacturing practices for pharmaceutical products

In general terms, resources were available, including qualified and trained personnel, premises, equipment

and services, materials, containers and labels, procedures and instructions, laboratories and equipment for

in-process and other controls. Manufacturing processes were generally defined and reviewed. Instructions

and procedures were generally available. Qualification and validation of equipment, manufacturing

processes and quality control testing methods were in place. Operators were instructed to carry out

procedures, and records were made for the production operations.

3. Sanitation and hygiene Most of the premises were generally maintained at an acceptable level of cleanliness. The company had

provisions for personal hygiene and sanitation in its production facility. Manufacturing areas are provided

with airlocks for personnel and materials entries and exits. Gowning procedures for access to the classified

manufacturing areas were in place. Cleaning, disinfecting and decontaminating procedures along with the

environmental monitoring program were in place to control the non-viable and viable contamination levels

in the production areas.

The cleaning and disinfection procedures for the classified areas and process equipment were spot checked.

4. Qualification and validation Overall, provisions for qualification and validation were in place and covers premises, equipment, utilities

and systems, processes and procedures at periodic intervals and when changes have been made. Validation

and qualification protocols and reports were spot checked as presented below.

Media simulation test: Provision for aseptic media simulation was in place.

The Media Fill Test batch manufacturing record was spot checked. The units were incubated 7 days at 20-

25°C, and then the vials were inverted and incubated 7 days at 30-35°C. A fertility test is performed after

incubation of filled vials. This Media Fill Test showed no growth for 31653 vials incubated.




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Chromatography column for bulk preparation Specification allows for reuse of column for up to the earlier of 330 batches or 4 years. This was based on a

retrospective validation in 2013 of the results from the previous 4 years showing results were in

specification [column colour, protein to HA ratio, ovalbumin trend]. Column velocity was at 30 cm/h. It was

indicated that this is set by the column manufacturer and that there was no testing on impact of different

flow rates. The column height specification is 30-50 cm. This was indicated to be column manufacturer’s

specification and there was no testing of the effect of column height on column efficiency. A column

efficiency test is performed at the start of each production season and after each 30 runs. The record of

number of uses is not recorded in the column log book but it was indicated that the manager maintains a

separate record of this and identifies the need for a test before use. The SOP in place indicates that if the

efficiency test fails the column should be repacked. There is no indication in the SOP about retest criteria.

However, in the last column efficiency test reviewed, there was an out of specification result. The column

was not repacked. Instead, a second test was performed. As the result was in specification, it was used.

Depyrogenation tunnel The last performance validation was in January-February 2017. These are performed yearly.

HEPA filter integrity and particle monitoring is performed every 6 months.

Temperature recording demonstrated an acceptable FH value. Thermocouples are placed in 10 positions

across vial row. The validation report records demonstrated that all tubes maintained a temperature above

250° for more than 45minutes and showed more than 4 log reduction in endotoxin during normal tunnel

operation conditions.

Pressure differential across filters and from room to the tunnel met the established specifications.

Still photographic records were taken of air flow visualisation tests in each zone in the tunnel, which

appeared to demonstrate suitable unidirectional airflow. However, no video records are maintained of these

tests. Measured air velocity was 0.45 to 0.55 m/s, 15-30 cm below the filter.

Autoclave: The following documents were reviewed:

- Filling equipment sterilization‘s validation protocol approved on 28 December 2016 and filling

equipment sterilization‘s validation report approved on 15 April 2017. The last validation was

conducted on January 2017, 3 cycles were performed following parameters change (increase of

drying cycle as it was observed that gowning used in grade A/B areas were wet after sterilization)

- “Use, maintenance and operation” SOP for the autoclaves located in the sterilization room approved

on 15 April 2017.

HVAC The procedures for the HVAC qualification were implemented.

The following documents were spot checked:

- Requalification protocol for HVAC clean areas approved on 18 November 2016;

- Clean room classification conducted at rest on 13 May 2016 for grade B and conducted on 16 May 2016

for grade A,

- Clean room classification for sterility testing room conducted at rest on 30 May 2016 (grade B) and on 27

May 2016 (grade A);

- “Airborne particle test SOP in clean area” version 2017-01.




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Compressed air: The compressed air is prepared from 2 oil free compressors in building number 3. Humidity, oil content,

non-viable and viable particles are tested yearly during the qualification. There was no monitoring in place

for the compressed air at the user points with product contact. The filter at the end user point is pre and post

integrity tested.

Pure steam: Superheat, non-condensable gas, dryness and condensate are tested every six months. The test results from

March, September 2016 and March 2017 were spot checked.

Water systems The results in form of graphs of PW and WFI for 2016 were spot checked. All the results were within the

established specifications. Chemical sanitation is performed yearly and steam sterilisation every three

weeks.

5. Complaints The provision for complaint handling was in place as per the procedure in place. QA department is responsible

for the investigation and handling of quality complaints. All complaints are registered and reviewed.

6. Product recalls The SOP for recall process was in place and includes a description of simulation of the recall process. No

actual recall for safety concerns has occurred in the previous five years. Mock recall was performed in

March 2016. Last delivery of the batch was in July 2015. As the simulated recall was performed 9 months

after last delivery, especially given the seasonal nature of flu vaccination, it is not likely that vials would

remain for recall balance. The SOP indicates that the company has 4 hours from the preparation of the

customer list to contact customers who then should reply within 6 hours. The report indicates all customers

(12 distributers) were contacted in the required time and had replied within 1.5H indicating there were no

vials remaining. The rapidity of response and the lack of any documentation to the effect, suggests that no

inquiries further down the distribution chain from the distributors had occurred. Hence the exercise may not

fully challenge the recall system to test its effectiveness should an actual recall be required.

7. Contract production, analysis and other activities There was no contract manufacturing for vaccines. Provision for contract testing was in place. The National

Institutes for Food and Drug Control (NIFDC) was subcontracted by Hualan to carry out the tests for

adventitious avian leukosis virus and avian adenovirus of the master seed lot used for the manufacturing of

Influenza Vaccine (Split virion), Inactivated.

8. Self-inspection, quality audits and suppliers’ audits and approval

The self-inspection was in place. The 2016 self-inspection report was reviewed. It covered instrument

validation, document qualification, and production process and computer records. No self-inspection had

taken place in 2017 and it was not clear if a schedule for self-inspection in 2017 had been established.

Suppliers’ audits and approval:

The following documents were reviewed:

- Quality agreement between Hualan and the local distributor dated 15 March 2013;

- Audit report of the local distributor conducted on 30 December 2014 (no observation was raised);

- “Materials classification SOP” approved on 20 April 2017:




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o Grade A materials (bacterial and viral seed, excipient and primary packaging) suppliers were

audited on site every 3 years;

o Grade B materials (raw materials used in production process) suppliers were audited on site

every 5 years;

o Grade C materials (materials with no direct impact on products, for instance, disinfectants)

suppliers were initially audited on site and then an annual assessment of the situation by

conference call (supply situation, change) was annually performed;

o Grade D materials (non-production materials and auxiliary materials) suppliers provide only

certificate documents;

o Since laying hens to be replaced every year, so hatching eggs supplier is audited every year.

9. Personnel Organizational charts showing the relationships between different departments, including QA, Production,

QC, Warehouse and Engineering with identification of the key personnel are provided. Curricula vitae and

the job responsibilities for key personnel, with qualification, experience and responsibility are provided.

10. Training The procedures for the personnel training and qualification were in place.

For initial qualification of the aseptic operations, internal lecture and observations of aseptic operations are

provided by the production supervisor and the QA. It is requested to participate in 3 Media Fill Test to be

certified for aseptic operations. The training records of the filling line operators was spot checked. The

filling line operators were initially qualified for aseptic operations. Annual training records along with the

questionnaire for effectiveness check of the training (minimum score to pass the test was 80%) were spot

checked. The gowning requalification of the operators working in grade A/B areas was performed annually.

The visual inspection has been spot checked and found satisfactory.

11. Personal hygiene The company had provisions for personal hygiene and sanitation in its production facility. Smoking, eating,

drinking, chewing, and keeping plants, food, drinks, smoking material and personal medicines was not

permitted in production, laboratory and storage areas. Wrist-watches, cosmetics and jewellery were not

observed as being worn in clean areas. Production areas are provided with changing rooms for personnel

entries and exits. Gowning procedures for access to the classified manufacturing areas were in place.

Changing rooms were provided with photos describing the gowning procedures.

12. Premises and equipment There are 8 buildings in the site, used as vaccine production workshop, warehouse and administration

offices.

Building I: Office building,

Building II: Recombinant Hepatitis B (Hansenula polymorpha) bulk workshop, Meningococcal

Polysaccharide Vaccine bulk workshop, Influenza (Split Virion) bulk workshop I, Medium preparation

center.

Building III: Filling and packing centre, testing laboratory, Water Preparation Workshop II, Influenza

Vaccine (Split Virion), inactivated bulk workshop II, Metrology Room, Bacterial and (virus) strain storage.

Building IV: Material warehouse area, packing area II

Building V: Animal center

Building VI: Finished product warehouse center




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Building VII: Incubation center

Building VIII: Engineering center

The Meningococcal polysaccharide bulk is manufactured in the dedicated workshop located in the first floor

of Building II.

The Influenza (split virion) bulk is manufactured in the dedicated workshop I located in the second floor in

Building II and in second floor of Building III.

The layouts of the premises and the flow charts of the manufacturing areas (including personnel, products and

material flows) were provided in the Site Master File and presented during the briefing meeting the first day of

the inspection.

Finished product warehouse centre (Building VI):

Material in this building is stored in high rise pallet stackers with robot loading and unloading. Staff entry

into the storage area is not routinely required. Stock management is via a computer controlled system. There

was QA controlled management of release status. At the initial temperature mapping of the storage facility,

160 probes were used. This identified the 16 coldest and hottest spots and these locations are used for

routine re-evaluations. These are performed twice yearly (summer and winter). Last reports from studies in

July 2016 and February 2017 were reviewed. Temperature measurements are taken every 5 minutes over

two days and for 8 over eight hours with the door to the controlled temperature area open and demonstrated

maintenance of specified temperature.

At the entrance zone there visible alarms for temperature excursions based on probes located at four points

in the stackers. The location of the probes for this were indicated to have been set by the equipment

manufacturer and not related to the temperature mapping study. Additionally routine engineering control

maintains temperature monitoring at 40 points within the warehouse with local alarms in the warehouse.

Material warehouse area (Building IV): - Ambient temperature warehouse for materials (i.e reagents, raw materials, excipients, primary and

secondary packaging materials), fitted with an automatic stacker system;

- “Cool storage” warehouse (10-20°C) for some materials (for instance, Triton- X100);

- Rejected materials storage;

- Sampling room was not visited.

Influenza Monovalent bulk production (workshop II in level 2 of Building III):Eggs candling room in

operation: the embryonated eggs were candled using an automatic candling machine fitted with a video

imaging system. The eggs were then transferred to the inoculation room via a conveyor system after

being sprayed by a disinfectant,

- Inoculation room in operation: the eggs were sprayed with ethanol solution and then were inoculated

with seed virus using an automatic inoculator machine. The needles were automatically sanitized with

sodium hypochlorite solution after each egg.

- Virus harvest room: following incubation in the virus incubation rooms, the eggs were candled and then

transferred to cold rooms (2-8°C). Following this step, eggs were transferred to virus harvest room. The

allantoic fluid containing virus was harvested from eggs using an automatic harvesting machine. The

fluid was collected into a vessel and then transferred via a pipeline to the ultrafiltration tank located in

the clarification and filtration room.




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- Virus inactivation room: the virus fluid was added in a mixing tank with formaldehyde and then the

mixture was transferred to the inactivation tank for holding during the inactivation period. The

inactivation of each batch was carried out in a single inactivation tank.

Filling area II (level 2 in Building III): - Vials cleaning and sterilization room for the filling line n°5 classified grade D;

- Vial filling line, grade A surrounded with grade B background with capping machine connected on line;

- Laundry room used for gowning washing for grades A, B and C;

- Cleaning room for filling equipment and caps:

- Sterilization room for filling equipment, gowning and caps;

- Assembly room for clean equipment storage and filter integrity testing,

- Liquid preparation room: monovalent bulks were transferred via a peristaltic pump under laminar air

flow, to a stainless steel tank beforehand cleaned and sterilized in place.

There was neither formulation activity nor visual inspection and packaging activities for Influenza vaccine

during the inspection week.

Laboratory controls (Building 3): The QC laboratory is divided into the general control area, sterile laboratory, microbial limit laboratory,

positive control laboratory. The general control areas are mainly used for the chemical or physical tests of

raw and subsidiary materials, in-process samples, intermediates, and final products. Among them, sterile

laboratory is a Grade A in B area, mainly used for sterility tests; microbial limit laboratory is a Grade C area,

mainly used for microbial limit tests; positive control laboratory is Grade C area, equipped with biosafety

cabinet, and used for positive bacteria tests in the sterility tests.

First floor:

- Culturing room (20-25°C) used for Media Fill Test incubation;

- Culturing room (30-35°C) used for Media Fill Test incubation, environmental monitoring controls

incubation and water samples incubation

Second floor:Laboratory (2): QC samples receipt;

- Instrument room (1): samples dilution were performed for the protein content testing (Influenza

vaccine);

- Laboratory (4): hemagglutinin antigen content testing laboratory;

- Laboratory (6): protein content testing (Influenza vaccine);

- Laboratory (7): incubation room for accelerated stability studies, final bulk bioburden and sterility

testing positive controls;

- Laboratory (9): phosphorus content for Meningococcal bulk (group A);

- Sterility testing incubation room;

- Autoclave: used to sterilize gowning and instruments for grade A/B area (sterility testing room);

- Seed storage for original seed lots (purchased from WHO), master seed lots and working seed lots: the

second storage location for working seeds (influenza and Meningococcal serotypes) is located in the

production facility (building 2);

- Cold storage room (stability samples and retention samples)

There was no testing observation during the tour:




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- Protein content testing for Influenza vaccine was finished when the tour started, the test records were

checked;

- There was sterility testing on going during the tour but this room claimed as grade A within grade B

background could not be observed from outside. A picture of the sterility testing room was provided to

inspectors.

13. Materials Provisions for incoming materials, intermediates and finished products are in place for reception, quarantine

and release processes. Appropriate storage conditions are provided. The list of key starting material from

animal sources used in the manufacturing processes was reviewed and found acceptable. These are supplied

from approved suppliers and subject to internal release.

“Material sampling SOP” approved on 14 April 2017 was reviewed:

- For sampling plan, the company followed the national sampling regulation (calculation rules to define

containers’ number to sample) from national cGMP;

- Identification test was conducted for each container of materials used for Influenza Vaccine, inactivated

for export only; this requirement was put on place in January 2017.

15. Documentation This section was not inspected in detail. However, documents were available and included SOPs, protocols

and records. SOPs were generally followed. Issuing of documents, formats were in general appropriate.

Policies for issuing, distribution, retrieval and archiving of the document were in place.

Influenza vaccine batch manufacturing record was spot checked and found adequate except there was no

indication in the batch record of time out of refrigeration.

The following documents were reviewed and found satisfactory:

- Column Equipment logbook (period: 06 February 2017 – 27 March 2017) used in the chromatography

room for influenza vaccine;

- Record of efficiency of chromatographic column in No 2 workshop from 03 February 2017 (used in the

chromatography room for influenza vaccine).

16. Good practices in production

Measures for controlling the risk of contamination and cross contamination were implemented through the

facility design including HVAC systems and manufacturing procedures and instructions and the

environmental controls. The HVAC systems in bio-positive and bio-negative areas are separated. The air

return and air exhaust in bio-positive areas are filtered through Class H14 HEPA filters. Critical processing

areas during the manufacturing are equipped with FFU; active virus areas are equipped with bio-safety

cabinet (BSL-II).

Influenza Vaccine: Seed storage was in secure storage. There was a system for automated phone contract of responsible people

in the event of storage temperature failure. However, there was no SOP describing emergency response

related to seed storage. There were two freezers for influenza master seed. It was stated that influenza

working seeds were held at two locations in building 2. Inventory was maintained of seed stock.




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Egg incubation center was located in appropriate building. Newly hatched eggs are received and pre-

incubated and then transferred to the production facility. Routinely, bulk manufacture commences in

January. There is a variable end time for the finish of a campaign of bulk production, around May. There are

3 virus incubation rooms for infected eggs. One batch is incubated per room. Eggs remain in the room for a

fixed period of time. Normally, 3-4 batches of finished product are filled each week. It was stated that the

maximum capacity for filling is 7 batches per week (total of vials and syringes). In the 2015 campaign, 28

batches were filled. The above constraints raise some uncertainty about the stated theoretical capacity of

production.

The production facility includes:

- Monovalent bulk production in level 2 is a dedicated area: the rooms used for handling live virus (virus

seed preparation room, inoculation room, virus incubation rooms, virus harvest room, clarification and

filtration room, virus inactivation room) were operated to provide containment of virus (dedicated HVAC

systems, negative pressure in the rooms, separate personnel flow). Virus seed preparation takes place under

grade A with grade B background; the other rooms were classified as grade C.

“Filling area II” in level 2:

- Formulation room (for filling lines) classified as grade A in a grade B background;

- Formulation room (for filling line) classified as grade A in a grade B background;

- Filling line (syringe presentation) with capping machine connected on line;

- Filling lines (vials presentation) with capping machine connected on line.

The filling lines are used for influenza vaccine and Hepatitis B vaccine. The equipment in contact with

product (filling pump, needles, silicone tubing, final bulk glass bottles used as “surge tank”) are dedicated

per product and each equipment is identified by a serial number.

When a new influenza strain is introduced, validation of the inactivation process is performed. The last

inactivation report was reviewed. Validation study was performed at normal production scale and based on

acceptable results; these batches were then released for routine production.

Environmental monitoring trending

The document Trend analysis for Influenza Vaccine “filling room EM monitoring” for filling lines (period

review: April 2016 to 18 October 2016) approved on 04 November 2016 was reviewed. No excursions was

recorded, all the presented results were within specifications.

17. Good practices in quality control QC Tour

The following documents were reviewed:

- Temperature check record for culturing room (20-25°C) used for Media Fill Test incubation from 01

January 2017;

- Log book for UV spectrophotometer used for influenza vaccine protein content;

- “Test record of protein content of influenza vaccine, inactivated”;

- “Bacteria seed administration machine account” (working seed inventory log book).

The records system for QC test results is paper based. From the software analysis of results (HPLC and

Total carbon testing equipment observed) a paper record is printed, verified by a second analyst and stored.

Individual login is required and record of access is maintained by the system. QC performs a monthly

backup of electronic records of test results. These are transferred to QA every 6 months.




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When microbial isolates are found during environmental monitoring, the identification performed is gram

staining and microscopic examination of cell shape. It was indicated that the company is in process of

purchase of a Vitek 2 compact machine for microbial identification with receipt expected within 2 months of

the inspection. It was indicated that environmental isolate stocks are not maintained and are not used for

growth promotion testing of media. In the last inspection this point was also noted.

Cold room storage of samples was secure. Within the cold room, there was separate shelving for stability

and retention samples. There was no other segregation of these samples.

Stability:

For routine production it was stated that samples from one batch of each type of bulk and one batch of final

product are placed on stability study at real time storage (2-8°C) and that where a variation has occurred 3

batches are placed on stability study. However, for 2016 (final lot production) there was stability data for 9

batches up to 9 month time point. At this point batches were all in specification. There was little decline in

HA content. However there was no statistical analysis, including trending of results.

Parameters measured in stability studies include appearance, pH, protein, HA, endotoxin, formaldehyde,

ovalbumin, abnormal toxicity and sterility.

There was some confusion, possibly due to language translation concerning stability studies under

accelerated conditions. In the culture room set at 20-25°C, the log book indicated that samples of a known

batch number had been stored in the room between 12 to 15 may, 2017. Initially it was indicated that this

was related to VVM usage. However, it was later indicated that stability studies are not performed at 25°C

and that sample storage was for conditioning of samples prior to transfer to 2-8°C for a stability study. This

was indicated to mimic time out of refrigeration during production. However, the reason for this remains

unclear as samples should have gone through normal production process before sample selection for a

stability study. In relation to a 2013 stability study under accelerated conditions (37°C) there was also

differing reasons stated at different times regarding the purpose of this assay. Strain change; for VVM

assignment; but eventually the presented protocol indicated the study related to a change of grade of

excipients (NaH2PO4.2H20 & NaH2PO4.12H20) from analytical grade to pharmaceutical grade. The

protocol for this study did not have a quality system (QS) numbering identification or any link to a number

for reports. There were numbers for the testing reports at different days (14 days and 21 days). However,

there was a separate overall concluding document with summary data that was not QS identified.

The 37°C stability data indicated the vaccine in specification at 14 days but out of specification at 21 days.

(HA content of H1N1 strain).

The basis for assignment of VVM remains unclear. In the 2014 inspection report it was indicated that 37°

and 25°C stability data from 2011 was reviewed and supported the VVM assignment. The reviewed 37°C

stability data during this inspection gives some assurance that VVM 7 may be suitable but the company

should clarify the data on which the VVM 7 assignment was made.

18. Distribution Shipping To date, there has not been supply of prequalified influenza vaccine through UN agencies. The company’s

opening presentation indicates that in 2016, 21 final lots (4.75 x 106 doses) and in 2017 (to date) 7 final lots

(1.44 x 106 doses) have been produced. All sales have been for domestic use. For domestic supply, vaccine

is distributed in active refrigeration trucks, there is no additional insulated packaging.

Vaccines in tertiary cartons are transferred directly from the final product warehouse (2-8°C) to these trucks

for distribution. With respect to international supply, vaccine would be returned from final product




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warehouse to Packaging (building 3) for packing into insulated containers. During the dossier review for

influenza vaccine, a full report of the shipping validation was submitted, reviewed and considered

acceptable. It was not reviewed further during the inspection.

PART 3: CONCLUSION Based on the areas inspected, the personnel met and the documents reviewed, and considering the findings

of the inspection, including the deficiencies listed in the Inspection Report, as well as the Corrective Actions

taken and planned, Hualan Biological Bacterin Co., Ltd. was considered to be operating at an acceptable

level for compliance with WHO GMP guidelines.

All the non-conformances observed during the inspection that were listed in the full inspection report as well

as those reflected in the WHO Public Inspection Report (WHOPIR), were addressed by the manufacturer, to

a satisfactory level, prior to the publication of the WHOPIR.

This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during

this period is positive.

prequalification team inspection services who public … · introduction brief summary of the...

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